Myocardial Infarction and Complete Heart Block

The clinical and electrocardiographic records of 20 patients with complete A-V block due to acute myocardial infarction have been analyzed. This study indicated that patients with an inferior wall myocardial infarction had, most commonly, a block above the bifurcation. The block was transitory, the patients had no Stokes-Adams attacks and the outcome was good. None of our patients required artificial pacing. On the other hand, patients with an anteroseptal myocardial infarction suffered from a bilateral bundle branch block (below the bifurcation). They had severe Stokes-Adams attacks and they all required artificial pacing. The destruction of the conducting system was extensive and the outcome was poor. Five out of seven patients treated with artificial pacing recovered the A-V conduction through the left bundle within a few days. However, in spite of this they all died.From this small series clearly defined clinical and electrocardiographic features can be identified in two different groups of cases.     

The Artificial Cardiac Pacemaker—Indications for Implantation

Extensive clinical experience has demonstrated that implantable cardiac pacemakers are safe and effective mechanisms for controlling symptoms and preventing the hazards of third degree heart block with Stokes-Adams syncope. Medical management of this disease does not provide reliable protection and life expectancy averages about two years after diagnosis. Hence the negligible surgical morbidity and mortality associated with pacemaker implantation justifies broad indications to implant one of the four commercially available battery-powered units.Elective implantation of a pacemaker should be considered in patients with persistent third degree heart block who have had: One or more episodes of Stokes-Adams syncope; surgical injury to the conduction system, regardless of syncopal attacks; evidence of low cardiac output with cardiomegaly secondary to bradycardia. Few if any other cardiac arrythmias are satisfactorily controlled by an electrical pacemaker.Emergency pacemaker control is obviously necessary for patients developing intractable or recurrent bouts of asystole. During the interval until an implantable unit can be obtained and sterilized, the patient may be controlled by intravenous isoproterenol or by an external pacemaker attached to a transvenous catheter electrode, a precordial skin electrode or a percutaneous myocardial wire electrode.     

Indications for Treatment of Complete Atrioventricular Dissociation

For purposes of correct treatment it is important to recognize that patients with complete atrioventricular dissociation fall into three groups: Group I—established third-degree heart block with and without Stokes-Adams attacks; Group II—periodic third-degree heart block with and without Stokes-Adams attacks; Group III—established third-degree heart block with cardiac failure. Most patients in Group I present no technical problems when a pacemaker is implanted. In Group II it is advisable to insert a temporary intracardiac catheter electrode and maintain a rate of 60 to 64 during the periods of third-degree heart block. Sudden reversion, in this group, from sinus rhythm can be fatal. Group III patients will often require a pacemaker set in excess of 74 beats until they are free of cardiac failure. Fifteen of 20 patients with complete atrioventricular dissociation showed marked functional improvement after insertion of a pacemaker. The development, in our laboratory, of a 4″ portable pacemaker impulse detector has been invaluable in locating the cause of failure in an implanted pacemaker.     

Statement of the ad hoc committee on the laboratory diagnosis of infectious and serum hepatitis.

A prospective study was carried out to determine the prognostic factors in patients with second-degree and complete heart block following acute myocardial infarction and to re-examine the indications for artificial transvenous pacing. Of the 117 consecutive patients with proved acute myocardial infarction, 15 developed advanced heart block (second degree and complete). The presence of the following factors, either alone or in combinations, were attended with poor prognosis: preceding Stokes-Adams syndrome, cardiogenic shock, congestive heart failure, complications secondary to cardiac arrest, anterior infarction and wide QRS complex. In the nine cases requiring artificial transvenous pacemaker because of Stokes-Adams attacks, congestive heart failure or frequent multifocal ventricular ectopic beats, there were five deaths. The remaining six patients, who were without complications and were not paced, all survived; these patients had normal QRS duration with heart rates above 60 per minute. This study indicates that prophylactic transvenous catheter insertion in acute heart block does not appear justified unless specific indication(s) arise. Postmortem studies revealed significant narrowing of all the major coronary vessels in all five fatalities. The overall mortality in this series of cases of acute heart block was 33%.     

The Implantable Cardiac Pacemaker

The transistorized implanted pacemaker is proving to be an effective and reliable method for long-term pacing of the heart. All patients suffering from Stokes-Adams seizures were first given a trial period of conservative therapy, including isoproterenol (Isuprel), ephedrine, atropine and steroids. Twenty-four pacemaker implants were performed on 23 patients over a 21-month period. The preoperative insertion of a pacemaker cardiac catheter was a very valuable safety precaution. In this way the heart could be safely and reliably paced during the period of preoperative assessment and during the critical periods of anesthetic induction and thoracotomy. Infection did not occur, probably because of careful gas sterilization of the units. Various models of pacemakers are compared, and the reasons for two pacemaker failures are presented. There were two early deaths and one late death in the series. The relationship of progressive coronary disease to recent infarction is stressed. Patients having intermittent heart block frequently showed the picture of “competing pacemakers” postoperatively, but without deleterious effect. Twenty patients, between 54 and 88 years of age, are alive and well at the time of reporting, with excellent pacemaker response and no further Stokes-Adams attacks.     

Artificial Cardiac Pacemakers

Nine patients with complete heart block and Stokes-Adams disease were treated with subcutaneously implanted, fixed-rate, artificial cardiac pacemakers. All of these patients were refractory to medical treatment and confined to bed by the frequency of their attacks. One patient died in uremia one month after operation; in the remaining eight, the implanted pacemakers are providing adequate stimulation at present. These patients are free of seizures and show an improvement in the amount of their physical activity. A fixed rate of 60 to 65 per minute was adequate in all cases. The results of our clinical experience with cardiac pacemakers is satisfactory, but the possibility of mechanical failure limits their use to situations in which the patient is incapacitated despite medical treatment.     

The nuclear envelope in muscular dystrophy and cardiovascular diseases

Considerable interest has been focused on the nuclear envelope in recent years following the realization that several human diseases are linked to defects in genes encoding nuclear envelope specific proteins, most notably A-type lamins and emerin. These disorders, described as laminopathies or nuclear envelopathies, include both X-linked and autosomal dominant forms of Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy with conduction system defects, limb girdle muscular dystrophy 1B with atrioventricular conduction disturbances, and Dunnigan-type familial partial lipodystrophy. Certain of these diseases are associated with nuclear structural abnormalities that can be seen in a variety of cells and tissues. These observations clearly demonstrate that A-type lamins in particular play a central role, not only in the maintenance of nuclear envelope integrity but also in the large-scale organization of nuclear architecture. What is not obvious, however, is why defects in nuclear envelope proteins that are found in most adult cell types should give rise to pathologies associated predominantly with skeletal and cardiac muscle and adipocytes. The recognition of these various disorders now raises the novel possibility that the nuclear envelope may have functions that go beyond housekeeping and which impact upon cell-type specific nuclear processes.     

Effect of atrio-ventricular conduction on the appearance of supraventricular arrhythmia and thrombotic complications in patients with chronic stimulation of cardiac ventricles in sick sinus syndrome]

Two hundred three patients with sick sinus node disease were treated with continuous ventricular stimulation between 1981 and 1985. To 1988, 168 patients aged between 26 and 88 years were followed-up for 5.1 years on the average. All these patients were divided into two groups: I (93 patients) with sinusal bradycardia, and group II (93 patients) with brady-tachycardia. Ventriculo-atrial conduction was seen in 82.61% of patients of group I in whom the implantation of electric stimulator produced the attacks of atrial fibrillation, and in 44.23% of patients without such attacks (p < 0.01); in 80.77% of patients of group II in whom atrial fibrillation became stable with time, and in 50.57% with intermittent atrial fibrillation (p < 0.01) ventriculo-atrial conduction was noted. It may be concluded, that the presence of ventriculo-atrial conduction in patients with prolonged stimulation of the cardiac ventricles favor the occurrence and stabilization of the paroxysmal atrial fibrillation and thrombotic complications.     

Changes at P183 of emerin weaken its protein-protein interactions resulting in X-linked Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive muscular dystrophy characterized by early contractures of the elbows, Achilles tendons and spine, slowly progressive muscle wasting and weakness, and cardiomyopathy associated with cardiac conduction defects. The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle. Mutations spanning the emerin gene have been identified in patients with EDMD. We present here the effect, on emerin protein expression, of two missense mutations identified in unrelated EDMD patients. These alterations predict the replacement of a proline residue at position 183 with either a histidine or a threonine. Biochemical analysis has demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from that of wild-type emerin, but that they have weakened interactions with nuclear lamina components. In comparison with the usual EDMD phenotype, patients with P183 missense mutations have a later age at onset of first symptoms, elbow contractures, ankle contractures, upper limb weakness and lower limb weakness, but there is no difference for the age at onset of cardiac involvement. This is the first report of protein studies on patients with missense mutations resulting in the clinical features of EDMD. These studies demonstrate the importance of proline 183 for the proper structure/function of emerin. Received: 29 September 1998 / Accepted: 14 January 1999     

Electrocardiographic abnormalities in patients with myotonic dystrophy.

In examining the incidence and progression of electrocardiographic abnormalities in 45 patients with myotonic dystrophy, 26 (58%) of whom at entry had at least 1 electrocardiographic abnormality, we found conduction abnormalities in 17 (38%). In 21 patients (47%), new abnormalities developed during follow-up (mean, 4.6 years). The overall incidence of electrocardiographic abnormalities increased to 78%, and the incidence of conduction defects increased to 62%. Second-degree or complete atrioventricular block did not develop in any of the patients. Pseudoinfarction patterns were common at entry and during follow-up and were not correlated with evidence of clinical coronary artery disease. There was no correlation between the presence of electrocardiographic abnormalities and apparent disease severity.     

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.     

Abnormal expression of a serine protease in human dystrophic muscle

The activities of serine protease in muscles from normal persons and from patients with progressive muscular and neuromuscular diseases have been determined. A significant increase in the level of serine protease was found in muscle of patients with Duchenne-type muscular dystrophy and with Becker-type muscular dystrophy, but the activity was not increased in muscle of a patient with amyotrophic lateral sclerosis.     

Myopathy in complex glycerol kinase deficiency patients is due to 3'' deletions of the dystrophin gene.

DNA samples from nine previously reported patients with X-linked recessive glycerol kinase deficiency, associated in seven of them with adrenal hypoplasia and in five with developmental delay and myopathy, have been studied for deletions of the Duchenne/Becker muscular dystrophy gene by probing with the entire cDNA for the dystrophin protein. All five patients with myopathy, including two in whom no deletions had been detected before, were found to have variable-sized deletions extending through the 3' end of this gene. The 5' deletion breakpoints are intragenic in four cases and have been mapped precisely on the exon-containing HindIII fragment map. A correlation was found between severity and progression of the muscular dystrophy phenotype and the sizes of the gene deletions. In cases in which there was glycerol kinase deficiency/adrenal hypoplasia microdeletion syndrome without myopathy, no deletions were found with the dystrophin cDNA.     

Myotonic dystrophy: RNA pathogenesis comes into focus

Myotonic dystrophy (DM)--the most common form of muscular dystrophy in adults, affecting 1/8000 individuals--is a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases.     

Cross‐sectional serum metabolomic study of multiple forms of muscular dystrophy

Muscular dystrophies are characterized by a progressive loss of muscle tissue and/or muscle function. While metabolic alterations have been described in patients’‐derived muscle biopsies, non‐invasive readouts able to describe these alterations are needed in order to objectively monitor muscle condition and response to treatment targeting metabolic abnormalities. We used a metabolomic approach to study metabolites concentration in serum of patients affected by multiple forms of muscular dystrophy such as Duchenne and Becker muscular dystrophies, limb‐girdle muscular dystrophies type 2A and 2B, myotonic dystrophy type 1 and facioscapulohumeral muscular dystrophy. We show that 15 metabolites involved in energy production, amino acid metabolism, testosterone metabolism and response to treatment with glucocorticoids were differentially expressed between healthy controls and Duchenne patients. Five metabolites were also able to discriminate other forms of muscular dystrophy. In particular, creatinine and the creatine/creatinine ratio were significantly associated with Duchenne patients performance as assessed by the 6‐minute walk test and north star ambulatory assessment. The obtained results provide evidence that metabolomics analysis of serum samples can provide useful information regarding muscle condition and response to treatment, such as to glucocorticoids treatment.     

Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.

Using positional cloning strategies, we have identified a CTG triplet repeat that undergoes expansion in myotonic dystrophy patients. This sequence is highly variable in the normal population. PCR analysis of the interval containing this repeat indicates that unaffected individuals have been 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat containing segment up to several kilobase pairs. The CTG repeat is transcribed and is located in the 3' untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy. This mRNA encodes a polypeptide that is a member of the protein kinase family.     

Treatment of lower extremity reflex sympathetic dystrophy with continuous intrathecal morphine infusion

Continuous intrathecal morphine infusion has been used in 3 patients with refractory lower extremity reflex sympathetic dystrophy syndromes. Two patients have experienced prolonged significant benefit.     

Effect of delta-aminolevulinic acid on frog nerve-muscle function

Effects of delta-aminolevulinic acid (ALA) on nerve-muscle function $\text{in vitro}$ have been examined using the frog sciatic gastrocnemius preparation. Levels of ALA that did not interfere with nerve conduction did inhibit the muscle's response to nerve stimulation for a period of 50 – 120 min. The amounts of ALA within muscle were declining at 2 hr after topical administration. It is suggested that some of the symptoms in acute attacks of intermittent porphyria may be attributable to effects from ALA.     

Does quantitative EMG differ myotonic dystrophy type 2 and type 1?

Genetic testing is considered the only reliable diagnostic approach in myotonic dystrophy. However it has recently been reported that a considerable number of patients with genetically proven types of the disease have unusual phenotypic presentation. The aim of our study was to evaluate motor unit reorganization reflected by various electrophysiological abnormalities in myotonic dystrophies and to compare findings between type 1 (DM 1) and type 2 myotonic dystrophy (DM2). Quantitative electromyography (EMG) recordings in 63 patients (33 with DM1 and 30 with DM2) from the biceps brachii (BB), rectus femoris (RF), first dorsal interosseus (FDI), and tibialis anterior (TA) muscles were analyzed. Mean amplitude and size index (SI) of motor unit potentials recorded in TA and RF muscles, mean potential duration in TA, and mean SI and the number of outliers with amplitude above the normal range in BB were significantly increased in DM2 as compared to DM1. Myotonic discharges were recorded more frequently in DM1 than in DM2. EMG findings significantly differ between DM1 and DM2. The presence of high amplitude potentials in lower limb muscles in DM2 patients, atypical for myogenic muscle lesions, could be explained by muscle fiber hypertrophy observed in muscle biopsies.