The ability to accurately and in a repeatable fashion, measure aortic valve dimensions during aortic valve repair is critical to the restoration of function in a diseased aortic valve, as for example in aortic insufficiency. Although several methods for measuring aortic valve dimensions have been shown to be feasible, they are approximate and lack the accuracy, robustness, and repeatability one would expect to support aortic valve repair surgery. In addition, they do not allow for the intra-operative measurement of aortic valves under conditions equivalent to the physiological (pressurized) state. A prototype medical device was designed, and 3-D printed at the University of Ottawa that would allow cardiac surgeons performing aortic valve repair to do just that. The prototype was tested for its accuracy and precision at the University of Ottawa Heart Institute using porcine aortic valves. Based on unsatisfactory results of this experimentation, namely, that the device was applying forces that were too large, a numerical simulation study was designed using a commercial finite element software LS-DYNA. This simulation study was used to explore the forces that the prototype device needed to apply to obtain end-diastolic pressurized dimensions of the aortic valve. The simulation study showed that one single device was likely not possible to obtain measurements in an aortic valve. However, a system of two devices could be imagined, one to measure the STJ diameter and free margin length of the aortic valve cusps, and one to measure the cusp height of the same valve, for the purposes of aortic valve repair.

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Calcific aortic valve disease is highly prevalent, especially in the elderly. Currently, the exact mechanism of the calcification process is not completely understood, limiting our ability to prevent or cure the disease. Ex vivo investigations, however, have provided evidence that the aortic valve's biological response is sensitive to mechanical forces, including fluid shear stresses, leading to the hypothesis that adverse fluid shear stress environment play a role in leading to valve calcification. This thesis seeks to investigate this hypothesis. A method for performing experimental measurement of time-varying shear stress on aortic valve leaflets under physiologic flow conditions was first developed, based on the Laser Doppler Velocimetry technique, and was systematically validated. This method was then applied to both the aortic surface and the ventricular surface of a normal tricuspid the aortic valve, and then on a congenital bicuspid aortic valve, using suitable in vitro valve models and an in vitro pulsatile flow loop. It was found that in the tricuspid valve, the peak shear stress on the aortic surface under adult resting condition was approximately 15-19 dyn/cm². Aortic surface shear stresses were elevated during mid- to late-systole, with the development of the sinus vortex, and were low during all other instances. Aortic surface shear stresses were observed to increase with increasing stroke volume and with decreasing heart rate. On the ventricular surface, shear stresses had a systolic peak of approximately 64-71 dyn/cm² under adult resting conditions. During late systole, due to the Womersley effect, shear stresses were observed to reverse in direction to a substantial magnitude for a substantial period of time. Further, it was found that a moderately stenotic bicuspid aortic valve can experience excessive unsteadiness in shear stress experienced by its leaflets, most likely due to the turbulent forward flow resulting from the stenosis, and due to the skewed forward flow. To demonstrate that the measured shear stresses can have an effect on the aortic valve biology, ex vivo experiments were performed in specific to determine the effects of these various shear stress characteristics on the biological response of porcine aortic valve leaflets, using the cone and plate bioreactor. It was found that unsteady shear stress measured in the bicuspid valve resulted in increased calcium accumulation. Further, it was found that low shear stresses and high frequency shear stresses resulted in increased calcium accumulation. Thus, shear stress was found to affect aortic valve pathology, and low and unsteady fluid shear stresses can enhance pathology.

<p><i>Chlamydophila pneumoniae</i> (<i>C. pneumoniae</i>) has been suggested as a stimulator of chronic inflammation in atherosclerosis. <i>C. pneumoniae</i> DNA was demonstrated in aortic biopsies in 50% of patients with stable angina pectoris or acute coronary syndrome undergoing coronary artery bypass grafting. <i>C. pneumoniae</i> mRNA, a marker of replicating bacteria, was demonstrated in 18% of the aortic biopsies. </p><p>Inflammation may have a role in the pathogenesis of thoracic aortic aneurysm, aortic dissection and aortic valve stenosis. <i>C. pneumoniae </i>DNA was demonstrated in aortic biopsies in 26% of thoracic aortic aneurysm patients and in 11% of aortic dissection patients undergoing thoracic surgery and in 22% of stenotic aortic heart valves from patients undergoing aortic valve replacement. No bacterial mRNA was demonstrated in these aortic biopsies, nor in the valves, suggesting that the infection has passed into a persistent state. <i>C. pneumoniae</i> DNA was demonstrated in peripheral blood mononuclear cells in only 5% of aortic valve stenosis patients and not in thoracic aortic aneurysm or aortic dissection patients, suggesting that the bacterium disseminated to the cardiovascular tissue long before the patient required surgery. The copper/zinc ratio in serum, a marker of infection/inflammation, was significantly elevated in thoracic aortic aneurysm patients, supporting an inflammatory pathogenesis. Patients positive for <i>C. pneumoniae</i> in the aortic valve had more advanced coronary atherosclerosis, further supporting a possible role for <i>C. pneumoniae</i> in atherosclerosis. </p><p>Mice were infected with <i>C. pneumoniae</i> that disseminated to all organs investigated (i.e. lungs, heart, aorta, liver and spleen). Trace element concentrations were altered in infected animals with an increased copper/zinc ratio in serum, a progressively increased iron concentration in the liver and a progressively decreased iron concentration in serum. Iron is important for <i>C. pneumoniae</i> metabolism, and a changed iron homeostasis was noted in infected mice by alterations in iron-regulating proteins, such as DMT1 and hepcidin.</p>

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p&lt;0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

Chlamydophila pneumoniae (C. pneumoniae) has been suggested as a stimulator of chronic inflammation in atherosclerosis. C. pneumoniae DNA was demonstrated in aortic biopsies in 50% of patients with stable angina pectoris or acute coronary syndrome undergoing coronary artery bypass grafting. C. pneumoniae mRNA, a marker of replicating bacteria, was demonstrated in 18% of the aortic biopsies. Inflammation may have a role in the pathogenesis of thoracic aortic aneurysm, aortic dissection and aortic valve stenosis. C. pneumoniae DNA was demonstrated in aortic biopsies in 26% of thoracic aortic aneurysm patients and in 11% of aortic dissection patients undergoing thoracic surgery and in 22% of stenotic aortic heart valves from patients undergoing aortic valve replacement. No bacterial mRNA was demonstrated in these aortic biopsies, nor in the valves, suggesting that the infection has passed into a persistent state. C. pneumoniae DNA was demonstrated in peripheral blood mononuclear cells in only 5% of aortic valve stenosis patients and not in thoracic aortic aneurysm or aortic dissection patients, suggesting that the bacterium disseminated to the cardiovascular tissue long before the patient required surgery. The copper/zinc ratio in serum, a marker of infection/inflammation, was significantly elevated in thoracic aortic aneurysm patients, supporting an inflammatory pathogenesis. Patients positive for C. pneumoniae in the aortic valve had more advanced coronary atherosclerosis, further supporting a possible role for C. pneumoniae in atherosclerosis. Mice were infected with C. pneumoniae that disseminated to all organs investigated (i.e. lungs, heart, aorta, liver and spleen). Trace element concentrations were altered in infected animals with an increased copper/zinc ratio in serum, a progressively increased iron concentration in the liver and a progressively decreased iron concentration in serum. Iron is important for C. pneumoniae metabolism, and a changed iron homeostasis was noted in infected mice by alterations in iron-regulating proteins, such as DMT1 and hepcidin.

Aortic valve (AV) disease is a major cause of cardiovascular-linked deaths globally. In addition, AV disease is a strong risk factor for additional cardiovascular events; however, the mechanism by which it initiates and progresses is not well-understood. We hypothesize that low and oscillatory flow is present on the fibrosa side of the AV and stimulates ECs to differentially regulate microRNA (miRNA) and mRNAs and influence AV disease progression. This hypothesis was tested employing both in vitro and in vivo approaches, high throughput microarray and pathway analyses, as well as a variety of functional assays. First, we isolated and characterized side-dependent, human aortic valvular endothelial cells (HAVECs). We found that HAVECs express both endothelial cell markers (VE-Cadherin, vWF, and PECAM) as well as smooth muscle cell markers (SMA and basic calponin). Using microarray analysis on sheared, side-specific HAVECs, we identified side- and shear-induced changes in miRNA and mRNA expression profiles. More specifically, we identified over 1000 shear-responsive mRNAs which showed robust validation (93% of those tested). We then used Ingenuity Pathway Analysis to identify key miRNAs, including those with many relationships to other genes (for example, thrombospondin and I&B) and those that are members of over-represented pathways and processes (for example, sulfur metabolism). Furthermore, we validated five shear-sensitive miRNAs: miR-139-3p, miR-148a, miR-187, miR-192, and miR-486-5p and one side-dependent miRNA, miR-370. To prioritize these miRNAs, we performed in silico analysis to group these key miRNAs by cellular functions related to AV disease (including tissue remodeling, inflammation, and calcification). Next, to compare our in vitro HAVEC results in vivo, we developed a method to isolate endothelial-enriched, side-dependent total RNA and identify and validate side-dependent (fibrosa vs. ventricularis) miRNAs in porcine aortic valvular endothelium. From this analysis, we discovered and validated eight side-dependent miRNAs in porcine endothelial-enriched AV RNA, including one miRNA previously identified in vitro, miR-486-5p. Lastly, we determined the relationship between important miRNAs (specifically miR-187 and miR-486-5p) and AV disease by modulating levels of miRNAs and performing functional assays. Preliminary studies overexpressing miR-187 in HAVECs have shown a reduction in inflammatory state through monocyte adhesion (p<0.05). Further, miR-486-5p overexpression reveals an increase in migration (p<0.05) and a trend for a decrease in early apoptosis, linking miR-486-5p to tissue remodeling in the AV. Better understanding of AV biology and disease in terms of gene-regulation under different hemodynamic conditions will facilitate the design of a tissue-engineered valve and provide alternative treatment options.

Background: Aortic stenosis (AS) is the most common heart valve disease in Europe and North America. Age-related calcification of the valve is the commonest cause of acquired AS, especially in patients older than 70 years.Conventional surgical aortic valve replacement (SAVR) and the novel, minimally invasive transcatheter aortic valve implantation (TAVI), effectively preserve left ventricular (LV) function, relieve symptoms and improve survival in patients with severe symptomatic AS. However, patients with impaired LV function may carry significant operative risk, and long recovery time. In addition, such patients might have other comorbidities, and hence adding another challenge. Thus evaluation of ventricular function before and after AVR, as well as critical evaluation of TAVI patients should contribute to better clinical outcome. Methods: We studied LV function by conventional echocardiography before and after SAVR in the following groups; (I) 86 patients (aged 71±10 years) with severe AS and LV dysfunction; (II) 112 consecutive elderly AS patients (aged 77±2 years) and compared them with 72 younger patients (aged 60±1 years); (III)66 patients (age 70±2 years, 53 male) who underwent AVR for severe AS with concurrent LV dysfunction; (IV) 89 consecutive patients with symptomatic severeAS who underwent successful TAVI, 45 of whom received trans-apical TAVI (TA)(age 80.8±4.9 year, 26 male) and 44 trans-femoral TAVI (TF) (age 82.9±5.8 year,22 male).The conventional echocardiographic measurements were made according to the guidelines. Severe AS was identified by aortic valve mean pressure gradient &gt;40mmHg or valve area &lt;1.0 cm2. LV systolic dysfunction was identified as ejection fraction (EF) &lt;50%. LV long-axis function was presented by mitral annular plane systolic excursion ( MAPSE ) at lateral wall and septal wall, which were measured from apical four-chamber view. Also from the same view, LV septal and lateral wall deformation using STE as well as global longitudinal systolic strain. The LV systolic twist as the net difference between apical rotation and basal rotation was measured from the parasternal apical and basal short-axis views in the TAVI patients. Results: Study I: In the low flow and high gradient group, operative (30-day) mortality was 10%, and peri-operative mortality was associated with lower mean LVEF, higher mitral E:A ratio, peak systolic pulmonary artery pressure (PSPAP), and higher serum creatinine (all p&lt;0.001), NYHA class III–IV, concomitant coronary artery bypass graft (CABG), urgent surgery, and longer bypass-time (all p&lt; 0.05). Mortality at 4 years was 17%. Univariate predictors of 4-year mortality were: lower EF (p&lt;0.001), presence of restrictive LV filling (p&lt;0.001), raised PSPAP (p&lt;0.001) and CABG (p=0.037). However, only EF&lt;40 % (p=0.03), the presence of restrictive LV filling (p=0.033) and raised PSPAP (p&lt;0.01)independently predicted mortality in this group.Study II: Elderly patients had higher NYHA class, more frequent atrial fibrillation (AF), coronary artery disease (CAD), emergency operation and use of bioprosthetic valves. They also had shorter E-wave deceleration time (DT) and larger left atria (LA) (p&lt;0.05 for all). 30-day mortality was 12% vs 4 % (Log Rank x2=3.02, p=0.08) and long term mortality was 18% vs 7% (Log Rank x2=4.38,p=0.04) in the two groups, respectively. Age was not related to mortality after adjustment for other variables. Among all variables, anemia (OR 4.20, CI:1.02–6.86, p=0.04), cardiopulmonary bypass (CPB) time (OR 1.02, CI 1.01–1.04,p&lt;0.01), significant patient prosthesis mismatch (PPM) (OR 5.43, CI 1.04–18.40,p&lt;0.05) were associated with 30-day mortality in elderly patients. Their long-term mortality was related to CBP time (OR 1.02, CI 1.00–1.05, p=0.04),PPM (OR 4.64, CI 1.33–16.11, p=0.02) and raised LA pressure: DT (OR 0.94, CI0.84–0.99, p=0.03) and pulmonary artery systolic pressure (PASP) (OR 1.12, CI1.03–1.19, p&lt;0.001).STUDY III: Following SAVR peak aortic pressure gradient (AOPG) decreased and indexed valve area increased (64±3 to 19±1 mmHg and 0.30±0.01 to 0.89±0.03 cm2/m2, p&lt;0.001 for both). LVEF increased (from 45±1 to 54±2%;p&lt;0.001), LV end diastolic and end-systolic dimensions fell (LVEDD index: from 33±1 to 30±1 mm/m2; and LVESD index: from 27±1 to 20±1 mm/m2; (p&lt;0.01 forboth). LV diastolic dysfunction improved as evidenced by the fall in E/A ratio (from 2.6±0.2 to 1.9±0.4) and prolongation of total filling time; (from 29.2±0.6 to31.4±0.5 s/min, p=0.01 for both). Among all echocardiographic variables, LV dimensions (LVEDD index, OR 0.70, CI 0.52–0.97, p&lt;0.05; LVESD index, OR 0.57, CI 0.40–0.85, p=0.005) were the two independent predictors of post-operative LV functional recovery on multivariate analysis. A cut-off value ofpre-operative LVESD index&lt;=27.5 mm/m2 was 85% sensitive and 72% specific inpredicting intermediate-term recovery of LV function after AVR (AUC, 0.72, p=0.002). STUDY IV: Before TAVI, there was no difference between the two patient groups in gender, age, body surface area (BSA) and baseline LV function. However, left ventricular mass index (LVMi), left atrial volume index (LAVi) and tricuspid regurgitation pressure drop (TRPdrop) were increased in the TA group (p&lt;0.05).One week after TAVI, aortic pressure gradient (AOPG) markedly dropped in thetwo groups (both p&lt;0.001), LVEDD index and LVESD index fell but EF andmyocardial strain remained unchanged. Overall cavity twist reduced (p&lt;0.048).Significant LVESD index reduction was only seen in TF group (p=0.02) with a slight increase in LVEF (p=0.04). Lateral MAPSE increased only in the TF group(p=0.02). LV longitudinal systolic strain remained unchanged in TA patients while apical lateral strain increased in TF group. LV apical rotation fell in the two groups but basal rotation increased only in the TA patients (p=0.02). LAVi reduced in bothgroups and to a greater extent in TF TAVI (p=0.006), as did TRPdrop (p&lt;0.001). Conclusion: SAVR and TAVI are two effective treatments for severe AS patients.The severity of pre-operative systolic and diastolic LV dysfunction is the major predictor of mortality following SAVR for low-flow and high gradient AS.Peri-operative AVR survival is encouraging in the elderly. Long term mortality in the elderly is related to PPM, LV diastolic dysfunction and secondary pulmonary hypertension. LV functional recovery was evident in most patients with LV dysfunction after SAVR. A lower prevalence of LV functional recovery in patients with large pre-operative LVESD index might signify the loss of contractile reserveand thus predict post-operative functional recovery. TAVI results in significant early improvement of segmental and overall ventricular function, particularly in patients receiving the trans-femoral approach. The delayed recovery of the trans-apical TAVI group, we studied, might reflect worse pre-procedural diastolic cavity function.

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IntroductionThe young adult patients with aortic valve insufficiency undergo aortic valve replacement (AVR) and are forced to take anticoagulation medications for the rest of life due to prosthetic valve. This leads to many post-operative complications and drastic outcomes. Whereas, the in-vogue alternative of aortic valve repair (AVr) is available and a lot more beneficial as well.Especially considering the surgeon’s skills for selected repair procedure, selectively chosen patient with mild to moderate grades of aortic valve insufficiency and no significant comorbidities present for at least five (5) years or longer time. AimThe aim of this study was to affirm ‘if all kind of outcomes of aortic valve repair are beneficial alternative to aortic valve replacement (AVR) for the patients suffering from aortic valve insufficiency for at least five (5) years or longer time. Material and MethodsInternet search using standard key words of ‘Aortic Valve Repair and Outcomes’ was used to find both white literature (officially published literature) and grey literature (unpublished or ongoing study/literature) with human, adult, English language and studies published after January 1st 2007 as limitations. Inclusion criteria was adult patients with aortic insufficiency with aortic valve repair as intervention with outcomes at least greater than five (5) years were considered. All the data was extracted using Microsoft excel for windows and was analyzed using GraphPad Prisma. Results20 studies comprising of 5369 patients were included in this systemic review, which included 2 randomized control trails, 7 clinical prospective studies, 8 retrospective studies and 3 observational studies. ConclusionThis study suggests that aortic valve repair is a beneficial alternative available for younger adults suffering from aortic valve insufficiency in longer time.