Introduction: There is progressive stiffening and dilatation of the aorta and large elastic arteries with aging as a result of the repetitive cyclic stress they are exposed to throughout life. Aortic stiffening has a number of detrimental effects including an increase in aortic pulse wave velocity and early wave reflection, isolated systolic hypertension, ventricular-vascular mismatch, impaired coronary blood flow reserve, and is the fundamental cause of heart failure in the elderly. The aim of this thesis is to provide proof of concept for the aortic wrap procedure; a surgical treatment of stiffening and dilatation of the ascending aorta with aging. The surgical procedure involves wrapping an elastic material around the ascending aorta of elderly patients, to reduce the stiffness and diameter of the ascending aorta towards that seen in youth. Methods: Proof of concept is investigated in the following studies. 1. The effect of the elastic wrap on the in-vivo stiffness of the normal aorta. 2. The effect of the elastic wrap on the in-vivo stiffness of the dilated and stiffened aorta. 3. The effect of the elastic wrap on the in-vitro stiffness of the aged human ascending aorta and on aortic pressure. 4. The effect of wrapping the aged human ascending aorta on pulse pressure (mathematical model). 5. The effect of chronic implantation on the structure of the normal aorta. 6. The mechanical properties of the ovine thoracic aorta and the elastic wrap material. Results: 1. Elastic wrap application increased the in-vivo stiffness of the normal aorta. 2. Elastic wrap application decreased the stiffness of the stiffened and dilated aorta. 3. Elastic wrap application decreased the in-vitro stiffness of the elderly human ascending aorta and pulse pressure. 4. A reduction in ascending aortic stiffness was sufficient to reduce ascending aortic pulse pressure. Conclusion: Application of the elastic wrap to the aged human ascending aorta is expected to reduce aortic stiffness, as well as systolic and pulse pressure, and to increase diastolic pressure with a reduction in cardiac load. The aortic wrap procedure may be an effective surgical procedure for the treatment of heart failure and isolated systolic hypertension.

Non-specific aortic arteritis remains a disease of unknown aetiology, in which the treatment is empiric, the indications for surgery controversial and the prognosis unpredictable. Most series emanate from the Far East, with few contributions from Africa. The pattern of disease as seen in-Cape Town has not been documented since the study of Schrire and Asherson in 1964, containing 18 cases. In this study at Groote Schuur and Red Cross Children's Hospital from 1952 to 1987, only patients who had been extensively investigated and subjected to angiography were included. strict· inclusion criteria excluded patients with specific forms of aortic arteritis. 220 patients were studied of which 77% were female. Mean age 25(1-66). 68% were "Coloured" or Asian, 24% Black and 8% White. Involvement of the entire aorta was seen in 62%. The· aortic arch was involved in 70% but isolated arch disease occurred in only 9%. Aortic bifurcation disease occurred in 30%, an unusually high incidence. 93% had occlusive disease. 50% had aneurysms, which usually occurred together with occlusive disease. 7 patients presented with ruptured aneurysm. Hypertension due to renal artery stenosis or to coarctation was the commonest presentation (76%). 103 (47%) patients had cardiac disease (hypertensive cardiac failure or aortic incompetence.) Upper or lower limb claudication was present in 77 patients with gangrene in only 11. 43 patients had clinical evidence of cerebrovascular disease. 54 patients are known to have died, with cardiac failure responsible for almost 50%. Follow-up of 5-20 years was possible in 40% of patients. Two-thirds showed no further progression in this period. Vascular reconstruction was performed in 43 patients (21%). Other treatment modalities included corticosteroids (11%) and antituberculous therapy (28%). Proven tuberculosis was present in only 20% of cases. The pattern of disease in Cape Town tends to be diffuse, usually with extensive branch vessel involvement, and thus seldom amenable to reconstructive vascular surgery. Hypertension and cardiac failure are the commonest presenting symptoms and the most frequent cause of death. The aetiology of this condition remains obscure and the pathogenetic link with Tuberculosis is controversial. A significant number of patients have "burnt out" disease, and prolonged survival has been observed.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Diseases of the aorta rank as the 20th leading cause of mortality in the US, contributing to 10,000 deaths annually. Thoracic aortic aneurysms are typically asymptomatic, often undetected until life-threatening aortic dissection or rupture occurs. Familial cases constitute one in five instances of thoracic aortic aneurysm and dissection (TAAD), with genetic causes being heterogeneous and known risk genes explaining only a small fraction of cases. We hypothesized that additional TAAD risk genes remain undiscovered. This thesis aims to investigate the genetic etiology of TAAD using genetic and genomic approaches. Our methodological approach included: 1) exome sequencing of DNA from TAAD patients with subsequent genomic analysis, integrating clinical data, and 2) single-cell RNA sequencing (scRNA-seq) of the developing (embryonic) mouse aorta. We sequenced 1650 DNA samples from 1429 TAAD patients and, after quality control, analyzed genomic data from 1278 unrelated TAAD patients of European ancestry. For controls, we used 145,103 unrelated individuals of European ancestry from the UK BioBank. We conducted a per-gene and per-domain burden analysis using a binomial test. To improve the power of detection of novel risk genes, we integrated case-control association of rare damaging variants with cell-type specific gene expression data from scRNA-seq of the ascending and descending aorta of 17 mouse embryos (harvested at the E15 stage) with the hypothesis that true risk genes are highly expressed early in development. Our analysis of known TAAD risk genes identified 52 pathogenic or likely pathogenic variants, explaining 4.1% of TAAD cases, and 75 variants of uncertain significance (5.9%). Next, two potential novel candidate genes emerged from the unbiased case-control analysis, which utilized AlphaFold domain-based annotation of protein structure: β-propeller domain of VPS8 (p = 8.8 × 10-9) and UTP11 (p = 3.9 × 10-8). scRNA-seq of the developing mouse aorta revealed significant cell-type-specific expression differences between the ascending and descending aorta, identifying five subtypes of vascular smooth muscle cells in the ascending aorta and four in the descending aorta. Differentially expressed genes between major aortic cell types were also identified. Both, VPS8 and UTP11 were found to expressed in all three major aortic cell types – vascular smooth muscle cells, fibroblasts, and endothelial cells. In conclusion, our case-control association analysis identified two promising candidate risk genes for TAAD (VPS8 and UTP11), warranting further investigation and confirmation in additional cohorts of patients with aortopathy.

Heart valve disease represents the second most common indication for cardiac surgery in the US, yet no therapy exists to slow down or revert its progression. Pharmacologic treatments are greatly in need for aortic and mitral valve disease and require a greater understanding of the underlying cellular mechanisms. Serotonin (5HT) dysfunction has been associated with heart valve disease, clinically observed in carcinoid syndrome or with the use of medications, such as the diet drug, Dexfenfluramine, a 5HT transporter (SERT) inhibitor and 5HT receptor (HTR) 2B agonist. Concurrently, Angiotensin II (AngII) and the renin-angiotensin system (RAS) greatly contribute to cardiac/valvular diseases. This dissertation explores the intersecting mechanisms by which 5HT and AngII contribute to aortic and mitral valve disease with an attempt to develop therapies to mitigate their progression. Three murine models were extensively utilized, mice lacking SERT (SERT KO) and wild-type mice receiving AngII infusion or Fluoxetine, a SERT inhibitor, with/without 5HTR2B inhibitors, to characterize histopathological, hemodynamic, and cellular level changes. Valvular interstitial cells (VICs) isolated from murine and human healthy valves were treated with various stressors known to be involved in valvular remodeling/5HT signaling, including 5HT, TGFβ1, AngII, and H2O2. Patients undergoing AV and MV surgery were prospectively enrolled in our study, with their valves isolated, genotyped for SERT promotor polymorphism, and studied for 5HT-related gene expression changes. We demonstrate that pathological, fibrotic thickening occurs to the AV and MV in response to AngII infusion, lack or inhibition of SERT in mice. AngII mice developed increased velocities and gradients across their AVs, a marker of hemodynamic compromised, and the cellular changes involved 5HT, TGFβ1 and other inflammatory pathways. Concurrent HTR2B blockade mitigated many of these changes. Most notably the MV in SERT KO mice demonstrated HTR2B upregulation and increasing levels of COL1A1. Both murine and human MVICs exposed to 5HT or TGFβ1 upregulated COL1A1, ACTA2 and/or HTR2B. Human AVICs treated with AngII in the setting of SERT downregulation displayed markers of osteogenic transdifferentiation, with these changes mitigated again by HTR2B blockade. Finally, patients with aortic stenosis and aortic insufficiency have lower levels of SERT than healthy patients, along with upregulation of various 5HT receptors. Presence of LL SERT promotor polymorphism is associated with faster progression of AI. We then further investigated the mechanisms by which SERT downregulation may enhance mitral and aortic valvulopathy by studying the activation of mechanically sensitive calcium channel, Piezo1, and the role of mechano-transduction. ScRNAseq results of both MR and MV cells demonstrated the presence of Piezo1 expression in different cell types on the mitral valve. Mitral valve interstitial cells in culture demonstrated Piezo1 Ca++ channel activity following administration of Yoda1, a Piezo1 agonist, with associated significant downregulation of SERT and diminished SERT function and upregulation of HTR2B. Taken together, this dissertation provides a novel and promising therapeutic target to mitigate aortic and mitral valve disease. Dysregulated AngII and 5HT, with SERT, HTR2B, and Piezo1 signaling, contribute to pathological remodeling to both valves, and preventing this signaling through Piezo1/HTR2B inhibition can prevent these changes.