Hypereosinophilia and Left Ventricular Thrombus: A Case Report and Literature Review.

Left ventricular thrombus (LVT) has historically been reported as a complication of acute left ventricular (LV) myocardial infarction. It is most commonly observed in cases of LV systolic dysfunction attributed to ischemic or nonischemic etiologies. Conversely, the occurrence of LVT in normal LV systolic function is an exceptionally rare presentation and is predominantly associated with conditions such as hypereosinophilic syndrome (HES), cardiac amyloidosis, left ventricular noncompaction, hypertrophic cardiomyopathy (HCM), hypercoagulability states, immune-mediated disorders, and malignancies. Notably, hypereosinophilia (HE) has been linked with thrombotic events. Intracardiac thrombus is a well-known complication of eosinophilic myocarditis (EM) or Loeffler endomyocarditis, both of which are considered clinical manifestations of HES. We present a case of a 63-year-old male with normal LV systolic function, HE, and noncontributory hypercoagulability workup, who presented with thromboembolic complications arising from LVT. Interestingly, the diagnostic evaluation for EM and Loeffler endocarditis was nonconfirmatory. Additionally, we performed a literature review to delineate all similar cases. This article also outlines the pathophysiology, diagnosis, and treatment approaches for hypereosinophilic cardiac involvement with a specific focus on LVT.

Ventricular assist device support in paediatric patients with restrictive cardiomyopathy-clinical outcomes and haemodynamics.

OBJECTIVES: Restrictive cardiomyopathy is rare and is generally associated with worse clinical outcomes compared to other cardiomyopathies. Ventricular assist device (VAD) support for these children is seldom applied and often hampered by the surgical difficulties. METHODS: All paediatric (<19 years) patients with a restricted cardiomyopathy supported by a VAD from the EUROMACS database were included and compared to patients with a dilated cardiomyopathy (retrospective database analyses). Participating centres were retrospectively contacted to provide additional detailed echo and Swan Ganz measurements to analyse the effect of VAD support on pulmonary artery pressure and right ventricular function. RESULTS: Forty-four paediatric VAD-supported patients diagnosed with restricted cardiomyopathy were included, with a median age at implantation of 5.0 years. Twenty-six of the 44 patient with a restricted cardiomyopathy survived to transplantation (59.1%), 16 died (36.4%) and 2 are still on ongoing VAD support (4.5%) after a median duration of support of 95.5 days (interquartile range 33.3-217.8). Transplantation probability after 1 and 2 years of VAD support in patients with a restricted cardiomyopathy were comparable to patients with a dilated cardiomyopathy (52.3% vs 51.4% and 59.5% vs 60.1%, P = 0.868). However, mortality probability was higher in the restricted cardiomyopathy cohort (35.8% vs 17.0% and 35.8% vs 19.0%, P = 0.005). Adverse event rates were high (cerebrovascular accident in 31.8%, pump thrombosis in 29.5%, major bleeding 25.0%, eventual biventricular support in 59.1%). In the atrially cannulated group, cerebrovascular accident and pump thrombosis occurred in twice as much patients (21.1% vs 40.0%, P = 0.595 and 15.8% vs 40.0%, P = 0.464; probably non-significant due to the small numbers). Pulmonary arterial pressures improved after implantation of a VAD, and 6 patients who were initially labelled as ineligible due to pulmonary hypertension could eventually be transplanted. CONCLUSIONS: VAD support in children with a restricted cardiomyopathy is rarely performed. Mortality and adverse event rates are high. On the other hand, survival to cardiac transplantation was 59.1% with all patients surviving the 1st 30 days after cardiac transplantation. Pulmonary arterial pressures improved while on support, potentially making cardiac transplantation a viable option for previously ineligible children.

Mexican Registry of Cardiomyopathies: baseline data, diagnostic strategies, and treatment approaches in Mexico.

Objectives: The study aimed to know the clinical, demographic, diagnostic, and treatments characteristics in patients with cardiomyopathies in Mexico. Methods: The Mexican Registry of Cardiomyopathies (REMEMI) is an observational, prospective and national study of patients with cardiomyopathies, which includes: Dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM) and arrhythmogenic cardiomyopathy of the right ventricle (ARVC). Results: A total of 1026 patients from most states of the Mexican Republic (19) were included, with 494 corresponding to DCM, 490 to HCM, 35 to RCM, and seven to ARVC. We found significant differences between the various cardiomyopathy phenotypes (p < 0.05) in the coexistence with diabetes, use of implantable defibrillator, presence of ventricular tachycardia, and NYHA functional class ≥ 1. There were no significant differences in age and predominant gender between each one. When analyzing by phenotype, we found that patients with HCM have limited use of diagnostic methods considered indispensable, such as cardiac magnetic resonance, Holter monitoring, and genetic testing in patients and their relatives. Conclusion: Seeking contemporary information through observational registries in Mexico is a valuable opportunity to understand the characteristics of the methods used in the study and treatment of diseases such as cardiomyopathies by Mexican physicians. It can provide information for the implementation of management guidelines and strategies to disseminate findings to improve healthcare in our country.

Objetivo: Conocer las características clínicas y demográficas, así como las herramientas diagnósticas y tratamientos utilizados en pacientes con miocardiopatías en México. Métodos: El Registro Mexicano de Miocardiopatías (REMEMI) es un estudio observacional, prospectivo y nacional de pacientes con diagnóstico de miocardiopatía, que incluye: miocardiopatía dilatada (MCD), miocardiopatía hipertrófica (MCH), miocardiopatía restrictiva (MCR) y miocardiopatía arritmogénica del ventrículo derecho (MAVD). Resultados: Se incluyó un total de 1026 pacientes provenientes de la mayoría de los estados de la República Mexicana (19), de los cuales 494 corresponden a MCD, 490 a MCH, 35 a MCR y 7 a MAVD. Encontramos diferencias significativas entre los diversos fenotipos de miocardiopatías (p < 0.05) en la coexistencia con diabetes, empleo de desfibrilador implantable, presencia de taquicardia ventricular y la clase funcional de la NYHA ≥ 1. No hubo diferencias significativas en la edad y sexo predominante entre cada uno. Al analizar por fenotipo encontramos que la MCH tienen poco empleo de métodos diagnósticos considerados como indispensables como la resonancia magnética cardiaca, el monitoreo Holter y el estudio genético en los pacientes y sus familiares. Conclusión: La búsqueda de información contemporánea a través de registros observacionales en México es una buena oportunidad para conocer las características de los métodos empleados en el estudio y tratamiento de enfermedades como las miocardiopatías por médicos mexicanos, y puede ofrecernos información para la implementación de guías de manejo y estrategias de difusión de los hallazgos para así mejorar el cuidado de la salud en nuestro país.

A clinical case of Takayasu disease: emphasis on cardiac manifestations.

Takayasu arteriitis (TA) is a rare systemic vasculitis, affecting large vessels, cardiac valves and myocardium. Cardiac involvement is a major cause of morbidity and mortality in such patients. This publication presents a clinical case of a patient with severe aortic regurgitation combined with restrictive cardiomyopathy. It is emphasized that surgical treatment is associated with potential difficulties in patients with TA due to its inflammatory nature, disease activity and multiorgan involvement.

Paediatric Restrictive Cardiomyopathy - Diagnosis and Challenges: A report of two cases.

Restrictive cardiomyopathy is one of the rarest forms of cardiomyopathies in paediatric patients characterised by impaired myocardial relaxation or compliance with restricted ventricular filling, leading to a reduced diastolic volume with a preserved systolic function. We report 2 cases-a 5-year-old boy who presented with abdominal distension and palpitation with family history of similar complaints but no definite genetic diagnosis as yet and a 5-year-old girl who presented with chronic cough and shortness of breath. Both cases were diagnosed in a tertiary care hospital in Muscat, Oman, in 2019 and are managed supportively with regular outpatient follow-up. This is the first series of reported cases of paediatric restrictive cardiomyopathy from Oman.

Challenging of ECMO application in pediatric restrictive cardiomyopathy: case report of a novel TNNI3 variant.

Background: Restrictive cardiomyopathy (RCM) represents a rare cardiovascular disorder stemming from filament-associated genes. Nonetheless, treating RCM presents considerable challenges, particularly concerning device implantation and mechanical support. Furthermore, elucidating the molecular function of specific variants holds promise in benefiting patients and enhancing prognosis, given the significant heterogeneity among RCM variants. Case presentation: The proband, an eight-year-old female, was admitted to our hospital post cardiopulmonary resuscitation due to sudden cardiac arrest. Echocardiography revealed bilateral atrial enlargement. Whole-exome sequencing uncovered a novel heterozygous mutation (c.509G>A, p.R170Q) in TNNI3. Evaluation using the MutationTaster application deemed c.509G>A pathogenic (probability = 0.99). Following clinical manifestations, imaging assessments, and genetic screening, the proband received an RCM diagnosis. ECMO was recommended along with continuous renal replacement therapy. However, persistent atrial flutter ensued post-ECMO withdrawal. Attempts to restore cardiac rhythm with cardioversion, metoprolol, and amiodarone proved futile. Subsequent heart failure led to the patient's demise due to cardiac shock. Based on crystal protein structural analysis, we observed that cTnI-R170Q and R170W exerted similar impacts on protein structural stability and formation. However, both differed significantly from cTnI-R170G, primarily influencing amino acid regions 32-79 and 129-149, involved in TnC and actin binding. Therefore, cTnI-R170Q was revealed to induce RCM via the same molecular mechanism as cTnI-R170W. Conclusion: Managing RCM remains a critical challenge. This study underscores the discouragement of device implantations for cardiac pump functional support in RCM, particularly for non-short-term scheduled HTx. Additionally, considering catheter ablation for atrial fibrosis-induced AFs is recommended. Mechanistically, cTnI-R170Q primarily diminishes troponin-actin interactions and destabilizes thin filaments.

Clinical Relevance of the Systematic Analysis of Copy Number Variants in the Genetic Study of Cardiomyopathies.

Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies.

Case report: eosinophilic myocarditis in hypereosinophilic syndrome: a journey to heart transplantation.

Introduction: Hypereosinophilic Syndrome (HES) is a rare disorder characterized by persistent elevation of eosinophils, leading to multi-organ infiltration and damage. Eosinophilic Myocarditis (EM) is one of its severe complications contributing significantly to morbidity and mortality. Herein, we describe the diagnostic and therapeutic challenges of EM, emphasizing the significance of early recognition and multidisciplinary management. Case presentation: A 51-year-old female with a history of EM, heart failure, and peripheral eosinophilia presented with NYHA class 3b symptoms. Laboratory findings revealed elevated peripheral eosinophil count, NT-Pro BNP, and characteristic electrocardiogram abnormalities. Imaging studies confirmed biventricular thrombi and myocardial abnormalities consistent with EM. Treatment involved Solu-Medrol for HES and heparin for ventricular thrombi, leading to initial clinical improvement. However, refractory heart failure necessitated urgent heart transplantation. Discussion: EM, an under-recognized complication of HES, poses diagnostic and management challenges. Management includes standard heart failure treatments, steroids, and emerging therapies like Mepolizumab. Early diagnosis and aggressive management are pivotal for improving outcomes in this rare and potentially fatal condition. Conclusion: Advancements in the detection of complications, surgical management, and therapeutic options have improved outcomes in HES. Ongoing research is essential to further understand and address the diagnostic and therapeutic challenges of HES and EM.

Biventricular assist device implant using biatrial cannulation for restrictive cardiomyopathy.

Preoperative calculations showed that the 9-mm inlet, 6-mm outlet, 25-cc pump chambers and 65-73 bpm would be optimal for a 5-year-old patient suffering from restrictive cardiomyopathy, with a body surface area of 0.59 m2 (1.5 L/min flow for a cardiac index of 2.5). After re-sternotomy and standard bicaval cannulation for cardiopulmonary bypass, the procedure was performed under normothermic conditions and on the beating heart. Biventricular support was established with the Berlin Heart Excor using biatrial cannulation. For left atrial cannulation, induced ventricular fibrillation was used. The 9-mm inlet cannulas were inserted into the left and right atria, respectively. The 6-mm outlet cannulas were implanted using 8-mm interposition vascular grafts for the aorta and the main pulmonary artery, respectively. Cannulas were tunnelled through the epigastric space, with systems crossing outside of the body. The 25-cc chambers were used for both right ventricular assist device and left ventricular assist device support, which subsequently showed full emptying and filling.

A novel multi-task machine learning classifier for rare disease patterning using cardiac strain imaging data.

To provide accurate predictions, current machine learning-based solutions require large, manually labeled training datasets. We implement persistent homology (PH), a topological tool for studying the pattern of data, to analyze echocardiography-based strain data and differentiate between rare diseases like constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). Patient population (retrospectively registered) included those presenting with heart failure due to CP (n = 51), RCM (n = 47), and patients without heart failure symptoms (n = 53). Longitudinal, radial, and circumferential strains/strain rates for left ventricular segments were processed into topological feature vectors using Machine learning PH workflow. In differentiating CP and RCM, the PH workflow model had a ROC AUC of 0.94 (Sensitivity = 92%, Specificity = 81%), compared with the GLS model AUC of 0.69 (Sensitivity = 65%, Specificity = 66%). In differentiating between all three conditions, the PH workflow model had an AUC of 0.83 (Sensitivity = 68%, Specificity = 84%), compared with the GLS model AUC of 0.68 (Sensitivity = 52% and Specificity = 76%). By employing persistent homology to differentiate the "pattern" of cardiac deformations, our machine-learning approach provides reasonable accuracy when evaluating small datasets and aids in understanding and visualizing patterns of cardiac imaging data in clinically challenging disease states.

Current Therapies and Future Horizons in Cardiac Amyloidosis Treatment.

PURPOSE OF REVIEW: Cardiac amyloidosis (CA) is a condition characterized by misfolding and extracellular deposition of proteins, leading to organ dysfunction. While numerous forms of CA exist, two subtypes dominate clinical prevalence: Transthyretin amyloid (ATTR) and immunoglobulin light chain amyloid. RECENT FINDINGS: The current scientific landscape reflects the urgency to advance therapeutic interventions with over 100 ongoing clinical trials. Heart failure treatment is affected by CA phenotype with poor tolerance of otherwise frequently used medications. Treating comorbidities including atrial fibrillation and valvular disease remains a challenge in CA, driven by technical difficulties and uncertain outcomes. Tafamidis is the first ATTR-stabilizer approved with a rapidly growing rate of clinical use. In parallel, various new therapeutic classes are in late-stage clinical trials including silencers, antibodies and genetic therapy. Managing CA is a critical challenge for future heart failure care. This review delineates the current standard-of-care and scientific landscape of CA therapy.

Multimodality imaging of eosinophilic myocarditis (loeffler's endocarditis) in a patient with idiopathic hypereosinophilic syndrome.

Eosinophilic myocarditis can result in endomyocardial fibrosis affecting both ventricles, leading to restrictive cardiomyopathy. Multimodality imaging is crucial for diagnosis, as demonstrated in this case of a patient presenting with symptoms of heart failure.

IgG4-Related disease with diffuse myopericardial involvement- value of CMR: a case report and literature review of cardiac involvement.

BACKGROUND: IgG4-related disease is a fibro-inflammatory disorder with an unknown etiology, which can affect multiple organ systems, including the cardiovascular system. While most reported cases of cardiovascular involvement are primarily associated with the aorta, there have been sporadic reports of isolated cardiac involvement. CASE PRESENTATION: This paper presents a documented case of IgG4-related systemic disease with symptoms indicative of restrictive cardiomyopathy. Subsequent Cardiac Magnetic Resonance imaging revealed diffuse myopericardial involvement, characterized by pericardial thickening and enhancement, accompanied by subepicardial and myocardial infiltration. Considering the rarity of cardiac involvement in our case, we conducted a thorough review of the existing literature pertaining to various patterns of cardiac involvement in IgG4-related disease, as well as the diagnostic modalities that can be employed for accurate identification and assessment. CONCLUSIONS: This case report sheds light on the importance of recognizing and evaluating cardiac manifestations in IgG4-related systemic disease to facilitate timely diagnosis and appropriate management.

Cardiac magnetic resonance feature tracking derived left atrial strain in the diagnosis of patients with constrictive pericarditis and restrictive cardiomyopathy.

Objective: To explore the diagnostic value of cardiac magnetic resonance feature tracking (CMR-FT) divided left atrial (LA) strain in differentiating constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). Methods: Patients with CP (n = 40) and RCM (n = 40), and another 40 normal control group were retrospectively enrolled over a period of 8 years at a tertiary cardiac centre. Left ventricular (LV) and biatrial strain and strain rate (SR) were measured. Atrial strain was used to differentiate between patients with CP and RCM. Then, patients were grouped according to their left ventricular ejection fraction (LVEF), either ≥50% or < 50%. A deeper analysis was done to evaluate the diagnostic value of atrial strain in these subgroups. Receiver operating characteristic curves (ROC) were used to assess the accuracy of myocardial strain based on CMR FT for the differential diagnosis of CP and RCM. Results: LV and LA strain and SR were significantly lower in patients with CP and RCM than those in the normal controls (P < 0.05). LA strain and SR were significantly lower in the RCM group than in the CP group (P < 0.05). In patients with either LVEF≥50% or＜50%, LA strain were lower in the RCM group than in the CP group (P < 0.05). ROC analysis showed that LA stored strain (LA-εs) had a good differential diagnostic value for CP and RCM, with an area under the curve (AUC) of 0.811 and an optimal cutoff value of 6.98%, above this value it tends to develop CP. Further, an excellent differential diagnostic value was found in patients with LVEF＜50%, with an AUC of 0.955. Conclusion: LA strain analysis obtained by CMR-FT provides good differential diagnostic value for distinguishing CP from RCM, especially in patients with LVEF＜50%.

Unusual coexistence of restrictive heart disease and Kallmann syndrome: a case report.

BACKGROUND: Kallmann-Morsier syndrome is a rare disease characterized by the association of congenital gonadotropic deficiency and anosmia or hyposmia. The cardiac manifestations associated with this syndrome are little known. Through this case, we will characterize the cardiac involvement of this disease in the light of what is already described in the literature. CASE PRESENTATION: We report the case of a young patient who presented with a picture of cardiac decompensation revealing restrictive heart disease. In her exploration, she was found to have primary amenorrhea, leading to the diagnosis of Kallmann syndrome. Medical treatment was optimized for the management of her cardiac decompensation as well as hormonal replacement treatment for her delayed puberty and growth. CONCLUSIONS: Cardiac manifestations in Kallmann-Morsier syndrome are few reported in the literature, and restrictive heart disease is uncommon with no cases report till now. This association suggests a possible common genetic origin that should be explored in the future.

Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy.

BACKGROUND: Restrictive cardiomyopathy (RCM) is characterized by impaired diastolic function with preserved ventricular contraction. Several pathogenic variants in sarcomere genes, including TNNI3, are reported to cause Ca2+ hypersensitivity in cardiomyocytes in overexpression models; however, the pathophysiology of induced pluripotent stem cell (iPSC)-derived cardiomyocytes specific to a patient with RCM remains unknown. METHODS AND RESULTS: We established an iPSC line from a pediatric patient with RCM and a heterozygous TNNI3 missense variant, c.508C>T (p.Arg170Trp; R170W). We conducted genome editing via CRISPR/Cas9 technology to establish an isogenic correction line harboring wild type TNNI3 as well as a homozygous TNNI3-R170W. iPSCs were then differentiated to cardiomyocytes to compare their cellular physiological, structural, and transcriptomic features. Cardiomyocytes differentiated from heterozygous and homozygous TNNI3-R170W iPSC lines demonstrated impaired diastolic function in cell motion analyses as compared with that in cardiomyocytes derived from isogenic-corrected iPSCs and 3 independent healthy iPSC lines. The intracellular Ca2+ oscillation and immunocytochemistry of troponin I were not significantly affected in RCM-cardiomyocytes with either heterozygous or homozygous TNNI3-R170W. Electron microscopy showed that the myofibril and mitochondrial structures appeared to be unaffected. RNA sequencing revealed that pathways associated with cardiac muscle development and contraction, extracellular matrix-receptor interaction, and transforming growth factor-ß were altered in RCM-iPSC-derived cardiomyocytes. CONCLUSIONS: Patient-specific iPSC-derived cardiomyocytes could effectively represent the diastolic dysfunction of RCM. Myofibril structures including troponin I remained unaffected in the monolayer culture system, although gene expression profiles associated with cardiac muscle functions were altered.

Role of the Alpha-B-Crystallin Protein in Cardiomyopathic Disease.

Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in CRYAB, the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.

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.

BACKGROUND: 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. PURPOSE: 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. STUDY TYPE: Retrospective. POPULATION: 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). FIELD STRENGTH/SEQUENCE: 3.0T/Balanced steady-state free precession sequence, recovery prepared echo-planar imaging sequence, and phase-sensitive inversion recovery sequence. ASSESSMENT: 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. STATISTICAL TESTS: 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. RESULTS: 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 (ß = 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). DATA CONCLUSION: PTTc and PBVi are associated with diastolic dysfunction and deteriorated LV deformation, and PTTc independently predicts MACE in patients with RCM. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Severe diastolic dysfunction as a clue to the cause of stroke: a case report.

Background: The echocardiographic determination of cardiac causes of stroke focuses on the presence of left ventricular thrombus, valvular vegetations, and patent foramen ovale. Transoesophageal echocardiogram (TEE) is indicated when the transthoracic echocardiogram (TTE) is inconclusive or when there is clinical suspicion of cardiac causes that may have been missed by TTE. The presence of severe diastolic dysfunction on TTE in the absence of any other cardiac abnormality or cardiac history is not usually considered a clue to the cause of stroke. Case summary: This is a case of a 52-year-old woman who presented with a stroke. Transthoracic echocardiogram was inconclusive for source of embolus. Transoesophageal echocardiogram revealed left atrial appendage (LAA) thrombus and severely hypokinetic LAA, despite the patient being in normal sinus rhythm (NSR). Retrospective analysis of diastolic function on the prior TTE revealed severe restrictive diastolic dysfunction with evidence of elevated left ventricular end-diastolic pressure. While technetium pyrophosphate scan was negative, magnetic resonance imaging was consistent with cardiac amyloid and further testing revealed multiple myeloma as the cause of the amyloid light chain amyloidosis. This case highlights the importance of scrutinizing diastolic function in patients with a source of embolus and careful assessment for LAA thrombus on TEE, despite NSR. Discussion: We present a patient with stroke with inconclusive TTE findings and eventual diagnosis of restrictive cardiomyopathy secondary to cardiac amyloidosis from an undiagnosed multiple myeloma. Severe restrictive diastolic function on TTE may be a clue to the discovery of LAA thrombus on TEE.

Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy.

Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.