Cardiac Conduction Block Research Articles

Expecting the Unexpected

Expecting the Unexpected

Electrophysiological effects of haloperidol on isolated rabbit Purkinje fibers and guinea pigs papillary muscles under normal and simulated ischemia

Overdoses of haloperidol are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. The aim of this experiment was to study the effect of haloperidol on the action potentials in cardiac Purkinje fibers and papillary muscles under normal and simulated ischemia conditions in rabbits and guinea pigs. Using the standard intracellular microelectrode technique, we examined the effects of haloperidol on the action potential parameters [action potential amplitude (APA), phase 0 maximum upstroke velocity (V(max)), action potential amplitude at 90% of repolarization (APD(90)), and effective refractory period (ERP)] in rabbit cardiac Purkinje fibers and guinea pig cardiac papillary cells, in which both tissues were under simulated ischemic conditions. Under ischemic conditions, different concentrations of haloperidol depressed APA and prolonged APD(90) in a concentration-dependent manner in rabbit Purkinje fibers. Haloperidol (3 micromol/L) significantly depressed APA and prolonged APD(90), and from 1 micromol/L, haloperidol showed significant depression on V(max); ERP was not significantly affected. In guinea pig cardiac papillary muscles, the thresholds of significant reduction in APA, V(max), EPR, and APD(90) were 10, 0.3, 1, and 1 mumol/L, respectively, for haloperidol. Compared with cardiac conductive tissues, papillary muscles were more sensitive to ischemic conditions. Under ischemia, haloperidol prolonged ERP and APD(90) in a concentration-dependent manner and precipitated the decrease in V(max) induced by ischemia. The shortening of ERP and APD(90) in papillary muscle action potentials may be inhibited by haloperidol.

Novel LMNA Mutation in a Taiwanese Family with Autosomal Dominant Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early-onset contractures, slowly progressive weakness, and muscle wasting in humeroperoneal muscles, and adult-onset cardiomyopathy with conduction block. We analyzed blood samples from an EDMD family, including a mother and two daughters, and found a novel mutation in codon 520 in exon 9 of the lamin A/C (LMNA) gene, resulting in a substitution of tryptophan (W) by glycine (G) in all three patients. The mother died after a stroke-like episode at the age of 43. The elder sister received pacemaker implantation, which improved symptoms of exercise intolerance and dizziness. These cases illustrate the necessity of correct diagnosis, evaluation, and follow-up of cardiac problems due to the wide clinical spectrum and high prevalence of cardiac conduction block in patients with autosomal dominant EDMD.

Trigger Finger as an Initial Manifestation of Familial Amyloid Polyneuropathy in a Patient with Ile107Val TTR

We describe a Japanese family with transthyretin Val107-related familial amyloid polyneuropathy (FAP). The clinical features were high-aged onset, sensorimotor polyneuropathy, carpal tunnel syndrome (CTS) and trigger finger. In addition, the proband showed cardiac conduction block and amyloid deposition in the sural nerve and dermis. Trigger finger may be a so far unknown clinical manifestation of Val107 FAP due to amyloid deposition in the connective tissue like CTS.

Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations

Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.

A missense mutation in the exon 8 of lamin A/C gene in a Japanese case of autosomal dominant limb-girdle muscular dystrophy and cardiac conduction block

A case of autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction block (LGMD1B) has been documented. In this family, 13 members, nine males and four females, had cardiac arrhythmia requiring pacemakers. The proband, a 67-year-old male, had longstanding proximal muscle weakness later associated with cardiac arrhythmia but showed neither rigid spine nor joint contracture. His muscle enzymes were within normal range and muscle biopsy showed myopathic changes. Gene analysis of the proband revealed Tyr481His mutation in the exon 8 of lamin A/C (LMNA) gene which is adjacent to the codon mutated in reported cases of familial partial lipodystrophy. This is the first report of muscular dystrophy shown to have a mutation of LMNA in a Japanese family as well as the first case of missense mutation in the exon 8 with LGMD1B phenotype.

Missense mutations in desmin associated with familial cardiac and skeletal myopathy.

Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.

Oral exfoliative cytology for the non-invasive diagnosis in X-linked Emery–Dreifuss muscular dystrophy patients and carriers

Emery–Dreifuss muscular dystrophy (EMD) is an inherited myopathy characterised by muscle contractures, progressive muscle wasting and weakness, with humeroperoneal distribution. Cardiac arrhythmia and heart conduction block are also important characteristics of this disease. The X-linked form of EMD is caused by the absence of emerin, encoded by the STA gene (Xq28). Emerin is normally localised in muscle and other tissues at the nuclear rim. Currently, muscle and skin biopsies are used for the immunohistochemical diagnosis. We demonstrate that emerin is present in the cheek oral mucosa, in the exfoliating epithelial cells, and we propose the collection of these cells as a new method for the diagnosis of X-linked EMD patients and the detection of carriers by immunofluorescence techniques: smears from healthy subjects contained about 98% emerin-positive cells, those from X-linked EMD patients contained none and those from carriers contained about 45%. The technique is completely non-invasive, simple, repeatable and inexpensive.

Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane.

X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscle disorder characterized by the clinical triad of progressive wasting of humero-peroneal muscles, early contractures of the elbows, Achilles tendons and postcervical muscles, and cardiac conduction block with a high risk of sudden death. The gene for EDMD on Xq28 encodes a novel protein named emerin that localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and some other non-muscle tissues. To investigate a possible physiological role for emerin, we examined the ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections. We found that the immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore. Emerin stayed on the cytoplasmic surface of the nuclear lamina, even after detergent treatment that solubilizes membrane lipids and washes out membrane proteins. These results suggest that emerin anchors at the inner nuclear membrane through the hydrophobic stretch, and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina. We speculate that emerin contributes to maintain the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux.

Childhood‐onset autosomal‐dominant limb‐girdle muscular dystrophy with cardiac conduction block

We report childhood-onset autosomal-dominant limb-girdle muscular dystrophy (LGMD) in a Chinese family with complete atrioventricular conduction block in the adult members. Six patients, including 5 men and 1 woman with an age of onset from 3 to 7 years, were affected. The grandfather had exercise intolerance since childhood and complete heart block with pace-maker placement at age 52. Three siblings had proximal muscle weakness and/or wasting since age 5 and heart block in their 40s. Two grandsons at the ages 7 and 3 showed exercise intolerance, and proximal muscle weakness and wasting. Sinus bradycardia was present in the elder grandson. Muscle enzymes were elevated in 3, particularly in childhood. Muscle biopsies from the proband showed myopathic changes with fatty degeneration, whorled fibers, and rimmed vacuoles. In adult patients, muscle magnetic resonance imaging scans disclosed atrophic changes and fatty degeneration in the gluteal, quadriceps, adductors, hamstrings, gastrocnemius, and soleus muscles, while in child probands the early atrophic changes were seen in the gluteal and hamstrings muscles. We conclude that this distinct family is characterized by childhood-onset autosomal-dominant LGMD with heart block and that prevention of sudden death in these patients is important. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 286–292, 1997.

A japanese family carrying a novel mutation in the emery‐dreifuss muscular dystrophy gene

We report on a Japanese family affected by Emery-Dreifuss muscular dystrophy carrying a novel mutation of the emerin (STA) gene. The cardinal clinical feature of the family was cardiac conduction block and mild myopathy. A deletion of 11 bp with a frameshift was identified in exon 6, causing truncation of the predicted protein. The relationship between mutation and phenotype is discussed.

Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder.

We have investigated a 15 year old girl with progressive external ophthalmoplegia, including bilateral ptosis and retinal rod and cone cell dysfunction with atypical retinal pigmentation, complicated by cerebellar ataxia, partial cardiac conduction block, and diabetes mellitus. In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially though to be psychosomatic. Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA. We therefore conclude that this patient has developed the Kearns-Sayre syndrome after a Pearson syndrome-like crisis in her first year of life.

Slow‐release verapamil poisoning

To present three cases of slow-release verapamil poisoning that demonstrate the prolonged absorption of the drug and the role of polyethylene glycol and high-dose calcium in management. Three patients with slow-release verapamil poisoning are presented. An 18-year-old woman took 2.3 g and developed hypotension and bradyarrhythmias 18 hours after ingestion, despite gastric lavage and administration of charcoal at three hours. A 23-year-old woman took 4.8 g and presented two hours later clinically unaffected. A 44-year-old woman presented 24 hours after taking 15-20 g. She had a systolic blood pressure of 50 mmHg, no measurable diastolic blood pressure and bradyarrhythmias. Case 1 responded to administration of 30 g of calcium and fluids intravenously. Case 2 was given polyethylene glycol on admission which resulted in passage of a tablet bezoar and no toxicity. Polyethylene glycol was ineffective in Case 3. She responded initially to high doses of calcium and other treatments, but subsequently died of hypotension and cardiac conduction block 39 hours after the overdose. The severity of poisoning with slow-release verapamil warrants aggressive pre-emptive treatment. Polyethylene glycol should be used routinely irrespective of the clinical state. High doses of calcium may be required to treat conduction block and hypotension.

Rigid spine syndrome associated with cardiomyopathy:Clinical and nosological considerations.

We report observations in a 32-year-old man with the following characteristics of rigid spine syndrome: humero-peroneal muscular atrophy and weakness; bradycardia, dilated cardiomegaly and complete cardiac conduction block; and severe fatty degeneration of the paravertebral and calf muscles. The latter showed a predominance of type 1 fibers, a deficiency of type 2A fibers, and an increase in type 2C fibers. The patient had no familial background of the disease. There was no contracture of the elbows. These findings, especially the severe cardiac involvement, suggest that the rigid spine syndrome can be difficult to distinguish from the Emery-Dreifuss form of muscular dystrophy.