Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study.

OBJECTIVES: The aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement. BACKGROUND: Long-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure. METHODS: Forty-two patients (27 male, 15 female; 9 to 65 years old, mean [+/-SD] age 29.6 +/- 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol. RESULTS: Thirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 +/- 15 years vs. 20 +/- 8.8 and 25 +/- 9.7 years, respectively), had significantly longer clinical follow-up (9.3 +/- 7.3 years vs. 1.2 +/- 2.1 and 3.4 +/- 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 +/- 150 g vs. 328 +/- 40 and 380 +/- 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients. CONCLUSIONS: LV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.

Long-term effects of dynamic aortomyoplasty.

Aortomyoplasty consists of wrapping the latissimus dorsi muscle (LDM) around the ascending aorta and electrostimulating it during diastole. The ascending aorta will act as an ectopic neo-ventricle compressed during diastole, thus reproducing the effects of long-term diastolic counterpulsation. In 5 goats, the right LDM was transferred to the thoracic cavity after removal of the second rib. The ascending aorta was enlarged by a pericardial patch and wrapped with the LDM. Postoperative electrostimulation was delivered in a counterpulsating manner. Hemodynamic studies were performed at 12 and 24 months postoperatively. Percent increase in the subendocardial viability index (diastolic pressure-time index/systolic tension-time index) was calculated using unassisted and assisted cardiac cycles with the stimulator off versus the stimulator on at a 1:1 ratio in the basal state and after acute heart failure was induced by the administration of high doses of propranolol hydrochloride. Diastolic counterpulsation of the ascending aorta resulted in significant improvement in the subendocardial viability index long term, both in basal state conditions and after induced cardiac failure. During heart failure, aortomyoplasty increased the cardiac output and decreased systemic vascular resistance. Histopathologic studies up to 24 months showed preservation of the histologic structure of the aortic wall and no evidence of thromboembolism. Tight adhesions developed between the aortic wall (including the pericardial patch) and the LDM. The diameters of the enlarged aortas showed no significant differences compared with diameters immediately postoperatively. In conclusion, aortomyoplasty produces chronic diastolic augmentation with preservation of aortic structure. After induction of heart failure, aortomyoplasty offers efficient circulatory support.

Prostaglandins and hypertension in chronic renal diseases.

The role of prostaglandin A (PG A) in the pathogenesis of renal hypertension has been studied. The concentration of endogenous PG A was measured in the peripheral plasma by radioimmunoassay in patients with chronic renal disease and in control subjects. The mean plasma concentration of PG A1 equivalents was as follows: 1. normotensive healthy volunteers (n=23): 115 +/- 15 pg/ml 2. patients in terminal renal failure on regular hemodialysis a) anephric patients (n=6): 51+/- 21 pg/ml b) patients retaining their own kidneys, all but one with hypertension (n=9): 231 +/- 51 pg/ml (P less than 0.01 versus control) 3. patients with chronic renal disease a) with hypertension (n=7): 204 +/- 60 pg/ml (P less than 0.01 versus control) b) without hypertension (n=11): 136 +/- 30 pg/ml. Renal hypertension was associated with high levels of PG A in peripheral blood. This increase is probably a secondary adaptative mechanism for the excretion of a greater fraction of the glomerular filtrate at a lower blood pressure. PG A may represent a circulating "antihypertensive hormones".

Experimental cardioplasty using the latissimus dorsi muscle flap.

This study was undertaken to examine the possibility of using the latissimus dorsi muscular flap, divided in two parts thus covering the surfaces of the heart, and inserting it into the thoracic cavity by means of a segmental resection of the second rib. After cadaver case studies, 15 operations were performed on 5 Beagle dogs. The first group of 5 operations consisted of a latissimus dorsi flap graft over the heart. The second group and third group of operations (3 and 6 months later) consisted of reoperating for muscular and cardiac biopsies and electrical stimulation tests on the heart-muscle complex. The latissimus dorsi flap provided a sizable mass of contractile tissue. The haemodynamic studies showed no compressive or constrictive phenomenon of the muscle on the heart and revealed the preservation of an appropriate cardiac output for short intervals of time (2 hours), through phasic electrostimulation of the flap. The histopathological studies showed conserved muscular structure. The technical feasibility, histological adaptability and electrophysiological properties of this muscular flap makes it appropriate to develop a functional stimulation programme and perhaps adequate for the treatment of dysplasic, ischemic, tumoral and other acquired or congenital myocardial diseases.

Fat in the heart. A feature unique to the human species? Observational reflections on an unsolved problem.

Fat that is well demarcated from underlying muscle is found on the right ventricular free wall and around epicardial coronary vessels. Fat is not present in the left ventricle in normal subjects. In right ventricular dysplasia, fat and fibrosis may massively displace right ventricular myocardial tissue. It is frequently associated with some clusters of fat and fibrosis in the left ventricle. Adipocytes may be also found within fibrous tissue. In this situation it may be associated with inflammatory cellular infiltrates in both ventricles and this is called metaplastic fat. All these findings may be seen and sometimes are associated to a variable degree in the same myocardial specimen. However, fat may be interspersed with right ventricular myocardial fibres but without fibrosis or signs of inflammation. This situation is observed in more than half of the normal hearts and represents an over-looked pathologic condition only observed in the human species. The term "fat dissociation syndrome" is proposed to identify this condition. This new understanding of right ventricular myocardial structure which may be investigated by MRI may have important clinical consequences.

[Causes of sudden death in athletes]. / Les causes de mort subite chez les sportifs.

Sudden death is rare in athletes, and it is only in recent years that significant series were collected, making it possible to draw the cardiological profile of athletes who died suddenly at the peak of exertion or while recovering. A study of the literature, both medical and paramedical, has yielded 53 cases in which the most frequent causes of sudden death were hypertrophic cardiomyopathy (26 p. 100), (arrhythmogenic right ventricular disease (19 p. 100), congenital abnormalities of coronary arteries (11 p. 100) and coronary atheromatous lesions (9 p. 100), to which must be added various other causes. This study clearly demonstrates the hitherto unrecognized importance of arrhythmogenic right ventricular dysplasia-a condition which, as recent data suggest, is not solely due to a myocardial development disorder but also to an infective disease, an acute of chronic myocarditis. In subjects with this condition, new exploratory methods might detect the presence of an arrhythmogenic substrate during medical screening of athletes, but in any case these causes of sudden death suggest that a fast rhythm disorder was involved in several of these deaths. This disorder could be treated if the attendants were trained to carry out cardiorespiratory resuscitation procedures or if they had access to a defibrillator which should be available on every sports field.

[Cellular electrophysiological and histopathological study of the effects of continuous electric current on the sheep heart]. / Etude électrophysiologique cellulaire et histopathologique des effets du courant électrique continu sur le coeur de mouton.

The energy released in electrode catheter ablation is spent on thermal, mechanical and electrical effects. The relative importance of these effects and their role in the adverse reactions of the method are controversial. Low-energy shocks have been shown to modify cellular electrophysiological and histopathological parameters in the sheep heart. The purpose of this study was to individualized the effects of the electric current itself, using an isolated electrode to suppress barotrauma and reduce the amount of energy delivered. Three fragments of epicardium, seven false tendons and eight loop-shaped strips were placed in an electrophysiology bath perfused with Tyrode's solution and subjected to an electric field induced by an 18 V battery without discharge from a condenser, so that all mechanical effects were suppressed. The electric field was supplied via an isolated electrode, thus preventing the current from leaking through the Tyrode's solution and forcing it across the fragments studied. The electrophysiological parameters were studied by the microelectrode method on both sides of the area subjected to the electric field. This was followed by a histological study. The current intensity was 15 mAmp, and the energy delivered in one second was 270 mJ. Membrane depolarization was constant, and no automatic of post-depolarization activity was observed after the electric current was applied. The two-dimensional conduction accounted for the absence of block in the epicardial fragments. In the false tendons a conduction block constantly appeared between the two electrodes, associated with a decrease in conduction velocity in the recovery phase (2.1 +/- 0.24 vs 1.8 +/- 0.23 m/s, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

[Prostaglandins in renovascular arterial hypertension]. / Les prostaglandines dans l'hypertension artérielle réno-vasculaire.

Prostaglandins (PG) A1, B1, E2, F2 alpha and plasma renin activity (PRA) were measured by radioimmunoassay in 8 patients with unilateral artery stenosis, 7 hypertensive patients with unilateral renal atrophy without stenosis ans 20 controls. The measurement of the PG and PRA in the hypertensive group was performed in the infra-renal inferior vena cava and in the two renal veins. PRA and PGA1 were significantly raised in the renovascular hypertensive patients but no significant change was observed in the group with unilateral renal atrophy. On the other hand, the PGE2 and PGF2 alpha were raised in both groups, especially in the renal veins on the stenosed or atrophic side. There was a positive significant correlation between PRA and PGA1 and PGB, but none with PGE2 or PGF2 alpha. This study suggests that the increase in PGA1 and PGE2 represents a secondary hypertensive mechanism which is diuretic and natiuretic. The increase of PGF2 alpha represents a direct mechanism of hypertension. Simultaneous measurement of the vasopressor (PRA and PGF2 alpha) and vasodepressor (PGA and PGE) systems may give a better diagnostic and prognostic approach to renovascular hypertension.

[Significance of lymphoplasmocytic infiltration in arrhythmogenic right ventricular dysplasia. Apropos of 3 own cases and review of the literature]. / Signification des infiltrats lymphoplasmocytaires dans la dysplasie ventriculaire droite arythmogène. A propos de 3 cas personnels et d'une revue de la littérature.

Three patients with typical histological signs of arrhythmogenic right ventricular dysplasia progressed to fulminating heart failure in 1 case and unexplained sudden death in the other two. There were signs of superacute myocarditis in the first case, previous healed pericarditis in the second and chronic myocarditis in the third case. These cases suggested the presence of an inflammatory process complicating the substrate of the dysplasia. Arrhythmogenic right ventricular dysplasia seems to be a developmental defect which is complicated in 50 to 70% of patients, according to a review of 74 cases reported in the literature, by a varying degree of myocarditis suggesting particular susceptibility of these patients to infection and explaining the presence of unusual amounts of fibrous tissue in some and the so called "progressive" nature of the disease in other patients.

[Nosologic frontiers of arrhythmogenic dysplasia. Quantitative variations of normal adipose tissue of the right heart ventricle]. / Frontières nosologiques de la dysplasie arythmogène. Variations quantitatives du tissu adipeux ventriculaire droit normal.

The increasing number of arrhythmogenic idiopathic cardiomyopathies with available histological studies by biopsy or peroperative sampling has prompted the need for data about the normal structure of the right ventricle. A retrospective study of right ventricular tissues was undertaken in 148 autopsies. The quantity of adipose tissue was scored 0 (only epicardial fat visible) to 4 (total replacement of the myocardium by adipose tissue). The topography of the adipocytes was also coded 0 to 4 according to the degree of intermyocytic penetration, irrespective of the total quantify of fat. The amount and extension of adipose tissue in the right ventricular wall was striking. Fifty called "normal" appearances with a myocytic wall of normal thickness and a separate layer of epicardial fat, were only present in 61 of the 148 cases. Adipocytes were present in variable numbers, often unexpectedly high in the majority of cases, with no relationship to the age or gender of the patient with frequent individualization of the myocardial bundles. These surprising findings in normal right ventricles should be born in mind when considering the diagnosis of arrhythmogenic right ventricular dysplasia (ARVD). The histopathological appearances of ARVD are very similar but also differ very significantly, at least in typical cases. The adipocytes are often present in large numbers but this is banal and non-specific. On the other hand, the bundles which penetrate the epicardial fat are usually fibro-muscular and not purely myocytic. In addition, arterioles suggesting segmental diversions are present within the fatty layer with non-specific inflammatory cells.(ABSTRACT TRUNCATED AT 250 WORDS)

[Morphologic study of cardiac cells in sheep before and after electric shock]. / Etude morphologique des cellules cardiaques de mouton avant et après choc électrique.

A combined electrophysiological and histopathological study was conducted on sheep myocardium fragments rich in easily identifiable conduction cells subjected to electric shocks of varying intensity. Tissue fragments were immersed in a thermostatically-controlled bath at 37 degrees C, perfused with a carbonated standard tyrode solution at the rate of 30 ml/min and stimulated at a constant bipolar 1 C/sec tension twice as high as the threshold of diastolic excitability. After measurement of reference values, electric shocks of 2 to 80 joules were delivered between two electrodes placed on both sides of the tissue fragment. The electrophysiological part of the study showed disorders of conduction which, depending on the energy delivered, were more or less complete and reversible. The histopathological part of the study showed that conduction tissue was extremely fragile, even to low-energy shocks. This fragility was in glaring contrast with the relatively modest damage suffered by myocytes. Liquefaction and/or coagulation of Purkinje's cells was also striking, as it extended over an area much wider than that subjected to the shock. Thus, with medium intensity shocks destroyed conduction bundles were seen to creep between myocytes that often were perfectly normal or showed rare hypercontraction bands. Some myocytes were in the process of degeneration or even eosinophilic necrosis, but except in case of violent shock these were more or less isolated elements in the vicinity of the stimulated area. The fragility of conduction tissue and its selective damage by low-intensity shocks may be explained partly by its low impedance which allows preferential passage of the electric current.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cellular electrophysiological effects of fulguration by low energy shock]. / Effets électrophysiologiques cellulaires de la fulguration par des chocs de faible énergie.

In spite of the increasing use of catheter ablation in the treatment of refractory ventricular and supraventricular arrhythmias, little information is available on the basic electrophysiological effects of the treatment. Although high-energy shocks are still usually delivered, the current trend is toward lower energies. We studied the electrophysiological effects of non-deflagrating anodic shocks of 2 joules on preparations of sheep ventricular myocardium and Purkinje's fibers. The shocks were delivered by a standard defibrillator between a small-area catheter electrode and a wide-area inert electrode. Action potentials were recorded by the standard microelectrode technique. After the shocks were delivered, the Purkinje's cells that were 5 mm distant from the shocked area on either side were depolarized in the -30 to -40 mV zone, but they progressively reverted to an almost normal resting potential. Recovery was bi-exponential, with time constants of about 1 min and 10 min respectively. Similarly, the conduction block induced by the electric shock in 100% of the cases was reversible in 50%. It must be noted that at the time of conduction recovery the pattern observed was that of electrotonic conduction where the distal action potential conducted was preceded by a pre-potential. This pattern always regressed progressively, with gradual disappearance of the pre-potential in the distal cells, suggesting that the unexcitable area had vanished or become smaller. Although a normal 1/1 conduction and normal action potentials returned in the cells that were 5 mm distant from the shocked area, recordings performed at a distance of 1 to 4 mm from that area disclosed alterations of action potentials that were usually irreversible.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cellular effects of electric shock. Definitions, physical principles, cellular electrophysiology and morphological analysis of the shocked areas]. / Effets cellulaires des chocs électriques. Définitions, principes physiques, électrophysiologie cellulaire et analyse morphologique des zones choquées.

In this experimental study the electrophysiological changes induced by electric discharges such as used clinically in some arrhythmias refractory to the usual treatments were investigated. With energies comprised between 2 and 80 joules profound modifications of the electrophysiological properties of muscle cells and conduction were observed. These modifications included loss of resting potential, inactivation of the fast sodium flux, increase in refractory periods of conduction and disorders of conduction through the shocked areas with, at most, complete block sometimes reversible when low-energy currents were used. With the same amounts of energy these effects were maximal when the current traversed tissues positioned between the electrodes and decreased in all other cases. Usually, with currents of 10 joules or more all electric activity ceased in a radius of about one centimetre around the shocked area.

[Congenital and acquired right ventricular dysplasia]. / Dysplasie transmise et dysplasie acquise.

Arrhythmogenic right ventricular dysplasia has been described as a developmental malformation occurring during foetal life. This explains a number of familial cases of this condition where dysplasia was the result of a genetic abnormality transmitted in an autosomal dominant mode with incomplete penetrance. Histological data of peroperative or post-mortem specimens of 27 cases showed a large number of grape-like lymphoplasmocytic infiltrations. These appearances suggest an inflammatory origin of the disease, most probably related to an infective etiology. The authors suggest that in addition to the congenital form there may also be a possibility of acquiring arrhythmogenic right ventricular dysplasia after an episode of myocarditis.

[Outcome of arrhythmogenic right ventricular dysplasia. Apropos of 4 cases]. / Modalités évolutives de la dysplasie ventriculaire droite arythmogène. A propos de 4 observations.

The authors propose a classification of the outcome of arrhythmogenic right ventricular dysplasia with reference to 4 selected cases with a follow-up period of over 9 years. In type I, the left ventricular ejection fraction is normal (EF > 50%) and the risk, exclusively arrhythmic, can be controlled by appropriate antiarrhythmic therapy. This is the commonest form of arrhythmogenic right ventricular dysplasia with different varieties according to the degree of dilatation of the right ventricle. In type II, there is a variable degree of left ventricular involvement (30 < EF < 50%) either by extension of a comparable disease process as observed in the right ventricle or by an isolated or superimposed phenomenon of myocarditis. This form is stable and may remain stable for many years providing the arrhythmias are correctly treated. In type III, progressive degradation of the myocardium is observed over a period of about 10 years with a clinical presentation comparable to that of certain arrhythmogenic dilated cardiomyopathies which are often hereditary. In this case, the patients have an arrhythmic risk associated with that of cardiac failure which becomes progressively irreversible. The histology shows interstitial fibrosis with biventricular lymphocytic infiltration suggesting an autoimmune phenomenon. Therefore, the classification of cases of arrhythmogenic right ventricular dysplasia depends on the potential evolutivity of the lesions. When the patient is seen in the early stages of the disease, the prognosis should be garded, especially in a hereditary form.

[Rare complication of extracorporeal circulation: diffuse coronary fibrosis; giant cell myocarditis]. / Complication surprenante de la circulation extra-corporelle : fibrose coronaire diffuse; myocardite à cellules géantes.

A 38 year old woman developed severe coronary stenosis several months after double valve replacement. Aorto-coronary bypass surgery was performed but the patient died of a peroperative myocardial infarction. Histological studies showed not only fibrous thickening of the intima of the whole coronary arterial tree, but also variable medial changes with inflammatory infiltration. In addition, inflammatory granulomata with giant cells were found in the myocardium. These coronary lesions and their association with a giant cell myocarditis cannot be satisfactorily explained by known pathological conditions. The usual mechanisms of coronary disease were not operative in this case. There remains the hypothesis of a primary change of the coronary wall related to either cannulation, anoxic arrest or perfusion fluid, or a combination of these factors. The coronary lesions could have developed by an immunological process which would also explain the giant cell myocarditis.

[Focal junctional tachycardia in adults. Anatomo-electrophysiological aspects apropos of a case]. / Tachycardie jonctionnelle focale de l'adulte. Confrontation anatomo-électrophysiologique à propos d'un cas.

The authors report the case of a 65 year old patient with focal junctional tachycardia complicating infectious myocarditis which had a fatal outcome. The ECG recordings showed episodes of tachycardia alternating with junctional rhythm at 90/min. There were signs of retrograde conduction. The anatomopathological findings were typical of acquired myocarditic lesions in the lower part of the atrioventricular node with congenital abnormalities, in particular a bifid node and His bundle with an accessory paraseptal atrioventricular bundle. This is the first description, to the best of the authors's knowledge, of junctional tachycardia associated with a latent pre-excitation.

[Holter and sudden death: value in a case of arrhythmogenic right ventricular dysplasia]. / Holter et mort subite: intérêt dans un cas de dysplasie ventriculaire droite arythmogène.

The authors report the first case of arrhythmogenic right ventricular dysplasia presenting with a sudden death due to primary ventricular fibrillation (ventricular fibrillation not preceded by ventricular tachycardia) recorded by the Holter method. The patient was a 56 year old man whose only complaint was near syncopal case is the fact that it is the first documented case of ventricular fibrillation revealing arrhythmogenic right ventricular dysplasia, the diagnosis of which was made at autopsy. In addition, the Holter recording showed the factors which triggered the arrhythmia: the "trigger" of 4 monomorphic ventricular extrasystoles during the minute preceding the ventricular fibrillation; the arrhythmogenic substrate giving rise to late ventricular potentials and, finally, the analysis of the R-R intervals suggesting a role of the sympathetic and parasympathetic nervous systems. Holter recordings could help identify subjects at high risk of severe ventricular arrhythmias.

[Congenital atrioventricular block and maternal lupus erythematosus. Histologic discovery of tumor of the atrioventricular node]. / Bloc auriculo-ventriculaire congénital et lupus érythémateux maternel. Découverte histologique d'une tumeur du noeud auriculo-ventriculaire.

A case of congenital atrioventricular block in a newborn whose mother presented with systemic lupus erythematosus (SLE) is reported. Despite intensive care the child died a few hours after birth. Serial sections of the heart could be examined. Histology provided information on the appearance and distribution of the lesions. In particular, the sinus node was small for the child's age, and its supplying artery was found to have a hyperplastic media with adventitial sclerosis; the interatrial and interventricular septa showed subendocardial fibrosis invading the adjacent myocardium. Owing to the scarcity of systematic histopathological examinations, such lesions have seldom been described. In addition, a tumour of the atrioventricular node, known as mesothelioma or hemolymphangioma, was discovered. This case is exceptional in that histopathological findings similar to those described in SLE, though rarely as numerous, were associated with a very rare tumour never hitherto described in such a young patient. The relationship between the two categories of lesions is discussed.

[Right precordial leads and sudden death. Relation with arrhythmogenic right ventricular dysplasia]. / Dérivations en précordiales droites et mort subite. Relation avec la dysplasie ventriculaire droite arythmogène.

Non-coronary ST-segment elevation during right sided chest pain has been described in subjects with episodes of ventricular fibrillation at rest. This syndrome has been attributed to functional phenomena or to structural myocardial changes. A personal case has features belonging to two categories: ST-segment elevation observed before, during and after episodes of arrhythmia was compared to 11 previously recorded ECG recordings. Right ventricular dysplasia was shown by electrocardiography, electrophysiology and echocardiography. In addition, ST-segment elevation is classified in 3 categories: triangular and dome-shaped are the most commonly observed forms during the arrhythmias: the third form with "saddle"-shaped appearances has not been previously described and would seem to be a minor equivalent observed during intercritical periods. This form is found in 30% of clinically documented cases of arrhythmogenic right ventricular dysplasia.