Non-invasive electrical imaging of the heart aims to quantitatively reconstruct information about the electrical activity of the heart from multiple thoracic ECG signals. The computational framework required to produce such electrical images of the heart from non-invasive torso surface signals is presented. It is shown reliable electrical images of the heart can be obtained under a controlled environment. This has been demonstrated using an anatomically realistic boundary element porcine torso model. The procedures required to create a subject specific model using a small number of control points and to create a specific heart model from three-dimensional ultrasound images using a linear fitting procedure are presented. From discrete ECG electrodes a continuous representation of the potential field over the entire torso surface can also be produced using this linear fitting procedure. The construction of the transfer matrices for the two predominant electrocardiographic sources (epicardial potentials and myocardial activation times) are described in detail. The transfer matrices are used to compute activation times within the heart and epicardial potentials on the heart surface. Myocardial activation times are computed using an algorithm based on the Critical Point Theorem while epicardial potentials are computed using standard Tikhonov and Truncated SVD spatially regularised methods as well as Greensite's spatial and temporal regularisation method. The regularisation parameters for the epicardial potentials are determined using a variety of methods (e.g., CRESO criterion, L-curve, zero-crossing). The potential and activation based formulations are compared in a comprehensive inverse simulation study. To try and capture the dynamic and variable nature of cardiac electrical activity, the study is performed with three different types of cardiac sources with a realistic porcine model. These simulations investigate the effect on the computed solutions of individual and combinations of modelling errors. These errors include corruption in the torso surface signals, changes in material properties and geometric distortion. In general, the activation based formulation is preferred over the epicardial potential formulations, with Greensite's method found to be the best method for reconstructing epicardial potentials. Under optimal conditions, the activation approach could reconstruct the activation times to within RMS. Both potential and activation based formulations were found to be relatively insensitive to changes in material properties such as lung conductivities and activation function shapes. When examining individual errors, the geometry and positions of the torso and heart had the greatest effects on the inverse solutions. The relative heart position needed to be determined to within to obtain results within of the solutions obtained under control conditions. When the modelling errors are combined to produce errors which can be expected in a clinical or experimental situation the activation based solutions were consistently more accurate than potential based solutions. The next necessary step in this project is the detailed validation of the results against in-vivo data. This step is necessary before such algorithms can be reliably used to aid in the assessment of heart function in a clinical environment.

Thesis (Ph.D.)--University of Western Sydney, 2008. / A thesis submitted to the University of Western Sydney, College of Health and Science, School of Nursing in fulfilment of the requirements for the degree of Doctor of Philosophy. Includes bibliographical references.

Abstract Natriuretic peptides have emerged as important candidates for the development of diagnostic tools in cardiovascular disease. Their increased concentrations have been found to be useful for ruling out disease of cardiac origin, as prognostic indicators, and in the follow-up of patients with heart failure. In order for natriuretic peptides to be efficient biomarkers, analytical problems in assay specificity and calibration need to be resolved. The aim of the present study was to elucidate circulating molecular components of N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) in human blood, and to develop reliable and novel assays for their measurement with clinical application. Reliable immunoassays for NT-proANP and NT-proBNP were set up based on recombinant calibrators and antisera against different epitopes. A novel immunoassay for detecting the activation of A- and/or B-type natriuretic peptide systems, referred to as NT-proXNP, was also developed. The chromatographic results of human plasma and serum samples indicated that NT-proANP and especially NT-proBNP are heterogeneous in human circulation. They are truncated at both termini, causing a serious risk of preanalytical errors. Further studies with recombinant peptides confirmed that the central parts of NT-proANP and NT-proBNP are stable in plasma and serum even at harsh storage conditions. Thus the most reliable assays are directed at the central portions of the molecule only. All developed assays were applicable to clinical samples of cardiac patients. NT-proXNP showed a diagnostic efficiency equal to or slightly better compared to individual NT-proANP and NT-proBNP assays. Furthermore, the prognostic value of NT-proANP and NT-proBNP was investigated in a population-based sample of men. Both peptides were strong predictors of mortality and its co-morbidities, adding to the prognostic value of conventional risk factors.

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.

Mammalian myocardial contractility is believed to be regulated by the amount of calcium contained in a highly labile superficial calcium pool. The purpose of the first part of this study was to determine the role of such sites in the positive inotropic effect of isoproterenol. Lanthanum, an ion known to be restricted to the extracellular space and which displaces the superficially-bound calcium, was selected as a tool for this investigation. In Langendorff preparations of the guinea pig heart, lanthanum decreased the basal contractility index (+dP/dtmax) in a concentration-dependent fashion (0.05-3 µM) and blocked the inotropic response of isoproterenol in a non-competitive manner (0.25-3 µM). Three µM lanthanum: 1) reduced basal contractility and the maximum response to isoproterenol by 97 and 95%, respectively; 2) had no significant effect (p>0.05) on basal and isoproterenol-induced cyclic AMP levels; and 3) had no effect on the kd of [³H]nitrendipine binding, but reduced the Bmax by 31%. While 1 µM lanthanum reduced basal contractility and the maximum response to isoproterenol by 90 and 70%, respectively, it had no effect on [³H]nitrendipine binding. These results suggest that the effects of such low concentrations of lanthanum (≤3 µM) are not related to a direct action on the calcium channels and are not mediated by an inhibition of isoproterenol stimulation suggest that superficially-bound calcium is required for the inotropic response of isoproterenol. The purpose of the second part of this study was to elucidate the biochemical nature of the superficial calcium binding sites, the sialic acids in particular, in the inotropic response of cardiotonic agents. To determine the role of the glycocalyx residues of sialic acids in excitation-contraction coupling and the inotropic response to cardiotonic agents, I studied the effect of removal of the sialic acids following neuraminidase treatment on the response to ouabain, isoproterenol, calcium and reduced extracellular sodium in Langendorff preparations of adult guinea pig hearts. Neuraminidase treatment (0.01 U/ml, 1 h) reduced the magnitude of the positive inotropic response to 2.5x10⁻⁷M ouabain and the maximum response to 5x10⁻⁷ M ouabain by about 46 and 30%, respectively, but did not prevent ouabain toxicity. Neuraminidase treatment did not affect the contractility produced by calcium concentration alterations up to 5 mM calcium or the positive inotropic effect produced by lowering external sodium to as low as 80 mM. The inotropic response to as high as 10⁻⁸ M isoproterenol was also not affected. The contractility response developed to calcium concentrations greater than 5 mM and to 5x10⁻⁸ M isoproterenol were significantly reduced (p<0.05) by neuraminidase treatment. The content of sialic acids in neuraminidase-treated hearts used in the above concentration-response reduced by 70.7, 66.1, 65.6 and 66.2%, respectively. Neuraminidase treatment had no effect on basal (Na⁺-K⁺)ATPase and Mg²⁺ -ATPase activities of (Na⁺-K⁺)ATPase-containing membrane preparations of the guinea pig left ventricle. Neuraminidase treatment neither influenced the sensitivity of the enzyme (Na⁺-K⁺)ATPase to ouabain inhibition nor did it affect the characteristics of [³H]ouabain binding to the preparation. These results suggest that the sialic acids of the glycocalyx in the guinea pig left ventricle play an important role in part of the inotropic response to subtoxic concentrations of ouabain. / Pharmaceutical Sciences, Faculty of / Graduate

The mechanical and biochemical effects of prostaglandins E₁ and F₁α were studied on rat heart using isolated right and left atria and the Langendorff perfused whole heart preparation. Preliminary experiments were performed to establish optimal perfusion conditions for the Langendorff preparation. Hearts were perfused at different perfusate temperatures and at different filling pressures. Heart rate and coronary flow rate were monitored at all combinations of perfusate temperature and filling pressure. A constant temperature water recirculating pump setting of 38°C and a filling pressure of 40 cm of H₂O were chosen as the optimal perfusion conditions. Hearts perfused under the above conditions responded normally to bolus injections of isoproterenol. Isoproterenol produced a dose dependent increase in the contractile force of the Langendorff preparation and the cyclic AMP increasing effect of isoproterenol preceeded the positive inotropic effect in a time course study. Prostaglandin E₁ (PGE₁) did not produce any effect on heart rate or tension development in the Langendorff preparation, when infused over a dose range of 0.03 Ug to 5.0 μg/min. Infusion of prostaglandin F₁α (PGF₁α) (0.1 to 5.0 μg/min) produced an increase in tension development which was associated with a negative chronotropic effect. The positive inotropic effect of PGF₁α was secondary to the drop in rate as the positive inotropic effect was completely abolished when the hearts were paced at 6 Hz. In the rat right atrium, PGE₁ produced a dose dependent increase in the rate which developed very slowly. PGE₁ had no effect on the tension development of the.rat left atrium. PGF₁α produced a slow, dose dependent positive chronotropic effect on the right atrium and a slight but not significant effect on the force of contraction of the left atrium. Both prostaglandins were equipotent in exerting their positive chronotropic effect on the right atrium. The PD₁ value for PGE₁ was 5.54 ±0.25 and for PG₁α 5.59 ± 0.18. In the right atrium 10⁻⁴ M PGE₁ increased the rate and cyclic AMP content without changing phosphorylase a activity or cyclic GMP content. PGE₁ (10⁻⁴M) slightly but not significantly increased the left atrial cyclic AMP con-; tent and did not change the cyclic GMP content. 10⁻⁴ M PGF₁α did not affect either right or left atrial cyclic AMP or cyclic GMP content. The effect of a 1 μg/min infusion of either PGE₁ or PGF₁α on the changes of cyclic AMP and cyclic GMP contents and phosphorylase a activity with time were studied in the Langendorff preparation. A 1 μg/min infusion of PGE₁ increased the myocardial cyclic AMP levels by about 57 per cent above control at 30 sees after starting the infusion and the cyclic AMP levels were still elevated by 50 per cent over control at the end of a one minute period of infusion. PGE₁ did not change cyclic GMP content or phos-phorylase a activity at any time point. A 1 ug/min infusion of PGF₁α did not alter cyclic AMP and cyclic GMP levels or phosphorylase a activity in the rat heart within one minute. These results supported the earlier reported observation that PGE₁ selectively increased rat myocardial cyclic AMP content without altering myocardial contractile force or phosphorylase a activity. PGE₁ might be selectively increasing a pool of cyclic AMP and activating a cyclic AMP-dependent protein kinase in the cardiac cells that is not associated with contractile force or phosphorylase activation. PGF₁α did not possess this selective effect of PGE₁. Cyclic GMP is not involved in the mediation of the actions of either PGE₁, or PGF₁α, on the rat heart. / Pharmaceutical Sciences, Faculty of / Graduate

The purpose of this study was to examine the relationship between training heart rate (THR) and the HR occurring at the Aerobic Threshold (AerTHR), and to examine the AerT as an index of training intensity in selected coronary artery disease (CAD), post-myocardial infarction (MI), and post-coronary artery bypass surgery (CABS) patients. Twenty male subjects (age=54.9; wt=73.7 kg; %body fat=25.8) were recruited on the basis of regular participation in a cardiac rehabilitation program (CRP) (3/week at 70 - 85% HRmax) for 6 months; no beta-adrenergic medication; and symptom-free during exercise. Field measurements of THR during the aerobic phase at CRP was carried out by computer-assisted portable telemetry with mean THR computed from each 30 minute value per subject. A maximal treadmill test starting at 2.5 mph at 0% grade with speed increasing 0.5 mph each minute was carried out using a Beckman MMC for 30 second determinations of respiratory gas values. The AerT was determined by visual inspection of the first departure from linearity of Ve and excess CO₂. VO₂max was 35.6 ±5.6 ml/kg/min⁻¹, with HRmax 166.2 ±11.8 bpm. Paired t-tests were performed; AerTHR was 124.8 ±15.3 bpm with THR 133.7 ±13.4 bpm (p < .03). Percent HRmaxAerT was 75.1 ±8.05 and %HRmaxTHR was 80.6 ±8.3 (p < .03). Mean %VO₂maxAerT (54.4 ±6.7) is consistent with other reported data showing .lower values in less trained individuals. Stepwise correlations were performed, and a regression equation was produced to predict AerT grom HRmax, height, and weight with a multiple r = .74 (p < .01). These data suggest that in this population, THR, as calculated by the relative percentage of maximum method, produces training intensities above the AerT expressed as absolute or relative percents of HRmax. This finding may have implications for optimal body fat reductions, patient compliance to the exercise program, and safety in CRP's. / Education, Faculty of / Curriculum and Pedagogy (EDCP), Department of / Graduate

The analysis of HRV is an advanced and noninvasive method which is used to investigate the involuntary nervous system. It is also one of the important parameters of its proper function. Heart rate variability can also be analyzed by entropy, which studies the discrepancy of the RR intervals of the HRV signal and thus can be used to diagnose cardiac diseases

Background: A 73-year-old man with a history of myocardial infarction and hypertension for 5 years suffered heart failure (NYHA III-IV). Methods: 2D echo indicated hypokinesia at septal, left ventricular anterior wall and apical regions. Coronary angiograms demonstrated 60% stenosis in distal left main and 99% stenosis in proximal and distal left anterior descending coronary arteries (LAD). Both proximal artery and middle left circumflex coronary artery (LC) had 90% stenosis, and diffuse stenosis of right coronary artery (RC) was found. Myocardial perfusion imaging using 99mTc-MIBI indicated defective perfusion of left ventricular apex, anterior wall and septal region and severe reduced perfusion of posterior inferior wall. Myocardial metabolic activities (18F-deoxyglucose) also showed comparable reductions. After exposing the heart, LAD, LC, and RC were all completely occluded and bypass procedure could not be completed. Autologous satellite cells were implanted without any complication and the patient had an uneventful recovery. Results: During the first 2 months, he remained in heart failure, and by the third month, he gradually improved and reached NYHA II. At fifth month after the procedure, significant increased ejection fraction (37.1-48.6%) and wall movement with modest reduction of left ventricular systolic diameter (48-45 mm) were observed. Imaging with 18F-deoxyglucose showed dramatic improvement in myocardial metabolic activity with similar improvement in myocardial perfusion (99mTc-MIBI). Conclusion: This is the first successful case of cellular cardiomyoplasty without any conjunctional procedure for patient with severe coronary heart disease and heart failure.

Background: Diastolic function (DF) guidelines have been simplified but lack extensive outcome data. Using a rural university heart failure (HF) database, we assessed whether DF grading could predict HF, HF readmission, and all-cause mortality (ACM). Methods: In this single-center retrospective study that included 613 patients in sinus rhythm hospitalized for HF (HF with preserved—254 patients, with mid-range—216 patients, and reduced ejection fraction—143 patients), we recorded demographics, Doppler-echo, Framingham HF score, laboratories, HF readmission, and ACM with follow-up to 2167 days. Results: Diastolic dysfunction (Ddys) parameters (left atrial volume index [LAVI] > 34 ml/m2, tricuspid regurgitation [TR] velocity > 2.8 m/sec, and E/e’ > 14) had moderate sensitivity (46.2%–65.0%) for predicting HF among all phenotypes combined with DF grading having moderate predictability and additive to a clinical composite for HF prediction (AUC =.677, P < 0.0001; difference =.043, P < 0.001) for combined phenotypes. Ddys parameters and Ddys severity (2016 ASE criteria: grade II and III) were significantly associated with HF readmission for decompensated HF within 60–2167 days of follow-up (LAVI > 34 ml/m2: HR 1.56 [1.26–2.19]; E/e’ > 14: HR 1.44 [1.21–1.99]; TR > 2.8 m/sec: H1.43 [1.19–1.88]; LV Dys grade II: HR 2.12 [1.42–2.96]; LV Ddys grade III: HR 2.39 [1.57–4.82]). Conclusion: The findings of this study highlight the clinical and prognostic relevance of determining the severity of LV Ddys in patients with HF with regard to HF verification and HF readmission.