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Annals of Pediatric Cardiology 2023A full-term male neonate presented on the 11 day of life with late-onset multisystem inflammatory syndrome-neonate (MIS-N) (cardioneurological compromise). Immediate...
A full-term male neonate presented on the 11 day of life with late-onset multisystem inflammatory syndrome-neonate (MIS-N) (cardioneurological compromise). Immediate anti-inflammatory modulation led to a gradual recovery of neurological and coronary lesions. However, temporal evaluation unmasked silent myocardial dysfunction in echocardiography validated further by elevated biomarkers, myocardial fibrosis in cardiac magnetic resonance imaging, and abnormal strain study persisting till 16 months of follow-up. This revealed a hitherto unknown and rare progression of MIS-N into dilated cardiomyopathy.
PubMed: 38817253
DOI: 10.4103/apc.apc_114_23 -
Signal Transduction and Targeted Therapy May 2024The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role... (Review)
Review
The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
Topics: Humans; Macrophages; Cardiovascular Diseases; Fibrosis; Inflammation; Animals
PubMed: 38816371
DOI: 10.1038/s41392-024-01840-1 -
Cell Reports Jun 2024Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin...
Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
Topics: Animals; Nucleotidyltransferases; Membrane Proteins; Mice; Nuclear Envelope; Signal Transduction; Extracellular Matrix; Myocytes, Cardiac; Lamin Type A; Cardiomyopathies; Disease Models, Animal; Mice, Inbred C57BL; Cardiomyopathy, Dilated; DNA Damage
PubMed: 38814785
DOI: 10.1016/j.celrep.2024.114284 -
Cureus May 2024A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was...
A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was less than 10%. Transthoracic echocardiography and cardiovascular magnetic resonance (CMR) imaging also revealed severe bicuspid aortic valve stenosis, dilated cardiomyopathy with LV hypertrophy, prominent LV trabeculations, and features suggestive of mild myocarditis with active inflammation. While myocarditis was suspected on CMR imaging, his mild degree of myocardial involvement did not explain the entirety of his clinical presentation, degree of LV dysfunction, or other structural abnormalities. An extensive work-up for his LV dysfunction was unremarkable for ischemic, metabolic, infiltrative, infectious, toxic, oncologic, connective tissue, and autoimmune etiologies. Genetic testing was positive for a () variant, which was deemed likely to be a unifying etiology underlying his presentation. The sarcomere gene allows beta-myosin expression in heart ventricles, with variants associated with hypertrophic and dilated cardiomyopathies, congenital heart diseases, myocarditis, and excessive trabeculation (formerly known as left ventricular noncompaction). This case highlights the diverse array of cardiac pathologies that can present with gene variants and reviews an extensive work-up for this unusual presentation of heart failure in a young patient.
PubMed: 38813076
DOI: 10.7759/cureus.61252 -
BMC Cardiovascular Disorders May 2024Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in...
Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in combination, are the most frequent, but underestimated, causes of SCD. Molecular autopsy is essential for prevention. Several studies have shown an association between genetic cardiomyopathies and viral myocarditis, which is probably underestimated due to insufficient post-mortem investigations. We report on four autopsy cases illustrating the pathogenesis of these combined pathologies. In two cases, a genetic hypertrophic cardiomyopathy was diagnosed in combination with Herpes Virus Type 6 (HHV6) and/or Parvovirus-B19 (PVB19) in the heart. In the third case, autopsy revealed a dilated cardiomyopathy and virological analyses revealed acute myocarditis caused by three viruses: PVB19, HHV6 and Epstein-Barr virus. Genetic analyses revealed a mutation in the gene coding for desmin. The fourth case illustrated a channelopathy and a PVB19/HHV6 coinfection. Our four cases illustrate the highly probable deleterious role of cardiotropic viruses in the occurrence of SCD in subjects with genetic cardiomyopathies. We discuss the pathogenetic link between viral myocarditis and genetic cardiomyopathy. Molecular autopsy is essential in prevention of these SCD, and a close collaboration between cardiologists, pathologists, microbiologists and geneticians is mandatory.
Topics: Humans; Myocarditis; Death, Sudden, Cardiac; Autopsy; Male; Adult; Female; Herpesvirus 6, Human; Parvovirus B19, Human; Cardiomyopathy, Dilated; Roseolovirus Infections; Cardiomyopathy, Hypertrophic; Parvoviridae Infections; Young Adult; Genetic Predisposition to Disease; Fatal Outcome; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Coinfection; Cause of Death; Mutation; Middle Aged
PubMed: 38811883
DOI: 10.1186/s12872-024-03913-z -
Circulation Jul 2024Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and...
BACKGROUND
Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy.
METHODS
We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation.
RESULTS
Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; <0.001). There was a similar trend in the addition of native T principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; <0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; =0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively).
CONCLUSIONS
Radiomic features extracted from native T, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.
Topics: Humans; Cardiomyopathy, Dilated; Extracellular Matrix; Female; Male; Middle Aged; Adult; Collagen; Myocardium; Aged; Fibrosis; Magnetic Resonance Imaging; Biopsy; Principal Component Analysis; Radiomics
PubMed: 38808522
DOI: 10.1161/CIRCULATIONAHA.123.067107 -
Korean Journal of Radiology Jun 2024This study investigated the feasibility and prognostic relevance of threshold-based quantification of myocardial delayed enhancement (MDE) on CT in patients with...
OBJECTIVE
This study investigated the feasibility and prognostic relevance of threshold-based quantification of myocardial delayed enhancement (MDE) on CT in patients with nonischemic dilated cardiomyopathy (NIDCM).
MATERIALS AND METHODS
Forty-three patients with NIDCM (59.3 ± 17.1 years; 21 male) were included in the study and underwent cardiac CT and MRI. MDE was quantified manually and with a threshold-based quantification method using cutoffs of 2, 3, and 4 standard deviations (SDs) on three sets of CT images (100 kVp, 120 kVp, and 70 keV). Interobserver agreement in MDE quantification was assessed using the intraclass correlation coefficient (ICC). Agreement between CT and MRI was evaluated using the Bland-Altman method and the concordance correlation coefficient (CCC). Patients were followed up for the subsequent occurrence of the primary composite outcome, including cardiac death, heart transplantation, heart failure hospitalization, or appropriate use of an implantable cardioverter-defibrillator. The Kaplan-Meier method was used to estimate event-free survival according to MDE levels.
RESULTS
Late gadolinium enhancement (LGE) was observed in 29 patients (67%, 29/43), and the mean LGE found with the 5-SD threshold was 4.1% ± 3.6%. The 4-SD threshold on 70-keV CT showed excellent interobserver agreement (ICC = 0.810) and the highest concordance with MRI (CCC = 0.803). This method also yielded the smallest bias with the narrowest range of 95% limits of agreement compared to MRI (bias, -0.119%; 95% limits of agreement, -4.216% to 3.978%). During a median follow-up of 1625 days (interquartile range, 712-1430 days), 10 patients (23%, 10/43) experienced the primary composite outcome. Event-free survival significantly differed between risk subgroups divided by the optimal MDE cutoff of 4.3% (log-rank = 0.005).
CONCLUSION
The 4-SD threshold on 70-keV monochromatic CT yielded results comparable to those of MRI for quantifying MDE as a marker of myocardial fibrosis, which showed prognostic value in patients with NIDCM.
Topics: Humans; Male; Cardiomyopathy, Dilated; Female; Middle Aged; Prognosis; Tomography, X-Ray Computed; Feasibility Studies; Contrast Media; Fibrosis; Magnetic Resonance Imaging; Myocardium; Adult; Aged
PubMed: 38807335
DOI: 10.3348/kjr.2023.1271 -
Yonago Acta Medica May 2024Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety... (Review)
Review
Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety of clinical manifestations, including progressive visual and hearing impairment, type 2 diabetes mellitus, dilated cardiomyopathy, and hepatic and renal dysfunction, in addition to obesity. Recent insights underline the pivotal involvement of the disease-associated gene () in cilia formation and function, leading to the classification of its clinical manifestations as a ciliopathy. This review delineates the diverse clinical indicators defining the syndrome and elucidates its pathological underpinnings.
PubMed: 38803594
DOI: 10.33160/yam.2024.05.010 -
Cardiology Research and Practice 2024Cardiomyopathy encompasses a broad spectrum of diseases affecting myocardial tissue, characterized clinically by abnormalities in cardiac structure, heart failure,...
BACKGROUND
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.
MATERIALS AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
PubMed: 38799173
DOI: 10.1155/2024/3131633 -
BioRxiv : the Preprint Server For... May 2024There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a...
BACKGROUND
There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines.
METHODS
We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility.
RESULTS
We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment.
CONCLUSIONS
We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for in cardiomyopathy.
PubMed: 38798547
DOI: 10.1101/2024.05.10.593618