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A case of complete heart block is presented in a patient whose brothers were known to have ankylosing spondylitis. Uveitis and sacro-iliitis are well recognised among HLA-B27-positive siblings of ankylosing spondylitis. However, heart block is a rare occurrence as a sole presentation in siblings of patients with ankylosing spondylitis.

A family of complete atrioventricular block (FCAVB) of adult onset was reported. A 36-year-old-female had 1 degree AH block, atrial and ventricular premature beats and mild sinus node dysfunction. Her father had complete AV block and died of it. A 57-year-old uncle and a 52 years-old uncle had bradycardia from 44, 5 years of age and 51 years of age, respectively, and their ECG showed complete AV block with narrow QRS waves. They were implanted with permanent pacemakers. Her grandmother died a sudden death of Adams-Stokes attack. Acquired heart diseases were not seen in any of the family Thus, this family was thought a FCAVB of adult onset.

An apparently identical deletion of 4.977 bp in length (position 8,483-13,459) was detectable in the mitochondrial DNA from skeletal muscle, heart muscle, kidney, and liver of a patient with Kearns-Sayre syndrome. The proportion of deleted genome varied from 60% for the skeletal muscle to 15% for heart muscle and kidney, and was below 5% in the liver. The mtDNA heteroplasmy of the liver was only detectable after amplification by PCR. In skeletal and heart muscle histochemical and immunocytochemical findings concerning cytochrome c oxidase were in good correlation with the proportion of deleted mitochondrial DNA.

Five generations of an Italian family with an autosomal dominant restrictive cardiomyopathy are described. Members of four generations were examined. Symptoms usually developed in the third or fourth decade but the disease did occur in childhood. Initially the condition was characterised by normal ventricular size and systolic function with increased diastolic filling pressures in both ventricles and consequent bi-atrial enlargement. Cardiac catheterisation showed a left ventricular filling pattern of "dip and plateau". The electrocardiogram typically showed non-specific changes in the ST segment and T wave and changes indicating considerable atrial enlargement, which were confirmed by echocardiography. Light microscopy of two endocardial biopsy specimens showed no specific features but excluded the endomyocardial fibrosis of eosinophilic heart disease, amyloid, and specific heart muscle diseases. At necropsy in one case examined under light microscopy extensive patchy fibrosis was found throughout the endocardium, myocardium, and subepicardium, but there were no features typical of eosinophilic heart disease. Histopathological and biochemical examination of skeletal muscle identified no abnormality. The disease often had an insidious course over five to ten years after presentation. Bundle branch blocks, leading to complete atrioventricular block, however, often occurred and may be the first manifestation. Some individuals who survived into the fifth decade developed a progressive, non-wasting skeletal myopathy.

A 57 year old patient with Charcot-Marie-Tooth syndrome developed complete A-V block due to trifascicular disease. The syndrome was present in 3 generations and the patient's mother had also complete A-V block. It is not known whether this interesting association is genetically determined or fortuitous.

Hereditary atrioventricular conduction defect is an uncommon cause of acquired complete heart block in children. We report a father and son, both of whom presented with seizures as the initial manifestation of acquired complete heart block and required permanent pacemaker implantation. A review of the variations of this entity and the histopathological findings of previously reported cases is presented. Family members of patients with acquired heart block of uncertain etiology should be examined for the presence of conduction abnormalities that may progress to complete heart block.

Complete congenital heart block is associated with the presence of maternal autoantibodies to small ribosomal nucleoproteins (such as anti-Ro) which cross the placenta and may be deposited at the site of cardiac damage. Ten such cases of congenital heart block, their mothers, and their siblings were studied. The seropositive mother of one case had a similar conduction defect (bifascicular block) to that in her affected child. None of the siblings examined had cardiac lesions. Six mothers had Ro or La antibody five to 17 years after the birth of the affected child. Four mothers examined 11-32 years after the birth of an affected child were seronegative. Three of these mothers had evidence of a connective tissue disorder. This evidence is consistent with a hypothesis that a maternal viral infection, associated with autoantibody production, leads to virus crossing the placenta, damaging the fetal heart, and eliciting local deposition of maternal antibody.

A genetic predisposition associated with HLA B27 for developing complete heart block with or without clinical or radiological signs of associated rheumatic disease has recently been found. In this electrophysiological study of 12 patients with spontaneous complete heart block and HLA B27 associated disease, of whom eight had ankylosing spondylitis, 10 had suprahisian second or third degree atrioventricular block (eight spontaneously and two during atrial pacing at rates below 90 impulses per minute) and one infrahisian block. One patient with narrow QRS complexes during complete heart block three months earlier had normal findings. Three patients also had sinus node malfunction and six had fascicular or bundle branch block. In HLA B27 associated disease the atrioventricular block seems to be preferentially located in the atrioventricular node, although the conduction system may be widely affected. The findings in this study indicate a further cause of high degree atrioventricular block with a predominantly suprahisian location in addition to acute inferior myocardial infarction, digitalis intoxication, and "congenital" heart block.

A kindred is described in which several members have evidence of sick sinus syndrome and of conduction disturbance. The data suggest that in this family the rhythm disturbances were transmitted as an autosomal dominant trait whose penetrance increase with age. The occurrence of Adams-Stokes episodes required pacemaker implantation in 6 patients. In one case the arrhythmia is associated with a cardiomyopathy of unknown origin. No pathological studies were conducted. In one case the His bundle electrogram was recorded.

Congenital complete heart block (CCHB) occurs in the offspring of mothers who have the HLA-A1;B8; DR3 haplotype and Ro (SS-A) autoantibodies. It has been shown that the presence of HLA-DR3 in mothers may facilitate Ro synthesis, but may not, by itself, be sufficient to induce CCHB in the offspring. However, maternal DR3 and Ro antibody seem to be independent factors associated with CCHB. Other HLA antigens, including class III (complement) genes, may also be necessary to induce CCHB in newborns since A1;B8; DR3 haplotypes, together with BfS and/or C4AQ0B1, are increased in Ro+ mothers of infants with CCHB compared with both controls and with Ro+ mothers whose offspring do not have CCHB. On the other hand, DR3 genes in a different HLA haplotype (i.e., B18; BfF1;DR3) are nonpathogenetic; this latter finding may be due to a DR3 gene's intrinsic difference or to the influence of neighboring genes. Also, a trend toward DR3 bias transmission is observed in DR3+ mothers who are also Ro+; fetal DR3 might protect the fetus against in utero death when Ro antibodies are present.

At least seven members of a family coming from southern Germany (Franconia) have manifested Emery-Dreifuss syndrome within four generations. This syndrome is characterized by slowly progressing atrophic pareses, generally in a humeroperoneal distribution, premature joint contracture, and cardiomyopathy with reduction of functional capacity. Up to now four members of this family have died from cardiac causes between the age of 39 and 46 years. Three family members have now been thoroughly examined; they showed typical muscular atrophies and contractures. The two older patients were diagnosed as having a cardiomyopathy with a complete atrioventricular block and ventricular tachycardia. Electromyographic and histological findings indicate a primary neurogenic process. Regular cardiological examinations combined with effective therapy (for example, implantation of a cardiac pacemaker and treatment with antiarrhythmic drugs) will be necessary in treating the serious arrhythmias. Progressive myocardial insufficiency required heart transplantation in one of our patients, which was successfully performed. Macroscopic and microscopic examination of the explanted heart showed a dilatative cardiomyopathy with hypertrophy and dilatation of both atria and ventricles, differences in the diameters of individual heart muscle cells, and a predominately focal interstitial fibrosis.

An Inuit family from Cape Dorset, Northwest Territories is described; six had documented complete heart block, one high grade atrioventricular block, one bi- or trifascicular block and all suffered syncope. One other member received a pacemaker for unknown reasons. Two of three middle-aged relatives had minor conduction abnormalities. All younger family members who were examined had no conduction problems. This suggests a heritable form of adult onset complete heart block, the largest series reported in the English literature.

Isolated reports of patients, including aviators, with congenital complete heart block suggest a benign prognosis. However, prospective studies of adolescents and adults with congenital complete heart block reveal an unpredictable incidence of impairment of consciousness and sudden death. Congenital complete heart block is, therefore, a contraindication to professional pilot status.

The Kearns-Sayre syndrome (KSS) is a distinctive type of progressive external ophthalmoplegia, characterized by pigmentary degeneration of the retina, heart block, elevated concentration of cerebrospinal fluid protein, and abnormal muscle mitochondria. Previously described cases have all been sporadic. Consequently, viral infections and autoimmune disorders have been proposed as etiologies. The occurrence of KSS in two brothers suggests that genetic factors may play a role in the pathogenesis of some cases.

The original Virginia family with X-linked muscular dystrophy with early contractures and cardiomyopathy (Emery-Dreifuss type) has been reinvestigated 25 years later. The findings confirm that a cardiomyopathy, presenting most often as atrioventricular block, is a significant feature of the disease, which is characterized by the triad of: 1) slowly progressive muscle wasting and weakness with a humero-peroneal distribution in the early stages; 2) early contractures of the elbows, Achilles tendons, and post-cervical muscles; and 3) a cardiomyopathy usually presenting as heart block (some female carriers may also develop heart block). Other reported families with X-linked Emery-Dreifuss muscular dystrophy as well as a rare autosomal variant are reviewed, and differentiation from scapulo-peroneal muscular dystrophy and the rigid spine syndrome is discussed.

This report describes a family showing muscular dystrophy and atrioventricular block with an x-linked hereditary transmission. Among a known pedigree of 101 family members, 12 males were found to have skeletal muscle involvement and six needed pacemakers around age 30 years. Unlike the x-linked muscular dystrophies of Duchenne and of Becker, the predominant skeletal involvement was in humeral muscles, was usually very mild, and did not produce incapacitation. Cardiac involvement consisted of various atrial arrhythmias and atrioventricular block. The few sporadic reports of other families that describe the same disease under different names are briefly reviewed. Recognition of this subtle muscular dystrophy is important for early detection of incipient complete atrioventricular block to prevent fatal complications by pacemaker insertion.

Four brothers with a maximum age difference of 20 years, the eldest of whom has been re-examined after a 10 year interval, have sinoatrial block, a supra-hisian atrioventricular block and paroxysmal atrial arrhythmias which have led to partial atrial standstill in the eldest: left anterior hemiblock is also present in the two youngest brothers. The condition is very well tolerated. This family is compared to the other 12 reported cases of familial idiopathic binodal block in the adult, an autosomal dominant condition with variable penetration. The diagnosis is reserved and justifies endocavitary investigation of the sinus node function and atrioventricular conduction in the four brothers and the most exposed members of their family. The mechanism of the condition is unknown. It seems to arise from variable degrees of nonspecific of the nodal and atrial tissues.

Two siblings with hypertrophic cardiomyopathy developed spontaneous complete heart block requiring permanent pacemaker implantation at similar ages (29 and 33 years). The clinical, morphological, and haemodynamic expressions of hypertrophic cardiomyopathy differed considerably in these two patients. The sister had severe functional limitation due to dyspnoea, pronounced and diffuse left ventricular hypertrophy (maximum ventricular septal thickness of 41 mm), and left ventricular outflow obstruction (peak subaortic gradient of 75 mm Hg under basal conditions). In contrast the brother was symptom free, had only modest left ventricular hypertrophy which was confined to the anterior ventricular septum (maximal thickness of 16 mm), and had no echocardiographic evidence of subaortic obstruction. These dissimilar findings in siblings with hypertrophic cardiomyopathy suggest that the predisposition to develop complete heart block was probably genetically transmitted, although it was unrelated to the phenotypic and clinical expression of the disease.

Available data support the idea that the neonatal lupus erythematosus syndrome results from an autoantibody produced in the mother and passed across the placenta to the fetus. Despite the evidence for the presence of the Ro(SSA) autoantigen both in the skin and heart and the almost universal presence of the Ro(SSA) autoantibody in mothers of infants with neonatal lupus, there are emerging data to suggest that La(SSB) and, rarely, nRNP antibodies play an important pathologic role in some cases of the neonatal lupus syndrome.

An oriental family with over 265 living descendants of a polygamous ancestor known to have had a slow pulse and syncopes was studied. Many examples of conduction defects, mainly right bundle branch block, left anterior hemiblock, bifascicular block and artioventricular block were detected. The transmission of the genetic defect was autosomal dominant, the incidence 43%, the penetration very variable, apparently affecting the male descendants predominantly, the expression probably congenital, but with complete heart block presenting at 75 years of age in one case. The localisation of the conduction defect is discussed: the distal extremity of the His bundle after the origin of part or all of the left posterior fascicle. This study, in its clinical and epidemiological context, demonstrates an inherited disease with both typical and "forme fruste" expressions. Compared with other series, it suggests the diverse nature of hereditary and familial conduction defects.

Paroxysmal complete atrioventricular (AV) block without associated electrocardiographic (ECG) abnormality is not a well recognized entity. A mother and her daughter had recurrent syncopal episodes, but a normal ECG. The episodes were preceded by nausea and vomiting. ECG during these episodes revealed complete heart block. In the mother, one episode was promptly reversed by atropine. Electrophysiological evaluation of the sinus and AV nodal function and atrial and ventricular effective refractory periods before and after autonomic blockade was normal. Provocative manoeuvres failed to induce AV block. Paroxysmal AV block was vagally mediated in one of the patients, as indicated by prompt response to atropine. In the second case, the vagal dependence could not be proved but appears to be the most likely explanation. It thus appears that paroxysmal, vagally mediated complete AV block should be seriously considered in patients with unexplained syncope.

New data on genetics, including an extensive pedigree and certain aspects of natural history, have been compiled on Family S, which is characterized by a hereditary progressive atrioventricular (A-V) conduction defect. Concordance analysis of heart block in affected parents and their offspring suggests as a working hypothesis transmission of diathesis for the defect by means of a Mendelian autosomal dominant factor. Regression of the defect in several relatives, including reversion from first degree heart block to normal A-V conduction, defies explanation at this time. However, rapport established with the unusually large (1,067 members) and cooperative kindred will permit longitudinal evaluation of these findings.

Eighteen members of a family were investigated for cardiac conduction abnormalities following the discovery of a second-degree atrioventricular block in a fetus at 35 weeks of gestation. The conduction disturbance was diagnosed by ultrasonography. Seven of the family members were diagnosed as suffering from sinus node dysfunction and/or various degrees of atrioventricular block. Three of them were children aged 9 months to 6 years and all were asymptomatic. The symptomatic family members were two adults. One of them had a pacemaker inserted for a complete atrioventricular block and Adam-Stokes attacks while the other had had several fainting attacks. The clinical, electrocardiographic and ultrasonographic findings of the family members are presented. Previous reports in literature have documented the dominant transmission of familial sinus node dysfunctions or of familial cardiac conduction disturbances. The coexistence of both dysfunctions in the same family has not been emphasized in previous reports. A review of these previously reported families, as well as our patients, suggests the need of investigation and follow-up of the families in which one member of any age is diagnosed as suffering from an "idiopathic" disturbance of the cardiac conduction system.

An increased prevalence of ankylosing spondylitis and other HLA B27-associated rheumatic diseases has recently been demonstrated in a group of men with permanent pacemaker-treatment. The purpose of the present study was to find out if HLA B27 was associated with severe bradyarrhythmias also in the absence of rheumatic disease. The frequency of B27 was determined in 83 permanently paced men with complete heart block, in whom presence of radiological or clinical signs of a B27-associated rheumatic disease had been excluded. Eighty-four healthy subjects were HLA typed for comparison. HLA B27 was found in 17% of the patients and in 6% of the controls, a significant difference with P = 0.017 (Fisher's exact test). The present study suggests that, in a subgroup of patients with complete heart block, the development of heart block is B27-associated, and that the pathophysiological mechanism is similar to that leading to ankylosing spondylitis. Another B27-associated disease manifestation has been demonstrated.

Certain genetic disorders occur with unusually high frequency in the Afrikaner population of southern Africa. Conditions of this type (reviewed in Part I of this article) include familial hypercholesterolaemia, progressive familial heart block, Huntington's chorea, porphyria variegata, Gaucher's disease, cystic fibrosis and familial colonic polyposis. This genetic situation is explicable to some extent on the basis of the demographic development of the Afrikaner population during the 14 generations since the arrival of the first immigrants from Holland more than 330 years ago.

A family with adult onset heart block (AOHB) and sinus bradycardia (SB) was investigated 5 yr after previous study. A 44-yr-old female previously 'normal' presented ECG evidence of 1st-degree and 2nd-degree atrioventricular block (AVB) with normal intraventricular conduction and episodic 3rd-degree AVB. His bundle electrocardiography (HBE) demonstrated A--H prolongation (245msec) with normal H--V time during sinus rhythm and 3rd-degree AV nodal block with a His bundle escape rhythm. Sinus node function served in first-order relatives. HBE and sinus node function were normal in a 38-yr-old sister with new SB. 37 families with familial 3rd-degree AVB were reviewed with attention to prognostic indices and electrophysiologic-pathologic correlates. The incidence of conduction abnormalities supported an autosomal dominant transmission with variable penetrance. Subsidiary pacemaker rate and QRS morphology showed no discriminative value with respect to prognosis. HBS identified A--H prolongation in 2 patients with AOHB and 2 with AOHB and SB, with coexistent H--V conduction delay in 2 cases of AOHB and SB with abnormal QRS morphology. Histopathology was variable, but the finding of multiple lesions in 2 of 5 patients with congenital heart block and each of 2 with AOHB and SB suggests that mixed conduction system disease is prevalent in familial heart block.

An examination is made on different members of a family in which, owing to hereditary transmission of dominant autosomal type, exist alterations that sometimes manifest with disorders of the intraventricular conduction, sometimes with more or less pronounced aspects of ventricular pre-excitation and some other time with anomalies of the ventricular repolarization phase. In examining the genealogical tree of the family, there are in the fourth generation five cases of short PQ-normal QRS syndrome and one case with ventricular repolarization anomalies; in the third generation six cases with left anterior hemiblock, one case with short PQ-normal QRS syndrome, one case with Wolff-Parkinson-White syndrome and three cases with ventricular repolarization anomalies; in the second generation three cases with bundle branch block associated with left anterior hemiblock. The clinical laboratory investigation permitted to exclude the presence of congenital or acquired heart diseases which, rather frequently are responsible for documented electrocardiographic anomalies; the morphology and cardiac volumetry, put in evidence by radiological examinations, remained within the limits of the normal.

Families of eight patients with the diagnosis of familiar cardiomyopathy were reviewed. It was possible to study 121 persons, 64 examined in the Instituto Nacional de Cardiología, and 57 through indirect questioning. It was found that in each of the families some disturbance in rhythm or conduction predominated. The evolution among the members of each family was similar, but was different in comparison with the other families. Those patients which presented complete A-V block died before 30 years of age, the majority of sudden death. The disturbances in rhythm or conduction most frequently observed were: complete A-V block, premature ventricular beats, lengthening of the Q-T, incomplete left bundle branch block, atrial fibrillation, Lown-Ganong-Levine syndrome, Wolff-Parkinson-White syndrome, premature supraventricular beats, incomplete right bundle branch block, ventricular fibrillation, and ventricular tachycardia. It can be concluded that: 1) familiar cardiomyopathy is, in reality, a group of distinct illnesses, with a genetic base; 2) the variability of the clinical findings, electrocardiography, and the evolution, depends on the particular type to which a given case corresponds; 3) it is possible that other varieties of familiar cardiomyopathy exist.

Sixty-five patients with a definite diagnosis of myotonic dystrophy (MD) and 34 of their presumably unaffected relatives were examined cardiologically, including ECG in all and echocardiography in 61 and 32 persons respectively, in order to investigate the frequency of cardiac abnormalities, their clinical importance and their potential value as a preclinical marker in the diagnosis of MD. Atrioventricular conduction (AVC) abnormalities were found in 18/33 (54%) of affected males and in only 5/32 (16%) of affected females (P = 0.0025). Intraventricular (IVC) conduction abnormalities were encountered with similar frequency in both sexes: in 12/33 (36%) of affected males and 10/32 (31%) of affected females. Mitral valve prolapses (MVP) were seen more often in affected females: 9/31 (29%) of affected males vs 15/30 (50%) of affected females have MVP (P = 0.16). A previously undescribed finding was that of pericardial effusions in 5 affected and in 1 unaffected person. All affected males with MVP also had conduction abnormalities, but cardiac findings were not interrelated otherwise. None of the cardiac abnormalities mentioned were age-related. Only 8/65 (12%) of patients had cardiac symptoms, all of which were the result of conduction defects. As far as can be judged from a transversal study, the value of cardiac examination of this kind as a preclinical test for the diagnosis of MD is modest. It is argued that IVC-abnormalities, but not AVC-disturbances or MVP, in clinically unaffected relatives may indicate that they are preclinical heterozygotes. The significance of pericardial effusion for the diagnosis of MD awaits further evaluation.

To characterize an unusual, sex-linked recessive neuromuscular disease, we studied two families with 37 males who had involvement of distal leg and proximal arm muscle groups. Electromyography and muscle biopsy in five subjects showed features of both neuropathy and myopathy. Bradycardia and syncope in 15 involved subjects were associated with early death (before the age of 50 years). Electrocardiograms in 15 others showed a spectrum of atrial abnormalities that ranged from abnormal P waves to permanent atrial paralysis and from first-degree atrioventricular block to complete heart block. No patient exhibited clinical muscle disease without electrocardiographic atrial disease. Dilated, hypertrophied left ventricles with normal indexes of function were found in three cases with permanent atrial paralysis and chronic junctional bradycardia. Cardiomegaly and cardiac failure were not present in the other cases. We conclude that permanent ventricular pacing (instituted four patients) is indicated in many of these patients to prevent serious sequelae.

Four members of a family presenting with sinus bradycardia, a short P-R interval, intraventricular conduction defects, recurrent supraventricular tachycardia (SVT), syncope, and cardiomegaly had His bundle studies and were found to have markedly shortened A-H intervals (30 to 55 msec.) with normal H-V times (35 to 50 msec.). Right atrial pacing at rates as high as 170 to 215 per minute failed to increase the A-H or H-V intervals significantly. The data are compatible with the presence of an A-V nodal bypass tract (James bundle) or even complete absence of an A-V node. Ventricular pacing and spontaneous ventricular premature beats resulted in a short ventriculoatrial conduction time (110 msec.) suggesting that if A-V nodal bypass tracts exist, they are utilized in an antegrade and retrograde fashion. None of the features of WPW syndrome was present. The mechanism of syncope in the mother and daughter was intermittent third-degree heart block. Both went on to develop permanent complete heart block despite electrophysiologic studies demonstrating 1:1 A-V conduction at extremely rapid atrial pacing rates and both required implantation of permanent pacemakers. The mechanism of syncope in the two brothers was possibly marked sinus bradycardia, but transient complete heart block has not been ruled out. Permanent pacemaker therapy was recommended for both. The nature of the cardiomegaly, which was mild in three patients, is not known. Although not well documented, several maternal relatives have had enlarged hearts, SVT, complete heart block, and syncope.

An autosomal dominant inherited ASD with conduction defects in one family is described. 6 members of 4 generations were fallen ill. In 4 patients the diagnosis was made clinically, in 2 sisters the diagnosis was confirmed by operation. Moreover, the last 2 patients had a mitral insufficiency--probably congenital. The ecg-findings of 4 patients additionally showed conduction defects in form of AV-and bundle branch blocks.