Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias.

Background: Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.

Methods And Results: We describe an individual with biallelic pathogenic variants, p.

Cardiomyocyte PAI-1 influences the cardiac transcriptome and limits the extent of cardiac fibrosis in response to left ventricular pressure overload.

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid-acting inhibitor of endogenous plasminogen activators (uPA and tPA). The global PAI-1 knockout mice (PAI-1KO) develop age-dependent cardiac-selective fibrosis, and young global PAI-1KO mice exhibit augmented susceptibility to developing cardiac fibrosis in response to hypertension. Here, we tested the hypothesis that cardiomyocyte PAI-1 is necessary to provide cardioprotective effects in a left ventricular pressure overload-induced murine model of cardiac hypertrophy and fibrosis using cardiomyocyte-specific PAI-1 knockout (cmPAI-1KO) mice.

Combined modality PET/MR for the detection of severe large vessel vasculitis.

Background: Large vessel vasculitis (LVV) can be characterized based on symptom severity, and this characterization helps clinicians decide upon treatment approach. Our aim was to compare the imaging findings of combined modality positron emission tomography/magnetic resonance (PET/MR) and inflammatory markers between severe and non-severe LVV. A retrospective query was performed to identify all patients with LVV who underwent PET/MR at our institution between January 2015 and January 2021.

Valve-sparing versus valve-replacing aortic root replacement in patients with aortic root aneurysm.

Background: Valve-sparing aortic root replacement (VSARR) is an alternative to valve-replacing aortic root replacement (VRARR) with valved-conduits based on recent guidelines for clinical practice. This study investigated outcomes of these two procedures in patients with nonstenotic valves.

Methods: Between January 7, 2007 and June 30, 2019, 475 patients with aortic root aneurysm without aortic stenosis underwent VSARR (151) or VRARR (324) techniques.

Deletion of Sphingosine 1-Phosphate receptor 1 in cardiomyocytes during development leads to abnormal ventricular conduction and fibrosis.

Sphingosine 1-Phosphate receptor 1 (S1P , encoded by S1pr1) is a G protein-coupled receptor that signals in multiple cell types including endothelial cells and cardiomyocytes. Cardiomyocyte-specific deletion of S1pr1 during mouse development leads to ventricular noncompaction, with 44% of mutant mice surviving to adulthood. Adult survivors of embryonic cardiomyocyte S1pr1 deletion showed cardiac hypertrabeculation consistent with ventricular noncompaction.

Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair.

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown.

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction.

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart.

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy.

Purpose Of Review: Dilated cardiomyopathy (DCM) frequently involves an underlying genetic etiology, but the clinical approach for genetic diagnosis and application of results in clinical practice can be complex.

Recent Findings: International sequence databases described the landscape of genetic variability across populations, which informed guidelines for the interpretation of DCM gene variants. New evidence indicates that loss-of-function mutations in filamin C (FLNC) contribute to DCM and portend high risk of ventricular arrhythmia.

Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of cardiomyopathy have been limited to small case series.

Methods: Clinical and genetic data were collected on 107 patients with pathogenic mutations and 81 patients with pathogenic plakophilin 2 () mutations as a comparison cohort.

Macrophages in Heart Failure with Reduced versus Preserved Ejection Fraction.

There is a growing number of individuals living with heart failure (HF) with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). Long-term prognosis remains poor in both cases, especially in HFpEF, which is rising in incidence and lacks effective therapeutics. In both HFrEF and HFpEF, there is evidence that elevated inflammatory biomarkers, implicating innate immune cells such as macrophages, are associated with worsened clinical outcomes.

Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation.

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that potently degrades angiotensin II to angiotensin 1-7. Previous studies showed that injection of the enzymatic ectodomain of recombinant ACE2 (rACE2) markedly increases circulatory levels of ACE2 activity, and effectively lowered blood pressure in angiotensin II-induced hypertension. However, due to the short plasma half-life of rACE2, its therapeutic potential for chronic use is limited.

A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis.

Hypertension-associated end-organ damage commonly leads to cardiac and renal fibrosis. As no effective anti-fibrotic therapy currently exists, the unchecked progression of fibrogenesis manifests as cardio-renal failure and early death. We have previously shown that FATp300-p300 with intrinsic factor acetyltransferase activity-is an essential epigenetic regulator of fibrogenesis, and is elevated in several fibrotic tissues.

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy.

Background: Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing.

Methods: Whole-genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias.

Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2.

SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo.

A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence.

Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence.

Sphingosine 1-phosphate receptor-1 in cardiomyocytes is required for normal cardiac development.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts via G protein-coupled receptors. The S1P receptor S1P1, encoded by S1pr1, is expressed in developing heart but its roles there remain largely unexplored. Analysis of S1pr1 LacZ knockin embryos revealed β-galactosidase staining in cardiomyocytes in the septum and in the trabecular layer of hearts collected at 12.

Genetics of Cardiac Developmental Disorders: Cardiomyocyte Proliferation and Growth and Relevance to Heart Failure.

Cardiac developmental disorders represent the most common of human birth defects, and anomalies in cardiomyocyte proliferation drive many of these disorders. This review highlights the molecular mechanisms of prenatal cardiac growth. Trabeculation represents the initial ventricular growth phase and is necessary for embryonic survival.