Mitochondrial defects can lead to cardiomyopathies, which can be particularly severe in children. However, many cases of pediatric cardiomyopathy have no known etiology. To address this, we sought to explore if mitochondrial genome defects might be a contributor, as this could offer insights into disease mechanisms and guide targeted interventions. We first sequenced cardiomyopathy-related genes in twenty-seven pediatric patients diagnosed with primary non-syndromic cardiomyopathy and performed whole mtDNA sequencing in both patients and thirty-one healthy controls. The initial sequencing identified pathogenic variants in seven patients but subsequent mtDNA sequencing revealed additional insights. Specifically, a variant in FOXRED1, encoding FAD-dependent oxidoreductase domain-containing protein-1 which functions in mitochondrial complex I stability, and another variant in cytochrome c oxidase-I, MT-CO1, crucial for aerobic metabolism, were identified in two siblings with hypertrophic cardiomyopathy. In another case with hypertrophic cardiomyopathy, a variant in cytochrome b, MT-CYB, is likely a key factor in the abnormal contraction of cardiac muscle contraction. Furthermore, a novel 12 S rRNA variant was found in a patient with left ventricular non-compaction, and this offers a promising explanation for the pathogenesis, given the gene's high expression in the left ventricle. Taken together, mtDNA variants act synergistically with others, potentially disrupting myocardial bioenergetics.

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by the deposition of insoluble amyloid fibrils in the myocardium, leading to abnormal cardiac function and heart failure. Diagnosis is often challenging due to its diverse symptoms and related comorbidities. Although endomyocardial biopsy is the gold standard for diagnosis, a complete diagnostic approach often includes non-invasive methods such as Cardiac Magnetic Resonance (CMR) and nuclear medicine techniques. Nuclear medicine bone-seeking agents are useful for diagnosing the transthyretin (ATTR) amyloidosis subtype. CMR is especially useful when echocardiography results are inconclusive or for differentiating cardiac amyloidosis from other conditions like hypertrophic cardiomyopathy. CMR provides a comprehensive evaluation of morphological and functional abnormalities, inversion time, late gadolinium enhancement, and can include advanced techniques such as T1 mapping and extracellular volume quantification for diagnostic and prognostic purposes. This review outlines how CMR and nuclear medicine are integral to the diagnostic process for cardiac amyloidosis, emphasizing their crucial roles and the synergy between various diagnostic techniques in assessing suspected cases. ESSENTIALS: REQUIRED SUMMARY STATEMENT: Nuclear medicine PYP scans and CMR play a pivotal role in the non-invasive diagnosis of cardiac amyloidosis, alongside other essential diagnostic modalities.

Neutrophils, the most abundant leukocytes in human blood, have long been recognized as critical first responders in the innate immune system's defense against pathogens. Some of the more notable innate antimicrobial properties of neutrophils include generation of superoxide free radicals like myeloperoxidase, production of proteases that reshape the extracellular matrix allowing for easier access to infected tissues, and release of neutrophil extracellular traps, extruded pieces of DNA that ensnare bacterial and fungi. These mechanisms developed to provide neutrophils with a vast array of specialized functions to provide the host defense against infection in an acute setting. However, emerging evidence over the past few decades has revealed a far more complex and nuanced role for these neutrophil-driven processes in various chronic conditions, particularly in cardiovascular diseases. The pathophysiology of cardiac diseases involves a complex interplay of hemodynamic, neurohumoral, and inflammatory factors. Neutrophils, as key mediators of inflammation, contribute significantly to this intricate network. Their involvement extends far beyond their classical role in pathogen clearance, encompassing diverse functions that can both exacerbate tissue damage and contribute to repair processes. Here, we consider the contributions of neutrophils to myocardial infarction, heart failure, cardiac arrhythmias, and nonischemic cardiomyopathies. Understanding these complex interactions is crucial for developing novel therapeutic strategies aimed at modulating neutrophil functions in these highly morbid cardiac diseases.

The prognosis for restrictive cardiomyopathy (RCM) is typically poor, which primarily influenced by the restrictive physiology. This study aimed to evaluate the prognostic significance of longitudinal strains and myocardial work (MW) indices in RCM patients and to create and validate a multivariable model for predicting major adverse cardiac events (MACEs). We enrolled 191 patients with RCM, divided into a training cohort of 128 and a validation cohort of 63, along with 132 healthy controls. Echocardiography was used to assess right ventricular free wall strain (RV-FWS), left ventricular global longitudinal strain (LV-GLS), left atrial peak strain (LAPS), right atrial peak strain (RAPS), and MW indices. Univariate and multivariate stepwise Cox regressions were applied to identify independent prognostic factors and develop a nomogram. With a median follow-up of 977 days, 111 patients experienced MACEs and 76 died. In patients with preserved left ventricular ejection fraction (LVEF), LV-GLS and MW indices were impaired. Longitudinal strains and MW indices were significantly associated with prognosis. We constructed a predictive nomogram including LAPS, RV-FWS, global myocardial work efficiency (GWE), and established clinical predictors, which demonstrated excellent discriminative and calibration properties. Thorough evaluation of longitudinal strains and MW indices is essential, particularly focusing on LAPS, RV-FWS, and GWE.

Restrictive cardiomyopathy (RCM) is characterized by impaired diastolic function and ventricular filling, often due to genetic and environmental factors. The MYH7 gene, encoding myosin heavy chain in muscle fibres critical for muscle contraction, has been implicated in RCM.

We describe the case of a female patient who was presented with recurrent chest tightness and shortness of breath. Based on imagining findings and genetic testing, she was diagnosed with MYH7-induced RCM. Her daughter inherited the same variant but presented with a hypertrophic phenotype.

MYH7-induced cardiomyopathy is a complex condition, associated with variable clinical presentation and phenotype. While imagining and endomyocardial biopsy play important roles in diagnosing RCM, their application might be limited for economic and safety reasons. Further research is needed to elucidate the pathogenesis and develop safer and cheaper approaches to diagnose MYH7-induced restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare cardiac disease characterized by impaired ventricular filling and relaxation, with preserved systolic function. This study investigates the genetic basis of RCM and its impact on clinical outcomes, particularly heart transplantation (HTx).

The aim of the study was to identify genetic variations associated with RCM and assess their impact on disease progression and HTx necessity.

A retrospective analysis was conducted on 94 RCM patients from Fuwai Hospital (2003-2021), diagnosed via echocardiography or pathological examination. Whole exome sequencing screened patient samples for variants in key genes associated with RCM, validated via Sanger sequencing. Histopathological analysis of explanted hearts included systematic sampling from ventricles and interventricular septum, with Masson's trichrome staining for fibrosis quantification.

Genetic variants were identified in 54% of patients, with a higher prevalence in HTx patients (73%) compared to non-HTx patients (27%). Myosin heavy chain 7 (MYH7) mutations were found in 15% of cases, significantly associated with HTx (P < 0.001) and atrial fibrillation (P = 0.025). Patients with MYH7 mutations exhibited extensive fibrosis in the interventricular septum compared to nonmutation patients (P < 0.05). The mean age at diagnosis was 47.8 years, with HTx patients diagnosed at a younger age (mean 36.0 years) and transplanted at a mean age of 37.4 years, compared to non-HTx patients diagnosed at a mean age of 57.9 years. The median follow-up time was 5 years.

Genetic variations, particularly in the MYH7 gene, are significant risk factors for RCM progression and HTx. Genetic screening may guide early interventions, while fibrosis and MYH7 pathways offer potential therapeutic targets.

Light-chain cardiac amyloidosis (AL-CA) is associated with structural and functional changes in the left atrium and left ventricle. This study aims to assess the value of the left atrioventricular coupling index (LACI) assessed by three-dimensional echocardiography (3DE) for predicting primary outcome in AL-CA.

Participants with biopsy-confirmed AL-CA from April 2022 to February 2024 were prospectively analysed. LACI, the ratio of left atrial volume min to left ventricular end-diastolic volumes, was calculated offline using EchoPAC 204. The primary outcome was defined as all-cause death.

Sixty-seven biopsy-proven AL-CA patients were studied (age: 62.98 ± 10.20 years; 67% male). The median follow-up was 121 days (range: 7 ∼ 732 days). All-cause mortality occurred in 26 (39%) patients. Multivariate Cox regression revealed a significant association of LACI after adjusting for NT-pro BNP, troponin T, moderate tricuspid regurgitation, pericardial and pleural effusion (adjusted HR: 10.58, p = 0.008). Kaplan-Meier curves displayed prognostic differences based on median LACI (cut-off : 0.57, p = 0.002). The likelihood ratio χ2 test showed that LACI added predictive value to Mayo 2004, European 2015 modification of Mayo 2004, and Mayo 2012 models (All p < 0.001).

3DE-based LACI is independently associated with all-cause mortality in AL-CA patients and augments prognostic value to traditional staging models.

Pregnancy is a period of substantial changes to the body's normal physiology, and the failure to adapt to these changes can lead to life-threatening pathology, particularly involving the cardiovascular system. In comparison to pre-pregnancy physiology, pregnant women have increased blood volume and physical demands which exert increased stress on the heart. This is important to consider in women with and without previously diagnosed cardiovascular disease, as the physiologic changes during pregnancy and postpartum can lead to sudden decompensation. The management of heart failure is particularly important as it remains the most common cardiovascular complication during pregnancy and is associated with substantial maternal and fetal morbidity and mortality. This is especially true in patients with pre-existing heart failure, who should receive counseling before conception and in certain cases be advised against pregnancy. For these reasons, healthcare professionals must be well-versed in the different strategies of diagnosis, management, treatment, and monitoring. This review will outline the pathophysiology, diagnostics, management, and general approach to heart failure in pregnant patients.

The purpose of this review is to highlight the utility of echocardiography in the diagnosis and management of cardiomyopathies.

Echocardiographic parameters function synergistically to guide decision-making ranging from early detection of disease and screening to risk stratification of complex disease. The collective wealth of information available from 2D/3D assessment, Doppler, diastology and strain makes echocardiography an invaluable decision aid.

Left ventricular thrombosis (LVT) is one of the most feared complications of both ischemic and non-ischemic cardiopathy, and despite its incidence having decreased over the years (mostly due to novel reperfusion therapies in acute coronary syndromes), it is still not negligible. If transthoracic echocardiography, possibly with the adjunction of echo contrast, represents the cornerstone in LVT diagnosis, sometimes it is found to be nonconclusive and advanced cardiovascular imaging, namely cardiac magnetic resonance, needs to be performed to fully exclude intraventricular masses or to better characterize them. Vitamin K antagonists always represented the anticoagulant of choice for the treatment of LVT; however, the recent spread of direct oral anticoagulants (DOACs) pushed clinicians to adopt them also in this setting despite the absence of robust evidence in their favor. If the optimal duration of anticoagulation for the treatment of LVT in non-ischemic cardiopathy is still a matter of debate, an initial treatment of 3-6 months seems to be reasonable in the setting of ischemic cardiopathy, with possible extension according to the follow-up findings. High-quality randomized studies are strongly needed to evaluate the potential role of prophylactic anticoagulation in high-risk patients and provide conclusive evidence for the use of DOACs in LVT treatment.

Acute heart failure (AHF) is a complex clinical syndrome characterized by the rapid or gradual onset of symptoms and/or signs of heart failure (HF), leading to an unplanned hospital admission or an emergency department visit. AHF is the leading cause of hospitalization in patients over 65 years, thus significantly impacting public health care. However, its prognosis remains poor with high rates of mortality and rehospitalization. Many pre-existing cardiac conditions can lead to AHF, but it can also arise de novo due to acute events. Therefore, understanding AHF etiology could improve patient management and outcomes. Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), non-dilated cardiomyopathy (NDLVC), and arrhythmogenic right ventricular cardiomyopathy (ARVC), that frequently present with HF. Patients with CMPs are under-represented in AHF studies compared to other etiologies, and therefore therapeutic responses and prognoses remain unknown. In DCM, AHF represents the most frequent cause of death despite treatment improvements. Additionally, DCM is the first indication for heart transplant (HT) among young and middle-aged adults. In HCM, the progression to AHF is rare and more frequent in patients with concomitant severe left ventricle (LV) obstruction and hypertrophy or severe LV systolic dysfunction. HF is the natural evolution of patients with RCM and HF is associated with poor outcomes irrespective of RCM etiology. Furthermore, while the occurrence of AHF is rare among patients with ARVC, this condition in NDLVC patients is currently unknown. In this manuscript, we assessed the available evidence on AHF in patients with CMPs. Data on clinical presentation, therapeutic management, and clinical outcomes according to specific CMPs are limited. Future HF studies assessing the clinical presentation, treatment, and prognosis of specific CMPs are warranted.

The newly proposed classification of cardiomyopathies, referred to as 'the Padua Classification', is based on both pathobiological basis (genetics, molecular biology, and pathology) and clinical features (morpho-functional and structural ventricular remodelling as evidenced by cardiac magnetic resonance). Cardiomyopathies are grouped into tree main categories and characterized by a designation combining both 'anatomical' and 'functional' features: hypertrophic/restrictive, dilated/hypokinetic, and scarring/arrhythmogenic; each cardiomyopathy group includes either genetic or non-genetic aetiologic variants. This novel approach aims to enhance the diagnostic accuracy and to support 'disease-specific' therapeutic strategies, with the objective to improve patient management and outcome.

An intriguing aspect of restrictive cardiomyopathies (RCM) is the microbiome role in the natural history of the disease. These cardiomyopathies are often difficult to diagnose and so result in significant morbidity and mortality. The human microbiome, composed of billions of microorganisms, influences various physiological and pathological processes, including cardiovascular health. Studies have shown that gut dysbiosis, an imbalance in the composition of intestinal bacteria, can contribute to systemic inflammation, a key factor in many cardiovascular conditions. An increase in gut permeability, frequently caused by dysbiosis, allows bacterial endotoxins to enter the bloodstream, activating inflammatory pathways that exacerbate cardiac dysfunction. Recent reports highlight the potential role of microbiome in amyloidogenesis, as certain bacteria produce proteins that accelerate the formation of amyloid fibrils. Concurrently, advancements in amyloidosis treatments have sparked renewed hopes, marking a promising era for managing these kinds of diseases. These findings suggest that the gut-heart axis may be a potential factor in the development and progression of cardiovascular disease like RCM, opening new paths for therapeutic intervention. The aim of this review is to provide a detailed overview of the gut-heart axis, focusing on RCM.

Over the last 20 years, the scientific progresses in molecular biology and genetics in combination with the increasing use in the clinical setting of contrast-enhanced cardiac magnetic resonance (CMR) for morpho-functional imaging and structural myocardial tissue characterization have provided important new insights into our understanding of the distinctive aspects of cardiomyopathy, regarding both the genetic and biologic background and the clinical phenotypic features. This has led to the need of an appropriate revision and upgrading of current nosographic framework and pathobiological categorization of heart muscle disorders. This article proposes a new definition and classification of cardiomyopathies that rely on the combination of the distinctive pathobiological basis (genetics, molecular biology and pathology) and the clinical phenotypic pattern (morpho-functional and structural features), leading to the proposal of three different disease categories, each of either genetic or non-genetic etiology and characterized by a combined designation based on both "anatomic" and "functional" features, i.e., hypertrophic/restrictive (H/RC), dilated/hypokinetic (D/HC) and scarring/arrhythmogenic cardiomyopathy (S/AC). The clinical application of the newly proposed classification approach in the real-world practice appears crucial to design a targeted clinical management and evaluation of outcomes of affected patients. Although current treatment of cardiomyopathies is largely palliative and based on drugs, catheter ablation, device or surgical interventions aimed to prevent and manage heart failure and malignant arrhythmias, better knowledge of basic mechanisms involved in the onset and progression of pathobiologically different heart muscle diseases may allow to the development of disease-specific curative therapy.

Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on causal variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care.

Left atrioventricular coupling index (LACI) is a novel biomarker, and the prognostic value of LACI to predict cardiovascular events has been validated. The present study aimed to explore the prognostic value of LACI in patients with light-chain (AL) amyloidosis.

We prospectively enrolled 179 patients with AL amyloidosis who underwent cardiovascular magnetic resonance imaging between December 2011 and January 2020. LACI was defined as the ratio between the left atrial volume and the left ventricular volume at end-diastole. The primary endpoint was all-cause mortality. Receiver operating characteristic curve was used to identify the optimal cut-off of LACI in predicting all-cause mortality. Univariable and multivariable Cox proportional hazard models were used to assess the association of LACI and primary endpoint.

During a median follow-up of 30 months, 118 (65.9 %) patients with all-cause mortality were documented. LACI was significantly higher in patients with primary endpoint compared to those without primary endpoint (55.4 %, interquartile range: 31.6 %-71.5 % vs. 39.4 %, interquartile range: 24.1 %-54.7 %, p = 0.001). The optimal cut-off for LACI to predict mortality was 49.3 %. In multivariate Cox regression analysis, LACI≥49.3 % (HR 1.907, 95 % CI 1.273-2.857, p = 0.002) was an independent predictor of all-cause mortality. On Kaplan-Meier analysis, patients at advanced Mayo stage (IIIa and IIIb) can be further risk stratified using LACI≥49.3 % (log-rank p = 0.035, p = 0.025).

The LACI provides powerful independent prognostic value in AL amyloidosis. The LACI has incremental prognostic value to predict all-cause mortality over the Mayo stage in patients at the advanced Mayo stage.

Cardiomyopathies, historically regarded as rare, are increasingly recognized due to advances in imaging diagnostics and heightened clinical focus. These conditions, characterized by structural and functional abnormalities of the myocardium, pose significant challenges in both chronic and acute patient management. A thorough understanding of the hemodynamic properties, specifically the pressure-volume relationships, is essential. These relationships provide insights into cardiac function, including ventricular compliance, contractility, and overall cardiovascular performance. Despite their potential utility, pressure-volume curves are underutilized in clinical settings due to the invasive nature of traditional measurement techniques. Recognizing the dynamic nature of cardiomyopathies, with possible transitions between phenotypes, underscores the importance of continuous monitoring and adaptive therapeutic strategies. Enhanced hemodynamic evaluation can facilitate tailored treatment, potentially improving outcomes for patients with these complex cardiac conditions.

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.

The arrhythmic burden and cardiovascular risks of cardiac amyloidosis compared with other types of restrictive cardiomyopathies (RCM), such as hemochromatosis and cardiac sarcoid, have not been well characterized in the literature. An increase in emphasis on screening has resulted in more diagnoses of cardiac amyloidosis and a larger data pool to analyze the cardiovascular outcomes of this cardiomyopathy.

We queried the National Inpatient Sample (NIS) database to identify all adult patients diagnosed with cardiac amyloidosis or other RCM between the years 2016 and 2019. Discharge-weighted analysis using survey regressions accounts for discharge weights and characteristics found to be significantly different between groups. A total sample size of 13 345 patients was obtained, including cardiac amyloidosis (N = 8365; 62.7%) and other RCM (N = 4980; 37.3%). Cardiac amyloidosis was associated with a significantly increased risk of stroke (Odds ratio = 3.91: 95% confidence interval = [2.15, 7.11], P < .001) and ventricular tachycardia (1.98 [1.35-2.91], P < .001). Cardiac amyloidosis had a decreased risk of atrial fibrillation (0.56 [0.47-0.68], P < .001). Significant differences in risk were not observed among the different types of heart block and supraventricular arrhythmias. In-hospital mortality was similar between the 2 groups (P = .72).

Cardiac amyloidosis was associated with an increased risk of stroke and ventricular tachycardia compared to other types of RCM. Significant differences in in-hospital mortality, bundle branch blocks, and supraventricular arrhythmias were not appreciated. A subgroup analysis comparing light chain (AL) and wild-type transthyretin (ATTR) amyloidosis outcomes would further delineate the cardiovascular risks of cardiac amyloidosis.

Restrictive cardiomyopathy (RCM) is a heterogenous cardiomyopathy with various causes, and genetic variants take an important part of the pathogenesis. Whole-exome sequencing (WES) is effective to discover genes that cause genetic diseases. By using WES, we attempted to identify the genetic cause of an RCM family and clarify the clinical diagnosis of the patient and then provide a personalized treatment plan.

Blood samples were obtained from the proband and his healthy parents. WES and Sanger sequencing were performed to identify the possible pathogenic gene. Co-segregation analysis was conducted for candidate variants, and the allele frequency was checked in databases including Ensembl, Exome Aggregation Consortium (ExAC) and Human Gene Mutation Database (HGMD). Furthermore, the potential effect of variant was predicted using various-free software such as SIFT, Polyphen-2 and Mutation Taster and the conservation was tested using multiple sequence alignments by ClustalX.

The proband was a 20 years old boy with severe heart failure symptoms including dyspnea, massive ascites, edema of both lower limbs and chest congestion. Echocardiography showed significant biatrial enlargement, normal left ventricular wall thickness and preserved systolic function of both ventricles. A missense mutation in FLNC (c.6451G>A, p.G2151S), encoded filamin-C was detected in proband by WES and Sanger sequencing, while it was not be found in his parents, we supposed that the FLNC mutation (c.6451G>A, p.G2151S) may be a de-novo mutation. Through multiple functional predictions, we found that it is a deleterious mutation and the mutation in filamin-C could alter its structure and normal function, contributing to RCM.

Here, an FLNC missense mutation (c.6451G>A, p.G2151S) known to be pathogenic in hypertrophic cardiomyopathy, was found to be associated with RCM, indicating the genetic overlap among cardiomyopathies. This study provides insights into Phenotype-Genotype Correlations of RCM in patients with FLNC mutations.

Cardiomyopathy is a group of disease characterized by structural and functional damage to the myocardium. The etiologies of cardiomyopathies are diverse, spanning from genetic mutations impacting fundamental myocardial functions to systemic disorders that result in widespread cardiac damage. Many specific gene mutations cause primary cardiomyopathy. Environmental factors and metabolic disorders may also lead to the occurrence of cardiomyopathy. This review provides an in-depth analysis of the current understanding of the pathogenesis of various cardiomyopathies, highlighting the molecular and cellular mechanisms that contribute to their development and progression. The current therapeutic interventions for cardiomyopathies range from pharmacological interventions to mechanical support and heart transplantation. Gene therapy and cell therapy, propelled by ongoing advancements in overarching strategies and methodologies, has also emerged as a pivotal clinical intervention for a variety of diseases. The increasing number of causal gene of cardiomyopathies have been identified in recent studies. Therefore, gene therapy targeting causal genes holds promise in offering therapeutic advantages to individuals diagnosed with cardiomyopathies. Acting as a more precise approach to gene therapy, they are gradually emerging as a substitute for traditional gene therapy. This article reviews pathogenesis and therapeutic interventions for different cardiomyopathies.

Cardiomyopathy is a prevalent cardiovascular disease that affects individuals of all ages and can lead to life-threatening heart failure. Despite its variety in types, each with distinct characteristics and causes, our understanding of cardiomyopathy at a systematic biology level remains incomplete. Mass spectrometry-based techniques have emerged as powerful tools, providing a comprehensive view of the molecular landscape and aiding in the discovery of biomarkers and elucidation of mechanisms. This review highlights the significant potential of integrating proteomic and metabolomic approaches with specialized databases to identify biomarkers and therapeutic targets across different types of cardiomyopathies. In vivo and in vitro models, such as genetically modified mice, patient-derived or induced pluripotent stem cells, and organ chips, are invaluable in exploring the pathophysiological complexities of this disease. By integrating omics approaches with these sophisticated modeling systems, our comprehension of the molecular underpinnings of cardiomyopathy can be greatly enhanced, facilitating the development of diagnostic markers and therapeutic strategies. Among the promising therapeutic targets are those involved in extracellular matrix remodeling, sarcomere damage, and metabolic remodeling. These targets hold the potential to advance precision therapy in cardiomyopathy, offering hope for more effective treatments tailored to the specific molecular profiles of patients.

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach.

Cardiomegaly is among the disorders categorized by a structural enlargement of the heart by any of the situations including pregnancy, resulting in damage to heart muscles and causing trouble in normal heart functioning. Cardiomegaly can be defined in terms of dilatation with an enlarged heart and decreased left or biventricular contraction. The genetic origin of cardiomegaly is becoming more evident due to extensive genomic research opening up new avenues to ensure the use of precision medicine. Cardiomegaly is usually assessed by using an array of radiological modalities, including computed tomography (CT) scans, chest X-rays, and MRIs. These imaging techniques have provided an important opportunity for the physiology and anatomy of the heart. This review aims to highlight the complexity of cardiomegaly, highlighting the contribution of both ecological and genetic variables to its progression. Moreover, we further highlight the worth of precise clinical diagnosis, which comprises blood biomarkers and electrocardiograms (EKG ECG), demonstrating the significance of distinguishing between numerous basic causes. Finally, the analysis highlights the extensive variation of treatment lines, such as lifestyle modifications, prescription drugs, surgery, and implantable devices, although highlighting the critical need for individualized and personalized care.

Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.

Filamin C (FLNC) is a member of a high-molecular weight protein family, which bind actin filaments in the cytoskeleton of various cells. In human genome FLNC is encoded by the FLNC gene located on chromosome 7 and is expressed predominantly in striated skeletal and cardiac muscle cells. Filamin C is involved in organization and stabilization of thin actin filaments three-dimensional network in sarcomeres, and is supposed to play a role of mechanosensor transferring mechanical signals to different protein targets. Under mechanical stress FLNC can undergo unfolding that increases the risk of its aggregation. FLNC molecules with an impaired native structure could be eliminated by the BAG3-mediated chaperone-assisted selective autophagy. Mutations in the FLNC gene could be accompanied by the changes in FLNC interaction with its protein partners and could lead to formation of aggregates, which overload the autophagy and proteasome protein degradation systems, thus facilitating development of various pathological processes. Molecular mechanisms of the FLNC-associated congenital disorders, called filaminopathies, remain poorly understood. This review is devoted to analysis of the structure and mechanisms of filamin C function in muscle and heart cells in normal state and in the FLNC-associated pathologies. The presented data summarize the results of research at the molecular, cellular, and tissue levels and allow us to outline promising ways for further investigation of pathogenetic mechanisms in filaminopathies.

Though pediatric cardiomyopathy is rare in children, there is significant associated morbidity and mortality. Etiology varies from inborn errors of metabolism to familial genetic mutations and myocyte injury. Major classes include dilated, hypertrophic, restrictive, and non-compaction. Diagnosis generally involves a combination of clinical history and echocardiography. The use of cross-sectional imaging is gaining popularity. Management varies between subtype and may involve a combination of medical and surgical interventions depending on clinical status.

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.

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.

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.

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.

Revisions to the heart allocation criteria in 2018 motivated an increased use of extracorporeal membrane oxygenation (ECMO) as a bridge to transplantation. Studies have demonstrated inferior post-transplant outcomes in patients bridged with ECMO but do not account for underlying diagnosis. Our objective was to elucidate the differential impact of ECMO on outcomes by heart failure (HF) etiology.

The United Network of Organ Sharing database was queried for adults who underwent isolated heart transplantation after October 2018. Patients were stratified by ECMO utilization at the time of transplantation and then by HF etiology. After baseline statistical comparisons, survival analysis relied on Kaplan-Meier estimates and Cox proportional models.

A total of 13,203 patients were included, of whom 761 (5.8%) were supported with ECMO. ECMO patients were younger (48 vs 54 years, p < 0.001), less likely to have diabetes (24% vs 30%, p < 0.001), smoke cigarettes (31% vs 41%, p < 0.001), or have prior cardiac surgery (29% vs 36%, p < 0.001), more likely to require dialysis (20% vs 5%, p < 0.001), and spent fewer days on the waitlist (59 vs 190, p < 0.001). After adjustment, ECMO was associated with increased mortality (hazard ratio 1.85, p < 0.001) in the full cohort. After incorporating HF etiology, this increased mortality risk persisted in all subgroups except restrictive cardiomyopathy and congenital heart disease (CHD).

Our findings illustrate that HF etiology is associated with differing outcomes when bridging with ECMO. ECMO patients with restrictive cardiomyopathy or CHD did not have increased mortality risk. With ECMO utilization increasing, these data are hypothesis-generating and serve as a basis for further studies.

Idiopathic restrictive cardiomyopathy (RCM) has a low incidence. This study aimed to determine the prognostic value of big endothelin-1 (ET-1) in idiopathic RCM.

We prospectively enrolled patients with idiopathic RCM from 2009 to 2017 and followed them up. The primary outcome was a composite of all-cause mortality and cardiac transplantation, and the secondary outcome was a composite of cardiac death and cardiac transplantation.

Ninety-one patients were divided into the high big ET-1 (>0.85 pmol/L, n = 56) and low big ET-1 (≤0.85 pmol/L, n = 35) groups, and 87 of them completed the follow-up. Big ET-1 concentrations (hazard ratio: 1.756, 95 % confidence interval [CI]: 1.117-2.760) and late gadolinium enhancement (LGE) (hazard ratio: 3.851, 95 % CI: 1.238-11.981) were independent risk factors for the primary outcome. Big ET-1 concentrations (C-statistic estimation: 0.764, 95 % CI: 0.657-0.871) and the combination of LGE and big ET-1 concentrations (C-statistic estimation: 0.870, 95 % CI: 0.769-0.970) could accurately predict the 5-year transplant-free survival rate, and 0.85 pmol/L was a suitable cutoff for big ET-1.

Big ET-1 and its combination with LGE may be useful to predict an adverse prognosis in patients with idiopathic RCM.

Cardiomyopathy encompasses a broad spectrum of diseases affecting myocardial tissue, characterized clinically by abnormalities in cardiac structure, heart failure, and/or arrhythmias. Clinically heterogeneous, major types include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RM), ischemic cardiomyopathy (ICM), among which DCM is more prevalent, while ICM exhibits higher incidence and mortality rates. Myocardial injury during cardiomyopathy progression may lead to myocardial fibrosis. Failure to intervene early and inhibit the process of myocardial fibrosis may culminate in heart failure. Cardiac fibroblasts constitute crucial cellular components determining the extent and quality of myocardial fibrosis, with various subpopulations exerting diverse roles in cardiomyopathy progression. Despite this, understanding of the cellular plasticity and transcriptional regulatory networks of cardiac fibroblasts in cardiomyopathy remains limited. Therefore, in this study, we conducted comprehensive single-cell analysis of cardiac fibroblasts in cardiomyopathy to explore differences in cellular plasticity and transcriptional regulatory networks among fibroblast subpopulations, with the aim of providing as many useful references as possible for the diagnosis, prognosis, and treatment of cardiomyopathy.

Cells with mitochondrial gene expression comprising >20% of total expressed genes were excluded. Differential expression genes (DEGs) and stemness genes within cardiac fibroblast subpopulations were subjected to Gene Ontology (GO) analysis of biological processes (BP) and AUCell analysis. Monocle software was employed to analyze the pseudo-temporal trajectory of cardiac fibroblasts in cardiomyopathy. Additionally, the Python package SCENIC was utilized to assess enrichment of transcription factors and activity of regulators within cardiac fibroblast subpopulations in cardiomyopathy.

Following batch effect correction, 179,927 cells were clustered into 32 clusters, designated as T_NK cells, endothelial cells, myeloid cells, fibroblasts, pericytes, SMCs, CMs, proliferating cells, EndoCs, and EPCs. Among them, 8148 fibroblasts were further subdivided into 4 subpopulations, namely C0 THBS4+ Fibroblasts, C1 LINC01133+ Fibroblasts, C2 FGF7+ Fibroblasts, and C3 AGT + Fibroblasts. Results from GO_BP and AUCell analyses suggest that C3 AGT + Fibroblasts may be associated with immune response activation, protein transport, and myocardial contractile function, correlating with disease progression in cardiomyopathy. Transcription factor enrichment analysis indicates that FOS is the most significant TF in C3 AGT + Fibroblasts, also associated with the M1 module, possibly implicated in protein hydrolysis, intracellular DNA replication, and cell proliferation. Moreover, correlation analysis of transcriptional regulatory activity between fibroblast subpopulations reveals a more pronounced heterogeneity within C3 AGT + Fibroblasts in cardiomyopathy.

C3 AGT + Fibroblasts exhibit increased sensitivity towards adverse outcomes in cardiomyopathy, such as myocardial fibrosis and impaired cardiac contractile function, compared to other cardiac fibroblast subpopulations. The differential cellular plasticity and transcriptional regulatory activity between C3 AGT + Fibroblasts and other subgroups offer new perspectives for targeting fibroblast subpopulation activity to treat cardiomyopathy. Additionally, stemness genes EPAS1 and MYC, along with the regulator FOS, may play roles in modulating the biological processes of cardiac fibroblasts in cardiomyopathy.

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L-1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L-1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (%V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of %V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.