Heart failure (HF) is one of the most significant public health problems we face today. HF is an epidemic, affecting more than 6 million Americans. In the years ahead, as the population ages and as the obesity problem worsens, HF prevalence will only increase. HF is not only common, but also deadly. The risk of sudden cardiac death (SCD) is several fold greater in patients with HF. SCD has been especially difficult to predict and prevent in HF because HF is a syndrome, defined by its symptoms. There is no canonical mechanism which relates HF remodeling at the molecular scale with the deleterious effects on whole heart function, importantly arrhythmogenesis. Connections between the underlying cellular and molecular changes known to occur in HF and the formation of arrhythmias which cause SCD must be found. This study will seek these missing connections and advance our understanding of arrhythmia mechanisms in HF. Using multiscale computational models, the relationships between the molecular aspects of HF and the pathological behavior of the whole organ can be made. The computer model will allow the interrelated processes which constitute these connections to be carefully dissected and revealed. At the molecular level, the HF remodeling changes that will be considered in this investigation have been studied previously only in isolation from each other. The first step will be to bring together what is known regarding HF molecular remodeling into a unified computer model of the single failing ventricular cell. The cell model will be adjusted using human experimental data to represent regional electrical and calcium properties throughout the heart. Using an image-based geometric mesh of the whole human heart, cells will be arranged in the ventricles. Heart fiber and laminar sheet orientations, and changes in tissue conductivity seen in HF will be incorporated. The predictive capability of this integrated model, from molecule to whole organ, will be validated using optical mapping experimental data from human hearts. We will test the hypothesis that heterogeneous changes in calcium cycling in HF lead to the loss of electrical heterogeneity observed. We will test whether structural remodeling in the single cell can lead to alterations in ion channel behavior which cause aberrant electrical sources to form. We will determine whether the reduced cell-to-cell coupling in HF facilitates the formation of propagating waves from these electrical sources. We will also test whether the heterogeneity of depressed calcium cycling can lead to spatially heterogeneous beat-to-beat alternations in electrical wave properties. This would create lines of block in the heart, allowing propagating wavefronts to reenter.
This research will reveal new connections between sub-cellular changes in the failing human heart and the observed increased risk of sudden death arrhythmia. Characteristic molecular changes, previously studied in isolation, will be integrated in a whole human heart computational model where detailed mechanisms can be dissected and examined. New insights from this investigation will inspire development of hypotheses that can be tested experimentally for improved strategies to prevent sudden death in human heart failure.
|Wright, Peter T; Nikolaev, Viacheslav O; O'Hara, Thomas et al. (2014) Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling. J Mol Cell Cardiol 67:38-48|