Doctoral Degrees (Cardiology)

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    Development of an improved approach to transcatheter heart valve heart valve replacement in younger patients
    (Stellenbosch : Stellenbosch University, 2024-03) Weich, Hellmuth Stephan von Heyderhoff; Doubell, Anton F.; Smit, Francis E.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Cardiology.
    ENGLISH ABSTRACT: Rheumatic heart disease [RHD] globally affects four times as many people as degenerative aortic valve stenosis, yet all the current transcatheter aortic valves are aimed at treating degenerative disease in mostly affluent societies. There is a lack of access to cardiac surgery in low- to middle income countries where RHD is prevalent and affects mostly younger patients. Less invasive transcatheter alternatives may improve this but current devices are not appropriate because they are not designed to anchor in less calcified anatomy and the bioprosthetic tissue used for their leaflets are not durable in younger patients. We aimed to address three challenges faced in the development of a TAVI valve suitable for use in younger patients, namely more accurate positioning of the device, better anchoring of the device and better durability. We postulated that a novel non-occlusive balloon [NOB] has the potential to deliver a balloon expandable transcatheter heart valve [THV] to the aortic position with greater accuracy and stability than current [occlusive] balloons. Such a balloon was tested in an acute sheep experiment. The balloon could be inflated in the aortic valve position without compromising the animals’ hemodynamics. The NOB holds promise for a deployment device for balloon expandable THVs in younger patients with less calcified aortic valves. We designed and 3D printed a novel anchor stent to improve anchorage in the aortic valve position. The aim of the stent was as a docking station for a THV, but the principle could potentially be applied to a THV itself. The stent anchored securely in an ex-vivo study but deployment in an ovine experiment was unpredictable. Our failure to anchor it however identified a number of areas for improvement allowing us to propose an alternate design to overcome these obstacles. Our team developed a THV and collaborated with the Frater Centre at the University of the Free State which has extensive experience with pericardial tissue processing. Our approach for improved durability of the bovine pericardial leaflet tissue in young people focused on reducing glutaraldehyde exposure and decellularization of the tissue. We manufactured 3 sets of THVs [one decellularized according to the Frater Center’s technique (DE), one decellularized in the same way but fixed with very low dose monomeric glutaraldehyde (DF) and one with an industry standard (Glycar ®) fixed with high dose glutaraldehyde]. These valves were implanted for 6 months in an ovine right ventricular outflow conduit. At explant, the DF and DE valves outperformed the Glycar ® valves in a number of areas: better hemodynamic performance and strength; no inflammatory response; no pannus formation in DE and limited on DF tissue; no calcification of either DE or DF. The most notable finding was that the DE tissue had no cellular ingrowth [essentially inert] but despite this, was not mechanically inferior to the two glutaraldehyde fixed tissues and comparable to the same tissue prior to implant. This finding is unique and warrants validation in longer term implants and higher pressure environments. Based on our results, these two novel tissues has the potential to perform better in younger patients. This work brings us three steps closer to finding a THV that can be accurately delivered, implanted in a stable position and prove to be durable in younger patients.
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    The Tygerberg Endocarditis Cohort (TEC) Study
    (Stellenbosch : Stellenbosch University, 2021, 2021-12) Pecoraro, Alfonso Jan Kemp; Doubell, Anton Frans; Herbst, Philippus George; Janson, Jacques Teran; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Cardiology.
    ENGLISH ABSTRACT: Background: The diagnosis of infective endocarditis (IE) is based on the modified Duke/ESC 2015 clinical criteria. The sensitivity of the criteria is unknown in South Africa, but high rates of blood culture negative endocarditis (BCNIE), coupled with a change in the clinical features of IE, may limit the sensitivity. Methods: The Tygerberg Endocarditis Cohort (TEC) study prospectively enrolled patients with IE between November 2019 and June 2021. A standardised protocol for organism detection, with management of patients by an Endocarditis Team, was employed. Patients with definite IE by pathological criteria were analysed to determine the sensitivity of the current clinical criteria. Results: Eighty (80) consecutive patients with IE were included of which 45 (56.3%) had definite IE by pathological criteria. In patients with definite IE by pathological criteria, 26/45 (57.8%) of patients were classified as definite IE by clinical criteria. BCNIE was present in 25/45 (55.6%) of patients and less than three minor clinical criteria were present in 32/45 (75.6%) of patients. The elevation of Bartonella serology to a major microbiological criterion of the modified Duke/ESC 2015 clinical criteria would increase the sensitivity (56.3% vs. 77.8%; p=0.07). Conclusion: The sensitivity of the modified Duke/ESC 2015 clinical criteria is lower than expected in patients with IE in South Africa, primarily due to the high rates of Bartonella-associated BCNIE. The elevation of Bartonella serology to a major microbiological criterion, similar to the status of Coxiella burnetii in the current criteria, would increase the sensitivity. The majority of patients with definite IE by pathological criteria had less than three minor criteria present.
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    Echocardiographic screening for subclinical rheumatic heart disease: Improving screening through simplification of the diagnostic criteria
    (Stellenbosch : Stellenbosch University, 2020-12) Hunter, Luke David; Herbst, Philip George; Doubell, A. F.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Cardiology.
    ENGLISH ABSTRACT: Rheumatic heart disease (RHD) remains one of the leading causes of cardiovascular morbidity and mortality in developing countries withSub-Saharan Africa being identified as an endemic area. The early detection and initiation of secondary prophylaxis in children with ‘latent’ RHD remain attractive primary health care interventions, particularly in endemic regions with no or limited access to specialist cardiac services. However, the current consensus-derived screening criteria endorsed by the World Heart Federation (WHF criteria) are overly complex, require the use of expensive echocardiographic equipment with Doppler functionality and identify a large borderline diagnostic group that demonstrates a predominantly benign outcome in longitudinal study. This raises concerns regarding the feasibility of large-scale screening in resource-poor regions and questions the utility of early echocardiographic case-detection of RHD. The primary purpose of this thesis was to critically appraise the performance of the WHF criteria and todetermine whether a set of screening criteria based on a novel, focused morphological and mechanistic evaluation would simplify the current WHF guideline and reduce the number of cases ‘misclassified’ with borderline RHD whilst maintaining a similar degree of sensitivity. A literature review was undertaken that critically appraised the performance of the current WHF criteria and its impact in African RHD screening programs. This highlighted important logistical and methodological shortcomings that have curtailed the implementation of large-scale RHD screening in RHD endemic regions. The five-year experience of a large-scale, high-risk RHD screening program (Echo in Africa [EIA] project) was analysed. The results from this project highlightRHD as an ongoing, significant healthcare challenge amongst underserved communities within the Western Cape, South Africa.The estimated prevalence of WHF ‘definite-’ and ‘borderline-RHD’ of 9.1 cases/1000 and 19.5 cases/1000 reported by EIA is significantly higher thanthatpreviously described in this region. Furthermore, a critical appraisal of the WHF criteria’s performance in the EIA cohort highlighted various redundant and ambiguous criteria that require revision.Inter-scallop separations (ISS) of the posterior mitral valve leaflet (PMVL) were described in both our high-and very low-risk populations. They were a common finding and the principal cause of WHF ‘pathological’ mitral regurgitation (MR) in the ‘borderline RHD’ group in both cohorts. This supported theirstatus as a normal and importantly, non-rheumatic variant.The reliability of the current WHF anterior mitral valve leaflet (AMVL) thickness assessment was evaluated and was demonstrated to be poor amongst readers despite controlling for systematic bias. This raised the possibility of introducing a non-measurement-based AMVL thickness evaluation. A novel screening definition of AMVL restriction was introduced, enabling the description of a variable spectrum of AMVL restriction amongst children.This definition reliably identified two subtypes of leaflet restriction: a normal, ‘gradual bowing’ variant that localised predominantly to the medial portion of the leaflet and a ‘distal tip’ variant seen to affect at least the central portion of the leaflet in all cases of WHF ‘definite RHD’ in this cohort. Finally, this thesis culminated in the development and evaluation of a novel set of morpho-mechanistic (MM) echocardiographic screening criteria for RHD. Together with an abbreviated ‘rule-out’ screening test, the MM criteria were assessed alongside the current WHF criteria in a gold standard RHD-negative cohort and a gold standard RHD-positivecohort. The MM criteria significantly reduced the false-positive rate of a borderline diagnosis inthe gold standard RHD-negative cohort (2.7/1000 vs 41.8/1000) whilst maintaining a similar screening sensitivity (99.7%) compared to the WHF criteria (95.9%) within thegold standard RHD-positivecohort. Similarly, the MM RHD ‘rule-out’ test performed well by excluding the majority of cases (98%) within the gold standard RHD-negative cohort while including all cases within the gold standard RHD-positive cohort. The work presented in this thesis addresses key research needs and gaps in our current understanding of ‘screen-detected’ latent RHD. It representsa significant contribution that will impact on policy, practice and further research in the field. The discovery that ISS of the PMVL are a normal finding and the principal cause of isolated ‘pathological’ MR in the borderline group represents a key element in solving the ‘borderline conundrum’. This discovery supported the adoption of a morpho-mechanistic screening approach over a predominantly functional MV assessment. Centred around a novel definition of AMVL restriction, the MM criteria significantly improve the specificity of RHD detection by markedly reducing the size of the borderline group. Importantly, this was achieved without a reduction in the sensitivity of the criteria when compared to the current WHF criteria. Together with a simple ‘rule-out’ test, the MM criteria bring us closer to the objective of implementing large-scale screening programs that identify children with latent RHD who will benefit from secondary prophylaxis.
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    Lupus myocarditis : diagnostic characteristics and outcome of myocardial injury
    (Stellenbosch : Stellenbosch University, 2020-12) Du Toit, Riette; Doubell, A. F.; Reuter, H.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Cardiology.
    ENGLISH ABSTRACT: Lupus myocarditis is a rare but serious manifestation of systemic lupus erythematosus (SLE). Through this dissertation I have aimed to describe the outcome of both clinical as well as subclinical myocardial injury in SLE. I have also aimed to define the diagnostic characteristics of myocardial injury, identified by cardiac magnetic resonance imaging with regards to clinical, echocardiographic and cytokine profiles.
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    Renal denervation restores autonomic imbalance and prevents atrial fibrillation in patients with hypertensive heart disease : a pilot study
    (Stellenbosch : Stellenbosch University., 2020-03) Heradien, Marshall Jacobus; Brink, Paul A.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Cardiology.
    ENGLISH ABSTRACT: Background: Atrial fibrillation (AF) is associated with increased cardiovascular morbidity and mortality, but it is uncertain if catheter-based renal denervation (RD) can reduce AF in patients with hypertensive heart disease (HHD). Methods: Patients who were ≥ 55 years old, in sinus rhythm, taking ≥ 3 anti-hypertensive drugs including a diuretic, with echocardiogram-confirmed HHD and suspected coronary artery disease, were randomised to undergo RD or sham procedure. Patients with renal impairment, significant valvular heart disease and untreated thyroid disease were excluded. The primary endpoint, the first episode of subclinical AF (SAF) lasting ≥ 6 minutes, was detected using an implantable loop recorder which was scanned every six months. Six-month follow-up (6MFU) office systolic blood pressure (SBP), cardiovascular mortality and restoration of autonomic imbalance were secondary endpoints. Results: Eighty patients were randomised: 42 underwent RD and 38 a sham procedure. After an average follow-up of three years, fewer RD patients experienced SAF: 6 of 42 patients (14.3%) vs 15 of 38 (39.5%) sham patients (odds ratio (OR), 0.26; 95% CI, 0.1 to 0.71, p = 0.01). Fast AF (ventricular rate ≥ 100 bpm) occurred in 10 sham patients (26.3%) vs 1 RD patient (2.4%): OR, 14.64; 95% CI, 1.77 to 120.91; p = 0.002). The incidence of cardiovascular death was higher in the sham than RD group (6 of 38 (15.8%) vs 1 of 42 (2.4%): OR, 7.69; 95% CI, 0.88 to 67.12; p = 0.049). Non-ST elevation myocardial infarction (NSTEMI) incidence was lower in the RD than sham group (2.3% vs 18.4%: OR, 0.108; 95% CI, 0.01–0.92; p = 0.02). The 6MFU between-group SBP difference was not significant (−3.8 mmHg; p = 0.49). Resting and one-minute recovery heart rate did not differ between groups at 6MFU. Conclusion: In patients with HHD, RD reduces subclinical and fast AF, NSTEMI and cardiovascular death independent of lowering blood pressure. RD was not associated with improvement of surrogate markers of autonomic imbalance.