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An unusual form of Naxos disease and its improvement by adjuvant low-dose colchicine therapy Article in Acta cardiologica · August 2013 DOI: 10.2143/AC.68.4.2988900 · Source: PubMed
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Acta Cardiol 2013; 68(4): 433-437
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doi: 10.2143/AC.68.4.2988900
An unusual form of Naxos disease and its improvement by adjuvant low-dose colchicine therapy Nazmi GULTEKIN1, MD; Emine KUCUKATES2, PhD 1Dept. of Cardiology and 2Laboratory of Clinical Microbiology and Molecular Cardiology, Istanbul University Cardiology Institute, Istanbul, Turkey.
Abstract We evaluated a female patient with an unusual form of Naxos disease, who presented with central cyanosis and clubbing, simulating congenital heart disease. Adjuvant low-dose colchicine therapy (0.5 mg once daily) showed positive effects and has been continued for six months. Colchicine has anti-inflammatory and anti-fibrotic properties. It inhibits mitosis by disrupting tubulin assembly and enhances cellular apoptosis. Follow-up showed improvement in the patient’s clinical status, with a dramatic disappearance of the electrical storm and reductions in cyanosis and palmoplantar hyperkeratosis. Low-dose colchicine may be safe and effective in patients with Naxos disease and may reduce related complications.
Keywords Naxos disease – electrical storm – colchicine therapy.
INTRODUCTION Naxos disease is a rare, autosomal recessive disease characterized by a triad of right ventricular dysplasia/ dilated cardiomyopathy, woolly hair and palmoplantar hyperkeratosis. Genetic studies have identified two causative genes, encoding for the proteins plakoglobin and desmoplakin, both of which are involved in cell-cell adhesion. A 2-base-pair deletion in the plakoglobin gene (Pk2157del2TG), which maps to 17q21, has been found to truncate the C terminal of plakoglobin, causing Naxos disease. In addition, two different mutations of the desmoplakin gene (Dsp7901del1G and DspG2375R) have been found to truncate the C-terminal of this protein, resulting in a similar cardiocutaneous syndrome in families from Ecuador and Israel. All of these mutations may lead to sudden death1-6. Naxos disease has been reported in regions around the Black Sea, including eastern Turkey, as well as in
Address for correspondence: Prof. Dr. Nazmi Gultekin, Dept. of Cardiology, Istanbul University Cardiology Institute, Istanbul, Turkey. E-mail:
[email protected] Received 11 April 2013; revision accepted for publication 29 May 2013.
northern Italy, Israel and Saudi Arabia1-10. Clinically, Naxos disease is similar to arrhythmogenic right ventricular dysplasia (ARVD). Patients present with ventricular arrhythmias, with some patients showing unusual presentations such as acute coronary syndrome and electrical storm presenting as ventricular tachycardia with syncope, heart failure, cyanosis and clubbing1-8. A type of Naxos disease presenting at a younger age with more pronounced left ventricular involvement has been described in families from India and Ecuador (Carvajal syndrome)3,5. Colchicine is a medication with a relatively low therapeutic index that has been used to treat gout. Colchicine and its derivatives have been recommended to treat patients with recurrent pericarditis and viral infections such as AIDS and chronic active hepatitis9,10. We encountered a patient with a variant of Naxos disease, presenting with central cyanosis and clubbing simulating congenital heart disease. Treatment with low-dose adjuvant colchicine was effective in this patient.
CASE REPORT A 54-year-old woman living in the city of Trabzon in the Black Sea region of Turkey with a history of cyanosis, clubbing with intermittent exacerbations of
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congestive heart failure and syncope was referred to our hospital for further evaluation. First evidence of disease, consisting of periodic episodes of palpitations and syncope, occurred 25 years earlier, after the birth of her fourth child. At the time of presentation, the patient had experienced cyanosis for 10 years and exacerbations of acute congestive heart failure for four years. Her family history included her mother, who underwent implantation of an internal cardiac/defibrillator (ICD) due to life-threatening arrhythmias at age 70. The two brothers and three sisters of the proband were healthy. Physical examination revealed central cyanosis, clubbing of digits, increased jugular vein pressure, hepatomegaly, oedema and ascites, woolly but no gray hair, alopecia, palmoplantar keratoderma, and squamous lesions on her arms and legs (figure 1). ECG at admission showed T wave inversion in the precordial leads of the right ventricle (V1–V3). Incomplete right bundle-branch
block (RBBB) and epsilon waves were evident. ECG recordings showed ventricular premature beats, atrioventricular nodal reentrant tachycardia (AVNRT), accelerated AVN rhythm, atrial fibrillation (AF), and monomorphic and polymorphic episodes of ventricular tachycardia (VT). AF and AVNRT that could lead to lethal arrhythmias such as torsades de pointes were also present (figure 2). Chest X-rays showed considerable right heart prominence. The pulmonary arteries were normal and the lung fields were clear. The methemoglobin (MetHb) concentration in the blood was normal, as shown spectrophotometrically. Arterial blood gas analysis showed a pH of 7.56, a PCO2 of 26 mmHg, a PO2 of 48 mmHg and an O2 saturation of 97%. Lung function tests (spirometry, lung volumes, flow volume loops and transfer factor) were all normal. Echocardiography showed a dilated, hypokinetic right ventricle (RV) with prominent apical trabeculae and dilatation of the RV outflow tract. The right atrium (RA) and left atrium (LA) were also dilated. Patent
Fig. 1 Clinical findings in our patient before (A-F) and after six months (G-J) of treatment with colchicine (A-F) Photographs before treatment showing woolly (red arrows) but no gray hair, palmoplantar hyperkeratosis and squamous lesions on the arms and legs, as well as clubbing and cyanosis. (D) A photograph of the patient 30 years earlier. (G-J) Photographs after treatment, showing reduced cyanosis on the patient’s face (G) and legs (H), and improved palmoplantar hyperkeratosis (J).
Naxos disease and colchicine therapy
Fig. 2 ECG recordings, showing paroxysmal episodes of ventricular tachycardia (VT) with an LBBB morphology (i.e. right ventricular VT), A-V nodal reentrant tachycardia, sinus rhythm, and epsilon waves (e). LBBB, left bundle-branch block; M, monomorphic; TdP, torsades de pointes; AVNRT, A-V nodal reentrant tachycardia; AVNT, accelerated A-V nodal tachycardia (AVNT); AF, atrial fibrillation (A-G).
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foramen ovale (PFO) was observed, along with slight contrast shunting from the LA to the RA. Estimated RV ejection fraction (EF) was 14%. Although the tricuspid valve structure was normal, moderate tricuspid regurgitation (TY) due to annular dilation was present. The interventricular septum (IVS) showed paradoxical movement. The patient’s pulmonary artery pressure (PAP) was 30 mmHg and EF was 60% with preserved LV systolic function. Pericardial effusion 2.5 cm in width was observed at the widest part surrounding the heart. No myocardial fatty tissue infiltration was observed on TTE (figure 3). Cardiac magnetic resonance imaging (MRI) has been found to accurately assess the structural and functional features of ARVD, including fibro-fatty infiltration, thinning of the RV myocardium, RV aneurysms, RV dilation, regional wall motion abnormalities and global systolic dysfunction. Cardiac MRI in our patient showed aneurysmal dilations of the diaphragmatic, apical and infundibular regions of the RV (the so-called ‘‘triangle of dysplasia’’), suggesting ARVD (figure 3).
Right-left heart catheterization and coronary angiography showed gradients of 20/0-12 mmHg (pO2, 46) in the RV apex, 25/18 mmHg (pO2, 44) in the pulmonary artery, 90/0-10 mmHg in the LV, and 90/60 mmHg in the aorta. There were no significant gradients in the mitral and aortic valves. Coronary arteries were normal, and there was no shunt between the right and left heart chambers.
TREATMENT At presentation, the patient was taking metoprolol 50 mg twice daily. Amiodarone perfusion protocol was started to prevent uncontrolled ventricular tachycardia. During an electrophysiologic study (EPS), the haemodynamic status of the patient deteriorated due to VT, and an ICD was inserted. At discharge, the patient was prescribed 100 mg/day of aspirin, metoprolol 50 mg twice daily, 100 mg/day L-thyroxine for hypothyroidism, and 40 mg furosemide once daily.
Fig. 3 Transthoracic echocardiography (TTE) and cardiac magnetic resonance images (MRI) results. TTE: LA, left atrium, RA, right atrium, RV, right ventricle, LV, left ventricle, RVOT, right ventricle outflow tract, LVOT, left ventricle outflow tract, IVS, inter-ventricular septum, T, trabeculations (D-sign). MRI: fibrofatty (FF) infiltration is shown at the apex. The arrows indicate aneurysmal dilation of the right ventricular (RV) apex and RV inflow tract, M denotes the aneurysmal dilation of the right ventricular outflow tract (RVOT), the third component of the “Marcus triangle”. RA, right atrium, IVS, inter-ventricular septum, IAS, inter-atrial septum, LVPW, left ventricle posterior wall, RVAW, right ventricle anterior wall, TV, tricuspid valve, LV, left ventricle, ICD, internal cardiac defibrillator (A-E).
Naxos disease and colchicine therapy
LOWDOSE ADJUVANT COLCHICINE THERAPY In addition to the above medications, the patient was prescribed 0.5 mg adjuvant colchicine once daily to prevent pericardial effusion and invasion of normal tissue by fibro-fatty tissues. The cardiac rhythm returned to AF, and then to sinus rhythm. Subsequent follow-up showed dramatic improvement in the patient’s clinical status, disappearance of the electrical storm, and marked reductions in cyanosis and palmoplantar hyperkeratosis (figure 1 G-J). The patient remains alive and clinically well.
DISCUSSION Naxos disease is a rare, autosomal recessive condition, which usually presents as RV cardiomyopathy associated with woolly hair, palmoplantar keratoderma and electrical storm. A variant of Naxos disease, which is much more rare, presents with central cyanosis resembling congenital heart disease7,8. One patient with arrhythmogenic RV cardiomyopathy and atrial right-to-left shunt presented with high pulmonary artery pressure and underwent cardiac transplantation due to refractory right heart failure but died one week after the operation7. Naxos disease may cause severe hypoxaemia resembling cyanotic congenital heart disease, although this condition may be treatable by a Glenn shunt8. We therefore thought that a Glenn shunt along with a De Vega would be the most appropriate treatment for our patient. Because the pulmonary artery pressure (25/18 mmHg)
was higher than that at the RV apex (20/0-12 mmHg), there was a possibility of Glenn shunt malfunction and superior vena cava syndrome. We therefore decided to insert an ICD due to polymorphic VT. RA pressure may increase secondarily to RV diastolic or systolic dysfunction, reversing the left to right atrium gradient and opening the flap of the foramen ovale causing severe hypoxaemia7. In our patient, however, PFO was not observed despite a prominent gradient, with a net difference causing severe hypoxaemia. Colchicine, which has been used for many centuries, binds to tubulin, blocks mitosis, and inhibits a variety of functions of polymorphonuclear leukocytes both in vivo and in vitro. Colchicine also interferes with the transcellular movement of collagen. The close proximity of lymphoid components and fibroblasts at inflammatory sites and the production of lymphokines, which influence fibroblast chemotaxis, proliferation, and protein synthesis, are now well recognized. Thus, colchicine may reduce immunopathic antifibroblastic properties9,10. To our knowledge, colchicine treatment of Naxos disease has not been reported previously. In conclusion, study of the present patient disclosed that Naxos disease may mimic cyanotic congenital heart disease with severe hypoxaemia. In addition, adjuvant low-dose colchicine may be beneficial in the treatment of this very rare disease. Further studies of colchicine and other tubulin inhibitor derivatives are needed in patients with hereditary disorders.
CONFLICT OF INTEREST: none declared.
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