Masato Maeda

An Atypical Variant of Fabry's Disease in Men with Left Ventricular Hypertrophy

BACKGROUND Fabrys disease is considered very rare. Left ventricular hypertrophy is one of the common manifestations in adults with classic hemizygous disease. Recently, several cases of an atypical variant of hemizygous Fabrys disease, with manifestations limited to the heart, have been reported. Therefore, we assessed the incidence of hemizygosity for Fabrys disease among male patients with left ventricular hypertrophy. METHODS We measured plasma alpha-galactosidase activity in 230 consecutive male patients with left ventricular hypertrophy. Clinical manifestations were assessed, endomyocardial biopsies were performed, and the patients were screened for mutations in the alpha-galactosidase gene. RESULTS Seven of the 230 patients with left ventricular hypertrophy (3 percent) had low plasma alpha-galactosidase activity (0.4 to 1.2 nmol per hour per milliliter; 4 to 14 percent of the mean value in normal controls). These seven unrelated patients, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities, which are typical manifestations of Fabrys disease. Endomyocardial biopsy was performed in five patients and revealed marked sarcoplasmic vacuolization in all five. Samples from four patients were examined by electron microscopy and revealed typical lysosomal inclusions with a concentric lamellar configuration in all four. Two patients had novel missense mutations in exon 1 (Ala20Pro) and exon 6 (Met296lle). The remaining five had no mutations in the coding region of the alpha-galactosidase gene, but the amounts of the alpha-galactosidase messenger RNA were markedly lower than normal. CONCLUSIONS Seven unrelated patients with atypical variants of hemizygous Fabrys disease were found among 230 men with left ventricular hypertrophy (3 percent). Fabrys disease should be considered as a cause of unexplained left ventricular hypertrophy.

Dystrophin-deficient myocardium is vulnerable to pressure overload in vivo

OBJECTIVE Dystrophin provides mechanical reinforcement to the membranes of myocytes. Dystrophin abnormalities are known to cause cardiomyopathy and skeletal muscle disorders; however, the pathogenesis of these abnormalities remains unclear. Dystrophin-deficient skeletal muscle is vulnerable to stresses such as stretch and hypo-osmotic shock. We investigated whether the myocardium of dystrophin-deficient (mdx) mice shows increased vulnerability to acute pressure overload in vivo. METHODS AND RESULTS Abdominal aortic banding was performed in 12-week-old mdx and control mice. The aortic pressure was measured by cannulation of the right carotid artery at the time of sacrifice. Systolic pressures in mdx mice at 0, 1, 2, 7 and 14 days after aortic banding were 100 +/- 11, 119 +/- 7, 123 +/- 4, 134 +/- 11 and 130 +/- 10 mmHg, respectively. Microscopic analysis revealed focal lesions in the left ventricular wall in banded mdx mice. These lesions consisted of damaged myocytes and inflammatory cells, and also of fibrosis at a late stage. Similar lesions were not observed in non-banded or banded control mice. The proportion of areas of lesions to total left ventricular area increased over time: 1.0 +/- 0.6% in mdx mice without aortic banding (sham, n = 6), and 1.7+/-1.4% 1 day (n = 6, vs. sham, NS), 2.6 +/- 1.9% 2 days (n = 7, vs. sham, P < 0.05), 6.3+ /- 6.5% 7 days (n = 13, vs. sham, P < 0.05) and 9.9 +/- 8.3% 14 days after aortic banding (n=15, vs. sham, P < 0.01). Furthermore, linear regression analysis revealed a significant correlation between percentage of lesion area and systolic pressure in mdx mice (P < 0.05). CONCLUSION Dystrophin-deficient myocardium is more vulnerable than normal myocardium to pressure overload in vivo. This result has two clinical implications: (1) the patients with dystrophynopathy, such as the Duchenne and the Becker types of muscular dystrophy and X-linked type of dilated cardiomyopathy, who develop arterial hypertension should be treated aggressively, and (2) they should avoid stresses that elevate blood pressure.

Fatiguing intermittent lower limb exercise influences corticospinal and corticocortical excitability in the nonexercised upper limb

BACKGROUND It has recently been reported that unilateral fatiguing exercise affects not only the motor area innervating the exercising muscle but also the ipsilateral motor area innervating homologous nonexercised muscle. OBJECTIVE This study was designed to clarify the effects of fatiguing intermittent lower limb exercise on the excitability of the motor cortex representation of nonexercised muscles in the arm. METHODS Eight subjects performed an intermittent leg press exercise composed of three bouts of 5-minute leg press (T1, T2, and T3) at 50% of maximal voluntary contraction separated by a 2-minute rest. Motor-evoked potentials (MEP), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF), using paired-pulse transcranial magnetic stimulation, were assessed in two nonexercised arm muscles (first dorsal interosseous muscle: FDI, n = 8; biceps brachii muscle: BB, n = 6) and one exercised leg muscle (quadriceps femoris muscle: QF, n = 6) before and immediately after each bout of exercise and for 30 minutes during recovery after the end of the third exercise bout (Experiment 1). Experiment 2 was the same as Experiment 1, except that the test pulse intensity was adjusted to produce a given amplitude of MEP(TEST) at each time point. RESULTS MEPs and SICI in the exercised QF muscle were depressed at all time points during and after fatigue. In contrast, MEPs in nonexercised arm muscles were facilitated from T1-T3 (T3, only FDI), but were then depressed for up to 20 minutes in the recovery period. SICI was reduced in both muscles during T1-T3 and remained depressed until 20 minutes into recovery. ICF was unchanged in arm muscles but depressed in QF over T1-T3. CONCLUSIONS The current study indicates that muscle fatigue induced by exercise of a large lower limb muscle group has powerful effects on the excitability of both SICI and the corticospinal projection to muscles of the nonexercised upper limb.

Cardiac dystrophin abnormalities in Becker muscular dystrophy assessed by endomyocardial biopsy

Duchenne and Becker muscular dystrophy (DMD/BMD) are allelic variants caused by mutations in gene-encoding dystrophin. Abnormal expression of dystrophin in skeletal muscle has been shown to correlate with severity of disease. However, in BMD the severity of skeletal and cardiac involvement are not well correlated. We studied the immunostaining pattern of cardiac dystrophin in endomyocardial biopsy specimens from 83 patients with heart disease. Immunohistochemical assessment of dystrophin in four patients with BMD and cardiomyopathy showed a variable distributions of myocytes with continuous, discontinuous, or absent membrane immunostaining patterns. These patterns were obviously different from patterns of other heart diseases. We conclude that the discontinuous immunostaining pattern of cardiac dystrophin is characteristic of BMD and that an absent pattern may be associated with more severe cardiac dysfunction. Because genetic analysis cannot determine the correct diagnosis in 35% of DMD/BMD cases, we recommend routine examination of immunostaining patterns of dystrophin in endomyocardial biopsy specimens in patients with cardiomyopathy suspected to be the result of BMD.

Unilateral grip fatigue reduces short interval intracortical inhibition in ipsilateral primary motor cortex

OBJECTIVE This study was designed to examine whether exhaustive grip exercise of the left hand affected intracortical excitability in ipsilateral motor cortex. METHODS Ten healthy male subjects (aged 21-24 years) participated in experiment 1 in which paired-pulse transcranial magnetic stimulation (TMS) was used to test corticospinal and corticocortical excitability in right (relaxed) first dorsal interosseous (FDI) muscle during the recovery period after exhaustive forceful grip exercise of the left hand. Seven of the same subjects participated in experiment 2, in which the intensity of the test stimulus was adjusted so that the amplitude of motor evoked potential (MEP(TEST)) was kept constant throughout the measurement. RESULTS In experiment 1, MEP(TEST) was slightly reduced from 5 to 15min after exercise whilst short interval intracortical inhibition (SICI) at interstimulus interval (ISI) of 2 and 3ms became less effective. Intracortical facilitation (ICF) was unchanged. In experiment 2 when the MEP(TEST) was maintained at a constant size there was again no change in ICF, and the reduction in SICI was still present at the same intervals. CONCLUSIONS We conclude that unilateral exhaustive grip exercise reduced the excitability of the corticospinal output of the ipsilateral motor cortex whilst simultaneously reducing the excitability of SICI. These results would be compatible with the idea that fatigue increases the tonic level of interhemispheric inhibition from the fatigued to the non-fatigued cortex. SIGNIFICANCE Muscle fatigue to the point of exhaustion has lasting effects on the excitability of intracortical circuits in the non-exercised hemisphere, perhaps via changes in the tonic levels of activity in transcallosal pathways.