glycogen and Cardiomyopathy--Hypertrophic

Danon disease is a rare X-linked dominant lysosomal disease due to the primary deficiency of lysosome-associated membrane protein 2 (LAMP2) gene. Cardiomyopathy, skeletal myopathy and mental retardation are the typical triad of Danon disease. More than 60 LAMP2 mutations have been reported. The molecular mechanism is defects in LAMP2 protein (due to LAMP2 mutation) which causes insidious glycogen accumulation in cardiac muscle cells and resulting in cardiac hypertrophy and electrophysiological abnormalities. However, there are significant differences between the male and female Danon disease patients with regard to clinical features and cardiac manifestations. The clinical symptoms are variable, from asymptomatic to sudden cardiac death. Wolff-Parkinson-White syndrome is more common in male than female patients. Hypertrophic cardiomyopathy is predominant in male patients, whereas the similar prevalence of hypertrophic and dilated cardiomyopathy in female patients. Male patients are diagnosed usually at teenage, whereas the diagnosis and events occurred approximately 15 years later in female than male patients. Heart transplantation is the reliable treatment once the occurrence of heart failure and should be considered as early as possible due to its rapid progression.

Topics: Cardiomyopathy, Hypertrophic; Echocardiography; Electrocardiography; Female; Glycogen; Glycogen Storage Disease Type IIb; Heart; Heart Transplantation; Humans; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Male; Mutation; Myocardium; Sex Factors; Wolff-Parkinson-White Syndrome

Topics: AMP-Activated Protein Kinases; Cardiomyopathy, Hypertrophic; Death, Sudden, Cardiac; Glycogen; Humans; Multienzyme Complexes; Mutation; Protein Serine-Threonine Kinases

To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.. We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function.. After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related.. rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment.

Topics: alpha-Glucosidases; Body Height; Body Weight; Cardiomyopathy, Hypertrophic; Child Development; Europe; Female; Glycogen; Glycogen Storage Disease Type II; Hearing Disorders; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Male; Muscle Hypotonia; Muscle, Skeletal; Respiration, Artificial; Treatment Outcome; United States

Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes.. Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure.. Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old.. This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.

Topics: alpha-Glucosidases; Cardiomyopathy, Hypertrophic; Genotype; Glycogen; Glycogen Storage Disease Type II; Humans; Muscle Hypotonia; Phenotype; Retrospective Studies; Treatment Outcome

Pompe disease, an autosomal recessive disorder caused by deficient lysosomal acid α-glucosidase (GAA), is characterized by accumulation of intra-lysosomal glycogen in skeletal and oftentimes cardiac muscle. The c.1935C>A (p.Asp645Glu) variant, the most frequent GAA pathogenic mutation in people of Southern Han Chinese ancestry, causes infantile-onset Pompe disease (IOPD), presenting neonatally with severe hypertrophic cardiomyopathy, profound muscle hypotonia, respiratory failure, and infantile mortality. We applied CRISPR-Cas9 homology-directed repair (HDR) using a novel dual sgRNA approach flanking the target site to generate a Gaa

Topics: alpha-Glucosidases; Animals; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen Storage Disease Type II; Humans; Infant; Mice; Muscle, Skeletal

Infantile-onset Pompe Disease (IOPD), caused by mutations in lysosomal acid alpha-glucosidase (Gaa), manifests rapidly progressive fatal cardiac and skeletal myopathy incompletely attenuated by synthetic GAA intravenous infusions. The currently available murine model does not fully simulate human IOPD, displaying skeletal myopathy with late-onset hypertrophic cardiomyopathy. Bearing a Cre-LoxP induced exonic disruption of the murine Gaa gene, this model is also not amenable to genome-editing based therapeutic approaches. We report the early onset of severe hypertrophic cardiomyopathy in a novel murine IOPD model generated utilizing CRISPR-Cas9 homology-directed recombination to harbor the orthologous Gaa mutation c.1826dupA (p.Y609*), which causes human IOPD. We demonstrate the dual sgRNA approach with a single-stranded oligonucleotide donor is highly specific for the Gaa

Topics: Age of Onset; alpha-Glucosidases; Animals; Cardiomyopathy, Hypertrophic; CRISPR-Cas Systems; Disease Models, Animal; Female; Gene Knock-In Techniques; Glycogen; Glycogen Storage Disease Type II; Humans; Infant; Male; Mice; Mice, Transgenic; Muscle Weakness; Muscle, Skeletal; Myocardium; RNA, Guide, Kinetoplastida

Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.

Topics: alpha-Glucosidases; Animals; Brain; Cardiomyopathy, Hypertrophic; Dependovirus; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Glycogen; Glycogen Storage Disease Type II; HEK293 Cells; Humans; Injections, Spinal; Male; Muscle Strength; Random Allocation; Single-Blind Method; Spinal Cord

Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in the GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 13 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of the Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates.

Topics: Adolescent; Adult; alpha-Glucosidases; Asian People; Base Sequence; Black or African American; Brazil; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Codon, Nonsense; Early Diagnosis; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Glycogen; Glycogen Storage Disease Type II; Humans; Infant; Male; Middle Aged; Muscle Hypotonia; Mutation, Missense; Sequence Analysis, DNA; Sequence Deletion; White People; Young Adult

The present investigation aimed to study the protective effect of intermittent normothermic cardioplegia in rabbit's hypertrophic hearts.. The parameters chosen were 1) the ratio heart weight / body weight, 2) the myocardial glycogen levels, 3) ultrastructural changes of light and electron microscopy, and 4) mitochondrial respiration.. 1) The experimental model, coarctation of the aorta induced left ventricular hypertrophy; 2) the temporal evolution of the glycogen levels in hypertrophic myocardium demonstrates that there is a significant decrease; 3) It was observed a time-dependent trend of higher oxygen consumption values in the hypertrophic group; 4) there was a significant time-dependent decrease in the respiratory coefficient rate in the hypertrophic group; 5) the stoichiometries values of the ADP: O2 revealed the downward trend of the values of the hypertrophic group; 6) It was possible to observe damaged mitochondria from hypertrophic myocardium emphasizing the large heterogeneity of data.. The acquisition of biochemical data, especially the increase in speed of glycogen breakdown, when anatomical changes are not detected, represents an important result even when considering all the difficulties inherent in the process of translating experimental results into clinical practice. With regard to the adopted methods, it is clear that morphometric methods are less specific. Otherwise, the biochemical data allow detecting alterations of glycogen concentrations and mitochondria respiration before the morphometric alterations should be detected.

Topics: Animals; Body Weight; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Glycogen; Heart; Heart Arrest, Induced; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Organ Size; Oxygen Consumption; Rabbits; Random Allocation; Statistics, Nonparametric

Cardiac dysfunction is a major cause of morbidity and mortality in patients with end-stage liver disease; yet the mechanisms remain largely unknown. We hypothesized that the complex interrelated impairments in cardiac structure and function secondary to progression of liver diseases involve alterations in signaling pathways engaged in cardiac energy metabolism and hypertrophy, augmented by direct effects of high circulating levels of bile acids. Biliary fibrosis was induced in male C57BL/6J mice by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) supplemented diet. After 3 weeks, mice underwent live imaging (dual energy x-ray absorptiometry [DEXA] scanning, two-dimensional echocardiography [2DE], electrocardiography, cardiac magnetic resonance imaging), exercise treadmill testing, and histological and biochemical analyses of livers and hearts. Compared with chow-fed mice, DDC-fed mice fatigued earlier on the treadmill, with reduced VO(2). Marked changes were identified electrophysiologically (bradycardia and prolonged QT interval) and functionally (hyperdynamic left ventricular [LV] contractility along with increased LV thickness). Hearts of DDC-fed mice showed hypertrophic signaling (activation of v-akt murine thymoma viral oncogene/protein kinase B [AKT], inhibition of glycogen synthase kinase-3beta [GSK3beta], a 20-fold up-regulation of beta myosin heavy chain RNA and elevated G(s)alpha/G(i)alpha ratio. Genes regulating cardiac fatty acid oxidation pathways were suppressed, along with a threefold increase in myocardial glycogen content. Treatment of mouse cardiomyocytes (which express the membrane bile acid receptor TGR5) with potent natural TGR5 agonists, taurochenodeoxycholic acid and lithocholic acid, activated AKT and inhibited GSK3beta, similar to the changes seen in DDC-fed mouse hearts. This provides support for a novel mechanism whereby circulating natural bile acids can induce signaling pathways in heart associated with hypertrophy.. Three weeks of DDC feeding-induced biliary fibrosis leads to multiple functional, metabolic, electrophysiological, and hypertrophic adaptations in the mouse heart, recapitulating some of the features of human cirrhotic cardiomyopathy.

Topics: Animals; Bile Acids and Salts; Bile Duct Diseases; Cardiomyopathy, Hypertrophic; Dicarbethoxydihydrocollidine; Disease Models, Animal; Fatigue; Fatty Acids; Fibrosis; Gene Expression; Glycogen; Heart; Male; Mice; Mice, Inbred C57BL; Myocardium; Oxygen Consumption; Phenotype; Receptors, Adrenergic, beta; Receptors, G-Protein-Coupled; Respiratory Function Tests; Signal Transduction

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder characterized by thickening of the heart and an increased incidence of sudden death. This study is aimed to determine the genetic cause of severe cardiac hypertrophy in an infant. An infant was assigned a diagnosis of ventricular preexcitation and severe biventricular HCM requiring septal myectomy. Genetic testing showed a novel heterozygous E506Q mutation of the adenosine monophosphate (AMP)-activated protein kinase (PRKAG2) gene. Endomyocardial biopsy samples did not demonstrate significant glycogen accumulation. Hypertrophic cardiomyopathy due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition.

Topics: AMP-Activated Protein Kinases; Cardiomyopathy, Hypertrophic; Electrocardiography; Glycogen; Humans; Infant; Male; Myocardium; Risk Factors

A 10-wk-old infant girl with severe hypertrophy of the septal and atrial walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the gamma2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMP-binding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; AMP-Activated Protein Kinases; Cardiomyopathy, Hypertrophic; Echocardiography; Electrocardiography; Fatal Outcome; Female; Glycogen; Glycogen Storage Disease; Humans; Infant, Newborn; Multienzyme Complexes; Mutation; Myocardium; Phosphorylase Kinase; Protein Serine-Threonine Kinases

Storage of glycogen is essential for glucose homeostasis and for energy supply during bursts of activity and sustained muscle work. We describe three siblings with profound muscle and heart glycogen deficiency caused by a homozygous stop mutation (R462-->ter) in the muscle glycogen synthase gene. The oldest brother died from sudden cardiac arrest at the age of 10.5 years. Two years later, an 11-year-old brother showed muscle fatigability, hypertrophic cardiomyopathy, and an abnormal heart rate and blood pressure while exercising; a 2-year-old sister had no symptoms. In muscle-biopsy specimens obtained from the two younger siblings, there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal.

Topics: Biopsy; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Codon, Nonsense; DNA Mutational Analysis; Exercise Tolerance; Female; Glucose Tolerance Test; Glycogen; Glycogen Storage Disease; Glycogen Synthase; Homozygote; Humans; Liver Glycogen; Male; Mitochondria; Muscle, Skeletal; Myocardium

Unexplained left ventricular hypertrophy often prompts the diagnosis of hypertrophic cardiomyopathy, a sarcomere-protein gene disorder. Because mutations in the gene for AMP-activated protein kinase gamma2 (PRKAG2) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy, we hypothesized that hypertrophic cardiomyopathy might also be clinically misdiagnosed in patients with other mutations in genes regulating glycogen metabolism.. Genetic analyses performed in 75 consecutive unrelated patients with hypertrophic cardiomyopathy detected 40 sarcomere-protein mutations. In the remaining 35 patients, PRKAG2, lysosome-associated membrane protein 2 (LAMP2), alpha-galactosidase (GLA), and acid alpha-1,4-glucosidase (GAA) genes were studied.. Gene defects causing Fabry's disease (GLA) and Pompe's disease (GAA) were not found, but two LAMP2 and one PRKAG2 mutations were identified in probands with prominent hypertrophy and electrophysiological abnormalities. These results prompted the study of two additional, independent series of patients. Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2. Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations. Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of two serum proteins.. LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon's disease) but can also present as a primary cardiomyopathy. The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation.

Topics: Adolescent; Adult; Aged; Algorithms; AMP-Activated Protein Kinases; Antigens, CD; Cardiomyopathy, Hypertrophic; Child; Diagnosis, Differential; Electrocardiography; Fabry Disease; Female; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type II; Humans; Hypertrophy, Left Ventricular; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Male; Middle Aged; Multienzyme Complexes; Mutation; Myocardium; Pedigree; Protein Serine-Threonine Kinases

Glycogen storage disease type II (Pompe's disease) is a rare inherited metabolic disorder, which often leads to infantile death from severe cardiomyopathy. This case of sudden death illustrates the features of the cardiac findings in the disorder, resulting from massive lysosomal accumulation of glycogen in the heart and other tissues. Pompe's disease should be considered in cases of unexplained infantile cardiomyopathy.

Topics: Biopsy; Cardiomyopathy, Hypertrophic; Death, Sudden, Cardiac; Echocardiography; Electrocardiography; Endothelium, Vascular; Fatal Outcome; Follow-Up Studies; Glycogen; Glycogen Storage Disease Type II; Humans; Infant; Lysosomes; Male; Radiography, Thoracic; Skin

A 14-year-old boy with mild mental retardation, myopathy, and nonobstructive hypertrophic cardiomyopathy (HCM) with clinical and histopathologic features consistent with lysosomal glycogen storage disease with normal acid maltase is described. The case illustrates the aggressive nature of the cardiomyopathy of this syndrome. This condition is associated with malignant ventricular arrhythmias, relentlessly progressive ventricular dilatation, dysfunction, and sudden death. It is important to recognize this unusual and malignant form of HCM to precipitate low early diagnosis by muscle biopsy. Patients with this condition would be excellent candidates for life-saving heart transplant as the myopathy and mental retardation are mild and nonprogressive. The underlying biochemical defect and mode of inheritance of this syndrome are unclear. However, a significant proportion are genetically related and thus, relatives may benefit from family screening.

Topics: Adolescent; Cardiomyopathy, Hypertrophic; Glucan 1,4-alpha-Glucosidase; Glycogen; Heart Failure; Humans; Intellectual Disability; Lysosomal Storage Diseases; Male; Syndrome

Topics: Animals; Carbohydrate Metabolism; Cardiomyopathy, Hypertrophic; Glycogen; Hydroxyl Radical; Lipid Peroxidation; Myocardium; Rats; Rats, Inbred Strains; Superoxides

We investigated the preventive effects of long-term treatment with the angiotensin converting enzyme inhibitor ramipril on myocardial left ventricular hypertrophy and capillary length density in spontaneously hypertensive rats. Rats were treated in utero and subsequently up to 20 weeks of age with a high dose (1 mg/kg per day) or with a low dose (0.01 mg/kg per day) of ramipril. Animals given a high dose of ramipril remained normotensive, whereas those given a low dose developed hypertension in parallel to vehicle-treated controls. At the end of the treatment period, converting enzyme activity in heart tissue was inhibited dose-dependently in the treated groups. Both groups revealed an increase in myocardial capillary length density together with increased myocardial glycogen and reduced citric acid concentrations. Left ventricular mass was reduced only in high dose- but not in low dose-treated animals. Our results demonstrate that early onset treatment with a converting enzyme inhibitor can induce myocardial capillary proliferation, even at doses too low to antagonize the development of hypertension or left ventricular hypertrophy. We hypothesize that potentiation of kinins is responsible for this effect, probably by augmenting myocardial blood flow, which is a well-known trigger mechanism of angiogenesis in the heart.

Topics: Administration, Oral; Age Factors; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Cardiomyopathy, Hypertrophic; Citrates; Citric Acid; Coronary Vessels; Dose-Response Relationship, Drug; Female; Glycogen; Hypertension; Hypertrophy; Maternal-Fetal Exchange; Microscopy, Electron; Myocardium; Peptidyl-Dipeptidase A; Pregnancy; Ramipril; Rats; Rats, Inbred SHR

Cardiac septal hypertrophy occurs after in utero ritodrine exposure. To assess the effect of septal hypertrophy on cardiac function we obtained M-mode echocardiograms on day 1 of life in 41 infants exposed to ritodrine and 22 control infants matched for gestational age. Mean duration of ritodrine exposure was 16.2 +/- 13.2 days (range 1 to 49 days). Disproportionate septal hypertrophy (DSH) was defined as an interventricular septal thickness/posterior wall thickness ratio (ST/PW) of greater than 1.3. Infants exposed to ritodrine in utero had DSH and increased right systolic time intervals compared with control values (P less than 0.05). A subgroup, those infants exposed for 2 weeks or longer, had not only DSH but also an absolute increase in septal thickness compared with control infants and infants exposed to ritodrine for less than 2 weeks. ST/PW correlated well with the duration of ritodrine exposure (r = 0.96); the longer the exposure the thicker the septum. Although all echocardiographic changes lasted for less than 3 months, we have no information regarding the effect on the fetus of maternal ritodrine exposure for longer than 7 weeks. Until such information is available, cardiac evaluation is recommended in neonates exposed to ritodrine in utero for longer than 7 weeks.

Topics: Cardiomyopathy, Hypertrophic; Echocardiography; Female; Glycogen; Heart Septum; Humans; Hypertension, Pulmonary; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Prenatal Exposure Delayed Effects; Ritodrine; Tachycardia

Macroscopically asymmetric hypertrophy of the interventricular septum is the characteristic change, though mild degrees can be seen in normal hearts and in combination with congenital or acquired heart disease. If asymmetric hypertrophy is severe, this alone characterises the condition. Concentric forms have, however, been described. At light microscopic level disarray and often extreme hypertrophy of myocardial fibres together with degenerative changes and interstitial fibrosis are typical. Overlap of individual features with 'ordinary' hypertrophy exists but if all criteria are considered in combination a high degree of diagnostic reliability can be achieved, frequently aided by severe accumulation of glycogen. In support semiquantitative studies will also be presented. The patterns of abnormal fibre arrangement differ in the two clinical types. In cases with obstruction the abnormal fibres are predominantly confined to the interventricular septum, whereas in cases without obstruction they are scattered focally throughout the ventricular walls. Unfortunately, these disturbances are not always present. Subdivisions based on histological changes by other workers will be mentioned. Brief reference will be made to experimental work that has shown that a possible endogenous mechanism may be operative in some of the patients with hypertrophic cardiomyopathy. It is concluded that the morphology of hypertrophic cardiomyopathy is sufficiently characteristic to separate it as a distinct entity and to ensure reliable diagnosis.

Topics: Cardiomyopathy, Hypertrophic; Glycogen; Heart Septum; Humans; Myocardium

A fragment of septum was removed for biopsy in 11 patients with obstructive cardiomyopathy who were undergoing surgery. Electron microscopi revealed an increase in the numbers of mitochondria, deposits of glycogen, and deforming fibrosis. As far as the components of muscle fibres are concerned, both lysis and synthesis of neosarcomeres are to be found, together with abnormalities of the Z band and disorientation of the myofibrils. The number and severity of these abnormalities were found to vary from patient to patient and also in different sections. Although these features are virtually constant in cases of obstructive cardiomyopathy, they are not specific for this condition; they are also found in cases of non-obstructive hypertrophic cardiomyopathy.

Topics: Cardiomyopathy, Hypertrophic; Fibrinolysis; Glycogen; Heart Ventricles; Humans; Mitochondria, Muscle; Myocardium; Myofibrils

Topics: Aortic Valve Insufficiency; Cardiomegaly; Cardiomyopathy, Hypertrophic; Glycogen; Histocytochemistry; Humans; Myocardium

Topics: Adolescent; Adult; Aged; Biopsy; Cardiomegaly; Cardiomyopathy, Hypertrophic; Child; Female; Glycogen; Heart Septum; Heart Ventricles; Humans; Intercellular Junctions; Male; Microscopy, Electron; Middle Aged; Mitochondria; Myocardium; Myofibrils; Ribosomes; Sarcoplasmic Reticulum

Topics: Adult; Aortic Valve Stenosis; Biopsy; Cardiomyopathy, Hypertrophic; Diagnosis, Differential; Glycogen; Heart Ventricles; Humans; Inclusion Bodies; Microscopy, Electron; Middle Aged; Mitochondria; Myofibrils

Topics: Adolescent; Adult; Cardiomyopathy, Hypertrophic; Cell Nucleus; Female; Glycogen; Heart Ventricles; Humans; Inclusion Bodies; Intercellular Junctions; Lysosomes; Male; Middle Aged; Mitochondria, Muscle; Myocardium; Myofibrils; Papillary Muscles; Ribosomes; Sarcolemma; Sarcoplasmic Reticulum

Topics: Acid Phosphatase; Beer; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Cobalt; Glycogen; Histocytochemistry; Humans; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Succinate Dehydrogenase

Topics: Adult; Biopsy; Blood Pressure; Cardiac Catheterization; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Edema; Female; Glycogen; Humans; Male; Microscopy; Microscopy, Electron; Microtubules; Middle Aged; Mitochondria; Myocardium; Sarcoplasmic Reticulum

Topics: Adolescent; Adult; Cardiomyopathy, Hypertrophic; Child; Female; Glycogen; Heart Ventricles; Humans; Male; Microscopy, Electron; Middle Aged; Muscle Proteins; Myofibrils

Topics: Adolescent; Adult; Cardiomyopathy, Hypertrophic; Cell Membrane; Child; Endocardium; Endoplasmic Reticulum; Female; Glycogen; Heart Ventricles; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Mitochondria, Muscle; Myocardium; Myofibrils