Global deletion of potassium channel Kv1.5 causes biventricular heart failure

Abstract

Background: Heart failure (HF) is a chronic disease with high morbidity and mortality among older populations. Chronic HF ultimately affects both the right (RV) and left (LV) ventricles and often presents with extra-cardiac outcomes including pulmonary hypertension (PH). Study of biventricular failure and its extra-cardiac consequences has been challenging in pre-clinical models, suggesting new models may be beneficial to uncover new mechanisms of disease. Potassium channels are implicit regulators of vascular tone and are strongly but independently associated with PH and LV dysfunction.

Aim: We hypothesized that deletion of the potassium rectifier channel Kv1.5 would cause biventricular HF, thus representing a new model from which to understand ventricle-specific mechanisms of HF.

Methods and Results: We used a model of global vasoconstriction by genetic deletion of potassium rectifier channel Kv1.5 (Kv1.5 KO). Male and female mice were studied at middle age (12-13 months) as this is when HF risk begins to increase with age. In response to Kv1.5 KO, both the LV and RV experienced elevated afterload. While Kv1.5 KO mice developed RV systolic dysfunction with hypertrophy and fibrosis, the LV developed mild hypertrophy and diastolic dysfunction. Consistent with biventricular remodeling, Kv1.5 KO mice also displayed higher liver and lung weights and exercise intolerance.

Conclusion: Deletion of Kv1.5 causes systemic and pulmonary vasoconstriction with distinct outcomes in the LV and RV. This model of biventricular dysfunction may be useful for studying extra-cardiac consequences of HF and understanding ventricle-specific mechanisms of disease.

Keywords

Kv1.5 / heart failure / right ventricle / middle-aged

References

[1] Benjamin EJ,Alonso A.Heart disease and stroke statistics-2019 update: a report from the American Heart Association.Circulation2019;139:e56-e528

[2] Levine AR,Gladwin MT.Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction.Trends Cardiovasc Med2019;29:207-17 PMCID:PMC6378124

[3] Melenovsky V,Lin G,Borlaug BA.Right heart dysfunction in heart failure with preserved ejection fraction.Eur Heart J2014;35:3452-62 PMCID:PMC4425842

[4] van de Veerdonk MC,Marcus JT.Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.J Am Coll Cardiol2011;58:2511-9

[5] Borgdorff MA,Dickinson MG,Berger RM.A cornerstone of heart failure treatment is not effective in experimental right ventricular failure.Int J Cardiol2013;169:183-9

[6] Tykocki NR,Jackson WF.Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles.Compr Physiol2017;7:485-581 PMCID:PMC5575875

[7] Archer SL,Dinh-Xuan AT.Molecular identification of the role of voltage-gated K⁺ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.J Clin Invest1998;101:2319-30

[8] Moudgil R,Archer SL.The role of K⁺ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension.Microcirculation2006;13:615-32

[9] Ohanyan V,Bardakjian R.Requisite role of Kv1.5 channels in coronary metabolic dilation.Circ Res2015;117:612-21

[10] Yuan XJ.Voltage-gated K⁺ currents regulate resting membrane potential and [Ca²⁺]_i in pulmonary arterial myocytes.Circ Res1995;77:370-8

[11] Vera-Zambrano A,Gallego N.Novel loss-of-function KCNA5 variants in pulmonary arterial hypertension.Am J Respir Cell Mol Biol2023;69:147-58

[12] Dutta S.Men and mice: relating their ages.Life Sci2016;152:244-8

[13] Strait JB.Aging-associated cardiovascular changes and their relationship to heart failure.Heart Fail Clin2012;8:143-64 PMCID:PMC3223374

[14] Bruns DR,Marcello NA,Walker WJ.The peripheral circadian clock and exercise: lessons from young and old mice.J Circadian Rhythms2020;18:7 PMCID:PMC7757608

[15] Yusifov A,Zumo JM.Cardiac response to adrenergic stress differs by sex and across the lifespan.Geroscience2021;43:1799-813 PMCID:PMC8492879

[16] Razeghi P,Alcorn JL,Frazier OH.Metabolic gene expression in fetal and failing human heart.Circulation2001;104:2923-31

[17] Harrison A,Ryan JJ.The right ventricle under pressure: evaluating the adaptive and maladaptive changes in the right ventricle in pulmonary arterial hypertension using echocardiography (2013 Grover Conference series).Pulm Circ2015;5:29-47 PMCID:PMC4405726

[18] Sundaram V.Gastrointestinal and liver issues in heart failure.Circulation2016;133:1696-703

[19] Hegemann N,Kim JH.Ultrasonographic assessment of pulmonary and central venous congestion in experimental heart failure.Am J Physiol Heart Circ Physiol2024;326:H433-40 PMCID:PMC11219047

[20] Haddad F,Murphy DJ.Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure.Circulation2008;117:1717-31

[21] Post JM,Archer SL.Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction.Am J Physiol1992;262:C882-90

[22] Yang T,Felipe A,Snyders DJ.K⁺ currents and K⁺ channel mRNA in cultured atrial cardiac myocytes (AT-1 cells).Circ Res1994;75:870-8

[23] Tanabe Y,Naito N.Over-expression of Kv1.5 in rat cardiomyocytes extremely shortens the duration of the action potential and causes rapid excitation.Biochem Biophys Res Commun2006;345:1116-21

[24] Yang Y,Lin X.Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation.J Hum Genet2009;54:277-83

[25] Kepenek ES,Tuncay E,Akar AR.Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca²⁺-handling in human heart failure.Mol Cell Biochem2020;463:33-44

[26] Umar S,de Lange E.Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension.Circ Arrhythm Electrophysiol2012;5:181-90

[27] Bozkurt B,Alexander K.HF STATS 2024: heart failure epidemiology and outcomes statistics an updated 2024 report from the heart failure society of America.J Card Fail2025;31:66-116

[28] Matsubara H,Inada M.Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy.J Clin Invest1993;92:1659-66 PMCID:PMC288324

[29] Wang Z,Francis Stuart SD.Aging disrupts normal time-of-day variation in cardiac electrophysiology.Circ Arrhythm Electrophysiol2020;13:e008093

[30] Kang LS,Dominguez JM 2nd,Dick GM.Aging and muscle fiber type alter K⁺ channel contributions to the myogenic response in skeletal muscle arterioles.J Appl Physiol2009;107:389-98 PMCID:PMC2724325

[31] Humbert M,Yaïci A.Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension.Eur Respir J2010;36:549-55

[32] Lahm T,Albrecht ME.17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension.Am J Physiol Lung Cell Mol Physiol2016;311:L375-88 PMCID:PMC5142461

[33] Foppa M,Gona P.Right ventricular volumes and systolic function by cardiac magnetic resonance and the impact of sex, age, and obesity in a longitudinally followed cohort free of pulmonary and cardiovascular disease: the framingham heart study.Circ Cardiovasc Imaging2016;9:e003810

[34] Flurkey K,Sinha YN,Finch CE.Transient shortening of estrous cycles in aging C57BL/6J mice: effects of spontaneous pseudopregnancy, progesterone, L-dihydroxyphenylalanine, and hydergine.Biol Reprod1987;36:949-59

[35] Brener MI,Ng VG.Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations.Circ Heart Fail2022;15:e009101

[36] Lambert M,Ghigna MR.Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload.Cardiovasc Res2021;117:2474-88