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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

Thesis (Ph. D.)--University of Washington, 1990. / Vita. Includes bibliographical references (leaves [270]-296).

Background: Stroke volume (SV) and aortic valve area calculations require the left ventricular (LV) outflow tract (LVOT) or aortic annular area calculations that involve squaring the respective diameters. Area calculation errors became evident with transcatheter aortic valve replacement where areas were underestimated due to an elliptical annulus. We hypothesized that LVOT and annular shape are more elliptical in patients with greater relative LV wall thickness (RWT) leading to underestimation of SV index using 2D Doppler echocardiography. Methods: We studied 203 consecutive patients referred to an outpatient noninvasive laboratory for Doppler echocardiograms which included acceptable 3-dimensional images. 3-dimensional assessment of the LVOT at 3–5 mm from the valve insertion, at the site of valve insertion, and at the sinus of Valsalva (SOV) was performed with assessment of the minor axis (MN), major axis (MJ), and areas at mid-systole. SV index was calculated from LVOT and annular diameters obtained from 2-dimensional echo and from 3-dimensional LVOT areas. Results: An inverse relation of RWT with MN/MJ at mid-systole for the LVOT (r = 0.5812, P < 0.0001) and annulus (r = 0.6865, P < 0.0001) was noted. LVOT and annulus areas were similar among groups at mid-systole. SV index calculated from 2D LVOT dimensions was significantly smaller than using 3D LVOT areas (35.6 ± 8.9 vs 53.6 ± 16.1 mL, P < 0.0001). Conclusion: There is an inverse relation between MN/MJ and RWT at the LVOT and aortic annulus despite the LVOT and annular areas being similar across most geometries resulting in SV index underestimation calculated using LVOT diameters vs 3D LVOT areas.

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Left ventricular hypertrophy (LVH), the detection of which is recommended for routine risk prediction by all guidelines, is more prevalent in groups of African ancestry. This is in-part attributed to higher prevalence rates of obesity. The ability to detect LVH using electrocardiographic (ECG) criteria may be modified in groups of African ancestry. The impact of co-existent obesity on the ability to detect ECG-LVH in this ethnic group has not been determined. Moreover, whether estimated glomerular filtration rate (eGFR) or serum C-reactive protein (CRP concentrations are independently associated with LV mass index (LVMI) and can therefore be used to complement ECG criteria for LVH detection is uncertain. ECG voltage criteria for the detection of echocardiographic LVH were evaluated in 661 participants from a community sample of African ancestry (43% obese). Body mass index (BMI) was inversely associated with Sokolow-Lyon (SL) voltages (partial r=-0.27, p<0.0001) and no BMI-Cornell voltage relations were noted (p=0.21). BMI was associated with voltage criteria that incorporate only limb lead recordings (r=0.17-0.23), but these relationships were weaker than BMI-LVMI relations (r=0.36, p<0.01-p<0.0001 for comparisons of r values). All ECG criteria were as strongly related to blood pressure (BP) as LVMI. Sokolow-Lyon voltage-LVMI relations were noted only after adjustments for BMI (p<0.02) and SL voltages showed no performance for LVH detection. Cornell voltages showed significant performance in the non-obese (area under the receiver operating curve [AUC]=0.67±0.04, p<0.0005), but not the obese (AUC=0.56±0.04, p=0.08). ECG criteria which employ limb-lead recordings only (e.g. RaVL) showed better performance in non-obese than obese (AUC=0.75±0.04 and 0.59±0.04 respectively, p<0.005 for comparison) and markedly reduced specificity for LVH detection in obese (76%) than non-obese (92%, p<0.0001) despite similar sensitivities (32 vs 29%). Thus, in groups of African ancestry, obesity contributes toward a poor validity and performance of all voltage criteria for the detection of LVH. None of the current criteria are recommended for use in obesity in groups of African descent. Alternative approaches are required for LVH detection in these groups.In 621 randomly selected participants from the community sample [332 were normotensive (NT)], eGFR was associated with LVMI and LVM in excess of that predicted from stroke work (inappropriate LVM, LVMinappr) in all participants (LVMI: partial r=-0.18, p<0.0001; LVMinappr: partial r=-0.17, p<0.0001) and NT (LVMI: partial r=-0.23,p<0.0001; LVMinappr: partial r=-0.22, p<0.0001) separate from hypertensives. When replacing clinic BP with either aortic systolic BP (applanation tonometry and SphygmoCor software), 24-hour BP, aortic pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software), stroke work (for LVMI), LV end diastolic diameter (LVEDD), or circumferential wall stress in the regression models, eGFR retained strong associations with LVMI (p=0.01 to <0.0001) and LVMinappr (p<0.005 to <0.0001). Thus, strong relationships between eGFR and LVM occur at a community level irrespective of the presence of hypertension and independent of 24-hour and aortic BP, PWV, LVEDD,stroke work and wall stress. The independent relationships between eGFR and LVMI, support the notion that eGFR may be evaluated for LVH detection. In 361 randomly selected participants from a community with a high prevalence of CRP concentrations considered to be high-risk (54.0%), but without cardiovascular or renal disease, serum CRP concentrations were correlated with both LVMI and LVMinappr (p<0.0001). With adjustments for a number of potential confounders including age, systolic BP, waist circumference (or BMI), and glucose control (glycated haemoglobin), the relationships between serum CRP concentrations and both LVMI and LVMinappr (partial r=0.11, p<0.05 for both) persisted. The independent relationship between CRP and LVMI or LVMinappr translated into a higher multivariate-adjusted LVMI and LVMinappr values in the highest as compared to the lowest quartile of CRP (LVMI; highest quartile CRP=48.8±10.7, lowest quartile CRP=45.0±11, p<0.05; LVMinappr; highest quartile CRP=137±24, lowest quartile CRP=127±24, p<0.05). The independent relationships between CRP and LVMI, support the notion that CRP may also be evaluated for LVH detection. In 358 participants from a randomly selected community sample with a high prevalence of obesity (41%), a combination of CRP concentrations and eGFR above or below the median for the sample respectively showed significant performance (AUC=0.61±0.03, p<0.0005), but a low specificity for LVH detection (77%). When eGFR and CRP concentrations were employed to complement RaVL, although the overall performance did not improve (AUC=0.71±0.03, p<0.0005, RaVL alone: AUC=0.70±0.03), the specificity increased (93%) whilst sensitivity (25%) was in-line with previously reported sensitivities for LVH detection using ECG criteria in alternative population samples. Without changing overall performance, eGFR together with RaVL increased the specificity to 88% and CRP concentrations when considered together with RaVL increased the specificity to 87%. Thus, in a community sample where the specificity and performance of ECG criteria for LVH detection are poor, the use of eGFR and/or CRP concentrations to complement ECG criteria increase the specificity without altering the overall performance. In conclusion, the present thesis provides evidence to indicate that current ECG criteria for the detection of LVH are invalid in obese individuals of African ancestry, but that clinical markers of renal dysfunction and systemic inflammation, which are associated with LVMI independent of haemodynamic factors and co-morbidities may be employed to complement ECG criteria to improve the specificity for LVH detection.