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A Young Patient with Restrictive Cardiomyopathy and Severe Pulmonary Hypertension

Case Presentation

 A 24-year-old patient was first evaluated at our Institution 6 years ago because of 6-month history of paroxysmal atrial fibrillation and a suspicion of restrictive cardiomyopathy. The patient complained of decreased exercise tolerance and palpitations. Physical examination at the time revealed a tall man (179 cm, 84kg, BSA 2 m2) with barrel chest. Accentuated pulmonary component of the second tone was found. The patient was in sinus rhythm, right axis deviation and left atrial enlargement were present in 12-lead standard ECG. Chest X-ray revealed increased heart silhouette, left atrial enlargement and mild congestion in the pulmonary circulation. In echocardiographic examination, the sizes of both ventricles and right atrium were normal, however there was a significant left atrial enlargement (62 mm x 48 mm in 4-chamber view). LV and RV systolic functions were normal. There was no endocardial thickening. A Doppler echocardiographic study revealed a mitral restrictive filling pattern (E/A=2.7) and increased RVSP – approximately 45 mmHg (tricuspid regurgitation was slight), pulmonary acceleration time was 90 ms. In TEE there were no heart defects as well, proximal parts of coronary arteries were normal. Subsequently cardiac MR and chest CT were performed without revealing any pericardial pathology. There was no evidence of any systemic disease in the patient. In 24-hour Holter monitoring, the mean heart rate was 77 bpm, there were no pauses, no arrhythmia. Alfa-galactosidase activity in serum and leukocytes was normal, CK activity was normal 82 U/l, serum ferrum concentration was 205 μg/dl. In an exercise stress test, the patient attained 10.9 METs with Bruce protocol, of note he had prolonged postexertional tachycardia, 5 minutes after the exercise his heart rate in sinus rhythm was 110-120 bpm.

Myocardial Disease


   
Family history was negative with respect to heart failure, arrhythmias or cardiomyopathy. However, in clinical and noninvasive examinations, the patient’s mother was found to be in atrial fibrillation with ventricular response 70-100 bpm. A subsequent echocardiographic study revealed enlargement of both atria (LA>RA), no indirect signs of pulmonary hypertension. Myocardial thickness and contractility were normal. She had a detectable troponin I (0.04 ng/ml). A beta-blocker (metoprolol succinate 50 mg) was introduced along with antithrombotic therapy to prevent thromboembolic complications. The patient’s elder brother, although asymptomatic, was found to have mild left atrial enlargement in echocardiography.

Question 1: Based on the presented data, what other examinations could have been performed in the patient to clarify his condition?

For another 3 years, the patient suffered from recurrent episodes of paroxysmal atrial fibrillation with rapid ventricular response while on bisoprolol, uptitrated up to 10 mg and amiodarone were started. In addition, there was progression in his heart failure symptoms, the patient dropped out of his university studies (computer science).

Physically, jugular venous distention appeared, especially during effort, and the patient’s head became oedematous at faster walk. In addition, mild hepatomegaly was present, there was neither ascites, nor ankle edema. Since then, to control congestive symptoms, the patient required 2 diuretics (frusemide and hydrochlorothiazide), spironolactone 25-50 mg. Bisoprolol at 10 mg and amiodarone were continued. Standard 12-lead ECG revealed: sinus rhythm 72 bpm, minor right axis deviation, left atrial enlargement, incomplete right bundle branch block RSR’ in V1, tall R waves in RV leads suggestive of right ventricular hypertrophy. In echocardiography, a further increase in LA size (29 cm2), restrictive filling pattern, RV systolic pressure from slight TR was 100 mmHg. A cardiopulmonary study in this young man showed MVO2 of 22.3 ml/kg/min (50% of reference) and MVO2 at AT was 16.7ml/kg/min, there was a drop in systemic pressure from 170 to 150 mmHg during maximal exercise, and his maximum METs was 6.4. At that time (in 2006), a first approach was made to define contraindications for HTX better, and right heart pressures were as follows: PCWP 43/43/42 mmHg, PA 71/41/53 mmHg, thus the transpulmonary gradient (TG) was 11 mmHg, RA: 12/8/8 mmHg, RV: 71/5-13 mmHg and LV: 100/24-34mmHg. CO – 5.8l/min, PAR 1.88 Wood units, and SVR – 13.7 Wood units. His coronary angiography was normal. The decision was to repeat right heart catheterization in 6-12 months. In 2007, more pronounced limitation of exercise capacity (swelling of his head at mild exercise), NYHA III, a drop in MVO2 -20.5 ml/kg/min, MVO2 at AT 13.3 ml/kg/min, PAP 57/23/37 mmHg, increased TG of 15 mmHg  and PVR – 2.6 Wood units.

Question 2: Would you have referred the patient for heart transplantation at the time, knowing the criteria for disqualification from the procedure?

The patient was not entirely convinced to have cardiac transplant since he still could cycle on the level surface slowly for 1-2 hours. After a long discussion with the patient and his parents, we accepted the decision. Soon, the patient developed thyreotoxicosis due to amiodarone treatment that had to be controlled with thyreostatics. At the time, the patient was in atrial fibrillation, amiodarone was continued to control rapid ventricular response, he was hospitalized 3 times due to worsening of heart failure. Once the patient returned to euthyreosis, he spontaneously converted into sinus rhythm (Fig. 1).

12-lead standard ECG

Fig. 1: 12-lead standard ECG: sinus rhythm 62 bpm, right axis deviation, biatrial enlargement, RV hypertrophy, RSR’ V1, Q waves in leads II,III, aVF QRS=120ms, QT 490ms, ST-T changes in infero-lateral leads.
 
In 2009, there was a significant deterioration in exercise capacity, the patient was unwilling to leave his place. CMR was performed (Fig. 2) showing biatrial enlargement (LA>>RA), both ventricles of normal size and contracting well LVEF 69%, RVEF 56%; corrected LV mass was 71 g/m2, N:59-93; corrected RV mass was at the upper limit of normal: 28g/m2, N:14-30, myocardial thickness: IVSD 12, PW-9mm, of interest no late enhancement after gadolinium injection was found.

MRI four-chamber CINE SSFP view

Fig. 2 - MRI four-chamber CINE SSFP view - large dilatation of both atria (LA>>RA) with nondilated ventricles.

His Nt-proBNP level was not high (388 ng/ml), and the patient had detectable troponin I of 0.04 ng/ml. By the end of 2009, MVO2 was 14 ml/kg/min, and together with the patient, we decided once more to approach the issue of HTX, this time with the assessment of pulmonary vascular reactivity. During sinus rhythm of 70 bpm, right heart catheterization demonstrated again increased pulmonary artery pressures (PAP 71/29/47 mmHg), pulmonary capillary wedge pressures (PCWP 31/39/28 mmHg), thus TG was 19 mmHg. Cardiac output was normal (CO – 6.2 l/min), and pulmonary vascular resistance was increased (PVR – 2.8 Wood units), however SVR was normal: 12.4 Wood units. After aerolised iloprost inhalation TG dropped from 19 to 14 mmHg, but pulmonary artery systolic pressure was 64 mmHg. Due to the presence of pulmonary hypertension, we introduced sildenafil at 12.5 mg po, but after the second dose the patient developed atrial fibrillation and needed a cardioversion to return to sinus rhythm. No further attempts were made.

Question 3: Would you have referred the patient for heart transplantation at this time point?


Diagnosis, case resolution and treatment

Question 1:
What other examinations could have been performed in the patient?
The patient could have had endomyocardial biopsy performed. According to the guidelines (1), EMB is reasonable in the setting of heart failure associated with restrictive cardiomyopathy (Class of Recommendation IIa, Level of Evidence C). The first indication would have been to exclude systemic infiltrative disorders or storage diseases that could not be diagnosed otherwise, namely with the examination of extracardiac tissues, fluids. In our patient, there was neither Fabry disease, nor hemochromatosis, nor systemic diseases. There was no thickening of the myocardial walls, rendering infiltrative disorders rather unlikely. The use of both MRI and CT limited the significance of endomyocardial biopsy as a helpful tool to exclude pericardial diseases. In addition, there was no late enhancement after gadolinium injection showing lack of any evidence of structural damage of the myocardium. CPK was normal, thus rendering significant associated myopathy less possible.
Other important issues in restrictive cardiomyopathy are genetic studies (2-6). Thanks to the courtesy of Prof. Eloisa Arbustini, in the Pavia Centre for Inherited Cardiovascular Diseases, mutations in the following genes were excluded in the patient: MYH7, MYBPC3, TNNT2, TNNI3. Mutations in genes coding for other proteins like, desmin (DES) and alpha cardiac actin (ACTC) have also been associated with restrictive cardiomyopathy (5-6).

Question 2 and 3:

Would you have referred the patient for heart transplantation at the time, knowing the criteria for disqualification from the procedure?
Current guidelines state that heart transplantation should be considered in patients with the end-stage heart failure, with no serious co-morbidity and no alternative treatment options (7). Contraindications include irreversible high pulmonary vascular resistance (6-8 Wood units) and TG > 15 mmHg. There is no guideline how to approach patients who develop contraindications for heart transplantation first and indications for the procedure significantly later. This renders them ineligible for cardiac transplantation. A vasodilator challenge should be made when the pulmonary artery systolic pressure is ≥50 mmHg and either TG is ≥15 mmHg or PVR is >3 Wood units. In our patient, TG dropped from 19 to 14 mmHg, however PASP remained high >60 mmHg. ISHLT guidelines for listing patients for heart transplantation as relative contraindications show PAS exceeding 60 mmHg in conjunction with one of the three parameters (PVR> 5 Wood units, PVRI >6 or TG exceeding 16-20 mmHg) as important factors increasing the risk for early right heart failure and early death (8).
Therefore, we decided to try oral vasodilator, however due to most probably normal systemic vascular resistance – the attempt in the patient failed. Our patient was disqualified from HTX. Our cardiac surgeons considered him as being at too high a risk for developing right heart failure directly after HTX. A young doctor (LM) advised the patient to take Magnesium 2 x 0.5g in addition to his medication that was constant for the previous year apart from slight modifications of diuretics dosage, amiodarone according to QTc interval and serum concentration, acenocoumarol according to INR and kalium dosage).

Conclusion:

Two months later control Doppler echocardiographic study revealed that his pulmonary artery systolic pressure dropped down to 50-60mmHg. It was hard to believe in this, subsequent right heart catheterization confirmed the drop in pulmonary artery systolic pressure to 40mmHg, with elevated mean pulmonary wedge pressure of 24 mmHg. The patient’s condition slightly improved, his MVO2 increased up to 16.8 ml/kg/min. Another cardiac MRI revealed no significant changes with regard to both ventricles’ size and function in comparison to previous study, apart from a decrease in diameter of the pulmonary artery (37 mm→33mm). Thus, as for now, our patient does not have luckily any contraindications for HTX, and for the time being, does not meet any criteria for HTX either.
It is difficult to explain the spectacular response of the pulmonary artery systolic pressure to, most probably, introducing Magnesium in our patient with restrictive cardiomyopathy. Lack of late gadolinium enhancement on his CMR shows that there is no irreversible damage of the myocardium. Serum magnesium level, while on supplementation 1.0g daily (in a patient treated with diuretics and spironolactone) was normal: 0.89 mmol/l (N: 0.7-1.05 mmol/l).
The role of magnesium in human heart includes: influences in the energetic metabolism, in the excitement–contraction coupling, the adrenergic nervous activation and the renin–angiotensin–aldosterone system activation, and modification of the effect of drugs. Magnesium therapy has been associated with significant hemodynamic effects. Hemodynamically, magnesium therapy has been shown to reduce systemic vascular resistance and mean arterial pressure in animals and humans, to improve cardiac indexes, to increase coronary artery blood flow, and to reduce coronary vascular resistance (9-10).

References


1. Cooper LT, Baughman KL, Feldman AM, et al.: The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007, 50: 1914-1931.
2. Mogensen, J., Kubo, T., Duque, M. et al.. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J. Clin. Invest. 2003; 111: 209–216.
3. Peddy, S. B., Vricella, L. A., Crosson, J. E. et al.. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics, 117(5), 1830–1833.
4. Ware, S. M., Quinn, M. E., Ballard, E. T., Miller, E., Uzark, K., Spicer, R. L. Pediatric restrictive cardiomyopathy associated with a mutation in beta-myosin heavy chain. Clinical Genetics, 73(2), 165–170.
5. Burch M, Tomé-Esteban MT, Fenton M, Christiansen M, Andersen PS, Sebire N, Ashworth M, Deanfield JE, McKenna WJ, Elliott PM. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart. 2008; 94:1478-84.
6. Abrostini E, Pasotti M, Pilotto A, Pellegrini C, Grasso M, Previtali S, Repetto A, Bellini O, Azan G, Scaffino M, Campana C, Piccolo G, Viganò M, Tavazzi L. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. Eur J Heart Fail. 2006; 8:477-83.
7. Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology, Dickstein K, Cohen-Solal A, Filippatos G et al. Eur Heart J. 2008; 19:2388-442.
8. Mehra MR,  Kobashigaw J, Starling R et al.: Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates—2006 J Heart Lung Transplant. 2006 Sep; 25 (9):1024-42.
9. Whang R, Hampton EM, Whang DD. Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother 1994; 28:220-6.
10. Douban S, Brodsky MA Whang DD, Whang R.:Significance of magnesium in congestive heart failure Am Heart J 1996;132:664-71.

Notes to editor


Presented by Łukasz Mazurkiewicz and Zofia T. Bilińska, Dept. of Coronary Heart Disease and Structural Heart Diseases, 2Unit for Screening Studies in Inherited Cardiovascular Diseases. Institute of Cardiology, Warsaw.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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