Progressive heart failure (HF) post myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Non-pharmacological interventions, including stem cell therapy and spinal cord stimulation (SCS), are emerging novel therapeutic approach to prevent or treat HF. Nevertheless, the potential impact of these interventions on the susceptibility for ventricular tachyarrhythmias (VT/VF), which are the most common cause of sudden death in HF patients remains unknown. For stem cell therapy, sympathetic hyperinnervation as reflected by nerve spouting, lack of gap junction and immature electrophysiological phenotypes of the transplanted cells are potentially trigger and/or substrate for VT/VF after transplantation. Previous studies suggested that stem cell transplantation post-MI may induce cardiac nerve sprouting but their effects on gap junction expression are unclear. Furthermore, the effects of stem cell transplantation on cardiac nerve spouting and gap junction expression in chronic myocardial ischemia have not been addressed. In Chapter 3, we investigated bone marrow (BM) derived mononuclear cells (MNCs) and endothelial progenitor cells (EPCs) via direct intramyocardial transplantation in a porcine model of chronic myocardial ischemia. Our results showed that BM-MNCs or BM-EPCs transplantation was not associated with increased cardiac nerve sprouting, which might account for their low risk of proarrhythmias observed in clinical and experimental studies. In Chapter 4, we investigated the susceptibility to develop VT/VF after embryonic stem cells (ESCs) and their derived cardiomyocytes (ESC-CMs) transplantation in a murine model of MI. Moreover, the potential application of bioengineered ESC-CMs with over-expression of Kir 2.1 to reduce their susceptibility to induce VT/VF was also studied. Our results showed that transplantation of ESC or ESC-CMs reduced cardiac nerve sprouting and increased gap junction expression in the infarcted regions when compared with MI alone. The inducibility of VT/VF after ESC-CM transplantation was significantly higher than ESC transplantation or MI alone. On the other hand, over-expression of Kir2.1 improved the electrical maturation of ESC-CMs which significantly attenuated their vulnerability for VT/VF. These results suggested that the immature electrical phenotypes of ESC-CMs, rather than cardiac nerve spouting and changes in gap junction expression, plays an important role for proarrhythmias after stem cells transplantation, which can be eliminated by bioengineering of ESC-CMs. Dysregulation of the autonomic nervous system with increased sympathetic tone and decreased parasympathetic tone has been well documented in HF progression, and is proposed to play an important role in arrhythmogenesis. In Chapter 5, we performed acute thoracic SCS at T1-T2 level in an animal model of ischemic HF (MI+HF) induced by MI and rapid ventricular pacing. Our results showed that acute SCS significantly increased left ventricular (LV) contractile function as determined by echocardiographic measurement of LV ejection fraction (LVEF) and invasive hemodynamic assessment of +dP/dt. Furthermore, myocardial oxygen consumption also significantly decreased during SCS without any change in serum norepinephrine level. Nevertheless, acute SCS failed to prevent spontaneous VT/VF provoked by prolonged (>2 minutes) acute myocardial ischemia. Taken together, our results provide important insights into the potential mechanisms of proarrhythmias after stem cell transplantation as well as the acute beneficial effects SCS in ischemic HF. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

No description available.

Heart failure due to ischemic and dilated cardiomyopathy is a large and expanding public health problem, and ventricular arrhythmias are a common and potentially fatal complication of this condition. Despite extensive investigation, the mechanisms of ventricular arrhythmias in cardiomyopathy remain incompletely understood. This thesis examines these mechanisms, particularly with reference to the potential role of the underlying electrophysiologic substrate. It also evaluates the validity and utility of some of the tools commonly used to assist in the mapping and catheter ablation of ventricular arrhythmias. / The central rationale of this thesis is that the mechanisms of ventricular arrhythmogenesis in cardiomyopathy are optimally studied by comparing ischemic and dilated cardiomyopathy patients with spontaneous (rather than inducible) ventricular tachycardia to otherwise similar heart failure patients who have never developed clinical arrhythmias. This has been done in the two largest projects herein. In the setting of ischemic cardiomyopathy, it is demonstrated that there are large differences in the electrophysiologic substrate between the groups such that patients with clinical ventricular tachycardia have substantially greater endocardial scarring as inferred by the presence of low-voltage zones and scar-related electrograms compared to control cardiomyopathy patients with no spontaneous arrhythmias. Furthermore, there appear to be fundamental differences in the nature of the scarring process with ventricular tachycardia patients having more abnormal electrograms per unit area of low-voltage and more scar-related putative conducting channels (which may form critical diastolic isthmuses in tachycardia). / This was accompanied by a lower rate of ventricular tachycardia inducibility in the control patients. Taken together these findings point to a major role for the electrophysiologic substrate in ventricular arrhythmogenesis in the setting of ischemic cardiomyopathy. The situation in dilated cardiomyopathy is more complicated and although significant endocardial substrate differences were again seen in this context, there was marked heterogeneity in the group with ventricular tachycardia with some patients having extensive low-voltage zones and others having normal endocardial voltage. As the pericardium could not be accessed for ethical reasons in control patients with no clinical arrhythmia, the precise role of an abnormal epicardial substrate was not able to be defined in this study. Another project in this thesis examines potential improvements (in the form of a multielectrode mapping catheter) to a widely used electroanatomic mapping system that can assist in mapping ventricular tachycardia circuits and the substrates underlying them. A further project compares magnetic resonance imaging and electroanatomic substrate mapping in defining ventricular scarring in the context of cardiomyopathy. And finally, electroanatomic mapping is used to look at endocardial activation patterns and electrical dyssynchrony in cardiomyopathy patients with and without left bundle branch block. The demonstrated variability in these factors may underlie the significant non-response rates to cardiac resynchronization therapy. / In summary, it is apparent from this work that the electrophysiologic substrate plays a crucial role in mechanism of the ventricular arrhythmias seen in heart failure patients with ischemic and dilated cardiomyopathy. An improved understanding of these mechanisms may in turn lead to better diagnosis, risk stratification and ultimately management of heart failure patients suffering from, or at risk of developing these potentially lethal arrhythmias.

Thesis (Ph.D.)--University of Melbourne, Dept. of Medicine, The Royal Melbourne Hospital, 2010. / Typescript. Includes bibliographical references (leaves 164-202)

Thesis (Ph. D.)--University of Alabama at Birmingham, 2006. / Description based on information viewed Oct. 3, 2006; title from title screen. Includes bibliographical references (p. 87-90).

Thesis (M.S.)--University of Michigan, 1988.

Thesis (M.S.)--University of Michigan, 1988.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Description based on contents viewed Oct. 5, 2007; title from title screen. Includes bibliographical references (p. 19-20).

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 192-211).

Introdução: A morte súbita é a principal causa de morte na doença de Chagas, correspondendo de 55 a 65% dos casos. Observa-se que parte destas, ocorre em pacientes com função ventricular esquerda (FEVE) preservada, levando a acreditar que fatores desestabilizadores do substrato arritmogênico exercem um importante papel nestes eventos. Evidências já demonstraram a depressão parassimpática como fator contribuinte na gênese de arritmias diversas em presença de cardiopatia isquêmica. Assim, insiste-se na necessidade de se identificar precocemente quais os pacientes, no contexto da cardiopatia chagásica crônica, apresentam risco aumentado para o desenvolvimento de eventos arrítmicos complexos. Acredita-se que a avaliação autonômica identifique subgrupos distintos de risco. O presente estudo teve como objetivo determinar a sensibilidade do barorreflexo (SBR) em pacientes com doença de Chagas, nas formas indeterminada (GI) e arritmogênica com taquicardia ventricular não sustentada (GII) e com taquicardia ventricular sustentada (GIII) e, secundariamente, avaliar a associação entre a severidade da arritmia ventricular com o grau de comprometimento da SBR. Métodos: 42 pacientes foram submetidos à monitorização cardiovascular não invasiva pelo sistema Task Force ® onde foi determinada a SBR, utilizando o método da fenilefrina e analisada a variabilidade da frequência cardíaca (VFC) no domínio do tempo por meio da eletrocardiografia dinâmica de 24horas e a FEVE, por meio da ecocardiografia. Resultados: Observou-se diferença estatística significativa entre os grupos em relação à SBR em resposta à fenilefrina. O GIII apresentou o menor valor de SBR (6,09 ms/mmHg) quando comparado aos GII (11,84ms/mmHg) e GI (15,23ms/mmHg). Após comparação múltipla entre os grupos, verificou-se diferença significativa entre GI e GIII (p= 0,01). Quando se correlacionou SBR e densidade de extra-sístoles ventriculares (EV), observou-se que todos os pacientes portadores de baixa densidade de EV (< 10/hora) apresentavam SBR preservada (6,1ms/mmHg).Em contrapartida, entre aqueles com alta densidade de EV (>10/hora) somente 59% tinham SBR preservada (p=0,003). Nos pacientes com SBR deprimida (3,0-6,0 ms/mmHg) houve maior densidade de EV (p=0,01). Pacientes com SBR preservada apresentaram tanto função ventricular normal como moderadamente comprometida (66,7% com FEVE<40% e 79,5% com FEVE40%; p=0,62). O mesmo observou-se em pacientes com SBR moderadamente deprimida, (15,4% com FEVE<40% e 33,3% com FEVE40%; p=0,46). Não foi verificada correlação entre SBR e VFC. Ao se aplicar o modelo de regressão logística, observou-se que somente a SBR influenciou o aparecimento da taquicardia ventricular sustentada (p=0.028). Conclusão: A SBR está preservada na forma indeterminada da doença de Chagas e diminuída na forma arritmogênica. O comprometimento da SBR é progressivo e acompanha a evolução da doença, sendo mais intenso nos pacientes com arritmias ventriculares mais complexas. O grau de disfunção autonômica não se correlacionou com a função ventricular, mas, sim, com a densidade e a complexidade das arritmias / Introduction: Sudden death is the main cause of death in Chagas disease, corresponding to 55 to 65% of the cases. Some of these occur in patients with normal or almost normal left ventricular function (LVF), leading us to believe that factors that destabilize the arrhythmogenic substrate play an important role in these events. Evidences show parasympathetic depression to be a contributing factor in the genesis of diverse arrhythmias in the presence of ischemic heart disease. Thus, we insist on the need of an early identification of the patients, in the context of chronic Chagas heart disease, that are at increased risk of developing complex arrhythmic events. It is possible that autonomic assessment allows the identification of distinct risk subgroups. The objective of this study was to determine the baroreflex sensitivity (BRS) in patients with the indeterminate form of Chagas disease, (GI), and with the arrhythmogenic form of Chagas disease with nonsustained ventricular tachycardia (GII) and sustained ventricular tachycardia (GIII) and to assess the correlation between the severity of ventricular arrhythmia and the degree of BRS impairment. Methods: Forty-two patients were subjected to noninvasive cardiovascular monitoring using the Task Force® system. The phenylephrine method was used to determine BRS, 24- hour dynamic electrocardiography was used to analyze heart rate variability (HRV) over time and echocardiography was used to determine LVF. Results: A statistical difference was observed between the groups regarding their BRS to phenylephrine. GIII presented the lowest BRS value (6.09 ms/mmHg) when compared with GII (11.84ms/mmHg) and GI (15.23ms/mmHg). After multiple comparisons among the groups, a significant difference was found between GI and GIII (p=0.01). When BRS was correlated with ventricular extrasystole (VE) density, all patients who had low VE density (<10/hour) had preserved BRS (6.1ms/mmHg). On the other hand, only 59% of those with high EV density (>10/hour) had preserved BRS (p=0.003). In patients with moderately depressed BRS (3.0-6.0 ms/mmHg) there was a greater density of EV (p=0.01). Patients with preserved BRS had preserved or moderately compromised LVF (66.7% with LVF<40% and 79.5% with LVF40%; p=0.62) as had patients with moderately depressed BRS (15.4% with LVF<40% and 33.3% with LVF40%; p=0.46). There was no correlation between BRS and LVF. When the logistic regression model was applied, only BRS influenced the presence of sustained ventricular tachycardia (p=0.028). Conclusion: BRS is preserved in indeterminate Chagas disease and diminished in the arrhythmogenic form. The BRS impairment is progressive as the disease progresses, being more evident in patients with more complex ventricular arrhythmias. The degree of autonomic dysfunction did not correlate with ventricular function but with the density and complexity of the arrhythmias