Luca Soattin
Cardiac electrophysiologist with experience in small and large 'in vivo' models of atrial fibrillation, sinus node syndrome and heart failure. My main focus is to investigate the structural and electrical remodeling on pulmonary vein as a pro-arrhythmic site for atrial fibrillation.
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Papers by Luca Soattin
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 remod-
elling. 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 pro-
teomics 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.
Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the
underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional
rhythms in ion channels and assessed whether this mechanism was pertinent to the heart’s intrinsic diurnal susceptibility to VA.
METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte
nuclei at the beginning of the animals’ inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin
sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions.
Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open
chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular,
electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional
control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+
current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA.
Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion
channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts.
CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular
myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the
ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.
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 remod-
elling. 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 pro-
teomics 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.
Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the
underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional
rhythms in ion channels and assessed whether this mechanism was pertinent to the heart’s intrinsic diurnal susceptibility to VA.
METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte
nuclei at the beginning of the animals’ inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin
sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions.
Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open
chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular,
electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional
control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+
current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA.
Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion
channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts.
CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular
myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the
ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.