UC Merced

T-wave alternans are alternating beat-to-beat changes in the morphology of the electrocardiographic T-wave. Despite being the only indicator of ventricular fibrillation leading to sudden cardiac death (SCD), the molecular mechanisms of alternans remain unclear. At the cellular level, the beat-to-beat changes in the T-wave are paralleled with beat-to-beat changes in the electrical repolarization duration (action potential duration (APD) alternans) and in the myoplasmic Ca2+ levels (Ca2+ alternans). The study presented in this thesis aimed to understand how T-wave alternans are generated by assessing how the two cardiac properties, electrical (measured as the action potential) and contractile (Ca2+ dynamics, measured as Ca2+ transients), change under conditions favoring alternans. Research has pointed to the mishandling of Ca2+ as the source of T-wave alternans. However, the precise cause of this mishandling has not been established. In this thesis, we assessed three variables that modulate the handling of intracellular Ca2+: heart rate (HR), temperature, and autonomic nervous system (ANS) regulation. Studying these variables will allow us to determine what mishandling occurs in the presence of Ca2+ alternans. Tachycardia, or increased HRs, is a condition that favors the genesis of T-wave alternans. Thus, HR was used to induce alternans and to study what changes occur in the cardiac properties as the HR is increased. Since temperature dramatically affects the handling of intracellular Ca2+ content, we also assessed how temperature modulates Ca2+ alternans. In addition, the role of the ANS on Ca2+ alternans was studied because it is the body’s primary method of changing the HR and it also modulates Ca2+ cycling that may affect alternans. We hypothesized that insufficient Ca2+ re-uptake by the sarcoplasmic reticulum (Ca2+ storage sites inside the cell) during increased HRs, hypothermia, or ANS dysfunction produces Ca2+ alternans. Consequently, Ca2+ alternans cause beat-to-beat alternations in the AP repolarization leading to T-wave alternans. The major conclusion from this thesis is that increases in the HR and colder temperatures (conditions favoring alternans) primarily affect the Ca2+ transient relaxation. These results point to the importance of the SR re-uptake mechanisms in the genesis of Ca2+ alternans. The ANS, in particular the sympathetic nervous system, is capable of reducing Ca2+ alternans by improving the re-sequestering of intracellular Ca2+ into the SR. Thus, targeting SR-Ca2+ reuptake may be a possible intervention method in the treatment of T-wave alternans before SCD occurs.