**7. Graves' Disease and heart failure**

Early manifestations regarding heart failure may be present in patients with hyperthyroidism [7, 14, 79]*.* Majority of the patients with hyperthyroidism suffer from exercise intolerance and exertional dyspnea, due to the loss of skeletal and respiratory muscle strength. Hyperthyroid patients can demonstrate congestive heart failure symptoms regardless of prior cardiac injury. This phenomenon has inaccurately identified "high-output heart failure," in the presence of paradoxical features involving enhanced cardiac contractility and output characterized by thyroid hormone excess [7]. Decreased cardiac contractility, reduced diastolic compliance, and pulmonary congestion are true manifestations of the heart failure however these can be consequences of severe and chronic hyperthyroidism, tachycardia, and **atrial fibrillation also** [80–82]. The use of "high output heart failure" has not abandoned in late decades, considering the potential of the heart to enhance the output at both rest and exercise. However, In the setting of low vascular resistance and decreased preload, cardiac functional reserve is compromised thus lose the capacity of accommodating the demands of maximal or even submaximal exercise [83]. High-output heart failure may demonstrate dyspnea on exertion, fatigue, and fluid retention with peripheral edema, pleural effusion, hepatic congestion, and PAH [82]. Heart failure develops approximately in the 6% of thyrotoxic patients. Beyond that, dilated cardiomyopathy with reduced left ventricular systolic dysfunction occurs less than 1%, due to a tachycardia-mediated mechanism causing an elevated cytosolic calcium levels during diastole with impaired contractility of the ventricle and diastolic dysfunction, often with tricuspid regurgitation [84]. A research conducted by Yue *et al*., diastolic dysfunction was found to be more prominent in thyrotoxic patients older than 40 years of age, whereas in younger ones a demonstrated a reduction in peripheral vascular resistance and improved cardiac output were outstanding [85]. However, severe and chronic hyperthyroidism may exaggerate sinus tachycardia or atrial fibrillation; hence, produce rate-related left ventricular dysfunction and heart failure [86]. This clarifies the reason why several patients manifesting the combination of hyperthyroidism, low cardiac output, and impaired left ventricular function had AF at the time of diagnosis [7]. However, pre-existent ischemic or hypertensive heart disease may also contribute the to the development of heart failure in hyperthyroid patients [14, 86].

Mitral valve prolapse is more frequently reported in patients with Graves' Diseases. The latter may be a predisposing factor for the elonged the left atrial diameter and atrial fibrillation [87]. The risk for AF which may lead to congestive heart increases in the presence of low TSH levels, especially among patients over 60 years old [88, 89]. The high prevalence of pulmonary artery hypertension that comprises several signs of heart failure, such as neck vein distension and peripheral edema, may be caused by right heart strain [90, 91]. Similarly, reduced pulmonary compliance and skeletal muscle dysfunction may lead to the exercise intolerance and exertional dyspnea in such patients [14]. Distinctively, thyrotoxic cardiomyopathy represents a myocardial damage that caused by toxic effects as a result of excessive thyroid hormone activation. This condition leads to dynamic and structural changes such as myocyte energy production, intracellular metabolism, and myofibril contractile function. Left ventricular hypertrophy, heart rhythm disturbances, primary atrial fibrillation, dilation of the heart chambers, heart failure, PAH, and diastolic dysfunction constitutes the main manifestations [48].

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

Although, β-adrenergic blockage was contraindicated in previous decades in the treatment of thyrotoxic cardiac events, nowadays the use of such drugs considered as first-line therapy [92]. Digitalis and diuretics are not recommended in the heart failure accompanying pulmonary congestion [60].

The definitive treatment option for the hyperthyroidism is 131I-radioiodine [93]. Optimal hyperthyroidism treatment goals to establish an euthyroid state commonly represents a recovery from atrial fibrillation to sinus rhythm and a dissolution of the cardiac manifestations [76, 79]. Studies pointing out how crucial is an adequate and sufficient treatment concluded that the cardiovascular complications arising from thyrotoxicosis are the primary cause of death [94].

#### **8. Graves' Disease and arterial hypertension**

Thyroid hormone causes decreased resistance in peripheral arterioles through a direct effect on VSM cells and decreased mean arterial pressure, which, when sensed in the kidneys, activates the renin-angiotensin-aldosterone system and increases renal sodium absorption. T3 also induces erythropoietin synthesis, which leads to an increase in red cell mass. These changes combine to promote an increase in blood volume and preload. Hyperthyroidism has been identified as the second most common reason for isolated systolic hypertension [62]. Because of the reversible effects of hyperthyroidism hypertension, efficient hyperthyroidism treatment and the administration of β-blockade to achieve normocardia reverses hypertension, heart rate variability and arrhythmias. Iryna Tsymbaliuk et al. [95] reported that there are 95% arterial hypertension between Graves' hyperthyroidism patients, especially demonstrating high systolic blood pressure, as result of low vascular resistance, elevated resting heart rate and blood volume due to excess of thyroid hormones [95, 96]. Moreover, they showed that arterial hypertension was developed secondary to Graves' hyperthyroidism and associated with diminished quality of life. Restoring of euthyroid state resulted in elimination of arterial hypertension or stabilization of blood pressure levels in patients with a history of arterial hypertension, which is consistent with other studies.

The role of euthyroidism restoration is supported by findings from other studies showing the direct effect of hyperthyroid state on the cardiovascular system; in animal studies, the excess of thyroid hormones had a major impact on the cardiomyocytes, whereas beta-adrenergic or angiotensin receptor stimulations played a minor role [79, 97]. And in the study, as a result, improvement of cardiovascular parameters in relatively short follow up time was achieved after restoring of euthyroid state by antithyroid therapy accompanied by administration of beta-blockers and ACE inhibitors.

#### **9. Graves' Disease and pulmonary hypertension**

About 1/5 of pulmonary hypertension cases are shown to be concomitantly occurring with thyroid disease [98]. Pulmonary artery hypertension (PAH) is identified as mean pulmonary arterial pressure levels higher than 25 mm Hg at rest [81]. Increased pressure in the left atrium is transmitted backwardly to pulmonary veins. This activates baroreceptors ending up with a reflex contraction in the arterioles. Elevated pulmonary artery pressure aggravates the right ventricular workload. This overload forces the right ventricle to contract laboriously to maintain blood flow towards pulmonary vasculature. However, this process eventually leads to increased pulmonary resistance and PAH [48]. Although, current knowledge regarding hemodynamics of

PAH in hyperthyroidism has not well explained yet, decrease in PAH after establishing an euthyroid state may be considered as a supportive evidence for a causal relationship [99]. A current study asserts a direct relation between TSH receptor antibodies and PAH, thus a possible autoimmune-mediated pulmonary vascular remodeling may be conducted [101]. Hyperthyroidism should be excluded in patients with PAH; moreover, in case of coexisting hyperthyroidism and dyspnea, every patient should be examined for PAH either [98, 100].

PAH has been associated with thyroid dysfunction, mainly hyperthyroidism. It has been suggested that SVR lowering effect of thyroid hormone may not occur in the pulmonary vasculature [60]. PAH and atrioventricular valve regurgitation have been both documented with a high prevalence [90]. Various articles have revealed that hyperthyroidism may manifest as right heart failure and tricuspid regurgitation [91]. A research including of 23 cases with hyperthyroidism originating from Graves' Disease documented that 65% of those patients had PAH. Following an adequate treatment for the Graves' Disease, pulmonary artery pressure levels returned to normal values in almost all patients [100, 101].

Right heart failure and peripheral edema accompanying hyperthyroidism may be reasoned by this reversible increase in pulmonary artery pressure [60, 91]. Primary pulmonary hypertension is defined as the levels of pulmonary artery pressure above 25 mm Hg at rest and 30 mm Hg during exercise and frequently seen in young women. It has a progressive nature and mostly leads to right heart failure. A link between pulmonary hypertension and thyroid disease (i.e., hypothyroidism and hyperthyroidism) has been elucidated in recent [102]. Hypothyroidism rate was determined as 22% in a study including 40 patients with primary pulmonary hypertension [103]. There are several evidences indicating the importance of the autoimmune disease's role in both hypothyroid and hyperthyroid linked cases of primary pulmonary hypertension [91, 101, 103]. Thyroid dysfunction therefore should always be examined in the presence of primary pulmonary hypertension.
