Prognostic Markers of Ventricular Arrhythmia: Is further refinement of risk stratification possible? – A prospective study of patients with Implantable Cardioverter Defibrillators and Left Ventricular Systolic Dysfunction

The management and prevention of Sudden Cardiac Death remains a great challenge in modern Cardiology. Implantable Cardioverter Defibrillators (ICDs) have been shown to reduce mortality. Despite decades of research, the mechanisms are not fully understood and ICD treatment is crude, palliative and expensive. Nonetheless, outcome studies have helped to inform national and international guidance in the implantation of these devices. Patient selection is crucial to ensure correct patients are identified and appropriately treated. More refined and stringent risk stratification is needed to identify patients at high risk. This thesis examines non-invasive, readily measureable markers to see whether they can be used to assess the risk of ventricular arrhythmia in patients with cardiomyopathy who have indications for ICD implantation. Baseline data in the form of 12 lead electrocardiograms, echocardiography, 24 hour Holter monitoring and venous blood were obtained to analyse QT dispersion, Heart Rate Variability (HRV), QT Variability Index (QTVI), ECG restitution measures and NTproBNP levels in these patients. Patients were followed up for a two year period through the ICD clinic and appropriate therapy was recorded as a surrogate marker for ventricular arrhythmia. Patients with and without appropriate therapy were then compared to look for significant differences in the examined markers. The percentage of beats with a QT/TQ ratio>1 was associated with appropriate shocks when compared with no therapy (p=0.04). However, the result was not significant when all appropriate ICD therapy was compared with no therapy (p=0.06). This possibly reflects the period of time the heart spends on the more ‘unstable portion’ of the restitution slope in patients at highest risk. Median BNP was non-significantly higher in patients with arrhythmia compared to those who were shock free. None of the other examined markers were predictive of appropriate therapy. There is thus promise in the use of some non-invasive markers in the refinement of patient selection with LVSD being considered for ICD therapy

Stacked view of FTIR spectra of (AGAGACCAGAGA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).

<p>Stacked view of FTIR spectra of (AGAGACCAGAGA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).</p

Thermal denaturation.

<p>Ellipticity (A & B) and emission (C & D) measurement of <i>Cp</i>GAL as a function of temperature. Emission shows monotonous decrease in the intensity of λ_max with increasing temperature. (E) Represents residual enzymatic activity as a function of heat denaturation for 5 min, at respective temperatures.</p

Overlaid view of second derivative spectra of ctDNA and duplexes with their complexes of amsacrine at molar ratio of 1/10 (drug/nucleotide).

<p>Panel 1: ctDNA (blue) and complex (red), Panel 2: (AAAAAAAAAAAA)2 (blue) and complex (red) (b), Panel 3: (ATATATATATAT)2 (blue) and complex (red), Panel 4: (TTAATTAATTAA)2 (blue) and complex (red), Panel 5: (AGAGCAACAGAG)2 (blue) and complex (red), Panel 6: (AGAGACCAGAGA)2 (blue) and complex (red).</p

Stacked view of FTIR spectra of ctDNA (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10(d).

<p>Stacked view of FTIR spectra of ctDNA (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10(d).</p

Native spectra for <i>Cp</i>GAL.

<p>(A) Represents Far UV CD spectra, whereas (B) represents fluorescence emission spectra at different excitation wavelengths.</p

pH induced denaturation.

<p>Ellipticity (A), emission (B) and enzymatic activity (C) measurement of <i>Cp</i>GAL as a function of pH. The enzymatic activity was estimated at respective pH of incubation and at pH 2.8 (according to the standard activity assay protocol). (D) Represents fluorescence intensity of ANS binding. (E) Represents size exclusion chromatography (SEC) profile of <i>Cp</i>GAL at pH 2.0 and pH 4.0.</p

Chemical induced conformational changes.

<p>(A) & (B) represents GdHCl and urea mediated transitions of protein unfolding, respectively. (C) Represents free energy of unfolding, whereas (D) represents unfolding kinetics rate constants (Half Chevron plot) against GdHCl. Intercepts at y axis gives ΔG₀ and log K_obs, respectively.</p

Stacked view of FTIR spectra of (TTAATTAATTAA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).

<p>Stacked view of FTIR spectra of (TTAATTAATTAA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).</p

Stacked view of FTIR spectra of (AAAAAAAAAAAA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).

<p>Stacked view of FTIR spectra of (AAAAAAAAAAAA)2 duplex (a) and its complexes with amsacrine at different molar ratios (r) of 1/50 (b), 1/20 (c) and 1/10 (d).</p