Heart Failure (HF) and Arrhythmias

Heart Failure (HF), diabetes and arrhythmias are major disease foci for our work. Our seminal studies in HF, including an arrhythmogenic rabbit HF animal model, have led to a new paradigm in which systolic dysfunction is in large part due to reduced SR Ca content available for release, and that 3 factors are causative: a) reduced SERCA function, b) enhanced Na/Ca exchange (NCX) function and c) enhanced SR Ca leak. This paradigm extends to triggered arrhythmias in HF, where we’ve shown how the enhanced SR Ca leak (Ca waves) and NCX can cause delayed afterdepolarizations, and that reduced K current (IK1) allows those DADs to produce triggered arrhythmias. We have also shown that CaMKII is upregulated and more active in both HF and diabetes and have uncovered altered functional expression of numerous ion channels in both HF and diabetes that contribute to arrhythmias and systolic/diastolic dysfunction, as well as altered gene transcription (see also next section). Our 60+ papers on HF, diabetes and arrhythmias have had a strong impact on these fields at multiple levels.

 

1. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM:  Sodium-Calcium exchange contributes to mechanical dysfunction and triggered arrhythmias in heart failure.  Circ. Res.  88: 1159-1167, 2001.  Highlighted by an Editorial.  >900 citations

2. Yang Y, Guo T, Oda T, Chakraborty A, Chen L, Uchinoumi H, Knowlton AA, Fruen BR, Cornea RL, Meissner G, Bers DM. Cardiac myocyte Z-line calmodulin is mainly RyR2-bound and reduction is arrhythmogenic and occurs in heart failure. Circ Res. 114:295-306, 2014. 

3. Hegyi B, Bossuyt J, Griffiths LG, Shimkunas R, Coulibaly Z, Jian Z, Grimsrud KN, Sondergaard CS,. Ginsburg KS, Chiamvimonvat N, Belardinelli L, Varró A, Papp JG, Levijoki J, Izu LT, Boyd WD, Bányász T, Bers DM, Chen-Izu Y.  Complex electrophysiological changes in a porcine model of ischemic heart failure. Proc Nat Acad Sci (USA), 114:E3036-E3044, 2018.

4. Hegyi B, Morotti S, Liu C, Ginsburg KS, Bossuyt J, Belardinelli L, Izu LT, Chen-Izu Y, Bánayász T, Grandi E, Bers DM. Enhanced depolarization drive in failing rabbit ventricular myocytes: calcium-dependent and β-Adrenergic effects on late sodium, L-type calcium and sodium-calcium exchange currents.  Circ Arrhyhm Electrophysiol. 12: e007061; 2019

5. Ljubojevic-Holzer S, Herren AW, Djalinac N, Voglhuber J, Morotti S, Holzer M, , Wood B, Abdellatif  M, Matzer I, Sacherer M, Radulovic S, Wallner M, Ivanov M, Wagner S, Sossalla S, Von Levwnski D, Pieske B, Brown JH, Sedej S, Bossuyt J, Bers DM. Activation and nuclear accumulation of CaMKIIδC is a pivotal regulator of eccentric cardiac hypertrophy. Circ Res. 127:1159–1178, 2020.  Editor’s Pick

6. Hegyi B, Ko CY, Bossuyt J, Bers DM. Two-Hit Mechanism of Cardiac Arrhythmias in Diabetic Hyperglycemia: Reduced Repolarization Reserve, Neurohormonal Stimulation and Heart Failure Exacerbate Susceptibility. Cardiovasc Res. 117:2781-2793, 2021. Highlighted by Editorial