Outpatient Worsening Heart Failure in Patients with Transthyretin Amyloidosis with Cardiomyopathy in the HELIOS-B Trial.

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a fatal disease, caused by misfolded transthyretin depositing as amyloid fibrils in the heart. Because disease progression is common, practical and sensitive methods are needed to monitor patients and optimize treatment decisions. Outpatient worsening heart failure (HF) (oral loop diuretic intensification or initiation) is simple to assess and has been shown to be prognostic of mortality in patients with ATTR-CM.

Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease.

About 15% of congenital heart disease (CHD) patients have a known pathogenic copy number variant. The majority of their chromosomal microarray (CMA) tests are deemed normal. Diagnostic interpretation typically ignores microdeletions smaller than 100 kb.

Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart.

Pharmacokinetics and Pharmacodynamics of Patisiran in Patients with hATTR Amyloidosis and with Polyneuropathy After Liver Transplantation.

Background And Objective: Variants of the transthyretin (TTR) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition of misfolded TTR protein as amyloid in organs and tissues. Patisiran is an RNA interference (RNAi) therapeutic that suppresses the hepatic production of TTR protein. Patisiran improves multiple clinical manifestations of hATTR amyloidosis in patients without liver transplantation (LT).

Tiered sympathetic control of cardiac function revealed by viral tracing and single cell transcriptome profiling.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart, we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing.

Tiered Sympathetic Control of Cardiac Function Revealed by Viral Tracing and Single Cell Transcriptome Profiling.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing.

Congenital Aneurysm of the Muscular Interventricular Septum Associated With Bifascicular Block.

Isolated congenital aneurysm of the muscular interventricular septum is rare. We present a patient with congenital aneurysm of the basal muscular ventricular septum, who also develops conduction abnormalities with first-degree heart block, right bundle branch block, and left posterior fascicular block. The case details the natural history of the aneurysm over a 10-year period follow-up during which the patient remained asymptomatic with evidence of regression of the aneurysm.

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation.

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT.

The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 mice from two inbred strain crosses illustrates the fundamental role of epistasis.

Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia.

GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin.

Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart.

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs.

The Complex Genetic Basis of Congenital Heart Defects.

Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or inherited genetic abnormality can be identified as pathogenic in one-third of cases. We refer to them here as monogenic causes, insofar as the genetic abnormality has a readily detectable, large effect.

Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy.

Background: The thyroid hormone-inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown.

Methods: This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice).

Transgenerational cardiology: One way to a baby's heart is through the mother.

Despite decades of progress, congenital heart disease remains a major cause of mortality and suffering in children and young adults. Prevention would be ideal, but formidable biological and technical hurdles face any intervention that seeks to target the main causes, genetic mutations in the embryo. Other factors, however, significantly modify the total risk in individuals who carry mutations.

The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis.

Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina.

Reprogramming the conduction system: Onward toward a biological pacemaker.

Diseases of the cardiac conduction system can be debilitating and deadly. Electronic pacemakers are incredibly effective in the treatment of sinus and AV node dysfunction, yet there remain important limitations and complications. These issues have driven interest in the development of a biological pacemaker.

The maternal-age-associated risk of congenital heart disease is modifiable.

Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref.

Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.

A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo.

Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret.

Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry.