Valve Thickening Research Articles

P5993Comprehensive characterization of experimental aortic valve stenosis by multiparametric MRI

Abstract Background Recently, we established an experimental model of moderate aortic valve stenosis (AS) aiming to mimic human disease progression closely. Functional and structural MRI of a mouse model in experimental aortic valve stenosis has not been accomplished so far. Purpose Here, we aimed at developing comprehensive MRI approach for simultaneous assessment of changes in valvular, left ventricular and aortic morphology and function. Methods Male 12-week-old wildtype mice (C57Bl/6) were subjected to wire injury of the aortic valve to induce aortic valve stenosis. High resolution MRI at 9.4T was used to monitor subsequent functional and structural changes in the aortic valve, the ascending aorta, the left ventricle and aortic flow patterns. Results MRI permits accurate planimetry of the orifice and the thickness of the aortic valve, allows a reliable three-dimensional mapping of transvalvular aortic flow, simultaneously depicts aortic regurgitation in 3D fashion and permits assessment of left ventricular changes due to AS. In our model we observed a reduced valve orifice and an increase in valve thickness. Homogenous flow pattern under control converted to heterogenous and turbulent flow with progression of AS associated with increased aortic strain, aortic wall and left ventricular wall thickness. Conclusions In a murine model of aortic valve stenosis MRI is capable to reliably display a three-dimensional transvalvular aortic flow profile with concomitant quantification of structural and functional changes in aortic valve, left ventricle, and ascending aorta. This comprehensive functional imaging at high resolution and distinct reproducibility offers for the first time serial assessment of disease progression in an experimental model of aortic valve stenosis.

P3443Myotonic dystrophy type 1 in childhood: benign from a cardiac perspective?

Abstract Introduction/Purpose Patients with myotonic dystrophy (DM1) have an increased risk of cardiac conduction disease and ventricular tachycardia associated with sudden cardiac death. Whilst this is well-established in adults, there is little published data on cardiac abnormalities in paediatric patients. To our knowledge this is the largest described cohort of children with DM1. The aim of this study is to better understand the prevalence and type of cardiac abnormalities in paediatric patients with DM1. Methods We retrospectively studied consecutive patients referred to our paediatric quaternary institution between 31 December 2000 and 31 January 2019. The electronic patient record was reviewed for the presence of cardiac manifestations, including clinical assessment in clinic, echocardiogram, 12 lead ECG and 24-hour ECG. Results 60 children were identified with a diagnosis of DM1, 56 (93%) with the congenital form of the disease. The median age at diagnosis was 2.4 (IQR 1.2–24, n=52) months. 51 (85%) were under regular formal cardiac follow up. Cardiac symptoms (syncope, palpitations or chest pain) were present in 6 (10%). 12 lead ECGs were available in 50 (83%) and there was at least one echocardiogram performed in 57 (95%). There were 3 deaths (5%), 2 sudden and unexplained (aged 11 and 6.5 years old). 1 child (2%) underwent pacemaker implantation due to the presence of syncope and evidence of progressive conduction disease (Mobitz II AV block). During the period of follow-up, 37 (62%) patients had evidence of conduction disease on 12 lead ECG or Holter: 1st degree or higher AV block (35%, n=21), trifascicular block (6.7%, n=4), intraventricular conduction delay (32%, n=19), prolonged QTc (15%, n=9) and junctional rhythm (5% n=3). In addition to abnormalities of conduction, 27 (45%) patients had axis deviation and 12 (20%) abnormal repolarisation. Abnormalities were present in 8 (14%) of those with an echocardiogram. 2 (3.5%) had hypertrophic cardiomyopathy. Other abnormalities included bicuspid aortic valve, aortic root dilatation, dyskinetic septal motion, pericardial effusion, mitral valve thickening and perimembranous VSD. 24 (40%) patients had a signal averaged ECG of which 14 (58%) were positive in 1 or more vector. 3 (5%) patients had an exercise test with no arrhythmia or progression of conduction abnormalities. 1 patient had an invasive EP study showing a prolonged HV interval but no inducible ventricular tachycardia. Conclusions There appears to be a high incidence of cardiac involvement in children with DM1. Adverse events (death and pacemaker implantation) are represented in our cohort. More studies are required in order to establish how we might better identify those at risk of progression of conduction disease and ventricular arrhythmia. Regular and lifelong cardiac follow up is advisable but risk stratification and device implantation remains challenging.

P5987Novel model of intensity graded murine wire-induced aortic valve stenosis mimics distinct stages of human aortic valve pathology

Abstract Background Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. In fact, only invasive interventional or surgical replacement of severely diseased valves is recommended. This unmet medical need is likely attributed to the lack of a clear understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. Hypothesis Induction of a graded wire-induced aortic valve stenosis model in mice is feasible to reflect and study pathophysiological mechanisms underlying the progression of aortic valve stenosis. Methods We have tested and expanded the protocols of a novel wire-injury induced aortic valve stenosis mouse model. A spring coronary guide wire or a bare metal wire was used to apply shear stress to the aortic valve cusps with increasing intensity with ultrasound-guided monitoring in male 10 to 12-week-old C57Bl/6j mice. These protocols allowed the induction of distinct models with soft, moderate and intense wire injury. Functional analysis including maximum flow velocity (Vmax), ejection fraction, fractional shortening, left ventricular volumes, diameters and wall thickness were assessed by echocardiography before, one and four weeks after induction of aortic valve stenosis. Immunohistological analysis were performed after eight weeks (hematoxylin and eosin, von-Kossa staining, anti-CD68-staining). Results Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. Only 5% of the mice who received a moderate injury displayed a mild aortic regurgitation. In the group of mice with intense injury 50% of the mice had a mild and 18,75% had a moderate aortic insufficiency. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction after intense injury, while moderate injury did not show significant dilation of the left ventricle. Histological analysis revealed the three classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration and calcification eight weeks after injury. Conclusion Hereby, we demonstrate that the induction of a graded wire induced aortic valve stenosis model in mice mimicking relevant pathophysiological mechanisms is feasible to study disease progression. We extended existing protocols to induce moderate stenosis allowing to solely study aortic valve stenosis without relevant aortic valve regurgitation. Acknowledgement/Funding S.N. was funded by Else-Kröner-Fresenius-Foundation of the Medical Faculty of the University of Bonn

Aortic Valve Thickening as a Novel Risk Factor for Development of Aortic Incompetence after Left Ventricular Assist Device Implantation

Introduction The development of aortic incompetence (AI) after left ventricular assist device (LVAD) implantation occurs in 25-30% of all LVAD patients and contributes to increased morbidity. While the underlying pathophysiology is still unclear, previous pathology studies have shown that LVAD patients have accelerated aortic valve cusp remodeling when compared to other heart failure patients; this has been postulated to be the mechanism for AI in the LVAD population. A number of studies have attempted to identify populations that are at risk of developing AI, but none have assessed the effect of preoperative aortic valve sclerosis as a risk factor. We sought to assess the impact of preoperative aortic valve sclerosis on the development of AI in patients requiring LVAD support. Methods We retrospectively reviewed medical charts of patients implanted with Heartmate II (Abbott) and Heartware HVAD (Medtronic) LVADs at a large academic medical center between January 2011 and September 2018. We reviewed transthoracic echocardiography preoperatively and at 1, 3, 6, 9, and 12-months post LVAD implantation. Preoperative aortic valve thickening was predefined as mild or worse sclerosis on transthoracic echocardiogram. Patients with more than mild AI preoperatively or concomitant aortic valve replacement (AVR) were excluded from the analysis. Results A total of 660 echocardiography studies in 176 patients on LVAD support (mean age 55.1±14.0 years old, 84% male, 36.9% HVAD, 63.1% Heartmate2) were identified and analyzed. 25.5% were identified as bridge to transplant, 55.7% as destination therapy, 15.3% as bridge to decision and 3.4% as bridge to recovery. 21.6% were INTERMACS profile 1 and 71.0% were INTERMACS 2 and 3. 49.4% of the patients (n=87) had at least mild AI over the follow up period. The main risk factors identified for the development of AI post-operatively were aortic valve thickening on preoperative echocardiography (61.9% vs 42.4%, p = 0.014) and older age (58.9 ± 13.1 vs 51.4 ± 13.1, p = 0.003). On a multivariate analysis, patients with preoperative aortic valve thickening had a 2.1 times increased risk of developing mild or worse AI post LVAD implant (odds ratio of 2.1, p = 0.027). Conclusions Occurrence of aortic insufficiency is very frequent in patients on prolonged LVAD support. Our study is the first to show that preoperative aortic valve thickening is a significant risk factor for postoperative AI and should be included as a risk factor in decision making prior to LVAD implantation.

Image-Guided Fluid-Structure Interaction Simulation of Transvalvular Hemodynamics: Quantifying the Effects of Varying Aortic Valve Leaflet Thickness

When flow-induced forces are altered at the blood vessel, maladaptive remodeling can occur. One reason such remodeling may occur has to do with the abnormal functioning of the aortic heart valve due to disease, calcification, injury, or an improperly-designed prosthetic valve, which restricts the opening of the valve leaflets and drastically alters the hemodynamics in the ascending aorta. While the specifics underlying the fundamental mechanisms leading to changes in heart valve function may differ from one cause to another, one common and important change is in leaflet stiffness and/or mass. Here, we examine the link between valve stiffness and mass and the hemodynamic environment in aorta by coupling magnetic resonance imaging (MRI) with high-resolution fluid–structure interaction (FSI) computational fluid dynamics to simulate blood flow in a patient-specific model. The thoracic aorta and a native aortic valve were re-constructed in the FSI model from the MRI data and used for the simulations. The effect of valve stiffness and mass is parametrically investigated by varying the thickness (h) of the leaflets (h = 0.6, 2, 4 mm). The FSI simulations were designed to investigate systematically progressively higher levels of valve stiffness by increasing valve thickness and quantifying hemodynamic parameters known to be linked to aortopathy and valve disease. The computed results reveal dramatic differences in all hemodynamic parameters: (1) the geometric orifice area (GOA), (2) the maximum velocity V max of the jet passing through the aortic orifice area, (3) the rate of energy dissipation E ˙ diss ( t ) , (4) the total loss of energy E diss , (5) the kinetic energy of the blood flow E kin ( t ) , and (6) the average magnitude of vorticity Ω a ( t ) , illustrating the change in hemodynamics that occur due to the presence of aortic valve stenosis.

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

BackgroundExtracellular nucleotide metabolism contributes to chronic inflammation, cell differentiation, and tissue mineralization by controlling nucleotide and adenosine concentrations and hence its purinergic effects. This study investigated location-specific changes of extracellular nucleotide metabolism in aortic valves of patients with calcific aortic valve disease (CAVD). Individual ecto-enzymes and adenosine receptors involved were analyzed together with correlation with CAVD severity and risk factors.ResultsNucleotide and adenosine degradation rates were adversely modified on the aortic surface of stenotic valve as compared to ventricular side, including decreased ATP removal (1.25 ± 0.35 vs. 2.24 ± 0.61 nmol/min/cm2) and adenosine production (1.32 ± 0.12 vs. 2.49 ± 0.28 nmol/min/cm2) as well as increased adenosine deamination (1.28 ± 0.31 vs. 0.67 ± 0.11 nmol/min/cm2). The rates of nucleotide to adenosine conversions were lower, while adenosine deamination was higher on the aortic sides of stenotic vs. non-stenotic valve. There were no differences in extracellular nucleotide metabolism between aortic and ventricular sides of non-stenotic valves. Furthermore, nucleotide degradation rates, measured on aortic side in CAVD (n = 62), negatively correlated with echocardiographic and biochemical parameters of disease severity (aortic jet velocity vs. ATP hydrolysis: r = − 0.30, p < 0.05; vs. AMP hydrolysis: r = − 0.44, p < 0.001; valvular phosphate concentration vs. ATP hydrolysis: r = − 0.26, p < 0.05; vs. AMP hydrolysis: r = − 0.25, p = 0.05) while adenosine deamination showed positive correlation trend with valvular phosphate deposits (r = 0.23, p = 0.07). Nucleotide and adenosine conversion rates also correlated with CAVD risk factors, including hyperlipidemia (AMP hydrolysis vs. serum LDL cholesterol: r = − 0.28, p = 0.05; adenosine deamination vs. total cholesterol: r = 0.25, p = 0.05; LDL cholesterol: r = 0.28, p < 0.05; triglycerides: r = 0.32, p < 0.05), hypertension (adenosine deamination vs. systolic blood pressure: r = 0.28, p < 0.05) and thrombosis (ATP hydrolysis vs. prothrombin time: r = − 0.35, p < 0.01). Functional assays as well as histological and immunofluorescence, flow cytometry and RT-PCR studies identified all major ecto-enzymes engaged in nucleotide metabolism in aortic valves that included ecto-nucleotidases, alkaline phosphatase, and ecto-adenosine deaminase. We have shown that changes in nucleotide-converting ecto-enzymes were derived from their altered activities on valve cells and immune cell infiltrate. We have also demonstrated a presence of A1, A2a and A2b adenosine receptors with diminished expression of A2a and A2b in stenotic vs. non-stenotic valves. Finally, we revealed that augmenting adenosine effects by blocking adenosine deamination with deoxycoformycin decreased aortic valve thickness and reduced markers of calcification via adenosine-dependent pathways in a mouse model of CAVD.ConclusionsThis work highlights profound changes in extracellular nucleotide and adenosine metabolism in CAVD. Altered extracellular nucleotide hydrolysis and degradation of adenosine in stenotic valves may affect purinergic responses to support a pro-stenotic milieu and valve calcification. This emphasizes a potential mechanism and target for prevention and therapy.Graphic abstract.

Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells.

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism.

Protecting Offspring Against Fire: Lessons From Banksia Seed Pods.

Wildfires are a natural component in many terrestrial ecosystems and often play a crucial role in maintaining biodiversity, particularly in the fire-prone regions of Australia. A prime example of plants that are able to persist in these regions is the genus Banksia. Most Banksia species that occur in fire-prone regions produce woody seed pods (follicles), which open during or soon after fire to release seeds into the post-fire environment. For population persistence, many Banksia species depend on recruitment from these canopy-stored seeds. Therefore, it is critical that their seeds are protected from heat and rapid oxidation during fire. Here, we show how different species of Banksia protect their seeds inside follicles while simultaneously opening up when experiencing fire. The ability of the follicles to protect seeds from heat is demonstrated by intense 180 s experimental burns, in which the maximum temperatures near the seeds ranged from ∼75°C for B. serrata to ∼90°C for B. prionotes and ∼95°C for B. candolleana, contrasting with the mean surface temperature of ∼450°C. Many seeds of native Australian plants, including those of Banksia, are able to survive these temperatures. Structural analysis of individual follicles from these three Banksia species demonstrates that all of them rely on a multicomponent system, consisting of two valves, a porous separator and a thin layer of air surrounding the seeds. The particular geometric arrangement of these components determines the rate of heat transfer more than the tissue properties alone, revealing that a strong embedment into the central rachis can compensate for thin follicle valves. Furthermore, we highlight the role of the separator as an important thermal insulator. Our study suggests that the genus Banksia employs a variety of combinations in terms of follicle size, valve thickness, composition and geometric arrangement to effectively protect canopy-stored seeds during fire.

Graded murine wire-induced aortic valve stenosis model mimics human functional and morphological disease phenotype.

Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. This unmet medical need is likely attributed to an incomplete understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. We have tested and expanded the protocols of a wire-injury induced AS mouse model. For this model, coronary wires were used to apply shear stress to the aortic valve cusps with increasing intensity. These protocols allowed distinction of mild, moderate and severe wire-injury. Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction. Histological analysis revealed the classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration, fibrosis and calcification. This new mouse model of AS promotes functional and morphological changes similar to moderate and severe human AS. It can be used to investigate the pathomechanisms contributing to AS development and to test novel therapeutic strategies.

Acute Q Fever Endocarditis: A Paradigm Shift Following the Systematic Use of Transthoracic Echocardiography During Acute Q Fever.

As Q fever, caused by Coxiella burnetii, is a major health challenge due to its cardiovascular complications, we aimed to detect acute Q fever valvular injury to improve therapeutic management. In the French national reference center for Q fever, we prospectively collected data from patients with acute Q fever and valvular injury. We identified a new clinical entity, acute Q fever endocarditis, defined as valvular lesion potentially caused by C. burnetii: vegetation, valvular nodular thickening, rupture of chorda tendinae, and valve or chorda tendinae thickness. To determine whether or not the disease was superimposed on an underlying valvulopathy, patients' physicians were contacted. Aortic bicuspidy, valvular stenosis, and insufficiency were considered as underlying valvulopathies. Of the 2434 patients treated in our center, 1797 had acute Q fever and 48 had acute Q fever endocarditis. In 35 cases (72%), transthoracic echocardiography (TTE) identified a valvular lesion of acute Q fever endocarditis without underlying valvulopathy. Positive anticardiolipin antibodies (>22 immunoglobulin G-type phospholipid units [GPLU]) were independently associated with acute Q fever endocarditis (odds ratio [OR], 2.7 [95% confidence interval {CI}, 1.3-5.5]; P = .004). Acute Q fever endocarditis (OR, 5.2 [95% CI, 2.6-10.5]; P < .001) and age (OR, 1.7 [95% CI, 1.1-1.9]; P = .02) were independent predictors of progression toward persistent C. burnetii endocarditis. Systematic TTE in acute Q fever patients offers a unique opportunity for early diagnosis of acute Q fever endocarditis and for the prevention of persistent endocarditis. Transesophageal echocardiography should be proposed in men, aged >40 years, with anticardiolipin antibodies >60 GPLU when TTE is inconclusive or negative.

Transcatheter aortic valve replacement in patients with degenerative calcified rheumatic aortic stenosis: A 10-patient case series

BackgroundTranscatheter aortic valve replacement (TAVR) for patients with rheumatic heart disease (RHD) has not been well-known. This study aimed to assess characteristics and computed tomography (CT) findings of the aortic valve in old patients with RHD and to investigate the safety and efficacy in the patients who underwent TAVR. Methods and resultsOf 352 consecutive patients with severe aortic stenosis (AS) who underwent TAVR at the Sakakibara Heart Institute between 2013 and 2016, 10 patients (2.8%) were considered to have degenerative calcified rheumatic AS by transthoracic echocardiography. Young patients with rheumatic AS without any calcification were not indicated for TAVR in this study. They were likely to have previous pacemaker implantation, atrial fibrillation, anticoagulants, diuretics, reduced ejection fraction, mitral valve involvement, and high pulmonary artery pressure. CT was able to clearly visualize irregular valve thickening, commissure fusion, and a relatively small amount of calcification from the tip of the leaflet to the base of the aortic valve. Mortality at 30 days after TAVR was 0%, with a mean Society of Thoracic Surgeons Score of 7 ± 4%. Device success was 90%, and no patients met the safety endpoint at 30 days. ConclusionsCT was able to visualize the calcified aortic valve in old patients with RHD, and we demonstrate the safety and efficacy of TAVR in this specific population. Care should be taken for procedural success in particular characteristics with marginal calcified aortic valve, anticoagulant use with low body mass index, or concomitant mitral valve disease.

Transcatheter Aortic Heart Valves: Histological Analysis Providing Insight to Leaflet Thickening and Structural Valve Degeneration

ObjectivesThis study investigated processes causing leaflet thickening and structural valve degeneration (SVD). BackgroundAlthough transcatheter aortic valve replacement (TAVR) has changed the treatment of aortic stenosis, concerns remain regarding SVD, potentially related to valve thrombosis and thickening, based on studies using computed tomography (CT). Detailed histological analyses are provided to help attain insights into these processes. MethodsExplanted transcatheter heart valves (THVs) were evaluated for thrombosis, fibrosis, and calcification for quantification of leaflet thickness. Immunohistochemical and microscopy approaches were used to investigate SVD-associated mechanisms. ResultsTHVs (n = 23) were obtained from 22 patients (median 81 years of age; 50% male) from 0 to 2,583 days post TAVR. Maximal leaflet thickness increased relative to implant duration (ρ = 0.427; p = 0.027). THVs explanted after >2 years were thicker than those explanted after <2 years (p = 0.007). All THVs had adherent thrombus on both aortic and ventricular sides, which beyond 60 days was seen in combination with fibrosis and beyond 4 years had calcification. Early thrombus formation (<60 days) occurred despite rapid endothelialization with an abnormal hyperplastic phenotype. Fibrosis was observed in 6 patients on both the aortic and the ventricular THV surfaces, remodeled over time, and was associated with matrix metalloproteinase-1 expression. Five THVs showed overt calcification associated with adherent thrombus and fibrosis. ConclusionsThere is a time-dependent degeneration of THVs consisting of thrombus formation, endothelial hyperplasia, fibrosis, tissue remodeling, proteinase expression, and calcification. Future investigation is needed to further understand these mechanisms contributing to leaflet thickening and SVD.

OC85 TREATMENT OF AORTIC INSUFFICIENCY THROUGH AORTIC LEAFLETS REMODELLING: AN EXCELLENT ALTERNATIVE TO REPLACEMENT

Background and Aim: Aortic valve repair can be considered a valid alternative to replacement in patients with aortic regurgitation. Recent data report excellent results mainly for patients with aortic root dilatation associated with anatomically normal aortic valve. No data are up-to-date available about the results of the repair in patients with degenerative aortic valve (prolapse, thickness, perforation and/or retraction of the leaflets, congenital malformations). We analyzed retrospectively our data. Methods: From January 2011 to November 2017, we have treated 90 patients with degenerative aortic valve insufficiency (IA) through sugical remodelling of the aortic leaflets. The failure mechanism conditioned the choice of technique (shaving, correction of prolapse, raphe excision, use of pericardium, commissural re-orientation). Pre and postoperative transesophageal echocardiography as well as transthoracic echocardiography for follow-up were performed for each patient. Results: No in-hospital mortality was reported, two late deaths (2.22%)both for non cardiac cause. Three patiens (3.33%) needed, after repair, intraoperative aortic valve replacement while two (2.22%)at follow-up. Postoperative complications were low: 2 (2.22%)transient low output syndrome, 3 (3.33%)postoperative bleeding, 1 (1.11%)transient neurological deficit, 1 (1.11%)temporary renal failure, 3 (3.33%)acute myocardial ischemia. No thromboembolic and haemorragic events was referred, as well as endocarditis. Early or late recurrence of IA &gt; 2 was detected in 4 pts (4,44%). Conclusions: Remodelling of the aortic valve leaflets represents an attractive and valid alternative to aortic valve replacement in patients with aortic valve insufficiency, mainly in young patients. In our experience the results are excellent in terms of short and middle term survival, postoperative complications and freedom from reoperation. It remains to be established if the remodeling of the cusps is comparable to the replacement of the valve in terms of late results.

Case 3: A Term Newborn with Intrauterine Growth Restriction and Severe Fetal Brain Anomalies

A 29-year-old gravida 4, para 3 woman is seen by the maternal-fetal medicine team because of abnormal ultrasonographic findings at 34 weeks of gestation. The fetus has severe intrauterine growth restriction (IUGR) (<1st percentile) and multiple organ abnormalities, including microcephaly, small forebrain, scalloped parietal bones, bilateral ventriculomegaly, dilated third ventricle, splayed thalami, irregular falx, scattered intracranial calcifications, and a small, flattened forehead. Fetal echocardiography shows levorotation of the cardiac axis, tortuous ductus arteriosus, and tricuspid valve thickening. Her prenatal history is notable for travel to the Dominican Republic until 12 weeks of gestation. She denies any fever, insect bites, rash, conjunctivitis, or arthralgia. Findings on other prenatal laboratory screening are reassuring. After the induction of labor for IUGR, a male infant is delivered at 37 2/7 weeks of gestation via normal spontaneous vaginal delivery. Brief positive pressure ventilation is given in the delivery room for an initial low heart rate. The heart rate quickly recovers, but respiratory distress develops, requiring continuous positive airway pressure (CPAP). The infant is transferred to the NICU with the administration of CPAP. Upon admission, physical examination shows a boy with a birthweight of 2,140 g (2.8th percentile), length of 40.5 cm (<1st percentile), and head circumference of 29 cm (<1st percentile). Pertinent findings include microcephaly and global hypertonia, along with contractures of the upper and lower extremities (Fig 1). Figure 1. Contractures of upper and lower extremities. …

TIEG1 is upregulated in Lrp5/6-mediated valve osteogenesis.

We have previously demonstrated that Lrp5/6/β-catenin plays an important role in valve calcification with a specific osteogenic phenotype defined by increased bone mineral content and overall valve thickening. Recent studies indicate that TIEG1 may be involved in mediating the Wnt signaling pathway in bone, which is known to play critical roles in osteoblast differentiation and bone mineralization. Therefore, we sought to test the role of TIEG1 in mediating Wnt signaling, in an established model of hypercholesterolemic valve disease. Our previous model treated null mice with cholesterol diets: Lrp5 -/- /ApoE -/- mice versus wild-type control (n = 180). Group I (n = 60) normal diet, Group II (n = 60) 0.25% chol diet (w/w), and Group III (n = 60) 0.25% (w/w) chol diet + atorv was tested for gene expression for TIEG1, Lrp6, and Runx2. Real-time polymerase chain reaction confirmed that there is upregulation of the gene expression for TIEG1 and Runx2 in the hypercholesterolemic double knockout and single knockout valves as compared with controls with a mild increase in Lrp6. To confirm the mechanism, coexpression of β-catenin, TIEG1, and LEF1 in valve cells in vitro, led to the coactivation of the TOPFLASH reporter, which was further confirmed by the observation that TIEG1 and β-catenin colocalize with one another in the nucleus of valvular interstitial cells (VICs) following stimulation with transforming growth factor-β treatment, an established activator of TIEG1. Taken together, these data implicate an important role for TIEG1 in mediating valve osteogenesis.

TCT-69 Transcatheter Aortic Heart Valves: Histological Analysis Providing Insight to Leaflet Thickening and Structural Valve Degeneration

While transcatheter aortic valve replacement (TAVR) has drastically changed the treatment of aortic stenosis, concerns remain regarding structural valve degeneration (SVD) potentially related to valve thrombosis and thickening. Therefore, we aimed to investigate processes causing leaflet thickening

Cardiac features and effects of enzyme replacement therapy in Taiwanese patients with Mucopolysaccharidosis IVA

BackgroundCardiac abnormalities have been observed in patients with mucopolysaccharidosis (MPS) of any type, with the most documented abnormalities being valvular heart disease and cardiac hypertrophy. However, few studies have focused on the cardiac features of MPS IVA.MethodsWe reviewed the medical records, echocardiograms, and electrocardiograms of 32 Taiwanese patients with MPS IVA (16 males and 16 females; median age, 10.8 years; age range, 1.1 to 29.1 years) as well as the echocardiographic data of six patients who received enzyme replacement therapy (ERT) for 3–6 years.ResultsEchocardiographic examinations (n = 32) revealed mean z scores of left ventricular mass index (LVMI), interventricular septum diameter in diastole (IVSd), left ventricular posterior wall diameter in diastole (LVPWd), and aortic diameter of 0.94, 2.70, 0.39, and 3.26, respectively. Z scores > 2 were identified in 25%, 50%, 29%, and 69% of the LVMI, IVSd, LVPWd, and aortic diameter values, respectively. Diastolic dysfunction [reversed ratio between early and late (atrial) ventricular filling velocity (E/A ratio < 1)] was identified in four patients (13%), however, the ejection fraction was normal (50–75%) in all of the patients. Sixteen patients (50%) had valvular heart disease and most were of mild degree. Fourteen (44%) had valvular stenosis, and 10 (31%) had regurgitation. The z scores of LVMI, IVSd, LVPWd, and aortic diameter, the severity scores of aortic stenosis and regurgitation, and the existence of a thickened interventricular septum were all positively correlated with increasing age (p < 0.05). For the 14 patients with valve thickening, the z scores of LVMI, IVSd and aortic diameter were all larger than those of the 18 patients without valve thickening (p < 0.05). For two patients who started ERT at a younger age (1.4 and 2.8 years, respectively), the z scores for LVMI, IVSd, and LVPWd all decreased after ERT.ConclusionsA large proportion of the patients with MPS IVA had valvular heart disease and cardiac hypertrophy. Cardiac abnormalities worsened with increasing age in accordance with the progressive nature of this disease. ERT appeared to be effective in stabilizing or reducing cardiac hypertrophy, and better results may have been associated with starting ERT at a younger age.

α-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by α-galactosidase A (α-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because α-Gal A-deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate α-Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.-Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., α-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease.

Major orthopaedic surgery changes the composition of atherosclerotic aortic valves, without influencing valve thickness in ApoE-/- mice

Major orthopaedic surgery changes the composition of atherosclerotic aortic valves, without influencing valve thickness in ApoE-/- mice

Natural history of echocardiographic abnormalities in mucopolysaccharidosis III

BackgroundMucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder. MPS I and II patients often develop cardiac involvement leading to early mortality, however there are limited data in MPS III. The objective of this study is to describe cardiac abnormalities in a large group of MPS III patients followed in a longitudinal natural history study designed to determine outcome measures for gene transfer trials. MethodsA single center study of MPS III patients who were enrolled in the Nationwide Children's Hospital natural history study in 2014. Two cardiologists reviewed all patient echocardiograms for anatomic, valvular, and functional abnormalities. Valve abnormalities were defined as abnormal morphology, trivial mitral regurgitation (MR) with abnormal morphology or at least mild MR, and any aortic regurgitation (AR). Abnormal left ventricular (LV) function was defined as ejection fraction < 50%. Group comparisons were assessed using two-sample t-tests or Wilcoxon rank sum tests for continuous variables and chi-square or Fisher's exact tests for categorical variables. ResultsTwenty-five patients, 15 Type A and 10 Type B MPS III, underwent 45 echocardiograms. Fifteen patients (60%) demonstrated an abnormal echocardiographic finding with age at first abnormal echocardiogram within the study being 6.8 ± 2.8 years. Left-sided valve abnormalities were common over time: 7 mitral valve thickening, 2 mitral valve prolapse, 16 MR (8 mild, 8 trivial), 3 aortic valve thickening, and 9 AR (7 mild, 2 trivial). Two patients had asymmetric LV septal hypertrophy. No valvular stenosis or ventricular function abnormalities were noted. Incidental findings included: mild aortic root dilation (2), bicommissural aortic valve (1), and mild tricuspid regurgitation (3). ConclusionsIndividuals with Sanfilippo A and B demonstrate a natural history of cardiac involvement with valvular abnormalities most common. In short-term follow up, patients demonstrated only mild progression of abnormalities, none requiring intervention. Valvular disease prevalence is similar to MPS I and II, but appears less severe. These findings raise no specific concerns for gene transfer trials in patients in this age range.