Restrictive Cardiomyopathy Patients Research Articles

Whole exome sequencing identifies variants in the \(\textit{TNNI3}\) gene in vietnamese patient with restrictive cardiomyopathy - a case report

Restrictive cardiomyopathy (RCM) is a rare heart muscle disease in which the heart wall is rigid leading to diastolic dysfunction caused by abnormal elastic properties of the myocardium and/or intercellular matrix. The prognosis is generally poor, and RCM has a high mortality rate in pediatric patients. There are no curative treatments for RCM, so cardiac transplantation is the only effective treatment. Diagnosis RCM, clinical diagnosis can be challenging because clinical presentations and imaging manifestations of RCM are similar to other cardiomyopathies so it requires other specific diagnoses. Currently, pathogenic mutations in 22 different genes have been identified in patients with RCM. Identifying mutations in these genes helps discriminate RCM from other cardiomyopathies. Besides, next-generation sequencing (including whole genome sequencing, whole exome sequencing,...) has provided an effective tool for simultaneously analyzing mutations in many different genes. In this study, we conducted sequencing of the entire gene coding region (WES) in the patient and identified a compound heterozygote variants (c.289C>G, p.Arg97Gly and c.433C>T, p.Arg145Trp) in the TNNI3 gene. These variants were inherited from the patient's father and mother, who were heterozygous variant carriers. These variants were also identified as the pathogenic variants in the ClinVar database (accession number VCV001331910.2 and VCV000012426.28, respectively) and were the cause of the patient's disease. Our results suggest that WES can be used to definitively diagnose the genetic variants associated with RCM and show that genetic screening is essential for families of RCM patients.

Association of Pulmonary Transit Time and Pulmonary Blood Volume From First-Pass Perfusion Cardiac MRI With Diastolic Dysfunction and Left Ventricle Deformation in Restrictive Cardiomyopathy.

Patients with restrictive cardiomyopathy (RCM) have impaired diastolic filling and hemodynamic congestion. Pulmonary transit time (PTT) and pulmonary blood volume index (PBVi) reflect the hemodynamic status, but the relationship with left ventricle (LV) dysfunction remains unclear. To evaluate the PTT and PBVi in RCM patients, the association with diastolic dysfunction and LV deformation, and the effects on the occurrence of major adverse cardiac events (MACE) in RCM patients. Retrospective. 137 RCM patients (88 men, age 58.80 ± 10.83 years) and 68 age- and sex-matched controls (46 men, age 57.00 ± 8.59 years). 3.0T/Balanced steady-state free precession sequence, recovery prepared echo-planar imaging sequence, and phase-sensitive inversion recovery sequence. The LV function and peak strain (PS) parameters were measured. The PTT was calculated and corrected by heart rate (PTTc). The PBVi was calculated as the product of PTTc and RV stroke volume index. Chi-squared test, student's t-test, Mann-Whitney U test, Pearson's or Spearman's correlation, multivariate linear regression, Kaplan-Meier survival analysis, and Cox regression models analysis. A P-value <0.05 was considered statistically significant. The PTTc showed a significant correlation with the E/A ratio (r = 0.282), and PBVi showed a significant correlation with the E/e' ratio, E/A ratio, and diastolic dysfunction stage (r = 0.222, 0.320, and 0.270). PTTc showed an independent association with LVEF, LV circumferential PS, and LV longitudinal PS (β = 0.472, 0.299, and 0.328). In Kaplan-Meier analysis, higher PTTc and PBVi were significantly associated with MACE. In multivariable Cox regression analysis, PTTc was a significantly independent predictor of the MACE in combination with both cardiac MRI functional and tissue parameters (hazard ratio: 1.23/1.32, 95% confidence interval: 1.10-1.42/1.20-1.46). PTTc and PBVi are associated with diastolic dysfunction and deteriorated LV deformation, and PTTc independently predicts MACE in patients with RCM. 3 TECHNICAL EFFICACY: Stage 2.

Effects of diabetes mellitus on left ventricular function and deformation in patients with restrictive cardiomyopathies: a 3.0T CMR feature tracking study

BackgroundDiabetes mellitus (DM) is the most common metabolic disease worldwide and a major risk factor for adverse cardiovascular events, while the additive effects of DM on left ventricular (LV) deformation in the restrictive cardiomyopathy (RCM) cohort remain unclear. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients with RCM.Materials and methodsOne hundred thirty-six RCM patients without DM [RCM(DM−)], 46 with DM [RCM (DM+)], and 66 age- and sex-matched control subjects who underwent cardiac magnetic resonance (CMR) scanning were included. LV function, late gadolinium enhancement (LGE) type, and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured. The determinant of reduced LV global myocardial strain for all RCM patients was assessed using multivariable linear regression analyses. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between DM and decreased LV deformation.ResultsCompared with the control group, RCM (DM−) and RCM(DM+) patients presented increased LV end-diastolic index and end-systolic volume index and decreased LV ejection fraction. LV GPS in all three directions and longitudinal PDSR progressively declined from the control group to the RCM(DM−) group to the RCM(DM+) group (all p < 0.05). DM was an independent determinant of impaired LV GPS in the radial, circumferential, and longitudinal directions and longitudinal PDSR (β = − 0.217, 0.176, 0.253, and − 0.263, all p < 0.05) in RCM patients. The multiparameter combination, including DM, showed an AUC of 0.81(95% CI 0.75–0.87) to predict decreased LV GLPS and an AUC of 0.69 (95% CI 0.62–0.76) to predict decreased LV longitudinal PDSR.ConclusionsDM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients, indicating the importance of early identification and initiation of treatment of DM in patients with RCM.

Abstract 16843: Diastolic Dysfunction Due to Structual Changes in Mutant Troponin I May Cause Restrictive Cardiomyopathy; Cryo-Electron Microscopic Analysis Using Induced Pluripotent Stem Cell Derived Cardiomyocytes

Introduction: Restrictive cardiomyopathy (RCM) is characterized by ventricular diastolic dysfunction with preserved contraction. Since there is no effective treatment other than heart transplantation, the development of novel treatment strategy by elucidating pathophysiology of RCM is an important issue under the serious donor shortage.Various troponin I mutations have been reported in patients with RCM and given that troponin I regulates the inhibition of cardiac contraction, it is possible that structural changes in mutant troponin I cause diastolic dysfunction in RCM. Recently, cryo-electron microscopy (cryo-EM) has made it possible to analyze the structure of thin filaments of muscle fibers. In this study, we applied the technology of induced pluripotent stem cell (iPSC) to cryo-EM structural analysis of thin filaments in cardiomyocytes from RCM patients with troponin I mutations. Methods: We established an iPSC line from a pediatric RCM patient with heterozygous TNNI3 mutation (R170W). Then the iPSCs were differentiated to cardiomyocytes to compare the cellular physiological, structural features. Normal adult iPS cell derived cardiomyocytes (Ctrl-iPSC-CM) were used as control. We also extracted thin filaments from iPSC-CMs and analyzed their structure with cryo-EM. Results: PCR analysis revealed the percentage of mutant alleles in TNNI3 mRNA was about 80% in the differentiated RCM-iPSC-CM, which was similar to the results in the myocardium of the same patient. The RCM-iPSC-CM demonstrated slower diastolic rate and longer diastolic time by cell motion analyses than Ctrl-iPSC-CM. Immunostaining showed a disarrayed sarcomeres in the RCM-iPSC-CM. Tthe structure of the thin filaments extracted from the RCM-iPSC-CMs observed with cryo-EM was close to that in the presence of calcium (contractile myocardium), even though the filaments were purified in the absence of calcium. Conclusions: The iPSC-derived cardiomyocytes could effectively represent the diastolic dysfunction of RCM. The structures of thin filaments were possibly explained for the phenotype of restrictive cardiomyopathy.

Clinical features, etiology, and survival in patients with restrictive cardiomyopathy: A single-center experience.

Numerous prognostic factors have been proposed for cardiac amyloidosis (CA). The knowledge about other subtypes of restrictive cardiomyopathy (RCM) is scant. This study aimed to elucidate the etiology and prognostic factors of RCM as well as assess cardiac biomarkers: high-sensitive troponin T (hs-TnT), growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2, as mortality predictors in RCM. We enrolled 36 RCM patients in our tertiary cardiac department. All patients were screened for CA. Genetic testing was performed in 17 patients without CA. Pathogenic or likely pathogenic gene variants were found in 86% of patients, including 5 novel variants. Twenty patients died, and 4 had a heart transplantation during the study. Median overall survival was 29 months (8-55). The univariate Cox models analysis indicated that systolic and diastolic blood pressure, GDF-15, hs-TnT, NT-proBNP, left ventricular stroke volume, the ratio of the transmitral early peak velocity (E) estimated by pulsed wave Doppler over the early mitral annulus velocity (e'), tricuspid annulus plane systolic excursion, early tricuspid valve annular systolic velocity, the presence of pulmonary hypertension, and pericardial effusion influenced survival (P <0.05). A worse prognosis was observed in patients with GDF-15 >1316 pg/ml, hs-TnT >42 ng/l, NT-proBNP >3383 pg/ml, and pericardial effusion >3.5 mm (Kaplan-Meier analysis, log-rank test, P <0.001). Genetic testing should be considered in every RCM patient where light-chain amyloidosis has been excluded. Survival remains poor regardless of etiology. Increased concentrations of GDF-15, hs-TNT, NT-proBNP, and pericardial effusion are associated with worse prognosis. Further studies are warranted.

Abstract P1042: Stem Cell Models Reveal Sarcomere Inhibition As A Potential Treatment For Pediatric Restrictive Cardiomyopathy

Introduction: Pediatric Restrictive Cardiomyopathy (RCM) is a genetic cardiomyopathy resulting from profoundly increased stiffness of the wall of the cardiac ventricle with normal or low normal contractility. Treatment options are limited, with most patients necessitating heart transplant. Therapies that can improve diastolic function are needed for this severe disease. Recently, direct inhibition of the sarcomere with mavacamten, a cardiac myosin antagonist, has been shown to be effective in treating a related disease, Hypertrophic Cardiomyopathy (HCM), in adults. However, whether it would be useful for the diastolic dysfunction seen in RCM is unknown. Hypothesis: Treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients with mavacamten will rescue diastolic deficits. Methods: Cardiomyocytes were differentiated from induced pluripotent stem cells (iPSCs) originally derived from a pediatric patient with RCM, as well as a paired isogenic CRISPR-corrected line. Cells were treated with increasing doses of mavacamten and contractility and resting tension were measured using a novel traction force microscopy platform. Results: At baseline, RCM cells showed elevated contractility, resting tension, and calcium sensitivity compared to their isogenic control. Mavacamten treatment decreased both contractility and resting tension of RCM cardiomyocytes. Conclusions: Mavacamten improves both systolic and diastolic derangements in an hiPSC model of RCM.

Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) are characterized by thickening, thinning, or stiffening, respectively, of the ventricular myocardium, resulting in diastolic or systolic dysfunction that can lead to heart failure and sudden cardiac death. Recently, variants in the ACTN2 gene, encoding the protein α-actinin-2, have been reported in HCM, DCM, and RCM patients. However, functional data supporting the pathogenicity of these variants is limited, and potential mechanisms by which these variants cause disease are largely unexplored. Currently, NIH ClinVar lists 34 ACTN2 missense variants, identified in cardiomyopathy patients, which we predict are likely to disrupt actin binding, based on their localization to specific substructures in the α-actinin-2 actin binding domain (ABD). We investigated the molecular consequences of three ABD localized, HCM-associated variants: A119T, M228T and T247 M. Using circular dichroism, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all three mutations are destabilizing, suggesting a structural disruption. Importantly, A119T decreased actin binding, and M228T and T247M cause increased actin binding. We suggest that altered actin binding underlies pathogenesis for cardiomyopathy mutations localizing to the ABD of α-actinin-2.

Abstract 15247: A Novel Patient-Derived Stem Cell Model of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary to Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Abstract P2113: A Novel Patient-derived Stem Cell Model Of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary To Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Left ventricular strain-curve morphology to distinguish between constrictive pericarditis and restrictive cardiomyopathy.

AimsTo distinguish between constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) using cardiac magnetic resonance feature tracking (CMR‐FT) left ventricle (LV) diastolic time–strain curve patterns and myocardial strain.Methods and ResultsA total of 32 CP patients, 27 RCM patients, and 25 control subjects were examined by CMR‐FT and analysed for global strain, segmental strain, and LV time–strain curve patterns in the longitudinal, circumferential, and radial directions. Speckle tracking echocardiography (STE) strain imaging was performed in some cases. The peak global longitudinal strain (GLS) and global circumferential strain (GCS) of the RCM group were lower than those of the CP group. GLS [median (interquartile range) CP vs. RCM: −11.15 (−12.85, −9.35) vs. −6.5 (−8.75, −4.85), P < 0.001] and GCS (CP vs. RCM: −16.89 ± 5.11 vs. −13.37 ± 5.79, P < 0.001). In circumferential and radial directions, the strain ratios of the LV lateral/septal wall (LW/SW) of the CP group were significantly lower than those of the RCM group at the basal and mid segments. The CS ratio of LW/SW at the basal segment [CP vs. RCM: 0.95 (0.85, 1.25) vs. 1.43 (1.18, 1.89), P < 0.001] and mid segment [CP vs. RCM: 1.05 (0.92, 1.15) vs. 1.18 (1.06, 1.49), P = 0.026]. The RS ratio of LW/SW at the basal segment [CP vs. RCM: 0.97 (0.76, 1.37) vs. 1.55 (1.08, 2.31), P = 0.006] and mid segment [CP vs. RCM: 0.95 (0.70, 1.28) vs. 1.79 (1.32, 2.92), P < 0.001]. In the longitudinal and circumferential directions, the characteristic ‘plateau’ pattern of time–strain curves could be seen in the CP but not in the RCM during the diastole. The GCS ratio of 0–50%/50–75% diastolic period of the CP was higher than that of the RCM [CP vs. RCM: 17.01 (8.67, 23.75) vs. 5.38 (1.93, 11.24), P = 0.001], while the GCS ratio of 50–75%/75–100% diastolic period was lower than that of the RCM [CP vs. RCM: 0.36 (0.15, 1.67) vs. 1.12 (0.70, 5.58), P < 0.001]. The peak GLS (sensitivity, 85%; specificity, 78%) and the GCS ratio of 0–50%/50–75% diastolic period (sensitivity, 88%; specificity, 73%) had higher differential diagnosis value.ConclusionsThe CMR‐FT could distinctly differentiate CP from RCM based on LV myocardial strain and LV time–strain curve patterns. The characteristic ‘plateau’ pattern of the time–strain curve is specific for CP and not RCM and this curve can also be duplicated by STE.

Clinical characteristics of hypertrophic cardiomyopathy and restricted cardiomyopathy patients complicating with intracardiac thrombosis

Objective: To investigate the clinical characteristics of patients with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) complicating with intracardiac thrombosis. Methods: This is a retrospective observational study. Consecutive patients diagnosed with HCM or RCM and complicated with intracardiac thrombosis (including left and right atrium or ventricular thrombosis), who were admitted to the Heart Failure Care Unit of Fuwai Hospital, Chinese Academy of Medical Sciences, from September 2008 to September 2018, were enrolled in this study. Patients with myocardial infarction were excluded. The general clinical data of the enrolled patients, including demographic data, major complications, laboratory indicators, echocardiographic indicators, drug application and distribution of intracardiac thrombosis, were collected from electronic medical record system and analyzed. Results: A total of 98 patients were enrolled in this study, including 52 patients (53.1%) with HCM and 46 patients (46.9%) with RCM. The most common comorbidity was atrial fibrillation/flutter: 40 patients (76.9%) in HCM group and 36 patients (78.3%) in RCM group. Majority of patients received oral anticoagulants treatment: 43 patients (82.7%) in HCM group and 35 patients (76.1%) in RCM group. Intracardiac thrombosis was mainly located in the left atrium in both HCM group (39 cases (75.0%)) and RCM group (32 cases (69.6%)). Thrombosis was found in ≥ 2 chambers in 7 patients (7.1%). Rate of left atrial thrombosis was the highest (81.6% (62/76)) in HCM and RCM patients complicating with atrial fibrillation/flutter. Intra-aneurysmal thrombosis occurred in 4 out of 5 patients complicated with apical left ventricular aneurysm. The rate of left ventricular thrombosis in patients with left ventricular ejection fraction≥50% was 7.4% (4/54), which was significantly lower than that in patients with left ventricular ejection fraction<50% (34.5%(10/29)) (P<0.01). Conclusion: There are certain distribution characteristics of HCM and RCM patients with intracardiac thrombosis, and the left atrium is the most common site of thrombosis, more attention should be paid in HCM and RCM patients on the diagnosis and treatment of intracardiac thrombosis.

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.

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

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 and Post–Heart Transplant Outcomes for Children With Nondilated Cardiomyopathy

Although outcomes for pediatric cardiomyopathy (CMP) patients have improved, an understanding of outcomes by CMP phenotype is essential. This study assessed changes in waitlist and post-transplant survival in nondilated cardiomyopathy (DCM) patients over 2 decades, explored ventricular assist device (VAD) utilization in this cohort, and identified risk factors for waitlist and posttransplant mortality in the current era. Pediatric patients with a diagnosis of CMP listed for heart transplantation during three eras: Era 1: March 5, 1999 to December 31, 2004; Era 2: January 1, 2005 to December 15, 2011; and Era 3 (current era): December 16, 2011 to February 28, 2018 were included. Multivariable Cox proportional hazards regression was performed to assess waitlist and posttransplant survival. Compared with patients with DCM, those with hypertrophic and restrictive cardiomyopathy in the current era are less likely to be on VAD (23.4% vs 2.7% vs 4.5%); listed United Network for Organ Sharing Status 1A (75.6% vs 39.8% vs 34.8%), and more likely to have longer waitlist times (P < .01 for all). Only 3.3% hypertrophic and 2.4% restrictive cardiomyopathy patients had VAD implantation, although VAD use did not adversely impact waitlist survival in weighted non-DCM patients. Significant improvements have occurred in waitlist survival of hypertrophic and posttransplant survival of both types of non-DCM patients. Currently, waitlist and posttransplant survival is similar for all CMP phenotypes. VAD use is low in patients with non-DCM, although this did not increase waitlist mortality in adjusted analysis. Further studies in patients with non-DCM are needed to determine optimal timing and anatomic characteristics most likely to benefit from VAD implantation during the waitlist period.

Value of left ventricular myocardial strain derived from cardiac magnetic resonance tissue tracking on differentiating constrictive pericarditis from restrictive cardiomyopathy

Objective: To compare left ventricular myocardial mechanics detected by cardiac magnetic resonance tissue tracking(CMR-TT) between patients with constrictive pericarditis(CP) and restrictive cardiomyopathy(RCM),and see if those can be used to differentiate CP from RCM patients. Methods: A total of 23 patients with CP, 20 patients with RCM, who hospitalized in Beijing Anzhen Hospital from January 2014 to April 2019 were included in this study and 25 healthy subjects served as control group, all subjects underwent cardiac magnetic resonance examination. Myocardial mechanics were evaluated by 2-dimensional(2D) and 3-dimensional(3D) CMR-TT in terms of global longitudinal strain(GLS), circumferential strain(GCS), radial strain(GRS) and the lateral wall strain to septal wall strain ratio(lateral/septal ratio) of basal, mid-cavity and apical. The diagnostic area under the receiver operating characteristic curve (ROC) was evaluated for differentiating CP from RCM. Results: Age, sex and heart rate were similar between CP and RCM patients(all P>0.05). 2D-GLS, 3D-GLS, GCS and GRS in CP and RCM groups were significantly lower than those in normal control group(all P<0.05).3D-GLS value was significantly lower in RCM patients than in CP patients(P<0.05), the area under the curve (AUC)=0.787(sensitivity 80%, specificity 78%). 3D-GCS was significantly lower in CP group than in RCM group(P<0.05), the AUC=0.737(sensitivity 80%, specificity 65%). However, there was no significant difference between CP and RCM in 3D-GRS(P>0.05). Compared with RCM, the circumferential and radial lateral/septal ratios of the basal were significantly lower in CP group than in RCM group(both P<0.05), AUC=0.737(sensitivity 70%, specificity 83%) and 0.737 (sensitivity 60%, specificity 87%), respectively. The left ventricular myocardial mechanics strain curve of the CP,RCM and normal control were different. The CP patients presented as " rapidly down-a platform" form, the RCM presented as "slowly down" form, and normal control presented as "rapidly down" form. Conclusion: Evaluating the differences in the diastolic process of left ventricular myocardium and left ventricular myocardial mechanics strain curve is helpful to differentiate CP from RCM patients.

Comparison of Six-Month Outcomes in Restrictive Cardiomyopathy Patients before and after UNOS Allocation System Change

Restrictive cardiomyopathy (RCM) patients represent a spectrum of disorders. Given the greater emphasis for status exceptions for RCM pts in the new allocation system, we sought to assess whether this change in the allocation policy would affect the wait list and post-transplant outcomes in RCM pts. 89 RCM pts were identified in the UNOS registry that underwent heart transplant (HT) during a 6-mos period immediately before and after UNOS policy change. Comparisons between pt characteristics in the pre (n=62) and post (n=27) policy-change cohorts are reported using standard statistical methods; survival analysis performed using Cox proportional hazards modeling. The waitlist (WL) statuses of the pre pts were 1A (n=34), 1B (n=14), 2 (n=14) while the WL statuses of the post pts were 1 (n=2), 2 (n=13), 3 (n=5), 4 (n=4), 6 (n=2). For the pre and post policy groups, the age, gender, ethnicity, DM status, and ischemic times were similar. The RCM subtype (idiopathic, amyloid, sarcoid, chemo/XRT, and other) distribution was similar for the two groups. Donor age was greater following policy change (40.6 ± 13.0 vs 30.7± 13.0, p=<0.01). Median total days on WL trended towards fewer days for post group (16.0 days vs 33.0 days, p=0.06). IABP utilization was greater for the post policy change group (37% vs 5%, p=<0.01). There was no significant survival difference at 6 month. After UNOS policy change, the 6 months post HT mortality was unchanged in RCM pts as compared to pre-policy change. There was a trend towards shorter wait times and significantly greater utilization of IABP after policy change. Despite the emphasis on status exception for RCM pts, there were fewer overall HT done for RCM.

Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments.

TNNI3 encoding cTnI, the inhibitory subunit of the troponin complex, is the main target for mutations leading to restrictive cardiomyopathy (RCM). Here we investigate two cTnI-R170G/W amino acid replacements, identified in infantile RCM patients, which are located in the regulatory C-terminus of cTnI. The C-terminus is thought to modulate the function of the inhibitory region of cTnI. Both cTnI-R170G/W strongly enhanced the Ca2+-sensitivity of skinned fibres, as is typical for RCM-mutations. Both mutants strongly enhanced the affinity of troponin (cTn) to tropomyosin compared to wildtype cTn, whereas binding to actin was either strengthened (R170G) or weakened (R170W). Furthermore, the stability of reconstituted thin filaments was reduced as revealed by electron microscopy. Filaments containing R170G/W appeared wavy and showed breaks. Decoration of filaments with myosin subfragment S1 was normal in the presence of R170W, but was irregular with R170G. Surprisingly, both mutants did not affect the Ca2+-dependent activation of reconstituted cardiac thin filaments. In the presence of the N-terminal fragment of cardiac myosin binding protein C (cMyBPC-C0C2) cooperativity of thin filament activation was increased only when the filaments contained wildtype cTn. No effect was observed in the presence of cTn containing R170G/W. cMyBPC-C0C2 significantly reduced binding of wildtype troponin to actin/tropomyosin, but not of both mutant cTn. Moreover, we found a direct troponin/cMyBPC-C0C2 interaction using microscale thermophoresis and identified cTnI and cTnT, but not cTnC as binding partners for cMyBPC-C0C2. Only cTn containing cTnI-R170G showed a reduced affinity towards cMyBPC-C0C2. Our results suggest that the RCM cTnI variants R170G/W impair the communication between thin and thick filament proteins and destabilize thin filaments.

P4654Clinical and electrocardiographic features of restrictive cardiomyopathy in children

Abstract Introduction Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. The mean survival duration after a diagnosis of RCM is reported to be around 2 years in children and most need heart transplantations. Purpose This study aimed to determine the 12-lead electrocardiogram (ECG) diagnostic criteria of RCM based on the initial diagnostic electrocardiogram. Methods ECGs in pediatric cardiomyopathy patients were collected from 15 institutes in Japan between 1979 and 2013. We compared the ECG findings, especially of the P wave, in RCM patients between the cardiomyopathy group and healthy children group separately for each gender and the age. The ECGs in the healthy group were obtained from school heart screening in Japan of first-graders, and seventh-graders. Statistical significance was determined as p&lt;0.001. Results Among 376 registered cardiomyopathy patients, 63 had hypertrophic cardiomyopathy (HCM) (36%), 91 (24%) dilated cardiomyopathy (DCM), 106 (28%) a left ventricular myocardial noncompaction (LVNCs), 25 (7%) restrictive cardiomyopathy (RCM), 14 (4%) arrhythmogenic right ventricular cardiomyopathy (ARVC), and 5 (1%) other cardiomyopathies. Of the 25 RCM patients (9.9±3.4 years old, F:M=11:14), 36% were discovered during school heart screening. The first onset was an abnormal ECG in 9, symptoms of heart failure in 6, respiratory tract infections in 3, syncope in 1, and 6 with other. Of those patients, 2 (8%) had a family history of RCM, 24 (92%) no family history. A genetic diagnosis was performed in 5 of the 25 cases, and 3 had genetic abnormalities related to RCM. The mean follow-up period was 65±95 months (mean±standard deviation). During follow up, 19 patients (76%) survived, 6 (24%) died, 7 (28%) had heart transplantations, and 3 (12%) were waiting for heart transplantations with a left ventricular assist device. The P wave was bimodal in lead I or biphasic in lead V1 in 15 patients (93%), and 13 (81%) patients had both variations. We evaluated the duration and amplitude of the first and second component of the P wave as P1 and P2. The number of control and RCM patients (control/RCM), duration of P1+P2, and sum total absolute value of the amplitude of P1+P2 in lead V1 were 8350/5, 90±9/116±10ms, and 72±28/528±278μV in first grade boys, 8423/3, 91±10/120±22ms, and 66±28/326±229μV in first grade girls, 8943/1, 97±1/100ms, and 71±31/328μV in seventh grade boys, and 9183/5, 98±11/112±10ms, and 55±27/315±56μV in seventh grade girls. Although the number of patients in the RCM group was small, sum total absolute value of the amplitude of P1+P2 in lead V1 showed a significant difference in any group. Conclusion The ECG in children with RCM exhibits P wave abnormalities in almost all patients. In particular, not the P wave interval but P wave shape in I and V1 and the sum total absolute value of the amplitude of P1+P2 in lead V1 were observed differences.

Novel Trans-Septal Left Atrial VAD Cannulation Technique for Hypertrophic/Restrictive Cardiomyopathy

Purpose Left ventricular assist device (LVAD) outcomes for hypertrophic (HCM) or restrictive cardiomyopathy (RCM) with a small LV are unsatisfactory due to difficulty draining via an LV apical cannula. We developed a new transeptal cannulation technique to decompress the left atrium where the atrial septum is cannulated via the right atrium. Methods Retrospective review of our institutional experience with LVAD/BiVAD implantation in HCM or RCM patients from October 2016 to Aug 2018. Outcomes following implantation were analyzed, including subsequent interventions, quality of VAD output, and patient outcomes. Results In total, 5 patients underwent LVAD implantation with trans-septal left-atrial cannulation techniques (HCM = 4 patients, RCM =1). Two patients received Berlin Heart BiVADs, 1 received a Berlin Heart LVAD, 1 patient received PediMag BiVADs, and 1 patient received a Heartware LVAD. Total support days were 485 days. Three patients underwent successful heart transplant after 275, 111 and 62 days of support. One neonate with HCM died from sepsis 27 days after PediMag BiVAD placement. One RCM patient died 10 days after Berlin Heart BiVAD placement following extracorporeal membrane oxygenation due to ARDS. Total survival rate is 60%. All three survivors did not develop any neurological deficits or complications related to thrombus and were discharged home after heart transplant. Conclusion This novel trans-septal left-atrial LVAD cannulation strategy is a viable alternative cannulation technique for HCM or RCM patients with a small left ventricular cavity. This technique can be applied to a variety of pediatric and adult devices in children ranging from infants to adults.