HCN4, Sinus Bradycardia and Atrial Fibrillation

DiFrancesco, Dario

doi:10.15420/aer.2015.4.1.1

Cited by 5 publications

(5 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relevance of I f in cardiac pacemaking is underscored by the development of the heart rate reducing drug ivabradine, which is now prescribed in the clinical practice for ischaemic heart disease (Bucchi et al 2007). Importantly, several forms of bradycardia (DiFrancesco, 2015) and tachycardia (Baruscotti et al 2016) induced by mutations affecting the predominant SAN f-channel isoforms HCN4 have been described during the last years.…”

Section: Pacemaker Activity and Models Of Sinus Dysfunctionmentioning

confidence: 99%

See 1 more Smart Citation

Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond

Mesirca

Bidaud

Mangoni

2016

The Journal of Physiology

View full text Add to dashboard Cite

Pacemaker activity of the sino-atrial node generates the heart rate. Disease of the sinus node and impairment of atrioventricular conduction induce an excessively low ventricular rate (bradycardia), which cannot meet the needs of the organism. Bradycardia accounts for about half of the total workload of clinical cardiologists. The 'sick sinus' syndrome (SSS) is characterized by sinus bradycardia and periods of intermittent atrial fibrillation. Several genetic or acquired risk factors or pathologies can lead to SSS. Implantation of an electronic pacemaker constitutes the only available therapy for SSS. The incidence of SSS is forecast to double over the next 50 years, with Abstract figure legend Genetically modified mice carrying loss-of-function in Ca v 1.3 or HCN4 channels display bradycardia and heart block (experimental channelopathy). This condition is similar to some forms of inherited sino-atrial node dysfunction in humans. The G protein-activated K + current I KACh constantly imposes negative chronotropic and dromotropic effects on the heart rhythmogenic centres under physiological conditions (normal heart rate). However, the action of I KACh becomes detrimental under conditions of diseased heart impulse generation and eventually causes symptoms associated with bradycardia. In humans, these symptoms are managed by implantation of an electronic pacemaker, which constitutes the only currently available therapy. In mice, 'compensatory' genetic or pharmacological targeting of I KACh can rescue bradycardia. This strategy may open the way for new therapeutic options to handle disease of heart automaticity in humans.

show abstract

Section: Pacemaker Activity and Models Of Sinus Dysfunctionmentioning

confidence: 99%

“…). Importantly, several forms of bradycardia (DiFrancesco, ) and tachycardia (Baruscotti et al . ) induced by mutations affecting the predominant SAN f‐channel isoforms HCN4 have been described during the last years.…”

Section: Introduction: Cardiac Pacemaker Activity and Sinus Node Dysfmentioning

confidence: 99%

Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond

Mesirca

Bidaud

Mangoni

2016

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…In the SAN of many species, HCN4 is the most abundant isoform followed by HCN1 and to a lesser extent HCN2 [ 8 , 11 , 13 ]. The importance of f-channels to cardiac rhythmicity is demonstrated by the fact that mutations in HCN4 have been found in patients with several sinus arrhythmias, such as sinus bradycardia, inappropriate sinus tachycardia, sinus node disease but also with atrial fibrillation and ventricular non-compaction [ 17 ]. Moreover, alterations in either the physiological levels of HCN channel or in I f current properties have been linked to other arrhythmias and cardiomyopathy [ 9 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

A detailed characterization of the hyperpolarization-activated “funny” current (If) in human-induced pluripotent stem cell (iPSC)–derived cardiomyocytes with pacemaker activity

Giannetti

Benzoni

Campostrini

et al. 2021

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Properties of the funny current (If) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of If in human-induced pluripotent stem cell (iPSC)–derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that If density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate. If displayed the voltage-dependent block by caesium and reversed (Erev) at − 22 mV, compatibly with the 3:1 K+/Na+ permeability ratio. Lowering [Na+]o (30 mM) shifted the Erev to − 39 mV without affecting conductance. Increasing [K+]o (30 mM) shifted the Erev to − 15 mV with a fourfold increase in conductance. pCMs express mainly HCN4 and HCN1 together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of If. Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of If voltage-dependence (EC50 73.4 nM). The muscarinic agonists had opposite effects (Carbachol EC50, 11,6 nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an If with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human If-related sinus arrhythmias.

show abstract

“…68 The proposed mechanism of ivabradine leading to atrial fibrillation is genetic polymorphisms in HCN4 receptors resulting in an enhanced effect of ivabradine. 69 We hypothesize that individuals with genetic polymorphisms of HCN4 can have significant inhibition of the 2 primary pacemaker tissues of the heart (SA node and AV node). This would provide substrate for atrial tissue to discharge and convert sinus rhythm into atrial fibrillation.…”

Section: Side Effects and Contraindicationsmentioning

confidence: 99%

Ivabradine

Chaudhary

Garg

Krishnamoorthy

et al. 2015

J Cardiovasc Pharmacol Ther

View full text Add to dashboard Cite

Heart failure affects over 5 million people in the United States and carries a high rate of mortality. Ivabradine, a new agent has been added to the current medical options for managing heart failure. It is a selective funny current (If) inhibitor in sinoatrial node and slows its firing rate, prolonging diastolic depolarization without a negative inotropic effect. Ivabradine was only recently approved by Food and Drug administration after the results of Systolic Heart Failure Treatment with the If Inhibitor Ivabradine (SHIFT) trial, for a reduction in rehospitalizations from chronic heart failure. This trial assessed patients with stable heart failure with reduced ejection fraction and a heart rate of at least 70 beats per minute at rest on maximally tolerated beta-blocker therapy and demonstrated statistically significant reduction in heart failure hospitalization and deaths. Additionally, ivabradine has been associated with reduced cardiac remodeling, reduced heart rate variability, improvement in exercise tolerance, improved heart failure class of New York Heart Association, and better quality of life. It has also been tried in other conditions, such as inappropriate sinus tachycardia and cardiogenic shock, and is currently in phase II trial for patients with newly diagnosed multiple organ dysfunction syndrome.

show abstract

HCN4, Sinus Bradycardia and Atrial Fibrillation

Cited by 5 publications

References 58 publications

Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond

Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond

A detailed characterization of the hyperpolarization-activated “funny” current (If) in human-induced pluripotent stem cell (iPSC)–derived cardiomyocytes with pacemaker activity

Ivabradine

Contact Info

Product

Resources

About