Myocardial Dystrophy Research Articles

Tissue-resident Sca1+ PDGFRα+ mesenchymal progenitors are the cellular source of fibrofatty infiltration in arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (AC) is a disease of the heart involving myocardial dystrophy leading to fibrofatty scarring of the myocardium and is associated with an increased risk of both ventricular arrhythmias and sudden cardiac death. It often affects the right ventricle but may also involve the left. Although there has been significant progress in understanding the role of underlying desmosomal genetic defects in AC, there is still a lack of data regarding the cellular processes involved in its progression. The development of cardiac fibrofatty scarring is known to be a principal pathological process associated with ventricular arrhythmias, and it is vital that we elucidate the role of various cell populations involved in the disease if targeted therapeutics are to be developed. The known role of mesenchymal progenitor cells in the reparative process of both the heart and skeletal muscle has provided inspiration for the identification of the cellular basis of fibrofatty infiltration in AC. Here we hypothesize that reparative processes triggered by myocardial degeneration lead to the differentiation of tissue-resident Sca1+ PDGFRα+ mesenchymal progenitors into adipocytes and fibroblasts, which compose the fibrofatty lesions characteristic of AC.

Arrhythmogenic cardiomyopathy: A biventricular disease in search of a cure

Arrhythmogenic cardiomyopathy (AC), previously known as arrhythmogenic right ventricular (RV) cardiomyopathy/dysplasia, is a cause of sudden death (SD) in the young. It accounts for 5%–25% of SD in athletes in whom it is triggered by effort. AC is an autosomal dominant genetic disease, mostly because of mutations in genes encoding desmosomal proteins that bind the cells together. The arrhythmogenic substrate consists of fibrofatty replacement of the ventricular myocardium, which is the consequence of myocyte death (myocardial dystrophy).

The changing spectrum of arrhythmogenic (right ventricular) cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a clinically and genetically heterogeneous heart muscle disorder associated with ventricular arrhythmias and risk of sudden death. The disease is heredo-familial, and mutations in desmosomal genes have been identified in about half of patients. Recent experimental models confirm this disease develops after birth due to progressive myocardial dystrophy. Genotype-phenotype correlations, including magnetic resonance and pathology studies on heart specimens, are currently demonstrating that the spectrum of the disease is wider than initially thought and usually referred to with the adjective "right ventricular", with the evidence of biventricular or even isolated left ventricular forms, so that it is increasingly identified simply as "arrhythmogenic cardiomyopathy". A revision of the diagnostic criteria encompassing familial, electrocardiographic, arrhythmic, morpho-functional and histopathologic findings, has been made to improve diagnostic sensitivity and specificity, in particular of the concealed forms and left-dominant subtypes of the disease. Experimental models are mandatory to gain an insight into the cascade of cellular and molecular events leading from gene defect to myocardial dystrophy in ARVC.

Pathophysiology of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, particularly in the young and athletes. Mutations in five genes that encode major components of the desmosomes, namely junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2, have been identified in approximately half of affected probands. AC is, therefore, commonly considered a 'desmosomal' disease. No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion. Caution in the interpretation of screening results is highly recommended because a 'pathogenic' mutation is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression.

Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy

Myocyte necrosis underlies progressive myocardial dystrophy in mouse <i>dsg2</i>-related arrhythmogenic right ventricular cardiomyopathy

Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy

Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

Structural and functional changes in myocardial thin filaments in experimental hypothyrosis

Fluorescence resonance energy transfer study revealed decreased intermonomer mobility of Ca-actin and Mg-actin filaments of myocardial myofibrils in myocardial dystrophy caused by diffuse endocrine disorders, e. g. hypothyrosis. Cis374 axial distance in Ca-actin filament protomer increased in hypothyrosis. Intracellular pH has no effect on inter-monomer mobility of Ca-actin filament.

Treatment of inoperable coronary disease and refractory angina: spinal stimulators, epidurals, gene therapy, transmyocardial laser, and counterpulsation.

Intractable angina from refractory coronary disease is a severe form of myocardial ischemia for which revascularization provides no prognostic benefit. Inoperable coronary disease is also accompanied by a "vicious cycle" of myocardial dystrophy from a chronic alteration of the cardiac sympathetic tone and sensitization of damaged cardiac tissues. Several adjunctive treatments have demonstrated efficacy when revascularization is either unsuccessful or contraindicated. Spinal cord stimulation modifies the neurologic input and output of the heart by delivering a very low dose of electrical current to the dorsal columns of the high thoracic spinal cord. Neural fibers then release CGRP and other endogenous peptides to the coronary circulation reducing myocardial oxygen demand and enhancing vasodilation of collaterals to improve the myocardial blood flow of the most diseased regions of the heart. Randomized study has shown the survival data at five years is comparable to bypass for high-risk patients. Transmyocardial laser revascularization creates small channels into ischemic myocardium in an effort to enhance flow though studies have shown no improvement in prognosis over medical therapy alone. Enhanced external counterpulsation uses noninvasive pneumatic compression of the legs to improve diastolic filling of the coronary vessels and promote development of collateral flow. The compressor regimen requires thirty-five hours of therapy over a seven-week treatment period. Therapeutic angiogenesis requires injection of cytokines to promote neovascularization and improve myocardial perfusion into the regions affected by chronic ischemia. Phase 3 trials are pending. High thoracic epidural blockade produces a rapid and potent sympatholysis, coronary vasodilation and reduced myocardial oxygen demand in refractory coronary disease. This technique can be used as an adjunct to bypass surgery or medical therapy in chronic or acute unstable angina. Epidurals are easy to perform and often available for outpatient or inpatient use. The rapid anti-ischemic effect may complement therapeutic angiogenesis or other interventions with delayed onset to clinical benefit. A new era for interventional and implant cardiology is beginning to emerge as more clinicians, including cardiologists, gradually learn new procedures to safely provide more therapeutic options for patients suffering refractory angina.

Myocardial dystrophy in camel calves in the United Arab Emirates (field cases)

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Intoxication volontaire à l'urapidil: A propos d'une observation

Mixed antihypertensive drug intoxication poses a significant risk for patient mortality. In tandem to antihypertensives, hypolipidemic medicines (especially statins) are often prescribed. Among their well-known adverse effects belongs rhabdomyolysis. We report a case of fatal multi-drug overdose in a 65-year-old female alcoholic. The patient was unconscious at admission. Empty blister packs indicated the abuse of 250 tablets of urapidil, 42 tablets of verapamil/trandolapril, 50 tablets of moxonidin, 80 tablets of atorvastatin and 80 tablets of diacerein. Standard measures (gastric lavage, activated charcoal, mechanical ventilation, massive doses of vasopressors, volume expansion, diuretics and alkalinization) failed to provide sufficient drug elimination and hemodynamic support and the sufferer deceased on the fourth day. Dramatic elevations of serum myoglobin (34,020 μg/L) and creatine kinase (219 μkat/L) were accompanied by rise in cardiac troponin I and creatinine. Gas chromatography revealed ethanol 1.17 g/kg (blood) and 2.81 g/kg (urine). Thin layer chromatography and gas chromatography of gastric content and urine verified verapamil, moxonidin and urapidil fragment (diacerein method was unavailable). Atorvastatin and trandolapril concentrations (LC-MSn) equaled 277.7 μg/L and 57.5 μg/L, resp. (serum) and 8.15 μg/L and 602.3 μg/L, resp. (urine). Histology confirmed precipitates of myoglobin with acute necrosis of proximal renal tubules in association with striated muscle rhabdomyolysis and myocardial dystrophy. Cardiogenic-distributive shock in conjunction with acute renal failure due to the combined self-poisoning with vasoactive agents and atorvastatin were determined to be this decedent's immediate cause of death. The manner of death was assigned to be suicidal.

The athlete's heart: is big beautiful?

Development of the concept of "athlete's heart" is traced through early clinical and radiographic studies to modern echocardiography and magnetic resonance imaging. It is noted that the lower limits of criteria for the diagnosis of a "pathological" enlargement of the heart have frequently been revised in an upward direction, as the prevalence of large hearts has been recognised in both endurance and power sports competitors who are in good health. Belief that hypertrophic cardiomyopathy is the commonest cause of sports related death in young adults is traced to weak diagnostic criteria and frequent republication of a very small group of cases. Although the existence of a congenital myocardial dystrophy is now well established, this condition is extremely rare, and has no particular predilection for athletes. Genetically based screening tests may become available in the future, but the exclusion of young adults from sports participation on echocardiographic criteria appears costly and ineffective. For most people, the development of a large heart is not a pathological sign--rather, it is a desirable outcome that will enhance performance on the sports field, and will allow longer independence in old age.

Diminished release of atrial natriuretic factor in calves with a total artificial heart.

Venous hypertension after total artificial heart (TAH) replacement, a common problem in humans as well as experimental animals, is thought to be related to reduced release of atrial natriuretic factor (ANF) due to atrial damage. To verify this hypothesis, we stimulated the release of ANF in 6 calves before (-7 days) and after TAH replacement (+25, +50, +80, and +100 days) by the rapid (+ = 10 min) infusion of 2 L of Ringer's solution. In normal calves (-7 days) this procedure induced a rise in plasma concentration of ANF from 18.5 +/- 12 to 31.6 +/- 12 pmol/L (p < 0.05). After TAH the ANF release continuously decreased (analysis of variance, p < 0.02). Thus, ANF increased by 9.8 +/- 9.3, 6.8 +/- 17.5, 0.4 +/- 5.2, and 0.5 +/- 3.2 pmol/L at days 25, 50, 80, and 100, respectively. The central venous pressure increased by 3.4 +/- 1.5 mm Hg (before TAH) and by 6 +/- 2.9 mm Hg (after TAH) during this procedure. A decrease in plasma concentrations of aldosterone, most likely due to extracellular volume expansion and a decrease in total protein plasma concentrations and in hematocrit due to the dilution of blood, was seen in each experiment. Necropsy demonstrated massive atrial dilatation and myocardial dystrophy with atrial fibrosis. ANF granules were present to a small extent in every calf. We conclude that rapid intravenous infusion is an adequate stimulus to release ANF in normal calves. After TAH implantation the release of ANF by high venous pressure declines although ANF granules are still present in the damaged atrial stumps. Therefore, the loss of stimulated ANF could contribute to the observed increase in venous pressure in TAH calves although other pathophysiologic mechanisms cannot be excluded.

Cardiac Electrophysiology in Duchenne Muscular Dystrophy: From Basic Science to Clinical Expression

Cardiac Electrophysiology in Duchenne Muscular Dystrophy. Duchenne muscular dystrophy is an X‐linked recessive neuromuscular disorder that involves striated muscle fibers (skeletal, cardiac), smooth muscle Fibers (vasculature), and nervous system (neurons of central brain and cortex). The Duchenne dystrophy gene has been identified on the Xp21 locus of the short arm of the X chromosome. Dystrophin, the protein product of the gene, is present on and limited to myogenic cells in every tissue tested except the central nervous system, and is absent or nearly so in Duchenne dystrophy. However, the function of dystrophin and the pathogenesis of Duchenne dystrophy remain unclear. There is convincing morphological (gross, histologic, ultrastructural) and metabolic evidence (positron emission tomography) that myocardial involvement is found initially in the posterobasal left ventricular wall (cardiac phenotype). This regional localization of myocardial dystrophy is believed to account for the distinctive 12‐lead scalar electrocardiogram (ECG). Abnormalities of cardiac rhythm and conduction have been reported in Duchenne muscular dystrophy, but the pathogenesis of the electrophysiologic disturbances has not been established. Two variables are relevant to cardiac electrophysiologic involvement in Duchenne dystrophy: (1) the small vessel coronary arteriopathy (medial hypertrophy, luminal narrowing); and (2) abnormalities that might originate in the specialized cardiac tissues. The role of the coronary arteriopathy is presently speculative, and it is not currently known whether dystrophin is normally present on the cell membrane of normal cardiac specialized tissues, and if so, whether those tissues are dystrophin deficient in Duchenne dystrophy. Animal models (mouse, cat, dog) have shed light on the pathogenesis of skeletal muscle and myocardial involvement, less so on involvement of cardiac specialized tissues. The determinants of calcium homeostasis in dystrophin‐deficient myogenic cells (skeletal or cardiac) is unclear, and the relationship between dystrophin deficiency, calcium homeostasis, cellular response and phenotypic expression in skeletal muscle and myocardium is imperfectly understood. The purpose of this report is to bring together current genetic, molecular biological, biochemical, histopathological, and clinical information from human Duchenne dystrophy and from animal models bearing on the electrophysiologic expressions of the neuromuscular disease. (J Cardiovasc Electrophysiol, Vol. 3, pp. 394–409, August 1992)

Method of objectification of post-mortem differential diagnosis of coronary heart disease, acute alcohol poisoning and alcoholic myocardial dystrophy

A mathematical program has been created to improve and objectify the differential diagnosis of coronary heart disease, alcoholic myocardial dystrophy and acute alcohol poisoning. More than 100 cases of sudden death were analyzed using computer technology. The advantages of the method are its simplicity and the possibility of using it in any forensic medical examination bureau and in pathoanatomical practice.

Effect of?-tocopherol on conditioned-reflex activity in adrenalin-induced myocardial dystrophy in rats

Adrenolytic heart defect (AHD) proceeds with the breaking of higher adaptational reactions, i.e. the change of latent period of conditioned active prevention reaction and arising of retrograde amnesia. alpha-Tocopherol--antioxidant prevents the breaking of conditioned reflex activity and sharply reduces the mortality rate in AHD. More effective is the prophylaxis of the brain function breaking and lethality.

Clinical application of subforms of creatine kinase MM and macro creatine kinases

The subforms of MM isozyme of creatine kinase (ATP:creatine N-phosphotransferase, EC 2.7.3.2, CK) in sera obtained from healthy adults and patients were determined by agarose gel isoelectric focusing (IEF). The patients were classified into six groups according to serum CK-MM activities and IEF patterns. The IEF spectra offered useful information on cell hyperplasia, augmented cell membrane permeability, cell destruction and release time of CK-MM in the circulation from the cells for diagnosis, progress observation and prognosis, especially in the cases of chronic hepatic diseases, acute myocardial infarction and muscular dystrophy. Macro CKs were also determined by IEF. Macro CKs could be completely distinguished from each other, and CK isozymes consisting of macro CK type 1 could be presumed by isoelectric points.

Effect of prostaglandin E2 on development of adrenalin-induced myocardial dystrophy

Effect of prostaglandin E2 on development of adrenalin-induced myocardial dystrophy

Influence of Riboxine, uridine, uridine-5'-monophosphate, and guanosine on experimental myocardial dystrophy

Influence of Riboxine, uridine, uridine-5'-monophosphate, and guanosine on experimental myocardial dystrophy

Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): A prospective study of 25 patients

The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium.

Alterations in regional myocardial metabolism, perfusion, and wall motion in Duchenne muscular dystrophy studied by radionuclide imaging.

Studies at necropsy have shown that the cardiomyopathy of Duchenne muscular dystrophy selects the posterobasal and contiguous lateral left ventricular (LV) walls as initial and primary sites of myocardial dystrophy in the absence of small-vessel coronary artery disease in these areas. The present investigation was designed chiefly to determine whether a myocardial metabolic abnormality could be identified in these same areas during a patient's life. Positron emission computed tomography was used to study regional LV metabolism with 18F 2-fluorodeoxyglucose, and metabolism and/or perfusion was studied with 13NH3. In addition, all subjects had the following performed: thallium-201 scans, technetium-99m multiple-gated equilibrium blood pool imaging, electrocardiograms, vectorcardiograms, and M mode and two-dimensional echocardiograms. 18F 2-fluorodeoxyglucose activity was selectively increased in the posterobasal and posterolateral walls of the left ventricle in 11 of 12 patients with technically adequate images, indicating accelerated regional exogenous glucose utilization. 13NH3 activity was selectively decreased in the same areas in 13 of 15 patients, indicating either a regional metabolic alteration in uptake and trapping, a reduction in regional blood flow, or both. These data identify a myocardial metabolic abnormality concentrated in specific segments of the LV free wall in living patients with Duchenne dystrophy.