The term cardiomyopathy refers to a group of heart diseases that cause severe heart failure over time. Cardiomyopathies have been proven to be associated with ferroptosis, a non-apoptotic form of cell death. It has been shown that some small molecule drugs and active ingredients of herbal medicine can regulate ferroptosis, thereby alleviating the development of cardiomyopathy. This article reviews recent discoveries about ferroptosis, its role in the pathogenesis of cardiomyopathy, and the therapeutic options for treating ferroptosis-associated cardiomyopathy. The article aims to provide insights into the basic mechanisms of ferroptosis and its treatment to prevent cardiomyopathy and related diseases.

Hypertrophic cardiomyopathy (HCM) is a rare genetic heart disease characterized by a limited patient population and scarce research and treatment resources. This study aimed to identify HCM-associated proteins by integrating cardiac tissue data from the Gene Expression Omnibus (GEO) database with the latest protein quantitative trait locus (pQTL) dataset.

We analysed data from the GEO database. The GSE36961 dataset included 106 HCM samples and 39 healthy controls. The GSE180313 dataset included 13 HCM samples and 7 healthy controls. pQTL data were obtained from the plasma of 54 000 UK Biobank participants, covering 1463 proteins. HCM genome-wide association study (GWAS) data were sourced from the FinnGen study, which included 1125 HCM cases and 411 056 controls. We analysed the GEO dataset of cardiac tissue from HCM patients to identify differentially expressed genes (DEGs). These DEGs were compared with pQTL data to identify protein phenotypes suitable for Mendelian randomization (MR) analysis. A two-sample MR analysis was performed to assess the causal association between these protein phenotypes and HCM. The robustness of the study results was further assessed through sensitivity analysis of heterogeneity and horizontal pleiotropy tests. Two proteins were identified as causally associated with HCM risk: carbonic anhydrase 3 (CA3) [inverse variance weighted (IVW): odds ratio (OR) = 1.292, 95% confidence interval (CI) = 1.021-1.636, P = 0.033] and serpin family E member 1 (SERPINE1) [IVW: OR = 1.313, 95% CI = 1.063-1.621, P = 0.011]. Both proteins were associated with increased HCM risk, with no significant heterogeneity (P > 0.05) or evidence of horizontal pleiotropy (P > 0.05).

CA3 and SERPINE1 proteins may exert causal effects on HCM and may serve as characteristic markers and therapeutic targets for this condition.

Inherited cardiomyopathies are a major cause of heart failure in all age groups, often with an onset in adolescence or early adult life. More than a thousand variants in approximately one hundred genes are associated with cardiomyopathies. Interestingly, many genetic cardiomyopathies display overlapping phenotypical defects in patients, despite the diversity of the initial pathogenic variants. Understanding how the underlying pathophysiology of genetic cardiomyopathies leads to these phenotypes will improve insights into a patient's disease course, and creates the opportunity for conceiving treatment strategies. Moreover, therapeutic strategies can be used to treat multiple cardiomyopathies based on shared phenotypes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer reliable, high-throughput models for studying molecular and cellular characteristics of hereditary cardiomyopathies. hiPSC-CMs are produced relatively easily, either by directly originating them from patients, or by introducing patient-specific genetic variants in healthy lines. This review evaluates 90 studies on 24 cardiomyopathy-associated genes and systematically summarises the morphological and functional phenotypes observed in hiPSC-CMs. Additionally, treatment strategies applied in cardiomyopathic hiPSC-CMs are compiled and scored for effectiveness. Multiple overlapping phenotypic defects were identified in cardiomyocytes with different variants, whereas certain characteristics were only associated with specific genetic variants. Based on these findings, common mechanisms, therapeutic prospects, and considerations for future research are discussed with the aim to improve clinical translation from hiPSC-CMs to patients.

Hypertrophic cardiomyopathy remains underdiagnosed despite a growing number of effective treatment interventions that can improve care. Multimodality imaging has become integral to diagnosing and managing hypertrophic cardiomyopathy, providing a comprehensive assessment of the disease. In particular, it enhances the diagnostic accuracy and deepens the understanding of the mechanisms underlying patient symptoms, enabling targeted therapeutic approaches. Additionally, multimodality imaging allows for better risk stratification, assessment of therapy response, and guidance of interventions to deliver personalized medicine. The practical tools outlined in this review can help providers integrate multimodality imaging strategies to provide better care and improve the patient experience.

Hypertrophic cardiomyopathy (HCM) is an inherited condition characterized by left ventricular, non-dilated hypertrophy in the absence of another secondary underlying cause. There has been an ongoing increase in the diagnosis of HCM over the past couple of decades, prompting further work in the area of pharmacological and interventional therapies. This scoping review aimed to summarize the traditional therapeutic options for HCM and to explore emerging research on novel cardiac myosin inhibitors (CMIs) as a new option for pharmacologic management of HCM. A PRISMA search strategy was carried out to identify the pertinent literature on mavacamten and aficamten-two novel CMIs. Seventeen studies were included. Based on the results of the studies included in this review, cardiac myosin inhibitors have been proven to be a safe and efficacious second-line option for the management of HCM. In the foreseeable future, based on results of ongoing studies investigating patient outcomes and side-effect profile, CMIs may potentially play a larger role as part of standard treatment of HCM.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder in which left ventricular outflow tract obstruction critically affects symptoms and prognosis. Traditionally, left ventricular outflow tract obstruction was primarily attributed to septal hypertrophy with systolic anterior motion of the mitral valve. However, recent evidence highlights significant contributions from the mitral valve and papillary muscle anomalies, as well as an apical-basal muscle bundle observed in HCM patients. Accurate morphological assessment is essential when considering septal reduction therapy. While transesophageal echocardiography and cardiac magnetic resonance are recommended for assessing the anomalous structures, four-dimensional computed tomography offers superior spatial resolution and multiplanar reconstruction capabilities. These features enable the evaluation of details of the morphological anomalies, such as the apical-basal muscle band, papillary muscle anomalies, subaortic stenosis, and right ventricular outflow tract obstruction. Based on the detailed assessment of these morphological features, four-dimensional computed tomography has been utilized for planning of surgical correction in a comprehensive HCM center. This approach facilitates the intervention strategies and may improve outcomes in septal reduction therapy for obstructive HCM.

Altitude is a known factor in cardiovascular disease, but its impact on hypertrophic cardiomyopathy (HCM) patients remains unclear. This study aimed to determine whether living at high altitudes affects the extent of late gadolinium enhancement (LGE) and left ventricular (LV) strain in HCM patients.

This retrospective cross-sectional study was conducted across four hospitals located at different altitudes in China. A total of 256 HCM patients who underwent cardiac magnetic resonance (CMR) imaging between May 2019 and November 2021 were included. Patients were categorized into two groups: the high-altitude group (median interquartile range [IQR]: 1520.00 [1520.00, 1917.00] meters, n = 132) and the low-altitude group (86.45 [43.50, 150.75] meters, n = 124). The extent of LGE and global LV strain were assessed and compared between these groups.

The median age of the study population was 55 years (IQR: 46-63), with 59% of participants being male. The high-altitude group exhibited a significantly greater extent of LGE compared to the low-altitude group (median [IQR]: 8.10 [4.78, 19.98]% vs. 6.20 [1.89, 13.81]%; p = 0.008). Multivariable analysis identified altitude as an independent predictor of increased LGE extent (β = 4.41; 95% CI: 2.04 to 6.78; p < 0.001). Additionally, altitude was positively associated with LV strain in the longitudinal, circumferential, and radial directions (all p < 0.050).

HCM patients living at higher altitudes exhibit a significant increase in LGE extent and more favorable LV strain parameters.

Question Does altitude affect the extent of late gadolinium enhancement (LGE) and left ventricular strain in patients with hypertrophic cardiomyopathy (HCM)? Findings High altitude is associated with a significantly greater extent of LGE and less impairment in global longitudinal strain in HCM patients. Clinical relevance HCM patients living at higher altitudes exhibit a significant increase in LGE extent and the mismatch of left ventricular strains. Doctors should consider these findings to tailor treatment and follow-up plans for HCM patients living in high altitudes.

Maternal hemoglobin A1c (HbA1c) has been suggested to be a predictor of left ventricular hypertrophy (LVH) in the offspring of mothers with pre-gestational diabetes mellitus, although there is little data supporting this contention. We aimed to assess the relationship between maternal HbA1c and postnatal LVH.

We performed a retrospective cohort study of infants born to mothers with pre-gestational diabetes mellitus from 2015 to 2021 at our institution. The primary predictor was maternal HbA1c; neonatal left ventricular mass (LVM) z-score was the primary outcome; LVM z-score was considered as both a continuous variable and a binary variable by dichotomizing at 4 to define LVH. Additionally, we used linear regression to determine the relationship between maternal HbA1c and LVM z-score.

There were 116 infants who met inclusion (50% female). Mean maternal HbA1c was generally higher in infants with LVH compared to those without LVH (8.2% with LVH vs. 7.2% without LVH [p = 0.009] in the second trimester, and 7.8% vs. 7.0% [p = 0.025] in the third trimester; no significant difference for first trimester). A greater percentage of infants with LVH were intubated (36% vs. 6%, p < 0.001) and had longer average days of hospitalization (9 vs. 5, p = 0.044). Second and third trimester HbA1c was weakly associated with LVM z-score (R2 = 0.063, p < 0.001 and R2 = 0.068, p < 0.001, respectively); first trimester HbA1c was not significantly predictive of LVM z-score.

Second and third trimester HbA1c is modestly predictive of LVH in infants born to mothers with pre-gestational diabetes mellitus.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease that is characterized by left ventricular hypertrophy unexplained by secondary causes. Based on international epidemiological data, around 20,000-40,000 patients are expected to be affected in Austria. Due to the wide variety of clinical and morphological manifestations the diagnosis can be difficult and the disease therefore often goes unrecognized. HCM is associated with a substantial reduction in quality of life and can lead to sudden cardiac death, especially in younger patients. Early and correct diagnosis, including genetic testing, is essential for comprehensive counselling of patients and their families and for effective treatment. The latter is especially true as an effective treatment of outflow tract obstruction has recently become available in the form of a first in class cardiac myosin ATPase inhibitor, as a noninvasive alternative to established septal reduction therapies. The aim of this Austrian consensus statement is to summarize the recommendations of international guidelines with respect to the genetic background, pathophysiology, diagnostics and management in the context of the Austrian healthcare system and resources, and to present them in easy to understand algorithms.

Mitral valve (MV) leaflet elongation is recognized as a primary phenotypic expression of hypertrophic cardiomyopathy (HCM) that contributes to obstruction. This study investigates the correlation between MV length and genotype mutations in the two predominant genes, myosin-binding protein C (MYBPC3), and the β-myosin heavy chain (MYH7) in patients with obstructive HCM (OHCM). Among the 402 OHCM patients, there were likely pathogenic or pathogenic variations in MYH7 (n = 94) and MYBPC3 (n = 76), along with a mutation-negative group (n = 212). Compared to genotype-negative patients, genotype-positive individuals exhibited elongated MV length, thicker interventricular septum, and increased instances of late gadolinium enhancement. Notably, MYH7 mutations were associated with a more severe disease trajectory than MYBPC3 mutations. After adjusting for potential confounders, multivariate linear regression analysis revealed that MYH7 gene mutations and left ventricular volume were independently associated with MV leaflet elongation. The study indicates that mutations in MYH7 and hemodynamics factors are significant risk factors for elongated MV leaflet. Consequently, regular assessment of MV length, especially in patients with MYH7 mutation and enlarged LV volume, is crucial for timely preoperative strategic planning and improved prognosis.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal growth of the myocardium with myofilament disarray and myocardial hyper-contractility, leading to left ventricular hypertrophy and fibrosis. Where culprit genes are identified, they typically relate to cardiomyocyte sarcomere structure and function. Multi-modality imaging plays a crucial role in the diagnosis, monitoring, and risk stratification of HCM, as well as in screening those at risk. Following the recent publication of the first European Society of Cardiology (ESC) cardiomyopathy guidelines, we build on previous reviews and explore the roles of electrocardiography, echocardiography, cardiac magnetic resonance (CMR), cardiac computed tomography (CT), and nuclear imaging. We examine each modality's strengths along with their limitations in turn, and discuss how they can be used in isolation, or in combination, to facilitate a personalized approach to patient care, as well as providing key information and robust safety and efficacy evidence within new areas of research.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria. The classical paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces, reflected in the augmented QRS amplitude. However, the low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm. The theoretical background for voltage measured at the body surface is defined by the solid angle theorem, which relates the measured voltage to spatial and non-spatial determinants. The spatial determinants are represented by the extent of the activation front and the distance of the recording electrodes. The non-spatial determinants comprise electrical characteristics of the myocardium, which are comparatively neglected in the interpretation of the QRS patterns. Various clinical conditions are associated with LVH. These conditions produce considerable diversity of electrical properties alterations thereby modifying the resultant QRS patterns. The spectrum of QRS patterns observed in LVH patients is quite broad, including also left axis deviation, left anterior fascicular block, incomplete and complete left bundle branch blocks, Q waves, and fragmented QRS. Importantly, the QRS complex can be within normal limits. The new paradigm stresses the electrophysiological background in interpreting QRS changes, i.e., the effect of the non-spatial determinants. This postulates that the role of ECG is not to estimate LV size in LVH, but to understand and decode the underlying electrical processes, which are crucial in relation to cardiovascular risk assessment.

Hypertrophic obstructive cardiomyopathy (HOCM) and subaortic membrane (SAS) are distinct cardiac conditions, but their coexistence presents complex diagnostic challenges. We report the case of a 52-year-old male with HOCM and a concurrent subaortic membrane, highlighting the intricacies of diagnosis and management. The patient's presentation included symptoms of dyspnea and chest tightness, and diagnostic evaluations revealed a unique combination of dynamic left ventricular outflow tract (LVOT) obstruction from HOCM and fixed obstruction from the subaortic membrane. This case emphasizes the importance of a comprehensive diagnostic workup to guide appropriate treatment decisions when managing multiple cardiac abnormalities.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria, i.e. the increased QRS complex amplitude in defined leads. The classical ECG diagnostic paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces. These increased forces are reflected in the augmented QRS amplitude in the corresponding leads. However, the clinical observations document increased QRS amplitude only in the minority of patients with LVH. The low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm.

Cardiomyopathy, which is a genetically and phenotypically heterogeneous pathological condition, is associated with increased morbidity and mortality. Genetic diagnosis of cardiomyopathy enables accurate phenotypic classification and optimum patient management and counseling. This study investigated the genetic spectrum of cardiomyopathy and its correlation with the clinical course of the disease.

The samples of 72 Korean patients with cardiomyopathy (43 males and 29 females) were subjected to whole-exome sequencing (WES). The familial information and clinical characteristics of the patients were reviewed and analyzed according to their genotypes.

Dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction cardiomyopathy, and restrictive cardiomyopathy was detected in 41 (56.9%), 25 (34.7%), 4 (5.6%), and 2 (2.8%) patients, respectively. WES analysis revealed positive results in 37 (51.4%) patients. Subsequent familial testing identified ten additional familial cases. Among DCM cases, 19 (46.3%) patients exhibited positive results, with TTN variants being the most common alteration, followed by LMNA and MYH7 variants. Meanwhile, among HCM cases, 15 (60%) patients exhibited positive results with MYH7 variants being the most common alteration. In six patients with positive results, extracardiac surveillance was warranted based on disease information. The incidence of worse outcomes, such as mortality and life-threatening arrhythmic events, in patients with DCM harboring LMNA variants, was higher than that in patients with DCM harboring TTN or MYH7 variants.

Diverse genotypes were identified in a substantial proportion of patients with cardiomyopathy. Genetic diagnosis enables personalized disease surveillance and management.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac condition characterized by unexplained left ventricular hypertrophy without a hemodynamic cause. This condition is prevalent in the United States, resulting in various clinical manifestations, including diastolic dysfunction, left ventricular outflow obstruction, cardiac ischemia, and atrial fibrillation. HCM is associated with several genetic mutations, with sarcomeric mutations being the most common and contributing to a more complex disease course. Early diagnosis of HCM is essential for effective management, as late diagnosis often requires invasive treatments and creates a substantial financial burden. Disparities in HCM diagnosis and treatment exist between high-income and low-income countries. High-income countries have more resources to investigate and implement advanced diagnostic and treatment modalities. In contrast, low-income countries face challenges in accessing diagnostic equipment, trained personnel, and affordable medications, leading to a lower quality of life and life expectancy for affected individuals. Diagnostic tools for HCM include imaging studies such as 2D echocardiography, cardiovascular magnetic resonance (CMR), and electrocardiograms (ECGs). CMR is considered the gold standard but remains inaccessible to a significant portion of the world's population, especially in low-income countries. Genetics plays a crucial role in HCM, with numerous mutations identified in various genes. Genetic counseling is essential but often limited in low-income countries due to resource constraints. Disparities in healthcare access and adherence to treatment recommendations exist between high-income and low-income countries, leading to differences in patient outcomes. Addressing these disparities is essential to improve the overall management of HCM on a global scale. In conclusion, this review highlights the complex nature of HCM, emphasizing the importance of early diagnosis, genetic counseling, and access to appropriate diagnostic and therapeutic interventions. Addressing healthcare disparities is crucial to ensure that all individuals with HCM receive timely and effective care, regardless of their geographic location or socioeconomic status.

The diagnosis and management of hypertrophic cardiomyopathy (HCM) requires multimodality imaging. Transthoracic echocardiogram (TTE) remains the first-line imaging modality to diagnose HCM identifying morphology and obstruction, which includes left ventricular outflow obstruction, midcavitary obstruction and systolic anterior motion. Cardiac magnetic resonance imaging (CMR) can adjudicate equivocal cases, rule out alternative diagnoses and evaluate for risk factors of sudden cardiac death. Imaging with TTE or transesophageal echocardiogram can also guide alcohol septal ablation or surgical myectomy respectively. Furthermore, TTE can guide medical management of these patients by following peak gradients. Thus, multimodality imaging in HCM is crucial throughout the course of these patients' care.

Heart disease is a worldwide health menace. Both intractable primary and secondary cardiomyopathies contribute to malignant cardiac dysfunction and mortality. One of the key cellular processes associated with cardiomyopathy is cardiomyocyte death. Cardiomyocytes are terminally differentiated cells with very limited regenerative capacity. Various insults can lead to irreversible damage of cardiomyocytes, contributing to progression of cardiac dysfunction. Accumulating evidence indicates that majority of cardiomyocyte death is executed by regulating molecular pathways, including apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Importantly, these forms of regulated cell death (RCD) are cardinal features in the pathogenesis of various cardiomyopathies, including dilated cardiomyopathy, diabetic cardiomyopathy, sepsis-induced cardiomyopathy, and drug-induced cardiomyopathy. The relevance between abnormity of RCD with adverse outcome of cardiomyopathy has been unequivocally evident. Therefore, there is an urgent need to uncover the molecular and cellular mechanisms for RCD in order to better understand the pathogenesis of cardiomyopathies. In this review, we summarize the latest progress from studies on RCD pathways in cardiomyocytes in context of the pathogenesis of cardiomyopathies, with particular emphasis on apoptosis, necroptosis, ferroptosis, autophagy, and pyroptosis. We also elaborate the crosstalk among various forms of RCD in pathologically stressed myocardium and the prospects of therapeutic applications targeted to various cell death pathways.

In this case study, we present the evaluation of an orthotopic heart transplant (OHT) patient who presented with persistent shortness of breath and dizziness upon standing. The investigation uncovered the presence of progressive hypertrophic cardiomyopathy (HCM) in the transplanted heart, a condition first detected 11 years after the transplantation. Utilizing echocardiography with global longitudinal strain (GLS), we determined that the HCM likely originated from genetic predominance inherited from the heart donor rather than hypertensive disease. This finding highlights the significance of genetic factors in post-transplant complications and warrants further investigation into the long-term effects of heart transplantation on recipient health.

Malignant hypertrophic cardiomyopathy (HCM) phenotypes have potential risks of severe heart failure, fatal arrhythmia, and sudden cardiac death. Therefore, it is critical to predict the clinical outcomes of these patients. It was reported recently that the alpha kinase 3 (ALPK3) gene was involved in the occurrence of HCM. Herein we reported a girl with HCM, while whole-exome sequencing found novel compound heterozygous variants in ALPK3 gene, which identified a potential association.

We reported a 14-year-girl who suffered from clinical manifestations of cardiac failure, with sudden cardiac arrest before admission. The heartbeat recovered after cardiopulmonary resuscitation, though she remained unconscious without spontaneous breath. The patient stayed comatose when she was admitted. Physical examination indicated enlargement of the heart boundary. Laboratory results revealed a significant increment of myocardial markers, while imaging demonstrated hypertrophy of the left heart and interventricular septum. Whole-exome sequencing (WES) identified a compound heterozygous variant in ALPK3 gene consisting of c.3907_3922del and c.2200A>T, which was inherited from her parents. Both variants (p.G1303Lfs*28 and p.R734*) were disease-causing evaluated by MutationTaster (probability 1.000). The crystal structure of the complete amino acid sequence is predicted and evaluated by AlphaFold and SWISS-MODEL software (July, 2022), which revealed three domains. Moreover, both variants resulted in a wide protein-truncating variant and damaged protein function. Thus, a novel compound heterozygous variant in ALPK3 associated with HCM was diagnosed.

We described a young patient with ALPK3-associated HCM who experienced sudden cardiac arrest. Through WES, we identified a compound heterozygous variant in the ALPK3 gene, c.3907_3922del and c.2200A>T, which were inherited from the patient's parents and resulted in a truncated protein, indirectly causing the symptoms of HCM. In addition, WES provided clues in evaluating potential risks of gene variants on fatal clinical outcomes, and the nonsense and frameshift variants of ALPK3 were related to adverse clinical outcomes in HCM patients, which required implantable cardioverter defibrillator (ICD) timely.

Sudden cardiac death represents the leading cause of death worldwide; although the majority of sudden deaths occur in an elderly population with coronary artery disease, some occur in young and otherwise healthy individuals, as is the case of cardiomyopathies. The aim of the present review is to provide a stepwise hierarchical approach for the global sudden death risk estimation in primary cardiomyopathies. Each individual risk factor is analyzed for its contribution to the overall risk of sudden death for each specific cardiomyopathy as well as across all primary myocardial diseases. This stepwise hierarchical and personalized approach starts from the clinical evaluation, subsequently passes through the role of electrocardiographic monitoring and multimodality imaging, and finally concludes with genetic evaluation and electro-anatomical mapping. In fact, the sudden cardiac death risk assessment in cardiomyopathies depends on a multiparametric approach. Moreover, current indications for ventricular arrhythmia ablation and defibrillator implantation are discussed.

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic causes of heart disease. Since the initial description of HCM, there have been minimal strides in management options. Obstructive HCM constitutes a larger subset of patients with increased left ventricular outflow tract gradients causing symptoms. Septal reduction therapy (SRT) has been successful, but it is not the answer for all patients and is not disease modifying.

Current guideline recommendations include beta-blockers, calcium channel blockers, or disopyramides for medical management, but there lacks evidence of much benefit with these drugs. In recent years, there has been the emergence of cardiac myosin inhibitors (CMI) which have demonstrated positive results in patients with both obstructive and non-obstructive HCM. In addition to CMIs, other drugs have been investigated as we have learned more about HCM's pathological mechanisms. Drugs targeting sodium channels and myocardial energetics, as well as repurposed drugs that have demonstrated positive remodeling are being investigated as potential therapeutic targets. Gene therapy is being explored with vast potential for the treatment of HCM.

The armamentarium of therapeutic options for HCM is continuously increasing with the emergence of CMIs as mainstays of treatment. The future of HCM treatment is promising.

This study aims to validate and compare the feasibility of T1ρ and native longitudinal relaxation time (T1) mapping in detection of myocardial fibrosis in patients with non-ischaemic cardiomyopathy, focusing on the performance of both methods in identifying late gadolinium enhancement (LGE) grey zone.

Twenty-seven hypertrophic cardiomyopathy (HCM) patients, 16 idiopathic dilated cardiomyopathy (DCM) patients, and 18 healthy controls were prospectively enrolled for native T1 and T1ρ mapping imaging and then all the patients underwent enhancement scan for LGE extent and extracellular volume (ECV) values. In LGE positive patients, the LGE areas were divided into LGE core (6 SDs above remote myocardium) and grey zone (2-6 SDs above remote myocardium) according to the signal intensity of LGE. Both HCM and DCM patients showed significantly higher native T1 values and T1ρ values than controls no matter the presence of LGE (all P < 0.01). There were significant differences in native T1 and T1ρ values among four different types of myocardia (LGE core, grey zone, remote area and control, P < 0.0001). However, the T1ρ values of grey zone were significantly higher than control (P < 0.01), while the native T1 values were not (P = 0.089). T1ρ values were significantly associated with both native T1 values (r = 0.54, P < 0.001) and ECV values (r = 0.54, P < 0.001).

T1ρ mapping is a feasible method to detect myocardial fibrosis in patients with non-ischaemic cardiomyopathy no matter the presence of LGE. Compared with native T1, T1ρ may serve as a better discriminator in the identification of LGE grey zone.

Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.

We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes.

We identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.

We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.

The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes.

We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot.

Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation.

These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.

Hypertrophic cardiomyopathy (HCM), now recognized as a common cardiomyopathy of complex genomics and pathophysiology, is defined by the presence of left ventricular hypertrophy of various morphologies and severity, significant hemodynamic consequences, and diverse phenotypic, both structural and clinical, profiles. Advancements in cardiac multimodality imaging, including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography, with and without angiography have greatly improved the diagnosis of HCM, and enable precise measurements of cardiac mass, volume, wall thickness, function, and physiology. Multimodality imaging provides comprehensive and complementary information and hasemerged as the bedrock for the diagnosis, clinical assessment, serial monitoring, and sudden cardiac death risk stratification of patients with HCM. This review highlights the role of cardiac multimodality imaging in the modern diagnosis and management of HCM.

The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.

Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM.

Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile.

We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls.

We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.

Hypertrophic cardiomyopathy (HCM) is defined by the presence of left ventricular hypertrophy in the absence of other potentially causative cardiac, systemic, syndromic, or metabolic diseases. Symptoms can be related to a range of pathophysiologic mechanisms including left ventricular outflow tract obstruction with or without significant mitral regurgitation, diastolic dysfunction with heart failure with preserved and heart failure with reduced ejection fraction, autonomic dysfunction, ischemia, and arrhythmias. Appropriate understanding and utilization of multimodality imaging is fundamental to accurate diagnosis as well as longitudinal care of patients with HCM. Resting and stress imaging provide comprehensive and complementary information to help clarify mechanism(s) responsible for symptoms such that appropriate and timely treatment strategies may be implemented. Advanced imaging is relied upon to guide certain treatment options including septal reduction therapy and mitral valve repair. Using both clinical and imaging parameters, enhanced algorithms for sudden cardiac death risk stratification facilitate selection of HCM patients most likely to benefit from implantable cardioverter-defibrillators.

Cardiac masses are a rare cause of chest pain. They can often be missed on a chest radiograph performed to evaluate non-specific chest pain and are not readily evaluated with traditional laboratory testing. However, these masses can be visualized with point-of-care ultrasound.

We present a case of a 19-year-old female presenting with intermittent chest pain, palpitations, and weakness present for two months. The patient had previously been evaluated at our emergency department one week earlier and was diagnosed with anxiety before being discharged. Besides a tachycardic and labile heart rate, physical examination and laboratory testing were unremarkable. Point-of-care cardiac echocardiography subsequently demonstrated findings concerning for a cardiac mass.

Cardiac masses are a rare cause of chest pain and palpitations that are easily missed. The advent of point-of-care ultrasonography has afforded us the ability to rapidly assess for structural and functional cardiac abnormalities at bedside, and incorporation of this tool into the evaluation of patients with chest pain offers the ability to detect these rare pathologies.