**6. Graves' Disease and atrial fibrillation**

Patients with hyperthyroidism manifest more premature supraventricular depolarization and premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat), more nonsustained supraventricular tachycardias, and reduced heart rate variability [67]. The reduced variability is probably occurs as a consequence of decreased parasympathetic tone. These electrical stimulates may lead to paroxysmal atrial tachycardia, atrial fibrillation, and atrial flutter. The most frequent rhythm disorder is sinus tachycardia in hyperthyroidism [43]. Its clinical impact is overshadowed by atrial fibrillation. The rate of atrial fibrillation (AF) and other rare forms of supraventricular tachycardia in this disease varies between 2% and 20% The prevalence of atrial fibrillation in hyperthyroidism was determined as 13.8%, however peaked at up to 15% in patients over the age of 70 years. These results is significantly higher when compared to the rate of 2.3% in control group [66–69]. Atrial fibrillation often coexists with a rapid ventricular response. The occurrence of AF is more frequent in men and significantly increases with age, over 40 years in particular [69]. A current study revealed that the AF rate was below 2% in a cohort includes more than 13 k cases with hyperthyroidism. Early stage of disease or recognition may contribute to these result [70]. A stepwise increase in the prevalence was observed in the analysis based on age, especially peaked at ≈15% in patients >70 years old. This findings support data from the cohort of 40.628 hyperthyroid patients in the Danish National Registry. This database revealed that although 8.3% of the patients demonstrated an atrial fibrillation; male gender, the presence of ischemic or valvular heart disease or congestive heart failure were associated with the highest risk rates. Apparently, subclinical (mild) hyperthyroidism involves similar relative risk for atrial fibrillation as does overt disease [68]. This dilemma may be interpreted in favor of other accompanying diseases that occur in the older population. In unselected patients with atrial fibrillation, less than 1% were the

consequence of over-hyperthyroidism [71]. Consequently, although the abnormal thyroid function levels seems less reliable and indicative in the new-onset atrial fibrillation, establishing an euthyroid state and achieving sinus rhythm, justifies the value of TSH examining [7].

The left atrial size is enlarged in most of the patients with hyperthyroidism and AF rather than hyperthyroid people with sinus rhythm. Hyperthyroidism should not be accepted as the only reason for developing the new onset AF and possible underlying organic heart diseases should be investigated to avoid as serious cardiovascular events such as angina or heart failure. In an experimental study, connexin-40, a gap junction protein of myocardium which is essential for the transport of electrical activity upregulated by thyroid hormone in rats. This pathway may contribute to atrial fibrillation development in hyperthyroidism [72].

Atrial fibrillation generally reverts to sinus rhythm when an euthyroid state established. On the other hand, in young and early diagnosed patients β-Adrenergic blockade may be sufficient to regulate the ventricular rate. Higher dose may be required in case of elevated plasma clearance of β-blockers. Propranolol has an additional advantage by blocking T4 - T3 conversion in peripheral tissues. Nevertheless, cardio-selective β-blockers have a longer half-life and have similar cardiac effects. Intravascular administration of calcium blockers should be avoided considering the possible risk of a further fall in PVR: channel blockers, may cause potential adverse cardiovascular events such as blood pressure reduction via developing relaxation through smooth muscle cells of the resistance arterioles. Such treatment has been linked to acute hypotension and cardiovascular collapse [73]. Treatment of atrial fibrillation in the setting of hyperthyroidism includes β -adrenergic blockade. This can be accomplished with β 1-selective or nonselective agents, even in peroral usage, whereas treatments such as antithyroid therapy or radioiodine, which lead to a restoration of a chemical euthyroid state [7]. Although digitalis was an option in the treatment of hyperthyroidism and coexisting atrial fibrillation, due to the increased digitalis clearance and decreased sensitivity of the hyperthyroid heart to digitalis necessitated higher doses for optimal treatment beside leading to less predictable responses [74, 75]. How much risk does the systemic embolization include in the setting of thyrotoxicosis is yet unclear. It is still controversial whether to administer an anticoagulant therapy in patients with AF is efficient to prevent systemic embolization. Accordingly, each patient should be evaluated individually considering the risk of bleeding over embolization [76]. Hyperthyroidism in younger patients without any cardiac disease except for AF, the risk of anticoagulant therapy **may exceed its benefits**. However, it would be wise to administer anticoagulant drugs to older patients with previously diagnosed or suspected heart diseases or AF with longer duration. Oral anticoagulants doses should be trimmed considering that hyperthyroid patients will require less medication than euthyroid ones, **due to faster elimination of vitamin-K** dependent clotting factors [77]. Early diagnosis and full treatment radioiodine or thioureas demonstrated a reversion to sinus rhythm most patients within 2 to 3 months [70]. Older patients (>60 years old) with atrial fibrillation with longer duration are more resistant to spontaneous reversion to sinus rhythm. For this reason, electrical or pharmacological cardioversion are advised to attempt if the AF continues after an euthyroid state achieved chemically. Following an adequate treatment most of the patients turn into sinus rhythm permanently. Disopyramide (300 mg/d) administration after successful cardioversion, contribute to remain in sinus rhythm when compared to those not treated [76].

**Reversion and maintenance from AF to sinus rhythm is unusual before the euthyroid state is achieved**; therefore electrical cardioversion should be avoided before euthyroid condition. In another experimental study, the authors remarked the downregulator effects T3 via connexin-43 phosphorylation in diabetic rats. Thus, cardiac adaption to hyperglycemia reduced and the heart become **prones** to ventricular arrhythmias [78]**.**
