Development Of Restrictive Cardiomyopathy Research Articles

Endomyocardial fibrosis in a 7-year-old Nigerian child: a case report and review of the literature

<p>Endomyocardial fibrosis (EMF) is a poorly-understood idiopathic disorder characterized by the development of restrictive cardiomyopathy. It is a disorder of the tropics and subtropics and was once the second commonest cause of acquired heart disease in Nigeria. Its diagnosis is often made when the disease is advanced and the prognosis is invariably poor at this stage. Reports of EMF have become increasingly rare in recent years and it is frequently misdiagnosed. This report seeks to highlight EMF as a still present and potentially important cause of heart failure in Nigerian children. A 7-year-old male referred to the pediatric cardiology clinic with complaints of abdominal and facial swelling, with no difficulty in breathing and exercise intolerance. Examination revealed a classic “egg-on-stick” appearance. Apex was not displaced and heart sounds were distant. Liver was enlarged but non tender and there was demonstrable ascites. A 2D echocardiography showed massive right atrial enlargement with severe tricuspid regurgitation and fibrosis within the right ventricular cavity which was small. There was a moderate-sized pericardial effusion. Electrocardiogram showed right atrial enlargement with low-voltage complexes. Full blood count showed eosinophilia (20% total white blood cell count). Total serum protein and albumin were reduced. EMF, though increasingly rare, remains an important cause of childhood cardiac morbidity and mortality. A high index of suspicion is critical as the prognosis remains poor.</p><p> </p>

Molecular genetic features of the development of restrictive cardiomyopathy in Russian children

Aim. To identify the proportion of restrictive cardiomyopathy (RCM), as well as cardiomyopathy (CMP) with a restrictive type of hemodynamics among all cases of genetic CMP and to determine the relative frequencies and spectrum of nucleotide variants in Russian children with RCM, as well as to search for phenogenotypic correlations.Material and methods. The study included 689 children with CMPs. All children underwent a molecular genetic testing of the target regions of 419 genes responsible for various cardiomyopathies and channelopathies using the method of massively parallel sequencing (MPS).Results. In 668 (97,0%) children, pathogenic, likely pathogenic nucleotide variants, as well as nucleotide variants with unknown clinical significance, were identified. Of these, 45 (6,7%) patients were selected to determine the molecular genetic characteristics of RCM, 20 of whom had clinical symptoms and morphofunctional structure of RCMP (3,0%), while the remaining 25 (3,7%) children were diagnosed with another CMP type with a restrictive type of hemodynamics. In total, these patients had 41 nucleotide variants in 15 different genes, while 19 (46,3%) variants were pathogenic, 12 (29,3%) — likely pathogenic, 10 (24,4%) — uncertain clinical significance. Pathogenic and likely pathogenic variants were identified in a total of 38 (84,4%) patients, while in 19 (42,2%) patients, the pathogenic variants described earlier were found. The most common genetic marker of RCM in Russian children was TNNI3 gene mutations. In total, they were identified in 12 (25%) children: with RCP — 8 (40%) patients; with CMP with a restrictive type of hemodynamics — 4 (16%) patients. At the same time, the most common mutation of the TNNI3 gene was the nucleotide variant c.575G>A, leading to the amino acid variant p.R192H, described earlier in patients with RCM and identified by us in three (15%) unrelated children with RCM. In addition, a significant difference was found between the averaged values of N-terminal pro-brain natriuretic peptide in patients with mutations in the MYH7 and TNNI3 genes (0,0039, p<0,05), as well as between the peak flow gradient values in children with mutations in TNNI3 and FLNC genes (0,0016, p<0,05), TNNI3 and MYH7 genes (0,039, p<0,05).Conclusion. The results of this study indicate a significant genetic heterogeneity of RCM in Russian children and the need for further research aimed at finding genotype-phenotype associations in order to predict the course of the disease and select the proper therapy.

B2 Microglobulin and Bence Jones Proteinuria Guide the Diagnosis of Idiopathic AA Amyloidosis: A Journal to Diagnosis

Amyloidosis is a disease caused by the extracellular deposition of pathological insoluble fibrillary protein in multiple tissues and may result in severe organ dysfunction. There are two major forms of amyloidosis: AL amyloid and AA amyloidosis, which complicates any chronic inflammatory condition, including rheumatologic, chronic infections, and certain neoplasms. In small but increasing numbers, the chronic inflammatory state underlying AA amyloidosis remains obscure, despite extensive investigations, which are known as idiopathic. In the current case, the first extensive evaluation to determine the inflammatory disease was negative. The patient had B2 microglobulin elevation and Bence jones proteinuria, which are non-specific findings, but are not conclusive, for malignancies. The diagnosis of Idiopathic AA amyloidosis was guided by understanding the pathophysiology of B2 microglobulin and Bence jones proteinuria along with excluding all other etiologies. Unfortunately, the development of restrictive cardiomyopathy and ESRD within 3 months indicates a rapid progression and poor prognosis in this patient. Clinicians may not be familiar that B2 microglobulin and Bence jones proteinuria are also found in amyloidosis, which may delay the diagnosis. Inflammatory process and kidney injury due to AA amyloidosis caused previous markers positivity in our patient. It is plausible that delays in diagnosis may be multi-faceted and heavily influenced by the average age of the patient, the complexity and the rareness of the disease. Also, non-disease-specific symptoms may reduce the likelihood of a prompt diagnosis. Therefore, establishing the diagnosis is difficult, and early diagnosis requires high clinical suspicion.

Cardiovascular magnetic resonance in endomyocardial fibrosis

Endomyocardial fibrosis (EMF) is an idiopathic disorder of the tropical and subtropical regions of the world, considered endemic in tropical and subtropical Africa and is characterised by development of restrictive cardiomyopathy. Although accurate epidemiological data are lacking, EMF is estimated to be the most common form of restrictive cardiomyopathy globally. We report on a young patient presenting with a stroke diagnosed with EMF and review the role of cardiovascular magnetic resonance in evaluation of EMF.

Sudden death of an infant due to endocardial fibroelastosis - case report

Endocardial fibroelastosis (EFE) is an idiopathic disorder of the tropical and subtropical regions of the world that is characterized by the development of restrictive cardiomyopathy. It is characterized by proliferation of both elastic and collageneous fibers within the endocardium, causing diffuse or localized thickening. A three month old baby was admitted to a local hospital in Galle, with a history of sudden onset shortness of breathing for one day. Baby was found to be in a state of heart failure and died within few hours after admission. At the post-mortem examination, heart was found to be enlarged with dilated left ventricle. The endocardium of both ventricles was markedly thickened. Histopathology showed a thick layer of collagenous fibrous tissue and elastin fibres confirmed by Vangisen Elastin stain. The cause of death was given as endocardial fibroelastosis. The underlying mechanisms of myocardial fibrosis remain unclear. It is hypothesized that infectious, inflammatory and nutritional processes are involved in this process. This case highlighted the importance of special histology staining methods when arriving at the cause of death.

Dissection of Z‐disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach

BackgroundGenetic differences mediate individual differences in susceptibility to cardiomyopathy and severity of disease symptoms. Myopalladin (Mypn) is one of the genes associated with familial cardiomyopathies including dilated, hypertrophic and restrictive cardiomyopathy (RCM). Mutant knock‐in mice carrying the human Q529X‐MYPN mutation recapitulate the RCM phenotype the same as seen in the patients. The aim of this study was to investigate the regulation of Mypn and identify gene networks involved in RCM development.MethodsGene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomic data was collected from Mypn knock‐in and knock‐out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn gene pathway and evaluate co‐expression networks.ResultsWe found a wide range of expression variation in Mypn among the large cohort of BXD RI strains. Two upstream genetic loci, modulators of the expression of Mypn, have been identified on chromosomes 1 and 5. Candidate genes within those loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes that interact with Mypn, and constructed the Mypn gene network. Among them, well‐known cardiomyopathy‐associated genes such as Ldb3, Des, Actn2, Fhod3, Tpm2, and Syne1 were found to be members of this network. Several novel genes (Myo18b, Fhod3, Myom1, Bmp10, Myl4, Obscn, and Pdlim5) were also related to the Mypn network. In particular, two members (Syne1 and Myom1) have been confirmed at the protein level as high chance genes working as modifiers to induce cardiomyopathy.ConclusionsThrough a systematic genetic strategy we found several novel genes interacting with Mypn that may play an important role in the development of RCM. This work demonstrates that a systematic genetics approach is a powerful tool for constructing co‐expression networks that define the biological process categories within which similarly regulated genes function.Support or Funding InformationR01HL128350 (Lu L), R01 HL53392 and R01 HL087000 (Towbin JA)

Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice.

The E143K (Glu → Lys) mutation in the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans, but the mechanisms that underlie the development of defective cardiac function are unknown. Using transgenic E143K-RCM mice, we sought to determine the molecular and cellular triggers of E143K-induced heart remodelling. The E143K-induced abnormalities in cardiac function and morphology observed by echocardiography and invasive haemodynamics were paralleled by augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force. In vitro, E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility. E143K was also observed to reduce the level of myosin regulatory light chain phosphorylation while that of troponin-I remained unchanged. Small-angle X-ray diffraction data showed a decrease in the filament lattice spacing (d1,0) with no changes in the equatorial reflections intensity ratios (I1,1/I1,0) in E143K vs. WT skinned papillary muscles. The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals and these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction. Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes. Finally, proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands in E143K vs. WT hearts. As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM. Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling.

A Focused Review on the Pathophysiology, Diagnosis, and Management of Cardiac Amyloidosis

Amyloidosis is a systemic disorder that results from abnormal protein metabolism, producing amyloid fibrils that are subsequently deposited within vital organs. Cardiac involvement is typically associated with the specific subtypes of immunoglobulin lightchain, transthyretin, secondary amyloidosis, and dialysis-related amyloidosis. The hallmark of cardiac amyloidosis is the development of restrictive cardiomyopathy and heart failure, usually with a preserved left ventricular ejection fraction. The diagnosis is based on the integration of clinical signs and symptoms, echocardiography, cardiac magnetic resonance imaging, nuclear scintigraphy, electrocardiography, and cardiac biomarkers. Traditionally, management of heart failure symptoms and prevention of heart failure exacerbations have been the cornerstones of therapy. However, various treatments are currently under investigation that aim to eliminate or neutralize the underlying amyloidogenic substrate. Herein, we provide a focused review and discussion of the cardiovascular manifestations, epidemiologic and clinical characteristics, diagnostic modalities, and treatment strategies of cardiac amyloidosis.

Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach.

AIMTo investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in restrictive cardiomyopathy (RCM).METHODSGene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from Mypn knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn regulation, gene pathway and co-expression networks.RESULTSA wide range of variation was found in expression of Mypn among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of Mypn. Candidate genes within these loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes interacting with Mypn and constructed the gene network. Two novel members of this network (Syne1 and Myom1) have been confirmed at the protein level. Several members in this network are already known to relate to cardiomyopathy with some novel genes candidates that could be involved in RCM.CONCLUSIONUsing systematic genetics approach, we constructed Mypn co-expression networks that define the biological process categories within which similarly regulated genes function. Through this strategy we have found several novel genes that interact with Mypn that may play an important role in the development of RCM.

Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing.

BackgroundCardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis.Patients and MethodsWe used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification.ResultsPathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis.ConclusionsMultiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM.

How to recognize endomyocardial fibrosis?

Endomyocardial fibrosis is a disease of unknown cause, characterized by the development of restrictive cardiomyopathy. Although it is endemic in Africa, some cases have been described in Asia, South America and Europe, where a substantial unfamiliarity with this disease still exists. Moreover, differential diagnosis of endomyocardial fibrosis with other cardiomyopathies can be difficult, especially in asymptomatic patients and in initial stage of the disease. After initial echocardiographic analysis, the gold standard imaging technique is the cardiac magnetic resonance. Adjunctive diagnostic tools as endomyocardial biopsy can be considered in ambiguous cases and can help in patient management.

Insights into restrictive cardiomyopathy from clinical and animal studies

Cardiomyopathies are diseases that primarily affect the myocardium, leading to serious cardiac dysfunction and heart failure. Out of the three major categories of cardiomyopathies (hypertrophic, dilated and restrictive), restrictive cardiomyopathy (RCM) is less common and also the least studied. However, the prognosis for RCM is poor as some patients dying in their childhood. The molecular mechanisms behind the disease development and progression are not very clear and the treatment of RCM is very difficult and often ineffective. In this article, we reviewed the recent progress in RCM research from the clinical studies and the translational studies done on diseased transgenic animal models. This will help for a better understanding of the mechanisms underlying the etiology and development of RCM and for the design of better treatments for the disease.

Desensitizing Effect of N-terminal Truncated cTnI In RCM Myofibrils

Cardiac TnI (cTnI) mutations have been associated with the development of restrictive cardiomyopathy (RCM) characterized by a Ca2+ hypersensitivity and diastolic dysfunction in cardiac myofibrils. Whereas cTnI N-terminal deletion (cTnI-ND) caused by restricted proteolysis in cardiac adaptation to stress manifests a lower left ventricular end diastolic pressure and an enhanced ventricular diastolic function. By crossing the RCM cTnI R193H transgenic mice (cTnI193His) with cTnI-ND transgenic mice (cTnI-ND) that contain 100% cTnI-ND in the heart, we have obtained double TG mice containing both the cTnI R193H mutant and cTnI-ND. In this study, by using these TG mouse lines, we have investigated the desensitizing effect of cTnI-ND on the RCM cTnI mutant mice and myofibrils. Our survival data for these mice indicated that cTnI-ND greatly reduced the mortality of the RCM cTnI193His mice. Ca2+ sensitivity measured in skinned myofibrils confirmed that increased myofibril Ca2+ sensitivity was the major mechanism that resulted in impaired relaxation and diastolic dysfunction in RCM cTnI193His mice and that cTnI-ND could reverse the cellular dysfunction by desensitizing the myofibrils to Ca2+. The PKA stimulation assays showed that cTnI193His myofibrils were able to respond to PKA activation, resulting in a right-shift of pCa curve after PKA treatment. However, since the myofibrils from cTnI-ND hearts lacked Ser residues 23 and 24, they had no response to PKA stimulation, showing a similar pCa curve before or after PKA. Our data have, for the first time, demonstrated a desensitizing effect by an endogenous myofibril protein proteolysis without the intervention of β-adrenergic stimulation mediated cTnI phosphorylation. The desensitizing function in cTnI-ND hearts indicates that the removal of cTnI N-terminal extension by restricted proteolysis represents a novel mechanism to improve myofibril relaxation and cardiac diastolic function in cardiac adaptation to hemodynamic and inotropic stresses.

Effect of glutamine on doxorubicin-induced cardiotoxicity: an echocardiographic assessment.

Abstract Abstract #6143 Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent with a dose-dependent cardiotoxicity. Previous studies showed that dietary glutamine (GLN) reduced cardiac oxidative damages in rats treated with DOX through the increase of cardiac and blood glutathione, reduction of cardiac lipid peroxidation and reducing cardiac apoptosis. The present study aimed to examine further the effect of GLN on DOX-induced cardiac injury and to gain insight into the physiological aspects of this process by using high-resolution micro-ultrasound imaging and Doppler echocardiography.
 Materials and Methods: Female Fisher 344 rats (n=12) were randomized into 2 groups: (i) GLN-supplemented (n=6) and ii) controls (n=6). GLN-supplemented rats received 1g/kg/day GLN via gavage starting 1 week before DOX administration. DOX (12 mg/kg) was injected i.p. in all animals. Each animal was examined before DOX administration, 3 days, 7 days, and 10 days after DOX administration using ultrasound imaging system Vevo 770 (VisualSonics, Toronto, ON, Canada). RMVTM 716 "high frame" scan head, designed for real-time small animal imaging applications, was used. The short-axis imaging was taken in B-mode to view the left ventricle (LV) movement during diastole and systole. Anatomical M-mode was used to obtain LV measurements including LV end-diastolic and systolic inner diameters, LV posterior wall, LV ejection fraction (%EF) and LV fraction shortening (%FS). The LV filling was evaluated by pulsed-Doppler sampling of the mitral valve (MV) inflow. The peak E-wave velocity (E), peak A-wave velocity (A) and the MV E/A ratio were obtained. All data and images were saved and analyzed by Vevo 770 Analytic Software (VisualSonics, Toronto, ON, Canada).
 Results: Ten days after DOX treatment the control animals had: i) increased LV posterior wall end-diastolic thickness of an average from 1.7 mm before DOX administration to 1.8 mm and end-systolic from 2.9 mm to 3.7 mm; ii) reduction of the %EF by 10% and %FS by 14%; and iii) increased MVE by 30% with a resulting MVE/A ratio >2.0; all these suggestive of the development of restrictive cardiomyopathy (RCM). RCM, characterized by thickening and increased rigidity of the endocardium due to infiltration and fibrosis, restrictive ventricular filling with MVE/A >2.0 and in some cases reduction of the EF, has been reported in several clinical studies of patients treated with DOX. In GLN-supplemented rats of this study there was no statistically significant difference between posterior wall thickness before and after DOX administration, MVE/A ratio was maintained between 1.4 and 1.8; and EF was reduced by 2% only.
 Conclusions: The results from this study are in agreement with our previous data showing that GLN is able to reduce cardiac oxidative damages caused by DOX. This data further confirmed the safety of GLN supplementation and its cardioprotective effects during chemotherapeutic treatment with DOX.
 Acknowledgements: This work was supported by a grant from Susan G. Komen to VKT. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6143.

Abstract 843: Restrictive Cardiomyopathy Linked cTnI Mutation (K178E) Causes Severe Heart Failure and Early Mortality

Multiple mutations in cardiac troponin I (cTnI) have been linked to the development of restrictive cardiomyopathy (RCM) in human patients. Among them, K178E mutation has the worst clinical phenotype. K178E mutation may influence the inhibitory function through actin binding since previous studies have shown that amino acids number 173–181 bind to actin and increase the inhibitory effect of TnI. We modeled the mutation of lysine 178→glutamate (K178E) in human cTnI by cardiac specific expression of the mutated protein (cTnI 179Glu in mouse sequence) in transgenic mice. Multiple lines were generated with varying degrees of expression to establish a dose relationship. Increased resting tension in isolated cardiac myocytes and decreased myofibrillar compliance were the main manifestations in cellular function measurements. In vivo cardiac function measured by high-resolution ultrasonic imaging and Doppler echocardiography revealed a significant diastolic dysfunction characterized with decrease of left ventricular end diastolic dimension (LVEDD), decreased cardiac ejection fraction (EF) and left ventricular faction of shortening (FS) as well as a decreased cardiac output (CO). Doppler measurements showed a restrictive left ventricular filling pattern, i.e. reversed E/A ratio; decreased deceleration time (DT); decreased isovolumic relaxation time (IVRT). Enlarged left and right atria was a dramatic sign, which was observed in most of the transgenic mice, and was developed early and fast (at age of 2–3 weeks). Severely affected lines developed a pathology similar to that observed in human restrictive cardiomyopathy patients who carry the same mutation and with a high early mortality. Our data indicate the causality of this mutation for diastolic dysfunction and heart failure and provide a useful animal model for further understanding the thin filament structure-function relationships and the physiological function of triponin in cardiac contraction and relaxation. (Supported by NIH GM073621 and AHA0715116B) This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).

A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice

Cardiac troponin I (cTnI) mutations have been linked to the development of restrictive cardiomyopathy (RCM) in human patients. We modeled one mutation in human cTnI C-terminus, arginine192 → histidine (R192H) by cardiac specific expression of the mutated protein (cTnI 193His in mouse sequence) in transgenic mice. Heart tissue sections revealed neither significant hypertrophy nor ventricular dilation in cTnI 193His mice. The main functional alteration detected in cTnI 193His mice by ultrasound cardiac imaging examinations was impaired cardiac relaxation manifested by a decreased left ventricular end diastolic dimension (LVEDD) and an increased end diastolic dimension in both atria. The cardiac ejection fraction (EF) was not significant changed in 6- to 8-week-old cTnI 193His mice, however, the EF was significantly decreased in cTnI 193His mice at age of 11 months. These data indicate that individual genetic conditions and environmental factors participate together in the development of the cTnI mutation based-cardiac muscle disorders. This mouse model provides us with a tool to further investigate the pathophysiology and the development of RCM.