ABSTRACT
AIMS: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. METHODS AND RESULTS: We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. CONCLUSION: Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.
Subject(s)
Disease Models, Animal , Heart Failure , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Mice, Inbred C57BL , Proteomics , Sick Sinus Syndrome , Sinoatrial Node , Animals , Heart Failure/metabolism , Heart Failure/physiopathology , Heart Failure/genetics , Heart Failure/pathology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Sinoatrial Node/metabolism , Sinoatrial Node/physiopathology , Phosphorylation , Sick Sinus Syndrome/metabolism , Sick Sinus Syndrome/physiopathology , Sick Sinus Syndrome/genetics , Male , Inflammation Mediators/metabolism , Inflammation/metabolism , Inflammation/physiopathology , Inflammation/pathology , Heart Rate , Potassium Channels/metabolism , Potassium Channels/genetics , Computer Simulation , Models, Cardiovascular , Humans , Signal Transduction , Action PotentialsABSTRACT
The detection of a novel coronavirus in patients from the Arabian Peninsula in late 2012 raised serious concerns of a possible international outbreak. Ministries of health of the three affected countries invited missions from the World Health Organization to participate in a review of data and capacity to detect and respond to further cases. Recommendations were made for investigations to answer critical questions about human-to human transmission and the geographic extent of the virus. Additional recommendations were made to improve surveillance capacity by acquiring the capacity to test for the virus and enhance syndromic surveillance. Available evidence continues to suggest an unknown animal reservoir for the virus with sporadic zoonotic transmission as the primary epidemiological pattern of transmission. Human-to-human transmission, while it can occur, does not appear to be sustained in the community