Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and ...clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but ...little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants.
Dilated cardiomyopathy (DCM) is a primary cause of heart failure, life-threatening arrhythmias, and cardiac death. Pathogenic mutations have been identified at the loci of more than 50 genes in ...approximately 50% of DCM cases, while the etiologies of the remainder have yet to be determined. In this study, we applied whole exome sequencing in combination with segregation analysis to one pedigree with familial DCM, and identified a read-through mutation (c.2459 A > C; p.*820Sext*19) in the myosin light chain kinase 3 gene (MYLK3). We then conducted MYLK3 gene screening of 15 DCM patients (7 familial and 8 sporadic) who were negative for mutation screening of the previously-reported cardiomyopathy-causing genes, and identified another case with a MYLK3 frameshift mutation (c.1879_1885del; p.L627fs*41). In vitro experiments and immunohistochemistry suggested that the MYLK3 mutations identified in this study result in markedly reduced levels of protein expression and myosin light chain 2 phosphorylation. This is the first report that MYLK3 mutations can cause DCM in humans. The clinical phenotypes of DCM patients were consistent with MYLK3 loss-of-function mouse and zebrafish models in which cardiac enlargement and heart failure are observed. Our findings highlight an essential role for cardiac myosin light chain kinase in the human heart.
The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, ...and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure.
We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes.
We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.
•Novel pipeline combines scRNA-seq and smFISH with high-throughput image analysis.•Stress response shown by increased Myh7 expression was spatially heterogeneous.•Mitochondria-related genes inversely correlated with Myh7 in scRNA-seq data.
Decreased cell size in Myh7-positive cells suggests energy metabolism crisis.
Abstract Bland-White-Garland syndrome (BWG) is a congenital heart disease characterized by anomalous origin of left coronary artery from main pulmonary artery. The anomaly causes significant ...myocardial ischemia, mitral insufficiency, and high infant mortality. Several investigators have reported that the subjects who survived to adulthood showed extensive collateral flow from right coronary artery (RCA). We report a case of newly diagnosed BWG in an elderly patient who had well-developed collaterals from aneurysmal giant RCA and bronchial artery, which were identified by coronary angiography with multi-detector computed tomography. < Learning objective: Structural heart disease is occasionally hard to assess with invasive angiography. In this case, multi-detector computed tomography demonstrated complicated structure of anomalous coronary morphology including collateral sources from extra-cardiac anastomoses. The severity of anomaly related myocardial ischemia was evaluated by image fusion with radionuclide myocardial perfusion. Multimodal imaging approach can provide comprehensive and incremental information.>
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•Patients with dilated cardiomyopathy who achieved LVRR have a favorable prognosis, but it is still difficult to precisely predict LVRR in the clinical setting.•Immunostaining of DNA ...damage markers such as PAR in biopsy specimens from patients with dilated cardiomyopathy revealed that patients with LVRR showed a significantly smaller proportion of PAR-positive nuclei compared with those without LVRR.•The high proportion of PAR-positive nuclei was an independent prognostic factor for LVRR. Besides, it can predict clinical prognosis (death, heart transplantation, and ventricular assist device implantation) with good sensitivity and specificity.
This study evaluated myocardial nuclear staining for the DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in 58 patients with dilated cardiomyopathy. Patients with left ventricular reverse remodeling (LVRR) showed a significantly smaller proportion of PAR-positive nuclei and γ-H2A.X–positive nuclei in biopsy specimens compared with those without LVRR. Propensity analysis showed that the proportion of both PAR-positive and γ-H2A.X–positive nuclei were independent prognostic factors for LVRR. In conclusion, we showed the utility of DNA damage-marker staining to predict the probability of LVRR, thus revealing a novel prognostic predictor of medical therapy for dilated cardiomyopathy.
Cardiac sarcoidosis masked by malignant lymphoma Tobita, Takashige, MD; Hattori, Hidetoshi, MD; Serizawa, Naoki, MD ...
Canadian journal of cardiology,
08/2016, Letnik:
32, Številka:
8
Journal Article
Recenzirano
Abstract There is an association between sarcoidosis and lymphoma, termed “sarcoidosis-lymphoma syndrome”. Sarcoidosis is generally detected prior to lymphoma, but sarcoidosis could present after or ...even concurrently with the diagnosis of lymphoma. We describe a patient presenting with ventricular tachycardia and lymphadenopathy. A diagnosis of Hodgkin lymphoma was made histologically. The patient responded to treatment, but had persistent 18F-fluoro-deoxyglucose uptake in the lymph nodes and heart on follow-up positron emission tomography. Second biopsies of lymph node and endomyocardial both confirmed sarcoidosis. This finding suggests that we should maintain a high degree of suspicion for cardiac sarcoidosis in lymphoma patients.
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