Idiopathic Restrictive Cardiomyopathy Research Articles

Himalayan P in a Toddler with Idiopathic Restrictive Cardiomyopathy with a Brief Electrocardiographic Review

Although Himalayan P waves are not uncommon in congenital heart diseases involving the tricuspid valve, it is rare in pediatric idiopathic restrictive cardiomyopathy. We are presenting one of the tallest P waves in literature, the Himalayan P in a toddler with idiopathic restrictive cardiomyopathy. Additionally, we reviewed the literature on the value of electrocardiograms in the evaluation of restrictive cardiomyopathy.

A novel FLNC variation associated with restrictive cardiomyopathy with an unusually long clinical course — A case report

Restrictive cardiomyopathy (RCM) is a rare disease with varied aetiology. It is characterized by restrictive ventricular physiology leading to diastolic dysfunction and heart failure. Although the genetic background of the disease is poorly understood, idiopathic RCM is primarily a genetic disease with rapid disease progression and a poor prognosis. We used a targeted cardiomyopathy gene panel to identify a novel heterozygous filamin-C (FLNC) variant, NM_001458.5: c.3551G>T; p.Gly1184Val, in a patient from India. Although there are no specific treatment guidelines, our patient was successfully treated with loop diuretics, oral anticoagulation and mineralocorticoid receptor antagonists. We believe that the early medical intervention improved the patient's quality of life and led to favourable disease progression. We describe a RCM phenotype with an unusually long clinical course demonstrating the disease's progressive nature for over 18 years, which is likely associated with this novel variant.Our report also outlines the importance of considering genetic testing early during the diagnostic workup of idiopathic RCM cases.

Imaging of Idiopathic Restrictive Cardiomyopathy: A Multimodality Approach.

Imaging of Idiopathic Restrictive Cardiomyopathy: A Multimodality Approach.

Atomic force microscopy identifies the alteration of rheological properties of the cardiac fibroblasts in idiopathic restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare disease characterized by increased ventricular stiffness and preserved ventricular contraction. Various sarcomere gene variants are known to cause RCM; however, more than a half of patients do not harbor such pathogenic variants. We recently demonstrated that cardiac fibroblasts (CFs) play important roles in inhibiting the diastolic function of cardiomyocytes via humoral factors and direct cell–cell contact regardless of sarcomere gene mutations. However, the mechanical properties of CFs that are crucial for intercellular communication and the cardiomyocyte microenvironment remain less understood. In this study, we evaluated the rheological properties of CFs derived from pediatric patients with RCM and healthy control CFs via atomic force microscopy. Then, we estimated the cellular modulus scale factor related to the cell stiffness, fluidity, and Newtonian viscosity of single cells based on the single power-law rheology model and analyzed the comprehensive gene expression profiles via RNA-sequencing. RCM-derived CFs showed significantly higher stiffness and viscosity and lower fluidity compared to healthy control CFs. Furthermore, RNA-sequencing revealed that the signaling pathways associated with cytoskeleton elements were affected in RCM CFs; specifically, cytoskeletal actin-associated genes (ACTN1, ACTA2, and PALLD) were highly expressed in RCM CFs, whereas several tubulin genes (TUBB3, TUBB, TUBA1C, and TUBA1B) were down-regulated. These results implies that the signaling pathways associated with cytoskeletal elements alter the rheological properties of RCM CFs, particularly those related to CF–cardiomyocyte interactions, thereby leading to diastolic cardiac dysfunction in RCM.

Abstract 14365: Interrogating Diastolic Dysfunction Using a Novel Stem Cell Model of Restrictive Cardiomyopathy

Introduction: Diastolic dysfunction is an important cause of morbidity and mortality in both children and adults. Unfortunately, investigation of new therapies is limited by a lack of in vitro models of diastolic dysfunction. Idiopathic Restrictive Cardiomyopathy (RCM) is a serious genetic condition in which children have an isolated defect in myocardial relaxation. Though some of the genetic lesions have been identified, there is still an incomplete understanding of the mechanisms that lead to diastolic dysfunction in this condition. Hypothesis: Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation. Methods: Patients with RCM and a known pathogenic sarcomeric mutation were identified through speaking with providers in our heart failure and cardiac transplant program. hiPSCs were derived from patient blood samples and differentiated into cardiomyocytes. Isogenic controls were generated using CRISPR-mediated homologous directed repair. Calcium handling, contraction kinetics, and resting tension of RCM hiPSC-CMs were compared to control hiPSC-CMs on substrates with defined stiffness using high-throughput quantitative imaging techniques. Results: hiPSC-CMs derived from a patient with a pathogenic mutation in troponin T (TNNT2) display prolonged calcium kinetics and relaxation times compared to controls, as well as increased resting tension. Conclusions: RCM hiPSC-CMs represent a novel model of diastolic dysfunction that can be interrogated on a high-throughput platform. We plan to use these cells to perform proteome-scale functional screens, providing a novel opportunity to discover previously unknown contributors to diastolic dysfunction.

Idiopathic Restrictive Cardiomyopathy in Children

Idiopathic Restrictive Cardiomyopathy in Children

Cardiac Fibroblasts Play Pathogenic Roles in Idiopathic Restrictive Cardiomyopathy.

Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation. Although several mutations were reported in some patients, no mutations were identified in cardiomyocyte expressing genes of other patients, indicating that pathological mechanisms underlying RCM could not be determined by cardiomyocytes only. Cardiac fibroblasts (CFs) are a major cell population in the heart; however, the pathological roles of CFs in cardiomyopathy are not fully understood.Methods and Results:This study established 4 primary culture lines of CFs from RCM patients and analyzed their cellular physiology, the effects on the contraction and relaxation ability of healthy cardiomyocytes under co-culture with CFs, and RNA sequencing. Three of four patients hadTNNI3mutations. There were no significant alterations in cell proliferation, apoptosis, migration, activation, and attachment. However, when CFs from RCM patients were co-cultured with healthy cardiomyocytes, the relaxation velocity of cardiomyocytes was significantly impaired both under direct and indirect co-culture conditions. RNA sequencing revealed that gene expression profiles of CFs in RCM were clearly distinct from healthy CFs. The differential expression gene analysis identified that several extracellular matrix components and cytokine expressions were dysregulated in CFs from RCM patients. The comprehensive gene expression patterns were altered in RCM-derived CFs, which deteriorated the relaxation ability of cardiomyocytes. The specific changes in extracellular matrix composition and cytokine secretion from CFs might affect pathological behavior of cardiomyocytes in RCM.

Diagnostic value of P-waves in children with idiopathic restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. Almost all RCM patients are reported to have abnormal P-waves due to atrial overloading. This study aimed to reveal the characteristics of the P-waves in RCM patients and to suggest the diagnostic index of RCM in children with a 12-lead electrocardiogram (ECG). We retrospectively investigated 17 ECGs of children with idiopathic RCM during the initial visit at 15 institutes in Japan between 1979 and 2013. The RCM group was divided into four groups based on the age (elementary school [ES] and junior high school [JHS] students) and inception of the diagnosis (abnormal ECG on school-heart-screening [e-RCM] and some cardiovascular symptoms [s-RCM]), the ES/e-RCM (n = 5), ES/s-RCM (n = 4), JHS/e-RCM (n = 4), and JHS/s-RCM (n = 4) groups. As an aged-match control group, school-heart-screening ECGs of 1st-grade ES students (16,770 students) and 1st-grade JHS students (18,126 students) from Kagoshima in 2016 were adopted. For a comparison between the groups, we used the effect size "Hedge's g" by calculating the mean and standard deviation of the two groups. An effect size of 0.8 (or above) had an overlap of 53% (or less). The effect sizes of the sum of the absolute values of the forward and backward amplitudes in lead V1 (P1 + P2 V1) was the largest, and the ES/e-RCM, ES/s-RCM, JHS/e-RCM, and JHS/s-RCM were 15.8, 22.1, 9.4, and 10.3, respectively. A P1 + P2 V1 > 200μV was able to rule in all RCM patients, thus, we proposed 200µV as the cutoff value for screening purposes. In conclusion, the P1 + P2 V1 in the school-heart-screening may be useful for detecting asymptomatic or early-stage RCM in school-age children.

Waitlist Mortality of Patients With Amyloid Cardiomyopathy who Are Listed for Heart Transplantation and Implications for Organ Allocation

Outcomes of patients with amyloid cardiomyopathy (ACM) undergoing heart transplantation have been reported, but there are scant data concerning the waitlist mortality (WLM) of these patients. The aim of this study was to investigate whether patients with ACM have higher waitlist mortality compared to those with other types of cardiomyopathies. We queried the United Network for Organ Sharing registry for all patients (age ≥ 18 years) listed for heart transplantation between 2008 and 2015. We compared patients with ACM to those with dilated cardiomyopathy (DCM) or idiopathic restrictive cardiomyopathy (RCM) for WLM and waitlist mortality or delisting for deterioration (WLM/D). We identified 306 patients with ACM, 183 with RCM and 8416 with DCM. Patients with ACM were older (ACM 61 vs RCM 49 vs DCM 51 years, P < .001), were more likely to be male (82% vs 60% vs 73%, P < .001) but less likely to be listed as status 1A (16% vs 18% vs 23%, P< .001). After adjusting for baseline characteristics, ACM was associated with increased risk of mortality and mortality/delisting compared with DCM (HR 2.03 [1.36-3.04], P = .001 for WLM; HR 2.07 [1.55-2.78], P < .001 for WLM/D) but not with other RCMs (HR 1.28 [0.54-3.02], P = .58 for WLM; HR 0.97 [0.56-1.69], P = .91 for WLM/D). Patients with ACM are listed with lower acuity and have higher waitlist mortality compared with those with dilated cardiomyopathies. Further studies are needed to identify whether special prioritization should be considered for patients with ACM listed for heart transplantation.

Cardiac Magnetic Resonance Imaging in Infiltrative Cardiomyopathy

Infiltrative cardiomyopathies are a wide spectrum of disorders characterized by deposition of abnormal substances in the myocardium. These have a varied etiology and can be idiopathic, familial, or secondary to systemic disorders. The infiltrative process primarily causes a diastolic dysfunction resulting in heart failure with preserved ejection fraction. Common infiltrative cardiomyopathies encountered are cardiac amyloidosis, sarcoidosis, Fabry disease, iron overload cardiomyopathy, endomyocardial fibrosis, and idiopathic restrictive cardiomyopathy. Early and accurate detection of cause of infiltration is very important to improve outcomes through disease-specific therapies. Cardiac magnetic resonance (CMR) plays an important role in the diagnosis, avoiding the need of invasive endomyocardial biopsy in many cases. The use of postcontrast late gadolinium enhancement and T1 and T2 mapping sequences in CMR is improving diagnosis of infiltrative cardiomyopathy. In this review, we highlight the role of CMR in detection of different types of infiltrative cardiomyopathy.

Idiopathic Restrictive Cardiomyopathy in Children and Young Adults

Idiopathic restrictive cardiomyopathy (IRC) is a rare condition characterized by reduced ventricular compliance. Children with IRC have poor outcomes with most patients proceeding to cardiac transplantation. We sought to analyze our institutional experience and assess contemporary outcomes for children with IRC. We reviewed the medical record for patients (<21 years old) evaluated for a primary diagnosis of IRC between 1975 and 2013 at our institution. Demographic, clinical, echocardiographic, and catheterization data were abstracted. The patients were divided into 2 groups comprising a historical cohort (HC) (diagnosis: 1975 to 1993, n = 8) and a contemporary cohort (CC) (diagnosis: 1994 to 2013, n = 12). Twenty children were identified with IRC (mean age at presentation 9.7 ± 6.5 years, 55% female). Mean length of follow-up was 6.5 ± 8.4 years (range 0.1 to 35.6 years). In the CC, 7 of 12 patients (58%) progressed to cardiac transplantation (mean age of 9 ± 4 years at transplant, mean interval from diagnosis of IRC: 1.5 ± 0.9 years). Overall survival was improved significantly in the CC compared with the HC (80% vs. 38%, p = 0.02), but transplantation free survival was no different between the CC and HC over 5 years (38% vs 38%, p = 0.65). In the CC, elevation of mitral valve Doppler E/e' ratio on echocardiography was associated with increased mortality (p = 0.01). In conclusion, IRC continues has a poor prognosis. Early referral for transplantation was associated with improved overall survival in the modern era. Patients with markedly elevated E/e' ratio may have increased risk of death.

Update on restrictive cardiomyopathy

Abstract Restrictive cardiomyopathy (RCM) is a rare form of heart muscle disease accounting for just 2 to 5% of paediatric cardiomyopathies. It is characterised by increased myocardial stiffness and restrictive filling pattern in to the left ventricle. Idiopathic RCM with no obvious identifiable cause is the most common form of the disease. RCM can also be a secondary manifestation of miscellaneous systemic conditions. Typical examples include infiltrative and storage disorders, systemic inflammatory diseases, tumors and drug toxicity. RCM-specific mutations have been identified in several genes encoding sarcomeric proteins. Patients with RCM have heart failure symptoms related to diastolic dysfunction. Unfortunately, there is no curative treatment for RCM and the prognosis is generally very poor. Cardiac transplantation is the only effective treatment. High risk of sudden cardiac death justifies early listing especially in symptomatic children. When making the diagnosis of RCM, it is crucial to rule out constrictive pericarditis which presents with a similar clinical and haemodynamic picture. Unlike RCM it can often be cured surgically.

Clinical features of idiopathic restrictive cardiomyopathy: A retrospective multicenter cohort study over 2 decades.

Idiopathic restrictive cardiomyopathy (RCMP) has not been fully understood because this disease is difficult to diagnose. The present study aimed to assess the clinical profile and outcome of idiopathic RCMP from a multicenter cohort.This investigation is a retrospective study of consecutive patients with idiopathic RCMP at 10 centers in Korea between 1990 and 2010. We evaluated the clinical characteristics of the patients and prognostic factors associated with mortality using multivariate Cox proportional hazards regression analyses.The study included 53 patients (26 men, 49.1%). During a median follow-up of 1.7 years, 17 patients (32.1%) died and 5 patients (9.4%) received a heart transplant. The 5-year survival rate of the overall patients was 64.4% ± 7.8%. In multivariable analyses, the predictors of mortality were tricuspid regurgitation (TR) ≥ moderate (hazard ratio [HR] 32.55, P < .001) and left ventricular end-diastolic diameter (LVEDD) (HR 0.85, P < .001).Idiopathic RCMP showed unfavorable prognosis. Advanced TR and lower LVEDD are independent adverse predictors of mortality in patients with idiopathic RCMP.

Structural consequences of mutations associated with idiopathic restrictive cardiomyopathy.

Idiopathic restrictive cardiomyopathy (RCM, MIM# 115210) is the least common type of cardiomyopathies, often of genetic origin. Recently we described a spectrum of variants-classified as pathogenic, likely pathogenic and variants of unknown significance-in 24 patients suffering from idiopathic RCM. Pathogenic variants, detected in half of the RCM cases, were found in sarcomeric and cytoskeletal genes that have a predominant role in the development of RCM. Here we have analyzed the structural consequences of these missense variants and predicted their effect on the function of three large groups of domains: intrinsically disordered regions (IDRs), fibronectin-type III (FnIII) domains, and immunoglobulin-like (Ig) domains. Our findings indicate that pathogenic mutations are likely to disrupt interdomain interfaces, interfere with protein interactions, and affect protein stability, potentially destabilizing the multi-domain architecture of myofibrils and leading to myocardial stiffness in patients with idiopathic 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.

An unusual ECG pattern in restrictive cardimyopathy

Restrictive cardiomyopathy is the least common type of primary cardiomyopathies. Electrocardiographic recording is abnormal in 99% of patients with RCM. Biatrial enlargement, obliquely elevated ST segment with notched or biphasic late peaking T waves are considered characteristic ECG finding. Significant ST depression with T inversion mimicking subendocardial ischemia has also been reported in patients with RCM and is even suggested as a predictor of sudden cardiac death. We noted a similar ECG pattern in a 16 yr girl with Idiopathic restrictive cardiomyopathy. Coronaries were normal, stress perfusion imaging did not show any perfusion defect. This diffuse resting ST depression with T inversion in precordial & inferior leads along with ST elevation in aVR was persistent for more than six months.

Pathobiology of cardiomyopathies: Experience at a Tertiary Care Center

Background: Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with varied pathology. Pathology data from India are scarce. Methods: A retrospective, descriptive study of autopsies, as well as endomyocardial biopsy specimens, was done of patients with cardiomyopathy. The clinical and pathological features are described. Results: There were 32 patients with dilated cardiomyopathy. Two were pediatric, and two had arrhythmogenic right ventricular cardiomyopathy. Myocarditis was seen in 12 cases. In our endomyocardial biopsy data of 32 patients with restrictive cardiomyopathy (RCM), we found amyloid in 13 and idiopathic RCM in the remainder. Our genetic studies in cardiomyopathies suggest that the same genetic mutation may lead to different phenotypic manifestations with restrictive or hypertrophic cardiomyopathies in different families. Conclusions: This study gives insight into the pathology and etiology of some of the cardiomyopathies seen in India. They differ from the west, and now with the availability of genotyping and magnetic resonance imaging, more data should soon be available from more centers.

Clinical characterization of Idiopathic Restrictive Cardiomyopathy having rare variant (E949K) in β-cardiac myosin heavy chain gene

Background Idiopathic Restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) reflects the same or very similar disorders showing restrictive physiology with different names due to discretionary crosscuts in the LV wall thickness rather than two separate distinct diseases. The perspective of this study is to clinically evaluate the IRCM proband and comparison between the two distinct disease phenotype IRCM and HCM as an outcome of same genotype i.e.E949K in gene MYH7.

Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene

Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candidate gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chinese girl with restrictive cardiomyopathy. This study indicates that mutation in sarcomere protein genes may play an important role in idiopathic pediatric restrictive cardiomyopathy.

Idiopathic Restrictive Cardiomyopathy - Perspectives from Genetics Studies. Is It Time to Redefine These Disorders?

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in 33-66% of cases. Among these, the mutations most commonly involve TNNI3 and MYH7. There is a disproportionately high incidence of TNNI3 mutations in patients with restrictive physiology. De novo mutations are also frequently seen in this group of patients. IRC and hypertrophic cardiomyopathy (HCM) with restrictive phenotype reflect the same or very similar disorders with different names due to arbitrary cut offs in the left ventricular wall thickness rather than two separate distinct diseases. HCM with restrictive physiology should be considered part of a continuous spectrum with IRC. This is because patients with HCM with restrictive phenotype bear far greater clinical and genetic resemblance to IRC than to rest of the HCM cohort.