Neutrophil Extracellular Traps in Myocardial Tissue Drive Cardiac Dysfunction and Adverse Outcomes in Patients With Heart Failure With Dilated Cardiomyopathy.

BACKGROUND: The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated. METHODS: We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted. RESULTS: The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation. CONCLUSIONS: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes.

Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure.

Protein diversity can increase via N-myristoylation, adding myristic acid to an N-terminal glycine residue. In a murine model of pressure overload, knockdown of cardiac N-myristoyltransferase 2 (NMT2) by adeno-associated virus 9 exacerbated cardiac dysfunction, remodeling, and failure. Click chemistry-based quantitative chemical proteomics identified substrate proteins of N-myristoylation in cardiac myocytes. N-myristoylation of MARCKS regulated angiotensin II-induced cardiac pathological hypertrophy by preventing activations of Ca2+/calmodulin-dependent protein kinase II and histone deacetylase 4 and histone acetylation. Gene transfer of NMT2 to the heart reduced cardiac dysfunction and failure, suggesting targeting N-myristoylation through NMT2 could be a potential therapeutic approach for preventing cardiac remodeling and heart failure.

Prognostic Role of Circulating LTBP-2 in Patients With Dilated Cardiomyopathy: A Novel Biomarker Reflecting Extracellular Matrix LTBP-2 Accumulation.

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease related to heart failure. Extracellular matrix proteins have an important role in the pathogenesis of DCM. Latent transforming growth factor beta-binding protein 2 (LTBP-2), a type of extracellular matrix protein, has not been investigated in DCM. METHODS: First, we compared plasma LTBP-2 levels in 131 patients with DCM who underwent endomyocardial biopsy and 44 controls who were matched for age and sex and had no cardiac abnormalities. Next, we performed immunohistochemistry for LTBP-2 on endomyocardial biopsy specimens and followed the DCM patients for ventricular assist device (VAD) implantation, cardiac death, and all-cause death. RESULTS: Patients with DCM had elevated plasma LTBP-2 levels compared with controls (P < 0.001). Plasma LTBP-2 levels were positively correlated with LTBP-2-positive fraction in the myocardium from the biopsy specimen. When patients with DCM were divided into 2 groups according to LTBP-2 levels, Kaplan-Meier analysis demonstrated that patients with high plasma LTBP-2 were associated with increased incidences of cardiac death/VAD and all-cause death/VAD. In addition, patients with high myocardial LTBP-2-positive fractions were associated with increased incidences of these adverse outcomes. Multivariable Cox proportional hazard analysis showed that plasma LTBP-2 and myocardial LTBP-2-positive fraction were independently associated with adverse outcomes. CONCLUSIONS: Circulating LTBP-2 can serve as a biomarker to predict adverse outcomes, reflecting extracellular matrix LTBP-2 accumulation in the myocardium in DCM.

A case of COVID-19-associated fulminant myocarditis due to SARS-CoV-2 omicron BA.2 sub-lineage in an unvaccinated female.

COVID-19-associated myocarditis can be a lethal complication in previous variants, but it is not well understood in the Omicron variant. We present an unvaccinated case of COVID-19-associated fulminant myocarditis due to the Omicron BA.2 sub-lineage requiring mechanical circulatory support (MCS). A 66-year-old female without vaccination against SARS-CoV-2 was hospitalized due to COVID-19. On the next day, she was transferred to our hospital due to the development of fulminant myocarditis. After arrival, she was treated with Impella CP and venoarterial extracorporeal membrane oxygenation due to unstable hemodynamics. In addition to MCS, we treated her with inotropes, methylprednisolone, tocilizumab, and remdesivir. Left ventricular contraction gradually improved, and MCS was removed on day 8. Endomyocardial biopsy showed mild interstitial infiltration of CD3+-T lymphocytes and CD68+-macrophages with no remarkable necrosis or fibrosis. This case showed similar histological characteristics to COVID-19-associated myocarditis before the Omicron variant. The vaccination against the Omicron variant should be considered to prevent the development of severe illness, including fulminant myocarditis. Learning objective: Although the Omicron variant is thought to be generally less severe, COVID-19-associated fulminant myocarditis, as in this case, can occur. The vaccination against the Omicron variant should be considered to prevent from developing severe illness.

Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death.

BACKGROUND: Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD. CASE PRESENTATION: A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband's left ventricular ejection fraction remained relatively preserved, her son and nephew's left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator. CONCLUSIONS: In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.

Regressed coronary ostial stenosis in a young female with Takayasu arteritis: a case report.

BACKGROUND: Takayasu arteritis is a rare systemic vasculitis, which affects the aorta and its major branches, especially in young females. Diagnosis and treatment for Takayasu arteritis with coronary stenosis are important to prevent fatal complications. Immunosuppressive treatment such as corticosteroid is a common treatment for this condition. However, the effects of immunosuppressive treatment on inflammatory coronary stenosis caused by Takayasu arteritis remains unknown. CASE PRESENTATION: An 18-year-old female had chest oppression on effort and was referred to our hospital due to ST-segment depression in I, aVL, and V2-4 on electrocardiogram. Coronary angiography showed severe stenosis in the ostium of both the left main trunk and the right coronary artery. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography showed isolated inflammation of the aortic root. She was diagnosed with Takayasu arteritis and treated with combined immunosuppressive treatment with corticosteroid and tocilizumab, which decreased the FDG uptake in the aortic root. Four months after initiation of the immunosuppressive treatment, coronary angiography showed regression of the coronary ostial stenosis. Coronary artery bypass surgery was considered, but the patient rejected invasive revascularization for coronary artery disease. She did not have chest oppression or ST-segment depression after the immunosuppressive treatment. She had no cardiac events for 6 months after discharge. CONCLUSIONS: We described regressed coronary ostial stenosis in a young female patient with Takayasu arteritis. Immunosuppressive treatment might have a favorable effect on coronary ostial stenosis in Takayasu arteritis.