**5. Clinical manifestations and Hemodynamic Effects of Thyroid Hormones**

The clinical manifestations and the severity of the disease are strongly correlated to the duration of Graves' Disease and the patient age. More than half of the patients are symptomatic in time of diagnosis. The most frequent findings may be counted as nervousness, fatigue, a rapid heartbeat or palpitations, heat intolerance, and weight loss respectively. By age, weight loss and decreased appetite are frequently observed, whereas irritability and heat intolerance are less frequent. Atrial fibrillation is occasional below age 50. A firm, diffuse goiter of variable size presents in the 90% and 75% patients, respectively; when 50 years of age was hold as threshold [52].

Thyroid hormone has cardiovascular effects that include decreased SVR and increased resting heart rate, left ventricular contractility, and blood volume. Thyroid hormone reduce the peripheral arteriolar resistance and decrease mean arterial pressure, through the renin-angiotensin-aldosterone system. Also, T3 increases erythropoietin synthesis, which leads to an increase in red cell mass. Harmony of these effects contribute to increase in blood volume and preload. In hyperthyroidism, these combined mechanisms maximize cardiac output up to 300% higher when compared to control group. In hypothyroidism, the cardiovascular effects are diametrically opposite and cardiac output may decrease by 30–50% [53].

Thyroid hormone shows its affects rapidly and non-genomic pathway through heart and blood vessels. Beyond what is reported above, In the peripheral vascular system, the elevated oxygen consumption, metabolic remnants and relaxation of arterial smooth muscle fibers by thyroid hormone eventuate in peripheral vasodilatation [32]. This dramatical decrease in peripheral vascular resistance (PVR) has a great role in hemodynamic changes caused by thyroid hormones [54]. Decreased PVR results in bradycardia, a selective increased blood flow towards visceral organs eventually, cause a decrease in diastolic pressure thus widen pulse pressure. Vasodilatation without elevated renal blood flow results in a reduction in renal perfusion thus activates the renin-angiotensin cascade. Hence, sodium retention and increased blood volume occurs [46]. Moreover, thyroid hormones effects on erythropoietin secretion; hence cause to increase in red cell mass and the blood volume [55]. Increased diastolic relaxation and blood volume improves left ventricular end-diastolic volume (LVEDV). Reduced PVR and increased LVEDV in together, augment preload and impair afterload; thus the stroke volume increases. Improved stroke volume and heart rate increase cardiac output, which cannot be only a consequence of an increased metabolic rate [56]. The correlation between systemic vascular resistance and systemic blood flow in hyperthyroidism is investigated previously, focusing on arterial vasoconstrictors in particular. On the contrary to the normal subjects, atropine and phenylephrine succeeded to decrease peripheral blood flow and cardiac output by 34% in hyperthyroidism group [57].

Studies including large cohorts determined that blood pressure levels widened throughout the entire spectrum of thyroid function [58]. In this study, Asvold et al. reported a linear correlation between TSH and both systolic and diastolic blood pressure, however other studies did not find a correlation [59]. Basal metabolism is triggered by thyroid hormones and a complete response develops in almost every tissue and organ system in the body, as a consequence of increased metabolic demands, hemodynamic changes in cardiac output, SVR, and blood pressure occur. On several counts, such changes are similar to the physiological response to exercise [60]. Pulse pressure tends to be widened in case of hyperthyroidism. Some current reports have determined that despite the low SVR in hyperthyroidism, arterial stiffness is increased [61]. Thus excess thyroid hormone typically enforce systolic

blood pressure to rise, the increase can therefore be quite dramatic in older patients with atherosclerosis led to impaired arterial compliance. Hyperthyroidism has been identified as the second most common reason for isolated systolic hypertension [62]. Efficient hyperthyroidism treatment and the administration of β-blockade to achieve normocardia reverses these changes. In hypothyroidism, endothelial dysfunction and impaired VSM relaxation eventuate in lower SVR [63]. These effects lead to diastolic hypertension in ≈30% of patients, and thyroid hormone replacement therapy restores endothelial-derived vasorelaxation and blood pressure to normal in most [64].

Sinus tachycardia is the most frequent ECG disorder. Intraventricular conduction delay in the form a right bundle branch block is observed in approximate of 15% patients.

Alternative, unknown reasons may also be present for the occurrence of atrioventricular block Increased dispersion of QT interval corrected by the heart rate (QTcD) and pulmonary hypertension may also be present, however underlying mechanisms are yet unclear; the similar cardiac and hemodynamic changes accompanying with the autoimmune disorders in Graves' patients probably contribute to conduction problems [65]. Hyperthyroidism leads to shortened action potential and altered expression of L-type calcium channel 1D, enhances Na and K permeability, and affects Na pump density [66]. The forced preload increase and altered total blood volume impose burden on cardiac workload, hence frequently myocardial hypertrophy develops.
