Clinical significance of late potential in patients with duchenne muscular dystrophy

Kubo, Masahiro; Matsuoka, Suguru; Taguchi, Yoshiyuki; Akita, Hiroshi; Kuroda, Yasuhiro

doi:10.1007/bf00795373

Cited by 10 publications

(7 citation statements)

References 19 publications

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“…Myocardial fibrosis, the second leading cause of death in DMD [3], [7], [8], occurs in more than 96% of DMD hearts and causes cardiac dysfunction that leads to heart failure. Furthermore, fibrotic lesions in the myocardium can act as foci of ventricular arrhythmias that are common and often fatal in DMD patients [7], [9], [10]. Additionally, fibrosis of limb muscles causes permanent, immobilizing contractures that impede ambulation [11].…”

Section: Introductionmentioning

confidence: 99%

Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

et al. 2010

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BackgroundDuchenne muscular dystrophy (DMD) is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD.MethodologyWe use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial effects of short-term treatments.Conclusions/SignificanceOur findings demonstrate that arginine metabolism by arginase promotes fibrosis of muscle in muscular dystrophy and contributes to kyphosis. Our findings also show that long-term, dietary supplementation with arginine exacerbates fibrosis of dystrophic heart and muscles. Thus, commonly-practiced dietary supplementation with arginine by DMD patients has potential risk for increasing pathology when performed for long periods, despite reports of benefits acquired with short-term supplementation.

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Section: Introductionmentioning

confidence: 99%

Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

et al. 2010

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“…Also the root mean square voltage of the last 40 ms QRS was decreased. Patients with late potentials had more frequently ST-T depression, and ventricular arrhythmias than patients without [16]. In another study of 84 DMD patients, the prevalence of late potentials was 28% [56].…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

“…Late potential parameters were closely related to left ventricular wall motion abnormalities. In a controlled study on 26 DMD patients, late potentials were found in 31% [16]. The filtered QRS duration, late duration and increase in low-amplitude signals <40 µV were significantly prolonged.…”

Section: Duchenne Muscular Dystrophymentioning

confidence: 99%

“…By signal averaging and high-gain bandpass filtering (signal-averaged ECG), late potentials, which are high-frequency and low-amplitude signals in the terminal portion of the QRS complex, assumed to represent areas of slow conduction within the myocardium, can be discovered [9, 16]. On vector ECG, a decrease in amplitude or area under the QRS complex may reflect impaired membrane function or cell death [17, 18].…”

Section: Examinations To Assess Cardiac Involvementmentioning

confidence: 99%

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The Heart in Human Dystrophinopathies

2003

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Dystrophinopathies are due to mutations in the dystrophin gene on chromosome Xp21.1 and comprise the allelic entities Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilative cardiomyopathy (XLDCM). In all three entities, the heart is affected to various degrees, depending on the stage of the disease and the type of the mutation (cardiac involvement, CI). The pathoanatomic evidence of CI in dystrophinopathies is the replacement of myocardium by connective tissue or fat. In DMD/BMD, the left ventricular posterobasal and lateral walls are most extensively affected, sparing the right ventricle and the atrium. Degree and dynamics of CI vary among the three entities. In DMD/BMD, CI usually remains subclinical in the early stages of the disease. Typical initial manifestations of CI in DMD/BMD are sinus tachycardia, tall R1 in V1, prominent Q in I, aVL, V6 or in II, III, and aVF, increased QT dispersion and possibly autonomic dysfunction. Initially, echocardiography is normal or shows regional wall motion abnormalities in areas of fibrosis. With spreading of fibrosis, left ventricular dysfunction and ventricular arrhythmias additionally occur. In the final stages of the disease, systolic function may lead to heart failure and sudden death. Subclinical or clinical CI is present in about 90% of the DMD/BMD patients but is the cause of death in only 20% of the DMD and 50% of the BMD patients. XLDCM is a rapidly progressive, almost exclusively myocardial disorder, starting in teenage males as heart failure due to dilative cardiomyopathy (CMP), leading to death from intractable heart failure within 1–2 years after diagnosis. Therapy of arrhythmias and CMP in all three disorders follows the established cardiological recommendations. Due to its protective effect, ACE inhibitors are recommended already at the early stages of the disease. β-Blockers may be an additional option if indicated.

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“…It affects also the heart (myocyte degeneration, fibrosis and fatty infiltration), impairing ventricular repolarization, causing autonomic dysfunction, QTc prolongation and increase of QT dispersion, as an independent risk factor for ventricular arrhythmias of Lown grade III or higher [86][87][88]. Late ventricular potentials were reported in patients with Duchenne muscular dystrophy (31%), indicating the presence of a substrate for reentry ventricular arrhythmias, associated with local myocardial fibrosis, and identifying patients at high risk for sudden cardiac death [89]. Cardiac involvement was also mentioned in other dystrophinopathies, due to the replacement of myocardium by connective tissue or fat, but it remains subclinical in Duchenne and Becker muscular dystrophy [86].…”

Section: Cerebrogenic Arrhythmias and Ventricular Arrhythmia Risk In mentioning

confidence: 99%

Ventricular Arrhythmia Risk in Noncardiac Diseases

Mozoş¹

2014

Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

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diseases, to mention the main methods used to assess arrhythmia risk, as well as to elucidate their relation to long-term outcome. Dyslipidemia, obesity, diabetes mellitus, liver, hematologic, neurologic and psychiatric disorders, are discussed. Dyslipidaemia and ventricular arrhythmia riskElevated LDL cholesterol was associated with all manifestations of coronary artery disease including sudden cardiac death [7]. Hypercholesterolemia is not only atherogenic, but is also associated with autonomic imbalance, alteration of the contractile properties of the myocardium, increased oxidative stress and ventricular electrophysiological remodeling [8,9]. Myocardial electrical remodeling due to hypercholesterolemia caused prolonged action potential durations, longer QTc (heart rate corrected QT interval durations), conduction slowing and increased repolarization dispersion [9,10].Several clinical and autopsy studies demonstrated an association between elevated cholesterol levels and sudden cardiac death [11,12]. Gualdiero et al. reported a positive correlation between cholesterol level, QT dispersion and premature ventricular contractions in patients with isolated hypercholesterolemia, and normalization of serum cholesterol and QT dispersion and improvement of ventricular ectopic activity, with simvastatin [13]. Szabo et al. found significant correlations of QT interval duration and QT dispersion with total and LDL cholesterol, triglycerides and apoplipoprotein B, respectively, in patients with type IIb hyperlipoproteinemia, without myocardial ischemia, suggesting a direct effect of hyperlipidemia on ventricular repolarization [14]. LDL increases the cholesterol to phospholipid ratio in the cell membrane, enhancing membrane rigidity and impairing functionality of the ion channels and ventricular repolarization [14,15]. Ventricular repolarization is reflected by the QT interval on the ECG, which is regulated mainly by potassium channels. On the other hand, type II hyperlipoproteinemia is characterized by accelerated atherosclerosis, related to small dense LDL synthesis.It was also hypothesized that hypercholesterolemia causes repolarization abnormalities, probably, by beta or IK channel phosphorylation mediated mechanisms [9]. Hypercholesterolemia causes also endothelial dysfunction, with impaired microvascular vasodilatation, facilitating vasoconstriction, and electrical heterogeneity and extrasystolic activity [13]. The increase in the QT interval duration in cholesterol fed rabbits was lesser if L-Arginine was supplemented, suggesting a beneficial role of L-Arginine (a nitric acid precusror) in hypercholesterolemia induced repolarization characteristics [9]. L-Arginine increases endogenous nitric oxide, which may activate ATP dependent K channels, shortening the action potential [9].Late ventricular potentials were detected in patients with high and moderately elevated serum cholesterol [5,16].Cardiac Arrhythmias -Mechanisms, Pathophysiology, and Treatment 90

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Clinical significance of late potential in patients with duchenne muscular dystrophy

Cited by 10 publications

References 19 publications

Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

Arginine Metabolism by Macrophages Promotes Cardiac and Muscle Fibrosis in mdx Muscular Dystrophy

The Heart in Human Dystrophinopathies

Ventricular Arrhythmia Risk in Noncardiac Diseases

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