Atrial Fibrillation and Hyperthyroidism: a New Look at Their Relationship and Therapy with Lidoflazine K

Postgrad Med J: first published as 10.1136/pgmj.51.591.4 on 1 January 1975. Downloaded from

Postgraduate Medical Journal (January 1975) 51, 4-9.

Atrial fibrillation and hyperthyroidism: a new look at their relationship and therapy with lidoflazine K. BRUYNEEL*t H. VERHAEGEN* M.D. M.D. CH. DE VIL$ M.D. * Clinical Research Unit, St Bartholomeus Hospital, B-2060 Merksem, Belgium t Department of Internal Medicine, H. Hartziekenhuis, B-2500 Lier, Belgium

Summary Muggia, Stjernholme and Houle, 1970; Stern, Various kinds of dysrhythmias are found in association Jacobs and Duncan, 1970; Kernoff, Rossouw and with hyperthyroidism but especially atrial fibrillation. Kennelly, 1972), reversible bundle branch block The causal relationship of chronic atrial fibrillation (Digilio, 1938), ventricular ectopic beats (Rohrbach, and the endocrine disorder is controversial, as is its 1968), ventricular tachycardia (Ernstene, 1938; therapeutic management. Six patients with this parti- Fairhurst and Sash, 1959; Lyngborg and Jacobsen, cular combination of disorders were treated with 1972) and ventricular fibrillation (Boone, 1945; copyright. lidoflazine: a new anti-anginal drug with anti- Lyngborg and Jacobsen, 1972). These dysrhythmias, arrhythmic activity. All six patients returned to sinus although some are rare, have been described in rhythm on lidoflazine treatment although still hyper- patients of over 40 years of age who also had thyroid and remained in sinus rhythm during the coronary artery disease, hypertension or acute follow up period ranging from 5 to 14 months. This infections. Ernstene (1938) found 207 patients with occurred independently of antithyroid treatment. atrial fibrillation among 1000 patients with hyper- Some evidence is put forward that dysrhythmias and thyroidism, Bourel et al. (1969) twenty-four of most commonly chronic atrial fibrillation are triggered eighty-three patients, Rohrbach (1968) four of off by hyperthyroidism or other disorders but that they eleven patients with masked hyperthyroidism, http://pmj.bmj.com/ are maintained by permanent cardiac damage due to Sandler and Wilson (1959) eighty-four of 462 patients arteriosclerosis, hypertension, coronary heart disease and Jervell (1952) fifty-three of 279 patients. There- or rheumatic valve disease. fore, atrial fibrillation can be considered as the most Successful chemical cardioversions and main- common cardiac dysrhythmia associated with tenance of sinus rhythm can be obtained independent hyperthyroidism (Friedberg, 1966; Miyahara et al., of the thyroid function. Our results confirm the anti- 1969). It is common experience that no parallelism arrhythmic activity of lidoflazine. exists between heart rhythm and the severity of thyroid dysfunction (Friedberg, 1966). Sinus rhythm on October 1, 2021 by guest. Protected Introduction is not always restored by normalizing the thyroid Hyperthyroidism has been found to be associated function and DC shock, quinidine or combination not only with sinus tachycardia, one of its features, of drug therapy is often required to restore sinus but also with several dysrhythmias and conduction rhythm. disturbances such as atrial flutter (Ernstene, 1938), Lidoflazine, a new anti-anginal drug, has been first and second degree of a.v. block (Cookson, she,wn to have anti-arrhythmic activity, especially as 1959; Blizzard and Rupp, 1960; Hoffman and concerns supraventricular dysrhythmias such as Lowrey, 1960; Rosenblum and Delman, 1963; atrial fibrillation and flutter, in patients with arterio- Lanfranchi and Fauchier, 1973), third degree of sclerosis, rheumatic heart disease, hypertension, con- a.v. block (Davis and Smith, 1933; Steuer, 1936; genital heart disease and lone atrial fibrillation Address for reprints: Dr H. Verhaegen, Clinical Research (Miyahara et al., 1969; Piessens, Kesteloot and De Unit, St Bartholomeus Hospital, B-2060 Merksem, Belgium. Geest, 1970; Schlepper and Derro, 1972; Batlouni, t Present address: K. Oomsstraat 44, B-2000 Antwerp, unpublished report; De Vil and Bruyneel, 1974). Belgium. We have for the first time treated patients with Postgrad Med J: first published as 10.1136/pgmj.51.591.4 on 1 January 1975. Downloaded from

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0 Ha [.- E r: a, ca 1 W4 A oOue' 5^<0 0 co h E Postgrad Med J: first published as 10.1136/pgmj.51.591.4 on 1 January 1975. Downloaded from 6 K. Bruyneel, H. Verhaegen and Ch. de Vil chronic atrial fibrillation and hyperthyroidism with mercapto-imidazole. She has remained in sinus lidoflazine. It is the purpose of this study to demon- rhythm for 8 months despite two relapses of hyper- strate that lidoflazine converts atrial fibrillation thyroidism when she stopped methyl-mercapto- during the hyperthyroid as well as the euthyroid imidazole (Strumazol ®) therapy. state, and maintains sinus rhythm independent of the thyroid function. Case 2 The patient was treated with digitalis, methyl- Material and methods mercapto-imidazole and lidoflazine 60 mg t.i.d. Six consecutive patients with chronic atrial Follow-up not possible after discharge from fibrillation and hyperthyroidism were treated with hospital. lidoflazine tablets to obtain sinus rhythm. Atrial fibrillation was considered to be chronic when last- Case 3 ing continuously for at least 1 week without any The patient has remained in sinus rhythm for previous attacks of self-limiting atrial fibrillation or 14 months with lidoflazine 60 mg b.i.d. and lugol palpitations in the history. Special attention was solution, although she remains slightly hyperthyroid. given to the potassium metabolism of the patients. Potassium syrup (20 mEq potassium t.i.d.) was Case 4 generally given to all patients who had diuretics, The patient remained in sinus rhythm for 5 months laxatives, mild heart failure, ventricular ectopic taking only one tablet of lidoflazine a day during the beats on the resting ECG or low serum potassium last month. Such a low dosage treatment was con- value. sidered to be ineffective and stopped. Atrial fibrilla- Patients with manifest heart failure, special diets tion promptly returned and remained for another (low salt, low calorie) or acute coronary artery 4 months. The patient, who suffered from character disease were excluded unless conditions were altered. disturbances, refused to take lidoflazine tablets No other anti-arrhythmic drug was given except again. He died 12 hr after a trauma from multiple

digitalis when required in the presence of heart bone and skull fractures. copyright. failure or fast ventricular rhythm at rest (> 100 beats/min). Cases 5 and 6 Lidoflazine tablets of 60 mg were given, starting Both patients have remained in sinus rhythm for with one tablet a day during the first week with a 5 months while taking lidoflazine 60 mg b.i.d. and weekly increase of one tablet up to three tablets a day methyl-mercapto-imidazole. for the outpatients. The treatment was started with two or three tablets a day at once for the inpatients. Discussion Anti-hyperthyroid treatment was started before or The initial results of converting atrial fibrillation after the cardioversion. The cardioversion was to sinus rhythm and maintaining the rhythm during http://pmj.bmj.com/ initially attempted in the hospital but later as an out- mild to moderate severe hyperthyroidism look pro- patient treatment. Hyperthyroidism was believed to mising although our series is rather small. No rhythm be present according to the clinical features and disturbances have been observed or mentioned by symptoms and when plasma cholesterol was below the patients but continuous ECG monitoring has 150 mg%, PBI above 9y, basal metabolism above not been undertaken during the cardioversion period. + 30%, T3 resine uptake above 35%, T4 above No side effects or complications were noticed. Similar 12 mg%. cardioversion results of atrial fibrillation to sinus Atrial fibrillation and sinus rhythm were diag- rhythm during hyperthyroidism have been reported on October 1, 2021 by guest. Protected nosed by means of repetitive 12-lead ECG record- with quinidine (De Vil and Bruyneel, 1974) and ings at rest. Lidoflazine treatment was maintained at quinidine with propranolol (Levi and Proto, 1972). the dose of cardioversion or less for each patient. Therefore it is difficult to agree with other authors (Carlier, 1973) who consider attempts toconvert atrial Results fibrillation during hyperthyroidism to be utopian Sinus rhythm was obtained in all six patients since sinus rhythm will not remain so long as hyper- within half a day to 6 weeks (see Table 1). None of thyroidism exists, and most patients convert spon- the patients had a history of arterial embolism or taneously to sinus rhythm once hyperthyroidism is signs of mitral valve disease. Anticoagulants were effectively treated (Schrire, 1971; Carlier, 1973). Ern- given to one patient only (case 2). stene (1938) found that of sixty cases of established atrial fibrillation, thyroidectomy resulted in a sponta- Case 1 neous re-establishment ofsinus rhythm in twenty-one The patient continued her treatment of digitalis, patients within 10 days after surgery. Subsequently, lidoflazine 60 mg b.i.d., meprobamate and methyl- quinidine sulphate was started in twenty patients, Postgrad Med J: first published as 10.1136/pgmj.51.591.4 on 1 January 1975. Downloaded from

Atrialfibrillation and hyperthyroidism 7 which converted atrial fibrillation to sinus rhythm in rhythm and the latter can be maintained with anti- twelve. Six patients of the remaining group died with arrhythmic drugs during hyperthyroidism, inde- atrial fibrillation and thirteen others persisted in their pendently of the antithyroid treatment or thyroid dysrhythmia. function present (Levi and Proto, 1972; De Vil and Silver, Delit and Eller (1962) found atrial fibrilla- Bruyneel, 1974). tion to be present in 51% of the patients with thyro- (6) Hyperthyroidism does not only trigger off cardiac disease before and in 24% after radioactive atrial fibrillation but has been found to induce all iodine therapy. kinds of dysrhythmias and conduction disturbances Bock and Klein (1972) found dysrhythmias in in patients of over 40 years of age depending on fourteen of thirty-eight patients with hyperthy- concomitant pathophysiological conditions (Cook- roidism who were more than 60 years old. Tachy- son, 1959; Fairhurst and Sash, 1959; Lyngborg and arrhythmias were frequent during, as well as after, Jacobsen, 1972). radioactive iodine therapy, and generally resistant Therefore, there is no need to leave the hyper- to drug therapy. The authors very seldom observed thyroid patient, with his disturbing symptoms of a spontaneous remission to sinus rhythm in this palpitations or atrial fibrillation with fast ventricular age group. rate and decreased cardiac output and effort toler- Several authors (Erstene, 1938; Boone, 1945; ance (Benchimol, Lowe and Akre, 1965; Bouma and Jervell, 1952; Moe, 1968; Ticzon and Whalen, 1973) May, 1967), until stable euthyroid state is obtained have pointed out that atrial fibrillation may occur and hoping atrial fibrillation will spontaneously con- as an acute self-limiting form triggered off by hyper- vert to sinus rhythm. Although propranolol (Howitt thyroidism, pericarditis, pneumonia, influenza, pul- and Rowlands, 1966), guanethidine (Lee, Bronsky monary embolus, post-thoracotomy, gall bladder and Waldstein, 1962; Waldstein et al., 1964; Gold- disease, alcohol or heroin intoxication. This atrial stein and Killip, 1965) and reserpine (Canary et al., fibrillation remains chronic and refractory when 1957) have been shown to diminish palpitations in permanent cardiac damage (with or without atrial patients with hyperthyroidism, they do not convert enlargement due to rheumatic heart disease, hyper- atrial fibrillation to sinus rhythm, and a complete copyright. tension, arteriosclerosis and coronary heart disease) return to normal conditions of heart rate and cardiac is present. This explains why 75% of 207 patients output is not achieved. Propranolol (Howitt and with hyperthyroidism and atrial fibrillation wereolder Rowlands, 1967) and guanethidine (Goldstein and than 45 years (Ernstene, 1938) and atrial fibrillation Killip, 1965) should be used with caution in hyper- was found to be related with the duration ofexistence thyroidism since both drugs reduce blood flow to of hyperthyroidism (Willius, Boothby and Wilson, certain vascular beds out of proportion to the oxygen 1923). demand. Another alternative is offered by lidoflazine Other authors (Kulbertus, 1973) could not con- therapy. This original compound prolongs reactive firm this concept. However, some evidence that hyperaemia in mini pigs after coronary artery http://pmj.bmj.com/ atrial fibrillation is not caused by hyperthyroidism occlusion (Jageneau, Schaper and Van Gerven, itself but, more likely, is induced by the excess of 1969), reduces consumption of nitroglycerine tablets thyroid hormones and maintained only in the pre- and improves exercise tolerance in patients with sence of different kinds and degrees of cardiovas- coronary heart disease (Batlouni, Bertolami and cular damage, is given by the following facts. Duprat, 1968; Bernstein and Peretz, 1972; Piessens (1) Chronic atrial fibrillation associated with and De Geest, 1972). Lidoflazine converts atrial hyperthyroidism occurs only in patients of over 40 fibrillation to sinus in of the rhythm 70-80% on October 1, 2021 by guest. Protected years of age while atrial fibrillation in the younger patients suitable for cardioversion and the therapy patients remains paroxysmal (Boone, 1945). compares favourably with quinidine-induced con- (2) Only 20-25% of all hyperthyroid patients versions (De Vil and Bruyneel, 1974). develop chronic atrial fibrillation (Ernstene, 1938; The rate of pacemaker activity and depolarization Jervell, 1952; Sandler and Wilson, 1959; Rohrbach, (dV/dt) and amplitude of the action potential and 1968; Bourel et al., 1969). conduction velocity of in vitro cardiac muscle pre- (3) Onset and spontaneous conversion of atrial parations are reduced by lidoflazine. The duration fibrillation does not correspond to onset and of the action potential and of the effective refractory correction of hyperthyroidism (Willius et al., 1923; period is prolonged (Carmeliet and Xhonneux, Symons, Richardson and Wood, 1971). 1971). Lidoflazine may thus be compared to local (4) Not all efficiently treated hyperthyroid patients anaesthetics and other anti-arrhythmic drugs, such with atrial fibrillation subsequently spontaneously as quinidine. It has no obvious chronotropic (Keulen, regain sinus rhythm (Ernstene, 1938; Silver et al., 1973) or inotropic (Bruyneel, personal observation) 1962; Bock and Klein, 1972). effect in the resting state. Lidoflazine is not known to (5) Atrial fibrillation can be converted to sinus interfere with the thyroid hormone metabolism or Postgrad Med J: first published as 10.1136/pgmj.51.591.4 on 1 January 1975. Downloaded from

8 K. Bruyneel, H. Verhaegen and Ch. de Vil any of its diagnostic tests. Bernstein and Peretz CARLIER, J. (1973) Le traitement des complications cardia- to be ques de l'hyperthyroidie. Revue Medicale de Liege, 28, (1972) found QTc prolonged in their patients 601. with lidoflazine. Keulen (1973) found the QTc CARMELIET, E. & XHONNEUX, R. (1971) Influence of lido- unchanged. Increased incidence of ventricular flazine on cardiac transmembrane potentials and experi- dysrhythmias has been reported during lidoflazine mental arrhythmias. Naunyn-Schmiedebergs Archiv fur treatment in with atrial fibrillation and overt experimentelle Pathologie und Pharmakologie, 268, 210. patients COOKSON, H. (1959) The thyroid and the heart. British heart failure, enlarged heart size or conditions where Medical Journal, i, 254. decreased body potassium can be expected (Piessens DAVIS, A.G. & SMITH, H.L. (1933) Complete heart block in et al., 1970; Schlepper and Derro, 1972). This was hyperthyroidism following acute infections. American not the when classic selection criteria for Heart Journal, 9, 81. experience DE VIL, CH. & BRUYNEEL, K. (1974) Cardioversion and treat- cardioversion were applied (De Vil and Bruyneel, ment of chronic atrial dysrhythmias with quinidine or 1974). lidoflazine. Comparative study. Acta cardiologica, 29, No. The advantages of lidoflazine therapy seem to be 5. the absence of side effects and drug interference and DIGILIO, V.A. (1938) Reversible bundle branch block in a case of hyperthyroidism. American Heart Journal, 15, 116. the low dosage needed to maintain sinus rhythm ERNSTENE, A.C. (1938) Cardiovascular complications of with excellent results after cardioversion. Batlouni hyperthyroidism. American Journal ofthe Medical Sciences, (unpublished report) found twenty-eight of thirty 195, 248. patients with atrial fibrillation to be still in sinus FAIRHURST, B.J. & SASH, L. (1959) Ventricular tachycardia associated with thyrotoxicosis. British Medical Journal, rhythm 1 year after having been converted to sinus ii, 677. rhythm with lidoflazine. Twenty-four patients had FRIEDBERG, C.K. (1966) In: Diseases of the Heart, p. 1617. taken one tablet daily for 1 year as maintenance W. B. Saunders: Philadelphia. therapy. Our limited experience with lidoflazine in GOLDSTEIN, S. & KILLIP, T. (1965) Catecholamine depletion with atrial fibrillation accords in thyrotoxicosis. Effect of guanethidine on cardiovascular hyperthyroid patients dynamics. Circulation, 31, 219. with previous observations as concerns its efficacy HOFFMAN, I., & LOWREY, R.D. (1960) The electrocardiogram to convert atrial fibrillation to sinus rhythm and in thyrotoxicosis. American Journal of Cardiology, 6, 893. its maintenance. It confirms the intrinsic anti- HOWITT, G. & ROWLANDS, D.J. (1966) Beta sympathetic copyright. effect of lidoflazine which is obvious blockade in hyperthyroidism. 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