Progression Of Aortic Valve Disease Research Articles

Effects of intensive blood pressure control on left ventricular hypertrophy in aortic valve disease

Hypertension adds to the pressure overload on the left ventricle (LV) in combination with aortic valve (AV) disease, but the optimal blood pressure (BP) targets for patients with AV disease remain unclear. We tried to investigate whether intensive BP control reduces LV hypertrophy in asymptomatic patients with aortic stenosis (AS) or aortic regurgitation (AR). A total of 128 hypertensive patients with mild to moderate AS (n=93) or AR (n=35) were randomly assigned to intensive therapy, targeting a systolic BP <130 mm Hg, or standard therapy, targeting a systolic BP <140 mm Hg. The primary end point was the change in LV mass from baseline to the 24-month follow-up. Secondary end points included changes in severity of AV disease, LV volumes, ejection fraction and global longitudinal strain (GLS). The treatment groups were generally well balanced regarding the baseline characteristics. The mean (±SD) age of the patients was 68 ± 8 years and 48% were men. The mean BP was 145 ± 12/81 ± 10 mm Hg at baseline. Medication at baseline was similar between the 2 groups. The 2 treatment strategies resulted in a rapid and sustained difference in systolic BP (P < .05). At 24-month, the mean systolic BP was 129 ± 12 mm Hg in the intensive therapy group and 135 ± 14 mm Hg in the standard therapy group. No patient died or underwent AV surgery during follow-up in either of the groups. LV mass was changed from 189.5 ± 41.3 to 185.6 ± 41.5 g in the intensive therapy group (P=.19) and from 183.8 ± 38.3 to 194.0 ± 46.4 g in the standard therapy group (P < .01). The primary end point of change in LV mass was significantly different between the intensive therapy and the standard therapy group (-3.9 ± 20.2 g vs 10.3 ± 20.4 g; P=.0007). The increase in LV mass index was also significantly greater in the standard therapy group (P=.01). No significant differences in secondary end points (changes in severity of AV disease, LV volumes, ejection fraction and GLS) were observed between the treatment groups. Among hypertensive patients with AV disease, intensive hypertensive therapy resulted in a significant reduction in LV hypertrophy, although progression of AV disease was similar between the treatment groups. http://ClinicalTrials.gov (Number NCT03666351).

Transcatheter heart valve interventions for patients with rheumatic heart disease.

Rheumatic heart disease [RHD] is the most prevalent cause of valvular heart disease in the world, outstripping degenerative aortic stenosis numbers fourfold. Despite this, global resources are firmly aimed at improving the management of degenerative disease. Reasons remain complex and include lack of resources, expertise, and overall access to valve interventions in developing nations, where RHD is most prevalent. Is it time to consider less invasive alternatives to conventional valve surgery? Several anatomical and pathological differences exist between degenerative and rheumatic valves, including percutaneous valve landing zones. These are poorly documented and may require dedicated solutions when considering percutaneous intervention. Percutaneous balloon mitral valvuloplasty (PBMV) is the treatment of choice for severe mitral stenosis (MS) but is reserved for patients with suitable valve anatomy without significant mitral regurgitation (MR), the commonest lesion in RHD. Valvuloplasty also rarely offers a durable solution for patients with rheumatic aortic stenosis (AS) or aortic regurgitation (AR). MR and AR pose unique challenges to successful transcatheter valve implantation as landing zone calcification, so central in docking transcatheter aortic valves in degenerative AS, is often lacking. Surgery in young RHD patients requires mechanical prostheses for durability but morbidity and mortality from both thrombotic complications and bleeding on Warfarin remains excessively high. Also, redo surgery rates are high for progression of aortic valve disease in patients with prior mitral valve replacement (MVR). Transcatheter treatments may offer a solution to anticoagulation problems and address reoperation in patients with prior MVR or failing ventricles, but would have to be tailored to the rheumatic environment. The high prevalence of MR and AR, lack of calcification and other unique anatomical challenges remain. Improvements in tissue durability, the development of novel synthetic valve leaflet materials, dedicated delivery systems and docking stations or anchoring systems to securely land the transcatheter devices, would all require attention. We review the epidemiology of RHD and discuss anatomical differences between rheumatic valves and other pathologies with a view to transcatheter solutions. The shortcomings of current RHD management, including current transcatheter treatments, will be discussed and finally we look at future developments in the field.

M1 macrophage-derived extracellular vesicle containing tsRNA-5006c promotes osteogenic differentiation of aortic valve interstitial cells through regulating mitophagy.

Osteogenic differentiation of aortic valve interstitial cells (AVICs) plays a key role in the calcific aortic valve disease progression. Extracellular vesicles (EVs)-derived from M1-polarized macrophages (M1-EVs) orchestrated intercellular communication by delivering non-coding RNAs such as tRNA-derived small RNAs (tsRNAs) is crucial for cardiovascular disease. However, the role and mechanism of M1-EVs tsRNAs in osteogenic differentiation of AVICs remains largely unclear. M1-EVs and PBS treated-RAW 264.7 cell-derived EVs (NC-EVs) were incubated with AVICs and subjected to small RNA sequencing. Candidate tsRNA in M1-EVs was silenced to explore their effects on AVIC osteogenic differentiation and mitophagy. DiI-labeled M1-EVs were internalized by AVICs, resulting in significantly increased calcium nodule formation and expression of osteogenesis-related genes in AVICs, including RUNX2, BMP2, osteopontin, and SPP1, compared with NC-EVs. Small RNA sequencing revealed that 17 tsRNAs were significantly up-regulated such as tsRNA-5006c, while 28 tsRNAs were significantly down-regulated in M1-EVs compared with NC-EVs. Intriguingly, tsRNA-5006c-deleted M1-EVs treatment significantly reduced calcium nodule formation and expression of osteogenesis-related genes in AVICs relative to control group. Moreover, target genes of tsRNA-5006c were mainly involved in autophagy-related signaling pathways, such as MAPK, Ras, Wnt, and Hippo signaling pathway. Hallmarks of mitophagy activation in AVICs including mitophagosome formation, TMRM fluorescence, expression of LC3-II, BINP3, and PGC1α, were significantly elevated in the M1-EVs group compared with NC-EVs group, whereas M1-EVs tsRNA-5006c inhibitor led to a significant reduction in these indicators. M1-EVs carried tsRNA-5006c regulates AVIC osteogenic differentiation from the perspective of mitophagy, and we provide a new target for the prevention and treatment of aortic valve calcification.

New England Congenital Cardiology Association Bicuspid Aortopathy Registry (NECCA BAR): A regional preventive cardiovascular care collaboration

BackgroundBicuspid aortic valve is the most common congenital heart defect, and its association with proximal aortic dilation (aortopathy) increases risk for aortic aneurysm and dissection in adults. Maximal aortic root and ascending aortic dimensions are predictors of adverse cardiovascular outcomes. Recent single center data demonstrate medical therapy with beta or angiotensin II receptor blockers tempers aortic growth rates. Although randomized clinical trials may not be feasible, larger population studies would better inform bicuspid aortic valve preventive cardiovascular care. ObjectiveImprove regional pediatric bicuspid aortopathy collaboration with standardized medical management guidelines and patient care registry. MethodsThe New England Congenital Cardiology Association (NECCA) developed consensus-based prophylactic treatment guidelines for bicuspid aortopathy and designed a regional clinical registry (NECCA BAR) to study cardiovascular practice variation and short-term outcomes in subjects with moderate to severe bicuspid aortopathy. Individuals 6 months to 25 years of age with bicuspid aortic valve (all variants) and body surface area-adjusted aortic root or ascending aorta z score ≥ 4.0 SD, and/or absolute dimension ≥4.0 cm, are eligible for inclusion. Standardized bicuspid aortopathy medical management guidelines were established among New England congenital cardiology practices. The primary aims are to compare cardiovascular practice variation by guideline adherence (medical therapy and athletic participation), and evaluate medication effectiveness by comparing rates of annual change in aortic root and ascending aorta dimensions/z scores over 3 years. Additional endpoints include aortic valve disease progression (stenosis/regurgitation), incidence of aortic dissection, surgery, death, and incidence of adverse drug events. ResultsRecruitment in progress; data analysis pending. ConclusionWe describe the development of regional pediatric clinical care guidelines and a patient care registry designed to refine medical management of bicuspid aortopathy.

Abstract 13940: Whole Mount Confocal Microscopy of Mouse Aortic Valve Leaflet Innervation

Introduction: Within the aortic valve leaflets (AVLs) reside a heterogeneous cell population holistically referred to as valve interstitial cells (VICs). These cells maintain the highly organized trilaminar extracellular matrix (ECM) structure in the AVL and are involved in the pathological progression of aortic valve disease (AVD). Various cell types have been reported in the AVL, including an understudied subpopulation of neurons. Since the mid-2000s, little has been done to report the possible role these neurons have in tissue homeostasis. Typically, imbedded sections of tissue chosen from specific areas of the valves are used to visualize immunoreactivity of these proteins. These sections usually come from the belly region or annular sections of the valve and seldom depict the entire leaflet anatomy. Hypothesis: Whole mount immunofluorescence microscopy allows us to map the 3D localization of these neuroendocrine markers throughout the entire aortic valve. Methods: Here, we gathered high resolution confocal microscopy images in whole mount mouse aortic valve tissues of various neuroendocrine markers such as tyrosine hydroxylase, protein gene product 9.5, and calcitonin gene related peptide. Results: We note that neuroendocrine markers mainly localize near the free edge on the ventricular surface of AVL tissue. We do not see the long dendritic neurons seen in the mitral and tricuspid valves, instead these markers are present in cells of varying morphologies throughout. Conclusions: The data gathered in this study aids our future efforts in determining mechanosensitive neural regulation of aortic valve leaflet mechanics and ECM remodeling. Future experiments will assess neuromodulation of valve rigidity under mechanical strain.

Aortic valve disease in diabetes: Molecular mechanisms and novel therapies.

Valve disease and particularly calcific aortic valve disease (CAVD) and diabetes (DM) are progressive diseases constituting a global health burden for all aging societies (Progress in Cardiovascular Diseases. 2014;56(6):565: Circulation Research. 2021;128(9):1344). Compared to non‐diabetic individuals (The Lancet. 2008;371(9626):1800: The American Journal of Cardiology. 1983;51(3):403: Journal of the American College of Cardiology. 2017;69(12):1523), the diabetic patients have a significantly greater propensity for cardiovascular disorders and faster degeneration of implanted bioprosthetic aortic valves. Previously, using an original experimental model, the diabetic‐hyperlipemic hamsters, we have shown that the earliest alterations induced by these conditions occur at the level of the aortic valves and, with time these changes lead to calcifications and CAVD. However, there are no pharmacological treatments available to reverse or retard the progression of aortic valve disease in diabetes, despite the significant advances in the field. Therefore, it is critical to uncover the mechanisms of valve disease progression, find biomarkers for diagnosis and new targets for therapies. This review aims at presenting an update on the basic research in CAVD in the context of diabetes. We provide an insight into the accumulated data including our results on diabetes‐induced progressive cell and molecular alterations in the aortic valve, new potential biomarkers to assess the evolution and therapy of the disease, advancement in targeted nanotherapies, tissue engineering and the potential use of circulating endothelial progenitor cells in CAVD.

Patient-Specific Computational Fluid Dynamics Reveal Localized Flow Patterns Predictive of Post-Left Ventricular Assist Device Aortic Incompetence.

Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem. Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients' aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver. The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm2 [95% CI, -0.51 to 1.85]; P=0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, -0.07 to 0.019]; P=0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm2; mean difference [95% CI, 0.15-0.39]; P<0.001), whereas oscillatory shear index was not significantly different between both groups (95% CI, -0.009 to 0.001; P=0.17). Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.

Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.

Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.

Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis.

Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism. We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.

Severe aortic stenosis patient risk during the COVID-19 pandemic.

Aortic stenosis (AS) is a progressive aortic valve disease that can lead to heart failure, syncope and sudden death if not treated. Severe AS currently affects more than 2 million people over 65 years of age in the USA. The only treatment option for AS is valve replacement by either surgical aortic valve replacement (AVR) or the less invasive transcatheter aortic valve replacement (TAVR), also called transcatheter aortic valve implantation (TAVI). AVR requires intensive care unit (ICU) admission, whereas TAVR can be performed in a non-ICU setting. Both procedures are commonly associated with complications, such as stroke.1 Bleeding and thrombosis are also potential complications of these procedures. Given the considerable morbidity and mortality, patients with these postoperative complications are admitted to the ICU for management. SARS-CoV-2, which causes COVID-19, has become a pandemic and has caused high mortality rates among the elderly. Currently, there is no vaccine against SARS-CoV-2, and there is no effective treatment to treat patients with severe COVID-19. More than 730 000 people worldwide and over 160 000 in the USA have died from COVID-19 as of 10 August 2020 according to Johns Hopkins Coronavirus Resource Center; these figures are expected to continue to rise until there are effective vaccines and therapies. Treating patients with COVID-19 during this pandemic requires many medical resources. Importantly, acute respiratory distress syndrome and multiorgan failures, believed to be due to systemic and pulmonary thrombosis,2 3 are common symptoms of severe COVID-19 that require treatment in the ICU. Therefore, government officials have recommended ceasing almost all elective surgeries until the COVID-19 pandemic is under control.4 Although many patients with symptomatic AS can delay procedures intended to alleviate their symptoms, some may require life-saving procedures. In cases where life-saving procedures (AVR or TAVR) are required, …

Sports Participation and Exercise Restriction in Children with Isolated Bicuspid Aortic Valve

Our study was to apply the 2015 American Heart Association/American College of Cardiology Athletic Participation Guidelines to a group of otherwise healthy school age children and young adults with bicuspid aortic valve (BAV) and describe the potential competitive sports restriction as they age. We performed a retrospective chart review of children and young adults aged 5 to 22 years with isolated BAV with at least two echocardiograms between 2000 and 2013. Using task force guidelines, exercise restriction was recommended for any of the following: (1) any dilation of the aortic root, (2) any dilation of the ascending aorta, (3) moderate aortic stenosis, (4) severe aortic regurgitation; (5) left ventricular dilation or (6) reduced shortening fraction. Of the 345 patients with isolated BAV, 202 were considered restricted at study entry. The final cohort included 123 children and young adults. Over the course of follow up, 36% (44 of 123) met restriction criteria. The most likely cause for restriction was aortic dilation (34%). Progression of aortic valve disease occurred in a minority of patients (3%). There were no reports of death, dissection or catheter or surgical based intervention. In conclusion, we found that strict adherence to current guidelines would result in restriction of more than 1/3 of school age children and young adults with BAV from some form of competitive athletics during school age years. Strict application of the current guidelines in this age group may lead to over-restriction of youths from competitive sports.

P4642Prevalence and clinical significancy of bicuspid aortic valve diagnosed in the first year of life: a long term follow up in the paediatric age

Abstract Introduction and objectives Bicuspid aortic valve (BAV) is the most common congenital malformation, with an estimated prevalence ranging from 0,48 to 2%. Most of the studies describe complications associated with BAV, including aortic stenosis and regurgitation, infective endocarditis and aortic dilation and dissection. Very few studies have been performed in the neonatal and paediatric age, most lacking in long-term follow up. The aim of our study was to explore the prevalence of BAV and the progression of aortic valve disease and aortic dilation in paediatric patients followed from January 1996 to August 2018. Methods A prospective collection of Congenital Heart Disease (CHD) diagnosed in the first year of life was performed in our institution from January 1996 to August 2018. Patients affected by BAV were then followed yearly. BAV morphology, aortic valve dysfunction and aortic dimensions were measured. Comparisons were performed between right-left cusp fusion (R-L) and right-non coronary cusp fusion (R-N), according to Shaefer's classification. Rate of change of the ascending aorta size over time was analyzed, and aortic size values were normalized as the number of standard deviations above or below the mean size expected for body surface area (z scores). Results A total of 35,310 live births were screened. Incidence rate of total CHD, including small ventricular septal defects and BAV was19,57%. Sixty had BAV (8,73% of CHD), with an incidence of 17/1,000 live births. Male/Female ratio was 1.4. A positive family history was present in 5 (8.3%). In 12 patients (24%) BAV was associated to other CHD (9 Aortic Coarctation, 1 Atrio-Ventricular Septal Defect, and in two cases a critical neonatal aortic stenosis). BAV was isolated in 48 cases (80%), with an incidence of 13.6/1.000 live births. According to Shaefer's classification the most common was type 1 (R-L), with Right to Left cusps fusion (R-L 76%, R-N 21% and L-N 3%). Among patients with isolated BAV, after a median follow up of 11 [1–21] years an aortic stenosis was observed in 5 patients (10.4%, none severe), an aortic insufficiency in 13 (27%, in one case severe). A dilated ascending aorta (z-score&gt;2) was found in 11 patients (23%). An indication cardiac surgery due to severe aortic insufficiency was present in one case. No patient had indication for aortic aneurysm surgery. Conclusions Paediatric patients with isolated BAV warrant medical follow-up but progression towards severe valve dysfunction and/or dilation of the ascending aorta warranting cardiac surgery is very low.

Heterogeneous multi-laminar tissue constructs as a platform to evaluate aortic valve matrix-dependent pathogenicity

Designing and constructing controlled in vitro cell culture platforms is imperative toward pinpointing factors that contribute to the development of calcific aortic valve disease. A 3D, laminar, filter paper-based cell culture system that was previously established as a method of analyzing valvular interstitial cell migration and protein expression was adapted here for studying the impact of specific extracellular matrix proteins on cellular viability and calcification proclivity. Hydrogels incorporating hyaluronan and collagen I, two prevalent valvular extracellular matrix proteins with altered pathological production, were designed with similar mechanics to parse out effects of the individual proteins on cell behavior. Laminar constructs containing varying combinations of discrete layers of collagen and hyaluronan were assembled to mimic native and pathological valve compositions. Proteinaceous and genetic expression patterns pertaining to cell viability and calcific potential were quantified via fluorescent imaging. A significant dose-dependency was observed, with increased collagen content associated with decreased viability and increased calcific phenotype. These results suggest that extracellular composition is influential in calcific aortic valve disease progression and will be key toward development of future tissue-engineered or pharmaceutical calcific aortic valve treatments. Statement of SignificanceCalcific aortic valve disease (CAVD), a widespread heart valve disorder, is characterized by fibrotic leaflet thickening and calcific nodule formation. This pathological remodeling is an active process mediated by the valvular interstitial cells (VICs). Currently, the only treatment available is surgical replacement of the valve – a procedure associated with significant long-term risk and morbidity. Development of effective alternate therapies is hindered by our poor understanding of CAVD etiology. Previous work has implicated the composition and mechanics of the extracellular matrix in the progression of CAVD. These individual factors and their magnitude of influence have not been extensively explored - particularly in 3D systems. Here, we have bridged this gap in understanding through the employment of a heterogeneous 3D filter-paper culture system.

Phenotypes of aortic valve disease according to detailed anatomical classification of patients who underwent aortic valve replacement surgery.

The anatomy of the aortic valves plays an important role in the progression of aortic valve disease (AVD) and determination of the appropriate treatment strategy. We described and compared AVD phenotypes according to detailed anatomical classifications and assessed the accuracy of imaging diagnostics using surgical diagnosis as the gold standard. The study enrolled 602 patients (mean age 55.5±12.9 years; 74.1% male) who underwent their first aortic valve replacement surgery between June 2017 and March 2018 at Fuwai Hospital in Beijing, China. Clinical characteristics, histopathological diagnoses, preoperative transthoracic echocardiography (TTE), and other available imaging data were collected retrospectively from medical records. During surgery, 370 patients were diagnosed with a tricuspid aortic valve (TAV), 228 with a bicuspid aortic valve (BAV), and 4 with a quadricuspid aortic valve (QAV). The primary histopathological finding was myxomatous degeneration (48.4%) for those with TAV and fibrocalcification (57.9%) for those with BAV. Nearly all TAV patients (96.2%) had aortic regurgitation, while the majority of BAV patients had aortic stenosis (73.7%); the severity of stenosis and regurgitation varied across the subtypes of BAV. The overall diagnostic accuracy of preoperative TTE for aortic valve anatomy was 85.5%; accuracy was higher for TAV versus BAV (96.8% vs. 68.0%, P<.001). We identified different phenotypes of AVD among patients with different detailed anatomical classifications. In addition, the diagnostic accuracy of preoperative TTE for BAV was suboptimal, and more attention is needed to ensure an accurate anatomic diagnosis prior to surgical intervention.

The importance of genetics and genetic counselors in the evaluation of patients with bicuspid aortic valve and aortopathy.

Bicuspid aortic valve (BAV) is a common congenital heart defect, with an estimated frequency of 1-2% in the general population. BAV may occur as an isolated finding or as a feature of certain syndromes. This article discusses potential genetic causes of BAV, includes a list of current known and candidate genes associated with BAV, provides a hypothetical case demonstrating the importance of genetic testing and cascade screening, and highlights the value of genetic counselors specializing in cardiovascular genetics. Individuals with BAV are at significantly increased risk of progressive aortic valve disease and aortic root aneurysms. There is high heritability associated with BAV, and several specific genes have recently been associated with BAV. There is wide phenotypic variability among BAV malformations, including which cusps are involved and the degree of aortic root involvement. Genotype-phenotype correlations exist that impact treatment recommendations. Genetic testing can reduce morbidity and mortality by guiding management strategies and identifying asymptomatic relatives before significant complications occur. Identifying cases of BAV with an identifiable genetic cause can significantly impact patients and family members. The list of associated genes is constantly growing. Genetic counselors have an important role in the evaluation of families at risk of BAV.

Aortic regurgitation in patients with a left ventricular assist device: A contemporary review.

Aortic regurgitation (AR) developing while using a continuous-flow left ventricular assist device (CF-LVAD) affects 25% to 30% of patients within the first year of implantation and is increasingly being recognized as a cause of recurrence of symptomatic heart failure (HF). The underlying mechanisms are likely multifactorial, including changes in the leaflets of the aortic valve (AV), altered root biomechanics, and excessive left ventricular (LV) unloading, together promoting cusp remodeling and commissural fusion. Known risk factors for the development of AR while under support include advanced age, lower body surface area, systemic hypertension, large aortic root diameter, permanently closed AV, and duration of support. Further, variants in the anastomotic angle between the outflow graft and the ascending aorta have recently been recognized to induce structural changes in the aortic wall, contributing to the development and progression of AV disease. Nevertheless, it remains controversial as to whether AR on LVAD has an independent impact on prognosis, and no clear recommendation exists regarding its optimal diagnosis criteria and treatment. Herein we briefly review the literature and focus on the latest results regarding development of AR in patients supported with CF-LVADs. We also provide a structured echocardiographic approach for an accurate assessment of AV dysfunction in this challenging situation.

Natural history of mild aortic valve disease untreated at the time of rheumatic mitral valve replacement.

The aim of this study was to examine long-term clinical outcomes and to assess the eventual need for aortic valve replacement (AVR) in patients with mild aortic valve disease (AVD) at the time of mitral valve replacement. Between 1990 and 2015, 1231 patients undergoing mitral valve replacement were reviewed, stratifying subjects as those with AVD (n = 363) or without AVD (NA; n = 868). Primary end points were progressive AVD (grade ≥ II) and subsequent AVR. Overall mortality and valve-related complications served as secondary end points. Propensity score matching was used for risk adjustment (n = 320 in each group). No differences in postoperative complications or clinical outcomes were observed between groups. The 20-year overall survival was similar (before matching: NA 86.1% vs AVD 80.8%, P = 0.128; after matching: 83.5% vs 81.1%, P = 0.425). Of the entire cohort, progressive AVD was observed in 162 patients, and significant AVD (grade ≥ III) was observed in only 60 patients. Subsequent AVR was required in 37 patients due to mitral valve (MV) dysfunction or severe aortic stenosis. The 20-year freedom from significant AVD and subsequent AVR was significantly higher in the NA group than in the AVD group before and after matching (before: NA, 96.5% vs 73.7%, P < 0.001; AVD, 98.5% vs 82.3%, P < 0.001; after: 98.1% vs 73.3%, P < 0.001; 99.3% vs 82.5%, P < 0.001, respectively). Although progressive AVD did not significantly impact long-term survival during the follow-up period, those patients qualifying initially as mild AVD may eventually progress to significant AVD after the first 5 postoperative years. Therefore, aggressive echocardiography should be performed at 5-year lapse after mitral valve replacement to determine the appropriate timing of AVR.

Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice.

Aortic valve disease is a cell-mediated process without effective pharmacotherapy. CNP (C-type natriuretic peptide) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo. The aim of this study is to determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease. In cultured porcine valve interstitial cells, CNP inhibited pathological differentiation via the guanylate cyclase NPR2 (natriuretic peptide receptor 2) and not the G-protein-coupled clearance receptor NPR3 (natriuretic peptide receptor 3). We used Npr2+/- and Npr2+/-;Ldlr-/- mice and wild-type littermate controls to examine the valvular effects of deficient CNP/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured Npr2+/- fibroblasts was insensitive to CNP treatment, whereas aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice versus wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves, with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cGK (cGMP-dependent protein kinase) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 (cGMP-dependent protein kinase 1) in cultured porcine valve interstitial cells. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with bicuspid aortic valves than those with tricuspid valves. Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.

ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells.

Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease. Levels of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and α-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in α-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) κB and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-κB or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of α-SMA reduced and overexpression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. Matrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.