Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels

Henry, Brian L.; Gabris, Beth; Li, Qiao; Martin, Brian; Giannini, Marianna; Parikh, Ankur P.; Patel, Divyang; Haney, Jamie; Schwartzman, David; Shroff, Sanjeev G.; Salama, Guy

doi:10.1016/j.hrthm.2015.12.030

Cited by 59 publications

(67 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Henry and his group showed decreased Nav1.5 expression and slowed conduction velocity by reduction of sodium channel expression and augmentation of fibrosis among an aged rat atrial fibrillation model. The effect was reversed by relaxin treatment in all aged animals with atrial fibrillation . Although the role of aging on genetic variants in SCN5A remains unclear, it is reasonable to speculate that decreased sodium channel and increased fibrosis caused by aging will lead to a more serious phenotype for SCN5A mutation, such as what we observed in our SCN5A ‐E1784K family.…”

Section: Discussionsupporting

confidence: 61%

“…The effect was reversed by relaxin treatment in all aged animals with atrial fibrillation. 43 Although the role of aging on genetic variants in SCN5A remains unclear, it is reasonable to speculate that decreased sodium channel and increased fibrosis caused by aging will lead to a more serious phenotype for SCN5A mutation, such as what we observed in our SCN5A-E1784K family.…”

Section: Aging and Sodium Channelmentioning

confidence: 67%

See 1 more Smart Citation

Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

Veltmann

Barajas-Martínez

Wolpert

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundPhenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A‐E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype–phenotype relationship in a large family carrying SCN5A‐E1784K and SCN5A‐H558R polymorphism.Methods and ResultsClinical work‐up, follow‐up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A‐E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A‐H558R did not significantly alter the phenotype of SCN5A‐E1784K carriers. Fourteen SCN5A‐E1784K patients underwent implantable cardioverter‐defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow‐up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A‐E1784K and SCN5A‐H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole‐cell patch‐clamp techniques. Co‐expression of SCN5A‐E1784K and SCN5A‐WT reduced INa,P to 70.03% of WT, shifted steady‐state inactivation by −11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A‐E1784K was co‐expressed with SCN5A‐H558R.ConclusionsWe demonstrate a strong genotype‐phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A‐E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.

show abstract

Section: Discussionsupporting

confidence: 61%

Section: Aging and Sodium Channelmentioning

confidence: 67%

Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

Veltmann

Barajas-Martínez

Wolpert

et al. 2016

JAHA

View full text Add to dashboard Cite

show abstract

“…For example, TGF-β1-mediated fibrosis is triggered by Scn5a disruption 21 . In other studies, relaxin suppressed AF in aged rats 37 and in spontaneously hypertensive rats 38 through decreased atrial fibrosis, increased I Na , and increased atrial conduction velocity. As an alternative hypothesis, fibrosis in null mice may be triggered directly by the absence of β2 polypeptides during atrial development.…”

Section: Scn2b and Atrial Fibrillationmentioning

confidence: 71%

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias

Bao

Willis

Frasier

et al. 2016

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

Background Mutations in SCN2B, encoding voltage-gated sodium channel (VGSC) β2 subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2 subunits play critical roles in the establishment or maintenance of normal cardiac electrical activity in vivo. Methods and Results To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current density in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional re-entry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild type ventricles, as were levels of Nav1.5 protein, suggesting that similar to previous work in neurons, the major function of β2 subunits in the ventricle is to chaperone VGSC α subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared to wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than WT littermates. Conclusions Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.

show abstract

“…In the heart of spontaneously hypertensive rats (SHRs), relaxin treatment for two weeks ameliorates ventricular hypertrophy and fibrosis by reducing collagen content, leading to improved cardiac function25. Furthermore, relaxin also reverses atrial fibrillation by reducing fibrosis and hypertrophy, which is associated with an increase in Na + current density2627. The cardioprotective actions of relaxin are, at least in part, due to its ability to upregulate Notch signalling and inhibit the transforming growth factor-β (TGF-β)/Smad3 pathway, thereby preventing cardiac fibroblast-myofibroblast transition and limiting fibrosis28.…”

mentioning

confidence: 99%

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Leo

Prakoso

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis.

show abstract

Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels

Cited by 59 publications

References 23 publications

Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

Contact Info

Product

Resources

About