European Journal of Echocardiography Advance Access originally published online on June 25, 2008
European Journal of Echocardiography 2008 9(6):840-845; doi:10.1093/ejechocard/jen189
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Mitochondriopathy: a rare aetiology of restrictive cardiomyopathy
Christophe Thebault1,
Romain Ollivier1,
Guillaume Leurent1,
Pascale Marcorelles2,
Bernard Langella1 and
Erwan Donal1,*
1 Department of Cardiology, University Hospital Pontchaillou, 35033 Rennes, France
2 Department of Anapathology, University Hospital, Brest, France
Received 25 February 2008; accepted after revision 30 May 2008; online publish-ahead-of-print 25 June 2008.
* Corresponding author. Tel: +33 6 17 70 85 67. E-mail address: erwan.donal{at}chu-rennes.fr
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Abstract
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When diagnosing a restrictive hypertrophied cardiomyopathy,
most echocardiographists consider cardiac amyloidosis as a possible
cause, especially after the appearance of ‘granular’
sparkling echoes on a transthoracic echocardiography. However,
other infiltrative diseases (i.e. metabolic myopathies, Gaucher,
Hunter's, and Hurler's diseases) or storage cardiomyopathies
(haemochromatosis, Fabry's disease, glycogen storage, and Niemann–Pick
disease) should be considered. In this paper, we report on another
unusual cause of restrictive cardiomyopathy of which all cardiologists
should be aware.
Keywords: Mitochondriopathy; Restrictive cardiomyopathy; Heart failure
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Introduction
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When diagnosing a restrictive hypertrophied cardiomyopathy,
most echocardiographists consider cardiac amyloidosis as a possible
cause, especially after the appearance of ‘granular’
sparkling echoes on a transthoracic echocardiography (TTE).
However, other infiltrative diseases (i.e. metabolic myopathies,
Gaucher, Hunter's, and Hurler's diseases) or storage cardiomyopathies
(haemochromatosis, Fabry's disease, glycogen storage, and Niemann–Pick
disease) should be considered.
1 In this paper, we report on
another unusual cause of restrictive cardiomyopathy of which
all cardiologists should be aware.
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Case report
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A 54-year-old woman was referred for a TTE because of dyspnoea.
Her personal history consisted of bilateral sensory hearing
loss, a short stature (weight: 40 kg, BMI = 17.7 kg/m
2), and
diabetes mellitus diagnosed during an anaesthesiologist visit
for cochlear implant surgery. Her mother also suffered from
diabetes mellitus and deafness.
On admission, a physical exam showed marked signs of heart failure and a chest X-ray showed pleural effusion and cardiomegaly. An electrocardiogram revealed (Figure 1) sinus tachycardia, left ventricular (LV) hypertrophy with strain pattern, and intraventricular conduction disturbance. A TTE (Figures 2 and 3, see Supplementary data online, Video S1) (General Electrics Health Care, VIVID 7, Horton, Norway) showed a diffuse hypokinetic motion of the LV [LV ejection fraction (LVEF): 25% according to Simpson's method] with mild hypertrophy [interventricular septum diameter (IVSd): 13 mm] and a severe restrictive pattern without any caricatural atrial enlargement usually associated with amyloidosis. Her NT-pro-brain natriuretic peptide (NT-proBNP) level was 438 pg/ml (>222 pg/ml) with a normal renal function.
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Figure 2 Transthoracic echocardiography showing diffused LV hypertrophy with enlarged atrias, restrictive filling pattern with S' velocity and E' < 5 cm/s. The pulmonary vein flow shows a blunted S-wave and a large A-reversal wave (longer than mitral A-wave).
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No monoclonal gammapathy was found in her serum nor urine, and
no amyloid deposit was found on biopsy of the salivary glands.
A coronary angiography did not reveal any significant stenosis. After clinical stabilization, endomyocardial biopsies were performed to exclude localized cardiac amyloidosis and other restrictive cardiomyopathies. Myocytes' micro-vacuolization was noted with an absence of amyloid deposit. A high mitochondria density with abnormal size, shape, and glycogen overfill was noted on a light and electron microscopy (Figures 4 and 5).
The patient's deafness, short stature, and late diabetes mellitus
with hypertrophic cardiopathy were suggestive of mitochondrial
disease. A point mutation of the mitochondrial tRNA 3243 gene
was identified using polymerase chain reaction, confirming the
mitochondrial diabetes.
A cardiac MRI (clinical 3-T ACHIEVA®; Philips Medical Systems, Eindhoven, The Netherlands) was performed during the initial hospitalization: cine MRI (gradient echo) showed a global hypokinetic LV (LVEF: 34%). Measurement of the LV showed a moderate hypertrophy (LV mass: 107 g/m2, IVSd: 14 mm). Morphological sequences (T2-weighted spin echo sequences, ±fat saturation) did not show any significant hypersignal (Figures 6 and 7), contrary to the cardiac amyloidosis.2
The patient was treated with an angiotensin-converting enzyme
inhibitor, a beta-blocker, and a low dose of diuretics. An oral
co-enzyme Q10 (150 mg per day) was administered in light of
case reports showing favourable benefits for endogenous insulin
secretion, preventing hearing loss, reduced lactate production
during test exercise, and improvement in the exercise tolerance
3,4 and LV function.
5–7
A follow-up at 2 months showed an improvement on the TTE (LVEF 50%) (Figure 8, see Supplementary data online, Video S2) with remaining sparkling echoes. Her NT pro-BNP level had decreased (316 pg/ml) confirming the clinical status evaluation. Family screening has been launched: one of her two daughters was found positive for the mutation, but no evidence of clinical expression was present at the time of molecular diagnosis.
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Figure 8 Two-dimensional-strain analysis showing an impaired left ventricular longitudinal function initially and an improvement after 2 months of dedicated treatment. The radial strain improved slightly and the circonferencial strain stayed ‘identical’ after 2 months.
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Discussion
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Maternally inherited diabetes and deafness is found in 0.5–2.8%
of all diabetic patients.
8
The relationship between the gene mutation, myocardial hypertrophy, and dysfunction remains obscure. However, light and electron microscopy of endomyocardial specimens of MELAS-patients (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) with diabetes has shown abnormal mitochondria, with a marked increase in their number and size as we observed. These abnormalities of the cardiac mitochondria are considered to be a compensatory reaction to its metabolic alterations.9,10
Infiltrative pathologies are the most common aetiologies of restrictive cardiomyopathy, often characterized by echocardiographic restrictive pattern. A cardiac MRI could prove effective in distinguishing amyloid deposit from other infiltrative causes. Considering the specific imaging features on TTE and MRI for each aetiology, one has useful tools for quick screening when facing secondary infiltrative cardiomyopathy:2,11
- amyloidosis: concentric hypertrophy with sparkling echoes, enlarged atrias on TTE and diffused late gadolinium enhancement (LGE) on delay contrast enhancement MRI (DE-MRI)
- sarcoidosis: localized septal hypertrophy on TTE and LGE on mid-myocardial wall or epicardium on DE-MRI
- haemochromatosis: LV enlargement with no or mild hypertrophy on TTE and measure of cardiac iron load on relaxation time T2*
- Fabry's disease: concentric hypertrophy with post-hypertensive remodelling shape on TTE and LGE localized on basal inferolateral wall on DE-MRI
The restrictive pattern seen on the patient's TTE at admission disappeared and the systolic function improved after 2 months of treatment.
This observation is exceptional as it shows the MRI characteristics of cardiac mitochondriopathy as well as significant change in LV systolic function and diastolic filling pattern, noted after 2 months of conventional and Q-10 co-enzyme treatment.
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Supplementary data
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Supplementary data are available at European Journal of Echocardiography online.
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References
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- Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation (2006) 113:1807–16.[Abstract/Free Full Text]
- Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies. Eur Heart J (2005) 26:1461–74.[Abstract/Free Full Text]
- Donovan LE, Severin NE. Maternally inherited diabetes and deafness in a North American kindred: tips for making the diagnosis and review of unique management issues. J Clin Endocrinol Metab (2006) 91:4737–42.[Abstract/Free Full Text]
- Suzuki S, Hinokio Y, Ohtomo M, Hirai M, Hirai A, Chiba M, et al. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation. Diabetologia (1998) 41:584–8.[CrossRef][Web of Science][Medline]
- Salles JE, Moises VA, Almeida DR, Chacra AR, Moises RS. Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q10. Diabetes Res Clin Pract (2006) 72:100–3.[CrossRef][Web of Science][Medline]
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- Ohmoto N, Fujiwara Y, Kibira S, Kobayashi M, Saito T, Miura M. Cardiomyopathy showing progression from diffuse left ventricular hypertrophy to dilated phase associated with mitochondrial DNA point mutation A3243G: a case report. J Cardiol (2003) 41:21–7.[Medline]
- Nijveldt R, Serne EH, Sepers JM, Maassen JA, Cornel JH, Arnold AE. A man with diabetes and heart failure. Lancet (2004) 364:636.[CrossRef][Web of Science][Medline]
- Ueno H, Shiotani H. Cardiac abnormalities in diabetic patients with mutation in the mitochondrial tRNA(Leu(UUR)) gene. Jpn Circ J (1999) 63:877–80.[CrossRef][Medline]
- Momiyama Y, Atsumi Y, Ohsuzu F, Ui S, Morinaga S, Matsuoka K, et al. Rapid progression of cardiomyopathy in mitochondrial diabetes. Jpn Circ J (1999) 63:130–2.[CrossRef][Medline]
- Abergel E, Cohen A, Gueret P, Roudaut R. Echocardiographie de l'adulte. (2003) Estem Editions.
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Abstract
Introduction
