An extensive β1-adrenergic receptor gene signaling network regulates molecular remodeling in dilated cardiomyopathies.

We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor-linked (β1-AR-linked) gene signaling network (β1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member β1-GSN was identified by mRNA expression in transgenic mice overexpressing human β1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for Arg389Gly and Ser49Gly, Gln27Glu and Gly16Arg, and Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes.

Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination.

SARS CoV-2 enters host cells via its Spike protein moiety binding to the essential cardiac enzyme angiotensin-converting enzyme (ACE) 2, followed by internalization. COVID-19 mRNA vaccines are RNA sequences that are translated into Spike protein, which follows the same ACE2-binding route as the intact virion. In model systems, isolated Spike protein can produce cell damage and altered gene expression, and myocardial injury or myocarditis can occur during COVID-19 or after mRNA vaccination.

Dynamic Regulation of SARS-Cov-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium.

Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that mRNA expression of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cardiac myocyte receptor ACE2 is up-regulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for SARS-CoV-2 cell binding and entry was identified, the integrin encoded by .

Correction: Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

[This corrects the article DOI: 10.1371/journal.pone.

Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

Objectives: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling.

Background: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices.

Methods: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF).

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

Background: The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit.

Objectives: The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.

Histamine H Receptor Polymorphisms, Myocardial Transcripts, and Heart Failure (from the Multi-Ethnic Study of Atherosclerosis and Beta-Blocker Effect on Remodeling and Gene Expression Trial).

Myocardial H receptor activation contributes to heart failure (HF) in preclinical models, and H receptor antagonists are associated with decreased HF incidence. This study evaluated whether H histamine receptor (HRH2) single nucleotide polymorphisms (SNPs) are associated with HF incidence and whether myocardial transcript abundance is associated with HF recovery. The association of SNPs in HRH2 with incident HF was characterized using Cox proportional hazards regression among participants in the Multi-Ethnic Study of Atherosclerosis.

Myocardial microRNAs associated with reverse remodeling in human heart failure.

Background: In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling.

Methods: Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.

Sex-related differences in age-associated downregulation of human ventricular myocardial β1-adrenergic receptors.

Background: With increasing age, human ventricular myocardium exhibits selective downregulation of β1-adrenergic receptors (β1-ARs). We tested the hypothesis that sex differences exist in age-related changes in β1-ARs.

Methods: Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy.

Therapeutic Molecular Phenotype of β-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy.

Background: When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca(2+)-ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.

Assist devices fail to reverse patterns of fetal gene expression despite beta-blockers.

Background: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1 alpha (HIF-1 alpha), a transcriptional factor in hypoxic signaling.

Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling.

The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear.

Serial gene expression profiling in the intact human heart.

Background: In chronic heart failure due to a dilated cardiomyopathy phenotype, the molecular bases for contractile dysfunction and chamber remodeling remain largely unidentified.

Methods: To investigate the feasibility of measuring global gene expression serially in the intact failing human heart, we performed repeated messenger RNA (mRNA) expression profiling using RNA extracted from endomyocardial biopsy specimens and gene chip methodology in 8 subjects with idiopathic dilated cardiomyopathy. In patients treated with beta-blocking agents or placebo, myocardial gene expression was measured in endomyocardial biopsy material and radionuclide ejection fraction was measured at baseline and after 4 to 12 months of treatment.

Hypoplastic left heart syndrome myocytes are differentiated but possess a unique phenotype.

Introduction: Hypoplastic left heart syndrome (HLHS) is the term used to describe a group of congenital malformations characterized by marked underdevelopment of the left side of the heart. HLHS accounts for nearly 25% of cardiac deaths in the first year of life. Although much has been reported regarding diagnosis, gross morphology and surgical treatment, no information on gene expression in HLHS myocytes is available.

Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype.

Background: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying.

Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.

Background: Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy.

Methods: We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo.

Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression.

Background: We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs).

Methods And Results: To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha-MHC with increased beta-MHC expression compared with left ventricles from age-matched controls.

Myosin heavy chain isoform expression in the failing and nonfailing human heart.

In the heart, the relative proportions of the 2 forms of the motor protein myosin heavy chain (MyHC) have been shown to be affected by a wide variety of pathological and physiological stimuli. Hearts that express the faster MyHC motor protein, alpha, produce more power than those expressing the slower MyHC motor protein, beta, leading to the hypothesis that MyHC isoforms play a major role in the determination of cardiac contractility. We showed previously that a significant amount of alphaMyHC mRNA is expressed in nonfailing human ventricular myocardium and that alphaMyHC mRNA expression is decreased 15-fold in end-stage failing left ventricles.

Myosin heavy chain gene expression in human heart failure.

Two isoforms of myosin heavy chain (MyHC), alpha and beta, exist in the mammalian ventricular myocardium, and their relative expression is correlated with the contractile velocity of cardiac muscle. Several pathologic stimuli can cause a shift in the MyHC composition of the rodent ventricle from alpha- to beta-MyHC. Given the potential physiological consequences of cardiac MyHC isoform shifts, we determined MyHC gene expression in human heart failure where cardiac contractility is impaired significantly.

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes.

Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium.

Background: The regulation of angiotensin II receptors and the two major subtypes (AT1 and AT2) in chronically failing human ventricular myocardium has not been previously examined.

Methods And Results: Angiotensin II receptors were measured by saturation binding of 125I-[Sar1,Ile8]angiotensin II in crude membranes from nonfailing (n = 19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n = 31) or ischemic cardiomyopathy (ISC; n = 21) and membranes from a limited number of right ventricles in each category. The AT1 and AT2 fractions were determined by use of an AT1-selective antagonist, losartan.

Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway.

In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs.

Cardiac adrenergic receptor effects of carvedilol.

Carvedilol is an adrenoceptor antagonist which modulates the activity not only of beta 1 and beta 2 but also of alpha 1 adrenergic receptors present on the cell surface membrane of the human cardiac myocyte. In the heart, carvedilol has approximately 7 times higher potency for beta 1 and beta 2 adrenoceptors, but in the doses 50-100 mg . day-1 used in clinical practice, it is essentially non-selective.