Journal of the Neurological Sciences 345 (2014) 189–192
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Cardiac involvement in chronic progressive external ophthalmoplegia Fabio Galetta a, Ferdinando Franzoni a,⁎, Michelangelo Mancuso a, Daniele Orsucci a, Leonardo Tocchini a, Riccardo Papi a, Giuseppe Speziale b, Carlo Gaudio c, Gabriele Siciliano a, Gino Santoro a a b c
Department of Clinical and Experimental Medicine, University of Pisa, Italy Department of Cardiac Surgery, Anthea Hospital, GVM Care & Research, Bari, Italy Department of Heart and Great Vessels Attilio Reale, Sapienza University, Rome, Italy
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 20 July 2014 Accepted 21 July 2014 Available online 28 July 2014 Keywords: Mitochondrial myopathies Chronic progressive external ophthalmoplegia Diastolic function Echocardiography Tissue Doppler imaging Integrated backscatter
a b s t r a c t Myocardial involvement has not been extensively investigated in mitochondrial myopathies. The aim of the study was to assess the myocardial morpho-functional changes in patients with chronic progressive external ophthalmoplegia (PEO). Twenty patients with PEO and 20 controls underwent standard echocardiography with tissue Doppler imaging (TDI) and integrated backscatter (IBS) analyses. These techniques are capable of providing non-invasively the early, subtle structural and functional changes of the myocardium. TDI myocardial systolic (Sm) and early (Em) and late (Am) diastolic velocities of left ventricular walls were determined. The systo-diastolic variation of IBS was also determined. Patients with PEO exhibited lower Sm, lower Em, and higher Am, and a reduced Em/Am ratio than controls (p b 0.001 for all) at interventricular septum and lateral wall levels. In PEO patients, septal and posterior wall cyclic variations of IBS were significantly lower than those in controls (p b 0.001). Patients with PEO showed myocardial wall remodeling characterized by increased fibrosis and early left ventricular systo-diastolic function abnormalities. Although cardiac involvement in PEO is generally considered to be limited to the cardiac conduction system, left ventricular dysfunction may be present and should receive more attention in the management of these patients. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Mitochondrial diseases are disorders caused by the impairment of the mitochondrial respiratory chain [1]. The genetic error can affect mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Clinical phenotypes are polymorphic and range from pure myopathies to multisystemic disorders. The estimated prevalence of mitochondrial disorders is 1–2 in 10,000 [2], which makes them among the commonest inherited neuromuscular disorders. Chronic progressive external ophthalmoplegia (PEO), which includes Kearns–Sayre syndrome, is a mitochondrial disorder with large deletions of mitochondrial DNA [3]. The most common clinical presentation of these syndromes is adult-onset progressive ophthalmoplegia, due to weakness of the external eye muscles. PEO is accompanied by a proximal myopathy with ragged-red fibers and mild reduction in the activities of respiratory-chain enzymes [4]. Different syndromes have been identified, but the range of their clinical presentation is quite wide with multiorgan involvement including ⁎ Corresponding author at: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. Tel.: + 39 050993060, + 39 3483838842 (mob); fax: +39 0584940345. E-mail address: [email protected] (F. Franzoni).
http://dx.doi.org/10.1016/j.jns.2014.07.044 0022-510X/© 2014 Elsevier B.V. All rights reserved.
cardiac abnormalities [5]. Cardiac involvement of patients with PEO is generally considered to be limited to the cardiac conduction system [6,7]. Hypertrophic or dilated cardiomyopathy is much less frequent and seems to be a late-onset phenomenon [6,7]. To clarify the characteristic clinical features of cardiac involvement and the effect of mitochondrial mutations on the heart, we evaluated cardiac structure and function in patients with PEO by standard echocardiography with tissue Doppler imaging (TDI) and integrated backscatter (IBS) analyses, two techniques capable of detecting and quantifying non-invasively the early, subtle structural and functional changes of the myocardium [8,9]. 2. Materials and methods We studied 20 patients (15 females, 5 males; mean age 55.3 ± 12.9 years) with PEO, previously diagnosed patients in neurology clinic. Nine patients were also affected by proximal myopathy. Eleven patients harbored multiple mtDNA deletions, seven patients harbored a mtDNA single deletion, one the mtDNA A1555G mutation, and one the mtDNA A3243G mutation. Mitochondrial disease was diagnosed based on clinical signs and symptoms, as well as standard biochemical and molecular analyses (e.g., muscle respiratory chain activities, mtDNA gene analysis) [10]. Biochemical respiratory chain analysis on muscle sample
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homogenate was performed in 16 patients with standard methods [11]. Patients with mtDNA multiple deletions underwent nDNA gene sequencing for research of ANT1, Twinkle, POLG1 and 2 mutations, linked to mitochondrial disorders caused by defect in intergenomic signaling [1]. Only patients 4 and 17, two sisters, resulted positive for ANT1 mutation [12]. In the other cases with multiple deletions, mutations in POLG1, POLG2, Twinkle and ANT1 were not found. OPA1 is at present under analysis. All patients who were taking pharmacologic supplements with antioxidant activity (e.g., ascorbate, vitamin E, α-lipoic acid, coenzyme Q10) interrupted such therapies at least 1 month before the beginning of the study. In addition, 20 healthy volunteers (15 females, 5 males; mean age 54.9 ± 13.5 years) were recruited to form the control group. The entire study population's demographic characteristics, biochemical parameters, lipid values and ECGs were obtained. Exclusion criteria were as follows: overt hypothyroidism or hyperthyroidism, acute coronary syndrome, prior myocardial infarction and coronary artery disease, congestive heart failure, left ventricular (LV) hypertrophy, reduced LV ejection fraction (b50%), chronic obstructive pulmonary disease, significant valvular heart disease, pacemaker implantation, atrial flutter or fibrillation, hypertension (resting blood pressure ≥ 140/90 mm Hg), diabetes mellitus, medications known to alter cardiac conduction, peripheral vascular diseases, neurological disease, pericarditis, congenital heart disease, alcohol abuse, renal or hepatic disease and poor echocardiographic imaging. Approval for the study was obtained by the local ethics committee. All subjects included in the study signed an informed consent with careful explanation of the study procedures. 2.1. Echocardiographic analysis 2.1.1. Conventional echocardiography All patients were evaluated by transthoracic M-mode, two dimensional (2D), pulsed-wave (PW), continuous wave (CW), color flow and tissue Doppler imaging (TDI). All examinations were performed with the Sonos 5500 ultrasound system (Philips Medical Systems, Andover, MA) with a 2–4 MHz transducer at a depth of 16 cm. During echocardiography, continuous single-lead ECG recording was obtained. All patients were imaged in the left lateral decubitus position. 2D and conventional Doppler examinations were obtained in the parasternal and apical views according to the guidelines of the American Society of Echocardiography [13]. LV diameters and wall thickness were measured by M-mode echocardiography. The mitral valve inflow pattern [E-wave, A-wave, E/A ratio and isovolumic relaxation time (IVRT)] was measured using the pulsed wave Doppler. LV mass was calculated according to the “Penn convention” [14]. 2.1.2. Tissue Doppler echocardiography Tissue Doppler echocardiography has become an established component of the diagnostic ultrasound examination. It permits an assessment of myocardial motion using Doppler ultrasound imaging. The technique uses frequency shifts of ultrasound waves to calculate myocardial velocity: this is similar to routine Doppler ultrasound to assess blood flow, but its technological features focus on lower velocity frequency shifts. TDI was performed by transducer frequencies of 3.5 to 4.0 MHz, adjusting the spectral pulsed Doppler signal filters to acquire the Nyquist limit of 15 to 20 cm/s was reached and using the minimal optimal gain. Myocardial TDI of systolic and diastolic velocities of the basal lateral segment and of the basal interventricular septum in the apical 4-chamber view was measured at the end of echocardiographic studies. The sample volumes were placed in the center of myocardial segments. The acoustic power and filter frequencies of the echocardiographic system were set to the lowest values possible to minimize noise. From the obtained patterns, the systolic myocardial velocity (Sm), the early diastolic myocardial velocity (Em), the late diastolic myocardial
velocity (Am) at the time of atrial contraction, and the ratio of Em/Am of both the left ventricular walls were determined. In addition, the isovolumetric relaxation time (IVRT) of each segment was measured as the interval from the aortic component of the second heart sound to the peak of the early diastolic wave. All parameters were measured during three consecutive cardiac cycles and their mean value was calculated. 2.1.3. Integral backscatter analysis Ultrasonic tissue characterization by IBS provides an approach for defining the physical state of cardiac muscle tissue that complements the assessment of ventricular wall motion and chamber dimensions by conventional two-dimensional echocardiography [15]. The hypothesis underlying its use is that pathologic changes of myocardial structure and function result in alterations in the fundamental physical properties of tissue that can be quantified with indexes dependent on frequencydependent ultrasonic attenuation and backscatter. IBS analysis was performed using a special software package, available as an option of the Sonos 5500, as previously described [15]. Briefly, this system is capable of providing either conventional twodimensional envelope-detected echocardiographic images or IBS images in which the gray level is displayed proportional to the integrated backscattered power. The backscatter can be measured in dB from an operator-defined region of interest (ROI). A maximum of 60 frames displayed at a real-time frame rate of 30 Hz (30 frames/s) are captured into cine-loop memory and subsequently stored in an optical disk in a digital format with the same resolution as the scan converter memory (512 × 512, 8 bits). This system has the possibility to display the transmit power, log compression and time-gain compensation values on a screen; this permits to adjust the system to the same values at every examination. Conventional B-mode images of parasternal long-axis view were obtained in each subject. The IBS was measured by placing an elliptic ROI at the center of the mid-anterior septum and of the midposterior wall, and time–intensity curves of backscatter were derived. The average power of the IBS contained within the ROI was measured and displayed in dB for a total of 60 time frames. The magnitude of the cyclic variations of IBS (CV-IBS) was calculated as the average in three consecutive cardiac cycles of the difference between the enddiastolic IBS value, coinciding with the peak of the R wave at ECG, and the value at the end-systole, typically corresponding to the end of the T wave. All measurements were made offline, by a single observer blinded to the patient details. 2.2. Reproducibility and reliability of data Our laboratory has established reference data for inter- and intraobserver variations for standard and TDI echocardiographic parameters: inter-observer variation was 1.4 ± 4.6%, and intra-observer variation was 0.9 ± 2.6%. We previously determined inter-observer variability of cIBS values in 10 echocardiographic recordings that were measured by two observers at randomly selected cross-sections. The interobserver variability of CV-IBS values was 1.1 ± 3.0%. Likewise, we determined the intra-observer variability of CV-IBS values in 10 echocardiographic recordings that were measured two times by one observer at randomly selected cross-sections. The intra-observer variability of CV-IBS values was 0.5 ± 3.2%. 2.3. Statistical analysis All data were expressed as mean ± standard deviation (SD). The analysis of variance (one-way ANOVA) and the linear correlation analysis were used. Differences were considered significant when p b 0.05. All statistical procedures and curve fitting for regression analysis were performed by means of personal computer using StatView version 5.0 (SAS Institute Inc., Cray, NC, USA).
F. Galetta et al. / Journal of the Neurological Sciences 345 (2014) 189–192
3. Results
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Table 2 Echocardiographic parameters of the study groups (mean ± SD).
Clinical features are illustrated in Table 1. ECG analysis showed the absence of abnormalities in ventricular repolarization in the patients and the control subjects; one PEO patient had a left bundle branch block and three PEO patients an incomplete right bundle branch block. Standard echocardiography and pulsed Doppler transmitral flow velocity profile data are given in Table 2. Patients with PEO had completely normal LV systolic function and were comparable with control group. There were no significant differences in M-mode measurements of cardiac dimensions of subjects with PEO compared with control subjects. No left ventricular wall motion abnormalities were seen in any patients or control subjects. Instead, the parameters of Doppler transmitral flow velocity profile showed that the indices for LV diastolic function were lower in PEO patients with respect to controls (peak E: 58.8 ± 6.5 vs 72.5 ± 8.4 cm/s, p b 0.01; E/A ratio: 0.87 ± 0.12 vs 1.05 ± 0.32, p b 0.01). Regarding TDI measures (Table 3), the PEO patients exhibited lower Sm peak (septum: 7.6 ± 0.9 vs 9.9 ± 0.8 cm/s; lateral wall: 8.6 ± 0.8 vs 10.8 ± 0.6 cm/s, p b 0.001), lower Em peak (septum: 9.8 ± 1.5 vs 12.1 ± 1.2 cm/s; lateral wall: 10.2 ± 1.4 vs 12.4 ± 1.6 cm/s, p b 0.001), higher Am peak (septum: 10.5 ± 1.8 vs 9.9 ± 1.5 cm/s; lateral wall: 10.6 ± 1.2 vs 8.9 ± 1.8 cm/s, ns), and a reduced Em/Am ratio (septum: 0.93 ± 0.06 vs 1.22 ± 0.08 cm/s; lateral wall: 0.96. ± 0.08 vs 1.39 ± 0.10 cm/s, p b 0.001). The IVRTs significantly increased in PEO patients as compared to control subjects (septum: 90.6 ± 5.1 vs 78.8 ± 6.1 ms; lateral wall: 92.4 ± 5.3 vs 76.8 ± 7.1 ms, p b 0.001). In PEO patients, CV-IBS was significantly lower than that in control subjects, at both septum (5.7 ± 1.8 dB vs 9.3 ± 1.2 dB, p b 0.001) and posterior wall level (7.8 ± 2.1 dB vs 11.6 ± 2.2 dB, p b 0.001). No correlation was found between the TDI parameters or CV-IBS values and the humoral variables or the molecular analyses. 4. Discussion The major finding of the present study was that PEO is associated with pre-clinical impairment of LV function as compared to healthy individuals. This was demonstrated by the decrease of TDI-derived velocities of systolic and diastolic myocardial function, and the reduction of CV-IBS, an index of myocardial contractile performance. All these preclinical cardiac findings were identified by TDI or IBS and not by standard Doppler echocardiography. Cardiac involvement is not a general feature of ocular myopathy. Berenberg et al. [16] reported that clinical manifestations of cardiac disease occur in 57% of patients with Kearns–Sayre syndrome. However, these symptoms are mostly due to cardiac conduction defects such as prolonged intraventricular conduction time, bundle branch blocks, and complete AV block. Symptoms of heart failure are rarely described. The uncommon occurrence and late onset of cardiomyopathy in PEO
Characteristic
PEO (n = 20)
Control (n = 20)
LVEDD (mm) LVESD (mm) LVEDV (mL) LVESV (mL) IVS (mm) PW (mm) LVMI (g/m2) LVEF (%) LA (mm) E (cm/s) A (cm/s) E/A ratio DT (ms) IVRT (ms)
48.2 30.5 82.7 27.7 9.1 8.4 85.8 64.2 35.0 58.8 67.5 0.87 216.5 86.4
47.4 31.3 83.4 27.1 9.0 8.3 84.4 64.7 33.5 72.5 68.4 1.05 211.5 84.8
± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.6 3.1 16.2 8.0 0.6 0.5 12.4 9.5 8.7 6.5⁎ 7.2 0.12⁎ 35.4 9.3
± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.8 4.2 18.0 5.3 0.5 0.7 16.2 11.4 6.1 8.4 9.6 0.32 36.3 7.6
LVEDD: left ventricular end diastolic diameter; LVESD: left ventricular end systolic diameter; LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; IVS: interventricular septum; PW: posterior wall; LVMI: left ventricular mass indexed; LVEF: left ventricular ejection fraction; LA: left atrium; E: early diastolic mitral inflow velocity; A: late diastolic mitral inflow velocity; DT: deceleration time; IVRT: isovolumetric relaxation time. ⁎ p b 0.01.
may be due to the relatively low abundance of rearranged mtDNA molecules in the myocardium. However, McComish et al. reported that hypertrophy of the myocyte and accumulation of normal mitochondria were observed in the biopsy specimen from a patient with ocular myopathy [17]. LV systolic and diastolic functions have been previously investigated by a non-invasive technique in PEO, but the degree of cardiac involvement is very low in different studies. Akaike et al. studied five patients with PEO [5] by means of carotid pulse recording and Doppler echocardiography. The ratio of the pre-ejection period to ejection time was increased in two patients. Echocardiography showed LV dilatation and diffuse hypokinetic wall motion in both cases. The Doppler pattern of LV filling in the three remaining patients showed a decrease in the ratio of peak flow velocity in early diastole to that in late diastole, with an increase in deceleration time. Also Anan et al. [6] studied mitochondrial mutations and cardiac changes in patients with Kearns–Sayre syndrome and ocular myopathy. Cardiac involvement was evaluated by chest radiograph, ECG, His-bundle electrogram, and echocardiogram. All 3 patients with Kearns–Sayre syndrome had large deletions of mitochondrial DNA and disturbances in cardiac conduction. ECG abnormalities were found in 2 of 6 patients with ocular myopathy who showed large deletions of mitochondrial DNA. Patients did not exhibit abnormal LV function. In keeping with Akaike, we showed an impairment of LV function in patients with PEO using TDI and IBS analyses. In the present study, we Table 3 Tissue Doppler imaging parameters of the study groups (mean ± SD).
Table 1 Clinical characteristics of the study groups (mean ± SD). Characteristic
PEO (n = 20)
Control (n = 20)
Age (years) Sex (M/F) Height (cm) Weight (kg) Body mass index (kg/m2) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) Glucose (mg/dL) Creatinine (mg/dL)
55.3 ± 12.9 5/15 168.5 ± 6.4 66.5 ± 8.5 23.6 ± 1.7 70.5 ± 6.3 124.6 ± 5.9 75.4 ± 5.2 195.0 ± 29.6 118.5 ± 17.2 42.6 ± 7.1 155.8 ± 31.2 95.5 ± 5.6 0.79 ± 0.18
54.9 ± 13.5 5/15 170.6 ± 8.2 67.2 ± 7.3 23.8 ± 1.6 69.2 ± 5.4 124.3 ± 5.4 76.2 ± 4.3 189 ± 28.3 115.0 ± 18.1 43.5 ± 5.8 158.4 ± 24.1 97.5 ± 11.3 0.77 ± 0.14
Characteristic
PEO (n = 20)
Interventricular wall Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio IVRTs (ms)
Control (n = 20)
7.6 9.8 10.5 0.93 90.6
± ± ± ± ±
0.9⁎ 1.5⁎ 1.8 0.06⁎ 5.1⁎
9.9 12.1 9.9 1.22 78.8
± ± ± ± ±
0.8 1.2 1.5 0.08 6.1
Lateral wall Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio IVRTs (ms)
8.6 10.2 10.6 0.96 92.4
± ± ± ± ±
0.8⁎ 1.4⁎ 1.2 0.08⁎ 5.3⁎
10.8 12.4 8.9 1.39 76.8
± ± ± ± ±
0.6 1.6 1.8 0.10 7.1
Sm: peak systolic mitral annular velocity; Em: early diastolic mitral annular velocity; Am: late diastolic mitral annular velocity; IVRT: isovolumetric relaxation time. ⁎ p b 0.001.
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performed a strict selection of patients, excluding those with confounding factors particularly affecting the cardiovascular system. We showed reduced systolic and diastolic TDI-derived indexes at both septum and lateral wall, thus confirming that PEO was associated with a preclinical impairment of LV systo-diastolic function. These results support the hypothesis that TDI may represent an independent marker of early LV dysfunction compared to standard echocardiography. In particular, in regard to LV systolic function, several investigators reported that pulsed TDI-derived Sm was well related to LV ejection fraction [18] and to peak positive dP/dt [19]. Alterations in Sm, similar to those observed in our patients, were reported in patients with hypertension or coronary heart disease [20], who had normal global systolic function by conventional parameters but abnormal midwall shortening. This may be explained by the low diagnostic value of the standard Doppler echocardiography in evaluating LV function, which can be influenced by multiple interrelated factors including heart rate, ventricular dimension and mass, and blood pressure. However, Sm has been shown to be a good measurement of global systolic function, and can detect abnormal systolic function in patients with heart failure and a normal ejection fraction [21]. In our series, we also found a decreased CV-IBS, suggestive of increased collagen content [22,23], and related to impaired myocardial contractility, both at the interventricular septum and the posterior wall. Quantitative characterization of myocardial texture by means of analysis of ultrasonic reflectivity has been experimentally and clinically shown to correlate with the collagen content of the myocardial tissue [22–24]. Although histopathological data are lacking, our results might suggest ultrastructural alterations of the myocardium in PEO patients. In fact, enlarged, abnormally structured, excessively augmented mitochondria and loss of myofibrils have been demonstrated in skeletal and heart muscle cells from patients with Kearns–Sayre syndrome [6]. Moreover, the impaired energy production in cardiac myocytes with increased lactate production, phosphocreatine depletion, and enhanced reactive oxygen species (ROS) generation can explain IBS findings. Besides energy deficiency, mechanical interference with sarcomere alignment and contraction, increased ROS and uncoupled respiration may be associated with impairment of LV function [25,26]. In conclusion, although cardiac involvement in patients with PEO is generally considered to be limited to the cardiac conduction system, LV dysfunction may be present and should receive more attention in the management of patients with mitochondrial disease. Pulsed TDI and IBS analyses offer additional means to conventional echocardiography for assessing LV function in these patients. The distinction between a pure presymptomatic state and the occurrence of the first signs of the disorder may be very subtle. This is however important, especially in cardiovascular disease, where life threatening events should be prevented in as many cases as possible. In fact, in these patients the cardiomyopathy can be fatal [27] and cardioembolic strokes have been reported as a complication [28,29]. We still believe that TDI and IBS, along with other established screening tools like conventional echocardiography and ECG, might play a complementary role in genetic screening of patients and family members with different kinds of cardiomyopathy. Conflict of interest None. References [1] Di Mauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348:2656–68.
[2] Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008;63:35–9. [3] Filosto M, Mancuso M. Mitochondrial diseases: a nosological update. Acta Neurol Scand 2007;115:211–21. [4] Auré K, Ogier de Baulny H, Laforêt P, Jardel C, Eymard B, Lombès A. Chronic progressive ophthalmoplegia with large-scale mtDNA rearrangement: can we predict progression? Brain 2007;130:1516–24. [5] Akaike M, Kawai H, Yokoi K, et al. Cardiac dysfunction in patients with chronic progressive external ophthalmoplegia. Clin Cardiol 1997;20:239–43. [6] Anan R, Nakagawa M, Miyata M, et al. Cardiac involvement in mitochondrial diseases. A study on 17 patients with documented mitochondrial DNA defects. Circulation 1995;91:955–61. [7] Oki T, Tabata T, Yamada H, et al. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–8. [8] Yalcin F, Kaftan A, Muderrisoglu H, et al. Is Doppler tissue velocity during early left ventricular filling preload independent? Heart 2002;87:336–9. [9] Sutherland GR, Stewart MJ, Groundstroem KW, et al. Color Doppler myocardial imaging: a new technique for the assessment of myocardial function. J Am Soc Echocardiogr 1994;7:441–58. [10] Bernier FP, Boneth A, Dennet X, Chow CW, Cleary MA, Thoburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002; 59:1406–11. [11] Di Mauro S, Servidei S, Zeviani M, et al. Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 1987;22:498–506. [12] Siciliano G, Tessa A, Petrini S, et al. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul Disord 2003;13:162–5. [13] Sahn DJ, De Maria A, Kisslo J, Weyman A. The committee on M-mode Standardization of the American Society of Echocardiography: recommendations regarding quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978;58:1072–83. [14] Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613–8. [15] Franzoni F, Galetta F, Cupisti A, Rolla M, Santoro G, Pentimone F. Ultrasonic tissue characterization of the myocardium in anorexia nervosa. Acta Paediatr 2003; 92:297–300. [16] Berenberg RA, Pellock JM, Di Mauro S, et al. Lumping or splitting? ‘Ophthalmoplegiaplus’ or Kearns–Sayre syndrome? Ann Neurol 1977;1:37–54. [17] McComish M, Compston A, Jewitt D. Cardiac abnormalities in chronic progressive external ophthalmoplegia. Br Heart J 1976;38:526–9. [18] Nagueh SF, Middleton KJ, Kopelen HA, et al. Doppler tissue imaging: a non-invasive technique for evaluation of left ventricular relaxation and filling pressures. J Am Coll Cardiol 1997;30:1527–33. [19] Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–80. [20] Palmes PP, Masuyama T, Yamamoto K, et al. Myocardial longitudinal motion by tissue velocity imaging in the evaluation of patients with myocardial infarction. J Am Soc Echocardiogr 2000;13:818–26. [21] Gulati VK, Katz WE, Follansbee WP, Gorcsan III J. Mitral annular descent velocity by tissue Doppler echocardiography as an index of global left ventricular function. Am J Cardiol 1996;77:979–84. [22] Ciulla M, Paliotti R, Hess DB, et al. Echocardiographic patterns of myocardial fibrosis in hypertensive patients: endomyocardial biopsy versus ultrasonic tissue characterization. J Am Soc Echocardiogr 1997;10:657–64. [23] Mimbs JW, O'Donnell M, Bauwens D, Miller JG, Sobel BE. The dependence of ultrasonic attenuation and backscatter on collagen content in dog and rabbit hearts. Circ Res 1980;47:48–58. [24] Pe´rez JE, Barzilai B, Madaras EI, et al. Applicability of ultrasonic tissue characterisation for longitudinal assessment and differentiation of calcification and fibrosis in cardiomyopathy. J Am Coll Cardiol 1984;4:88–95. [25] Bohlega S, Tanji K, Santorelli FM, Hirano M, al-Jishi A, Di Mauro S. Multiple mitochondrial DNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy. Neurology 1996;46:1329–34. [26] Sebastiani M, Giordano C, Nediani C, et al. Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J Am Coll Cardiol 2007;50:1362–9. [27] Hübner G, Gokel JM, Pongratz D, Johannes A, Park JW. Fatal mitochondrial cardiomyopathy in Kearns–Sayre syndrome. Virchows Arch A Pathol Anat Histopathol 1986; 408:611–21. [28] Kosinski CM, Mull M, Schwarz M, et al. Do normal D-dimer levels reliably exclude cerebral sinus thrombosis? Stroke 2004;35:2820–5. [29] Provenzale JM, Van Landingham K. Cerebral infarction associated with Kearns–Sayre syndrome-related cardiomyopathy. Neurology 1996;46:826–8.
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Cardiac involvement in chronic progressive external ophthalmoplegia Fabio Galetta a, Ferdinando Franzoni a,⁎, Michelangelo Mancuso a, Daniele Orsucci a, Leonardo Tocchini a, Riccardo Papi a, Giuseppe Speziale b, Carlo Gaudio c, Gabriele Siciliano a, Gino Santoro a a b c
Department of Clinical and Experimental Medicine, University of Pisa, Italy Department of Cardiac Surgery, Anthea Hospital, GVM Care & Research, Bari, Italy Department of Heart and Great Vessels Attilio Reale, Sapienza University, Rome, Italy
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 20 July 2014 Accepted 21 July 2014 Available online 28 July 2014 Keywords: Mitochondrial myopathies Chronic progressive external ophthalmoplegia Diastolic function Echocardiography Tissue Doppler imaging Integrated backscatter
a b s t r a c t Myocardial involvement has not been extensively investigated in mitochondrial myopathies. The aim of the study was to assess the myocardial morpho-functional changes in patients with chronic progressive external ophthalmoplegia (PEO). Twenty patients with PEO and 20 controls underwent standard echocardiography with tissue Doppler imaging (TDI) and integrated backscatter (IBS) analyses. These techniques are capable of providing non-invasively the early, subtle structural and functional changes of the myocardium. TDI myocardial systolic (Sm) and early (Em) and late (Am) diastolic velocities of left ventricular walls were determined. The systo-diastolic variation of IBS was also determined. Patients with PEO exhibited lower Sm, lower Em, and higher Am, and a reduced Em/Am ratio than controls (p b 0.001 for all) at interventricular septum and lateral wall levels. In PEO patients, septal and posterior wall cyclic variations of IBS were significantly lower than those in controls (p b 0.001). Patients with PEO showed myocardial wall remodeling characterized by increased fibrosis and early left ventricular systo-diastolic function abnormalities. Although cardiac involvement in PEO is generally considered to be limited to the cardiac conduction system, left ventricular dysfunction may be present and should receive more attention in the management of these patients. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Mitochondrial diseases are disorders caused by the impairment of the mitochondrial respiratory chain [1]. The genetic error can affect mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Clinical phenotypes are polymorphic and range from pure myopathies to multisystemic disorders. The estimated prevalence of mitochondrial disorders is 1–2 in 10,000 [2], which makes them among the commonest inherited neuromuscular disorders. Chronic progressive external ophthalmoplegia (PEO), which includes Kearns–Sayre syndrome, is a mitochondrial disorder with large deletions of mitochondrial DNA [3]. The most common clinical presentation of these syndromes is adult-onset progressive ophthalmoplegia, due to weakness of the external eye muscles. PEO is accompanied by a proximal myopathy with ragged-red fibers and mild reduction in the activities of respiratory-chain enzymes [4]. Different syndromes have been identified, but the range of their clinical presentation is quite wide with multiorgan involvement including ⁎ Corresponding author at: Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. Tel.: + 39 050993060, + 39 3483838842 (mob); fax: +39 0584940345. E-mail address: [email protected] (F. Franzoni).
http://dx.doi.org/10.1016/j.jns.2014.07.044 0022-510X/© 2014 Elsevier B.V. All rights reserved.
cardiac abnormalities [5]. Cardiac involvement of patients with PEO is generally considered to be limited to the cardiac conduction system [6,7]. Hypertrophic or dilated cardiomyopathy is much less frequent and seems to be a late-onset phenomenon [6,7]. To clarify the characteristic clinical features of cardiac involvement and the effect of mitochondrial mutations on the heart, we evaluated cardiac structure and function in patients with PEO by standard echocardiography with tissue Doppler imaging (TDI) and integrated backscatter (IBS) analyses, two techniques capable of detecting and quantifying non-invasively the early, subtle structural and functional changes of the myocardium [8,9]. 2. Materials and methods We studied 20 patients (15 females, 5 males; mean age 55.3 ± 12.9 years) with PEO, previously diagnosed patients in neurology clinic. Nine patients were also affected by proximal myopathy. Eleven patients harbored multiple mtDNA deletions, seven patients harbored a mtDNA single deletion, one the mtDNA A1555G mutation, and one the mtDNA A3243G mutation. Mitochondrial disease was diagnosed based on clinical signs and symptoms, as well as standard biochemical and molecular analyses (e.g., muscle respiratory chain activities, mtDNA gene analysis) [10]. Biochemical respiratory chain analysis on muscle sample
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homogenate was performed in 16 patients with standard methods [11]. Patients with mtDNA multiple deletions underwent nDNA gene sequencing for research of ANT1, Twinkle, POLG1 and 2 mutations, linked to mitochondrial disorders caused by defect in intergenomic signaling [1]. Only patients 4 and 17, two sisters, resulted positive for ANT1 mutation [12]. In the other cases with multiple deletions, mutations in POLG1, POLG2, Twinkle and ANT1 were not found. OPA1 is at present under analysis. All patients who were taking pharmacologic supplements with antioxidant activity (e.g., ascorbate, vitamin E, α-lipoic acid, coenzyme Q10) interrupted such therapies at least 1 month before the beginning of the study. In addition, 20 healthy volunteers (15 females, 5 males; mean age 54.9 ± 13.5 years) were recruited to form the control group. The entire study population's demographic characteristics, biochemical parameters, lipid values and ECGs were obtained. Exclusion criteria were as follows: overt hypothyroidism or hyperthyroidism, acute coronary syndrome, prior myocardial infarction and coronary artery disease, congestive heart failure, left ventricular (LV) hypertrophy, reduced LV ejection fraction (b50%), chronic obstructive pulmonary disease, significant valvular heart disease, pacemaker implantation, atrial flutter or fibrillation, hypertension (resting blood pressure ≥ 140/90 mm Hg), diabetes mellitus, medications known to alter cardiac conduction, peripheral vascular diseases, neurological disease, pericarditis, congenital heart disease, alcohol abuse, renal or hepatic disease and poor echocardiographic imaging. Approval for the study was obtained by the local ethics committee. All subjects included in the study signed an informed consent with careful explanation of the study procedures. 2.1. Echocardiographic analysis 2.1.1. Conventional echocardiography All patients were evaluated by transthoracic M-mode, two dimensional (2D), pulsed-wave (PW), continuous wave (CW), color flow and tissue Doppler imaging (TDI). All examinations were performed with the Sonos 5500 ultrasound system (Philips Medical Systems, Andover, MA) with a 2–4 MHz transducer at a depth of 16 cm. During echocardiography, continuous single-lead ECG recording was obtained. All patients were imaged in the left lateral decubitus position. 2D and conventional Doppler examinations were obtained in the parasternal and apical views according to the guidelines of the American Society of Echocardiography [13]. LV diameters and wall thickness were measured by M-mode echocardiography. The mitral valve inflow pattern [E-wave, A-wave, E/A ratio and isovolumic relaxation time (IVRT)] was measured using the pulsed wave Doppler. LV mass was calculated according to the “Penn convention” [14]. 2.1.2. Tissue Doppler echocardiography Tissue Doppler echocardiography has become an established component of the diagnostic ultrasound examination. It permits an assessment of myocardial motion using Doppler ultrasound imaging. The technique uses frequency shifts of ultrasound waves to calculate myocardial velocity: this is similar to routine Doppler ultrasound to assess blood flow, but its technological features focus on lower velocity frequency shifts. TDI was performed by transducer frequencies of 3.5 to 4.0 MHz, adjusting the spectral pulsed Doppler signal filters to acquire the Nyquist limit of 15 to 20 cm/s was reached and using the minimal optimal gain. Myocardial TDI of systolic and diastolic velocities of the basal lateral segment and of the basal interventricular septum in the apical 4-chamber view was measured at the end of echocardiographic studies. The sample volumes were placed in the center of myocardial segments. The acoustic power and filter frequencies of the echocardiographic system were set to the lowest values possible to minimize noise. From the obtained patterns, the systolic myocardial velocity (Sm), the early diastolic myocardial velocity (Em), the late diastolic myocardial
velocity (Am) at the time of atrial contraction, and the ratio of Em/Am of both the left ventricular walls were determined. In addition, the isovolumetric relaxation time (IVRT) of each segment was measured as the interval from the aortic component of the second heart sound to the peak of the early diastolic wave. All parameters were measured during three consecutive cardiac cycles and their mean value was calculated. 2.1.3. Integral backscatter analysis Ultrasonic tissue characterization by IBS provides an approach for defining the physical state of cardiac muscle tissue that complements the assessment of ventricular wall motion and chamber dimensions by conventional two-dimensional echocardiography [15]. The hypothesis underlying its use is that pathologic changes of myocardial structure and function result in alterations in the fundamental physical properties of tissue that can be quantified with indexes dependent on frequencydependent ultrasonic attenuation and backscatter. IBS analysis was performed using a special software package, available as an option of the Sonos 5500, as previously described [15]. Briefly, this system is capable of providing either conventional twodimensional envelope-detected echocardiographic images or IBS images in which the gray level is displayed proportional to the integrated backscattered power. The backscatter can be measured in dB from an operator-defined region of interest (ROI). A maximum of 60 frames displayed at a real-time frame rate of 30 Hz (30 frames/s) are captured into cine-loop memory and subsequently stored in an optical disk in a digital format with the same resolution as the scan converter memory (512 × 512, 8 bits). This system has the possibility to display the transmit power, log compression and time-gain compensation values on a screen; this permits to adjust the system to the same values at every examination. Conventional B-mode images of parasternal long-axis view were obtained in each subject. The IBS was measured by placing an elliptic ROI at the center of the mid-anterior septum and of the midposterior wall, and time–intensity curves of backscatter were derived. The average power of the IBS contained within the ROI was measured and displayed in dB for a total of 60 time frames. The magnitude of the cyclic variations of IBS (CV-IBS) was calculated as the average in three consecutive cardiac cycles of the difference between the enddiastolic IBS value, coinciding with the peak of the R wave at ECG, and the value at the end-systole, typically corresponding to the end of the T wave. All measurements were made offline, by a single observer blinded to the patient details. 2.2. Reproducibility and reliability of data Our laboratory has established reference data for inter- and intraobserver variations for standard and TDI echocardiographic parameters: inter-observer variation was 1.4 ± 4.6%, and intra-observer variation was 0.9 ± 2.6%. We previously determined inter-observer variability of cIBS values in 10 echocardiographic recordings that were measured by two observers at randomly selected cross-sections. The interobserver variability of CV-IBS values was 1.1 ± 3.0%. Likewise, we determined the intra-observer variability of CV-IBS values in 10 echocardiographic recordings that were measured two times by one observer at randomly selected cross-sections. The intra-observer variability of CV-IBS values was 0.5 ± 3.2%. 2.3. Statistical analysis All data were expressed as mean ± standard deviation (SD). The analysis of variance (one-way ANOVA) and the linear correlation analysis were used. Differences were considered significant when p b 0.05. All statistical procedures and curve fitting for regression analysis were performed by means of personal computer using StatView version 5.0 (SAS Institute Inc., Cray, NC, USA).
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3. Results
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Table 2 Echocardiographic parameters of the study groups (mean ± SD).
Clinical features are illustrated in Table 1. ECG analysis showed the absence of abnormalities in ventricular repolarization in the patients and the control subjects; one PEO patient had a left bundle branch block and three PEO patients an incomplete right bundle branch block. Standard echocardiography and pulsed Doppler transmitral flow velocity profile data are given in Table 2. Patients with PEO had completely normal LV systolic function and were comparable with control group. There were no significant differences in M-mode measurements of cardiac dimensions of subjects with PEO compared with control subjects. No left ventricular wall motion abnormalities were seen in any patients or control subjects. Instead, the parameters of Doppler transmitral flow velocity profile showed that the indices for LV diastolic function were lower in PEO patients with respect to controls (peak E: 58.8 ± 6.5 vs 72.5 ± 8.4 cm/s, p b 0.01; E/A ratio: 0.87 ± 0.12 vs 1.05 ± 0.32, p b 0.01). Regarding TDI measures (Table 3), the PEO patients exhibited lower Sm peak (septum: 7.6 ± 0.9 vs 9.9 ± 0.8 cm/s; lateral wall: 8.6 ± 0.8 vs 10.8 ± 0.6 cm/s, p b 0.001), lower Em peak (septum: 9.8 ± 1.5 vs 12.1 ± 1.2 cm/s; lateral wall: 10.2 ± 1.4 vs 12.4 ± 1.6 cm/s, p b 0.001), higher Am peak (septum: 10.5 ± 1.8 vs 9.9 ± 1.5 cm/s; lateral wall: 10.6 ± 1.2 vs 8.9 ± 1.8 cm/s, ns), and a reduced Em/Am ratio (septum: 0.93 ± 0.06 vs 1.22 ± 0.08 cm/s; lateral wall: 0.96. ± 0.08 vs 1.39 ± 0.10 cm/s, p b 0.001). The IVRTs significantly increased in PEO patients as compared to control subjects (septum: 90.6 ± 5.1 vs 78.8 ± 6.1 ms; lateral wall: 92.4 ± 5.3 vs 76.8 ± 7.1 ms, p b 0.001). In PEO patients, CV-IBS was significantly lower than that in control subjects, at both septum (5.7 ± 1.8 dB vs 9.3 ± 1.2 dB, p b 0.001) and posterior wall level (7.8 ± 2.1 dB vs 11.6 ± 2.2 dB, p b 0.001). No correlation was found between the TDI parameters or CV-IBS values and the humoral variables or the molecular analyses. 4. Discussion The major finding of the present study was that PEO is associated with pre-clinical impairment of LV function as compared to healthy individuals. This was demonstrated by the decrease of TDI-derived velocities of systolic and diastolic myocardial function, and the reduction of CV-IBS, an index of myocardial contractile performance. All these preclinical cardiac findings were identified by TDI or IBS and not by standard Doppler echocardiography. Cardiac involvement is not a general feature of ocular myopathy. Berenberg et al. [16] reported that clinical manifestations of cardiac disease occur in 57% of patients with Kearns–Sayre syndrome. However, these symptoms are mostly due to cardiac conduction defects such as prolonged intraventricular conduction time, bundle branch blocks, and complete AV block. Symptoms of heart failure are rarely described. The uncommon occurrence and late onset of cardiomyopathy in PEO
Characteristic
PEO (n = 20)
Control (n = 20)
LVEDD (mm) LVESD (mm) LVEDV (mL) LVESV (mL) IVS (mm) PW (mm) LVMI (g/m2) LVEF (%) LA (mm) E (cm/s) A (cm/s) E/A ratio DT (ms) IVRT (ms)
48.2 30.5 82.7 27.7 9.1 8.4 85.8 64.2 35.0 58.8 67.5 0.87 216.5 86.4
47.4 31.3 83.4 27.1 9.0 8.3 84.4 64.7 33.5 72.5 68.4 1.05 211.5 84.8
± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.6 3.1 16.2 8.0 0.6 0.5 12.4 9.5 8.7 6.5⁎ 7.2 0.12⁎ 35.4 9.3
± ± ± ± ± ± ± ± ± ± ± ± ± ±
2.8 4.2 18.0 5.3 0.5 0.7 16.2 11.4 6.1 8.4 9.6 0.32 36.3 7.6
LVEDD: left ventricular end diastolic diameter; LVESD: left ventricular end systolic diameter; LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; IVS: interventricular septum; PW: posterior wall; LVMI: left ventricular mass indexed; LVEF: left ventricular ejection fraction; LA: left atrium; E: early diastolic mitral inflow velocity; A: late diastolic mitral inflow velocity; DT: deceleration time; IVRT: isovolumetric relaxation time. ⁎ p b 0.01.
may be due to the relatively low abundance of rearranged mtDNA molecules in the myocardium. However, McComish et al. reported that hypertrophy of the myocyte and accumulation of normal mitochondria were observed in the biopsy specimen from a patient with ocular myopathy [17]. LV systolic and diastolic functions have been previously investigated by a non-invasive technique in PEO, but the degree of cardiac involvement is very low in different studies. Akaike et al. studied five patients with PEO [5] by means of carotid pulse recording and Doppler echocardiography. The ratio of the pre-ejection period to ejection time was increased in two patients. Echocardiography showed LV dilatation and diffuse hypokinetic wall motion in both cases. The Doppler pattern of LV filling in the three remaining patients showed a decrease in the ratio of peak flow velocity in early diastole to that in late diastole, with an increase in deceleration time. Also Anan et al. [6] studied mitochondrial mutations and cardiac changes in patients with Kearns–Sayre syndrome and ocular myopathy. Cardiac involvement was evaluated by chest radiograph, ECG, His-bundle electrogram, and echocardiogram. All 3 patients with Kearns–Sayre syndrome had large deletions of mitochondrial DNA and disturbances in cardiac conduction. ECG abnormalities were found in 2 of 6 patients with ocular myopathy who showed large deletions of mitochondrial DNA. Patients did not exhibit abnormal LV function. In keeping with Akaike, we showed an impairment of LV function in patients with PEO using TDI and IBS analyses. In the present study, we Table 3 Tissue Doppler imaging parameters of the study groups (mean ± SD).
Table 1 Clinical characteristics of the study groups (mean ± SD). Characteristic
PEO (n = 20)
Control (n = 20)
Age (years) Sex (M/F) Height (cm) Weight (kg) Body mass index (kg/m2) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) Glucose (mg/dL) Creatinine (mg/dL)
55.3 ± 12.9 5/15 168.5 ± 6.4 66.5 ± 8.5 23.6 ± 1.7 70.5 ± 6.3 124.6 ± 5.9 75.4 ± 5.2 195.0 ± 29.6 118.5 ± 17.2 42.6 ± 7.1 155.8 ± 31.2 95.5 ± 5.6 0.79 ± 0.18
54.9 ± 13.5 5/15 170.6 ± 8.2 67.2 ± 7.3 23.8 ± 1.6 69.2 ± 5.4 124.3 ± 5.4 76.2 ± 4.3 189 ± 28.3 115.0 ± 18.1 43.5 ± 5.8 158.4 ± 24.1 97.5 ± 11.3 0.77 ± 0.14
Characteristic
PEO (n = 20)
Interventricular wall Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio IVRTs (ms)
Control (n = 20)
7.6 9.8 10.5 0.93 90.6
± ± ± ± ±
0.9⁎ 1.5⁎ 1.8 0.06⁎ 5.1⁎
9.9 12.1 9.9 1.22 78.8
± ± ± ± ±
0.8 1.2 1.5 0.08 6.1
Lateral wall Sm (cm/s) Em (cm/s) Am (cm/s) Em/Am ratio IVRTs (ms)
8.6 10.2 10.6 0.96 92.4
± ± ± ± ±
0.8⁎ 1.4⁎ 1.2 0.08⁎ 5.3⁎
10.8 12.4 8.9 1.39 76.8
± ± ± ± ±
0.6 1.6 1.8 0.10 7.1
Sm: peak systolic mitral annular velocity; Em: early diastolic mitral annular velocity; Am: late diastolic mitral annular velocity; IVRT: isovolumetric relaxation time. ⁎ p b 0.001.
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performed a strict selection of patients, excluding those with confounding factors particularly affecting the cardiovascular system. We showed reduced systolic and diastolic TDI-derived indexes at both septum and lateral wall, thus confirming that PEO was associated with a preclinical impairment of LV systo-diastolic function. These results support the hypothesis that TDI may represent an independent marker of early LV dysfunction compared to standard echocardiography. In particular, in regard to LV systolic function, several investigators reported that pulsed TDI-derived Sm was well related to LV ejection fraction [18] and to peak positive dP/dt [19]. Alterations in Sm, similar to those observed in our patients, were reported in patients with hypertension or coronary heart disease [20], who had normal global systolic function by conventional parameters but abnormal midwall shortening. This may be explained by the low diagnostic value of the standard Doppler echocardiography in evaluating LV function, which can be influenced by multiple interrelated factors including heart rate, ventricular dimension and mass, and blood pressure. However, Sm has been shown to be a good measurement of global systolic function, and can detect abnormal systolic function in patients with heart failure and a normal ejection fraction [21]. In our series, we also found a decreased CV-IBS, suggestive of increased collagen content [22,23], and related to impaired myocardial contractility, both at the interventricular septum and the posterior wall. Quantitative characterization of myocardial texture by means of analysis of ultrasonic reflectivity has been experimentally and clinically shown to correlate with the collagen content of the myocardial tissue [22–24]. Although histopathological data are lacking, our results might suggest ultrastructural alterations of the myocardium in PEO patients. In fact, enlarged, abnormally structured, excessively augmented mitochondria and loss of myofibrils have been demonstrated in skeletal and heart muscle cells from patients with Kearns–Sayre syndrome [6]. Moreover, the impaired energy production in cardiac myocytes with increased lactate production, phosphocreatine depletion, and enhanced reactive oxygen species (ROS) generation can explain IBS findings. Besides energy deficiency, mechanical interference with sarcomere alignment and contraction, increased ROS and uncoupled respiration may be associated with impairment of LV function [25,26]. In conclusion, although cardiac involvement in patients with PEO is generally considered to be limited to the cardiac conduction system, LV dysfunction may be present and should receive more attention in the management of patients with mitochondrial disease. Pulsed TDI and IBS analyses offer additional means to conventional echocardiography for assessing LV function in these patients. The distinction between a pure presymptomatic state and the occurrence of the first signs of the disorder may be very subtle. This is however important, especially in cardiovascular disease, where life threatening events should be prevented in as many cases as possible. In fact, in these patients the cardiomyopathy can be fatal [27] and cardioembolic strokes have been reported as a complication [28,29]. We still believe that TDI and IBS, along with other established screening tools like conventional echocardiography and ECG, might play a complementary role in genetic screening of patients and family members with different kinds of cardiomyopathy. Conflict of interest None. References [1] Di Mauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348:2656–68.
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