Differential proteome profile, biological pathways, and network relationships of osteogenic proteins in calcified human aortic valves.

Calcific aortic valve disease (CAVD) is the most common heart valve disease requiring intervention. Most research on CAVD has focused on inflammation, ossification, and cellular phenotype transformation. To gain a broader picture into the wide range of cellular and molecular mechanisms involved in this disease, we compared the total protein profiles between calcified and non-calcified areas from 5 human valves resected during surgery. The 1413 positively identified proteins were filtered down to 248 proteins present in both calcified and non-calcified segments of at least 3 of the 5 valves, which were then analyzed using Ingenuity Pathway Analysis. Concurrently, the top 40 differentially abundant proteins were grouped according to their biological functions and shown in interactive networks. Finally, the abundance of selected osteogenic proteins (osteopontin, osteonectin, osteocalcin, osteoprotegerin, and RANK) was quantified using ELISA and/or immunohistochemistry. The top pathways identified were complement system, acute phase response signaling, metabolism, LXR/RXR and FXR/RXR activation, actin cytoskeleton, mineral binding, nucleic acid interaction, structural extracellular matrix (ECM), and angiogenesis. There was a greater abundance of osteopontin, osteonectin, osteocalcin, osteoprotegerin, and RANK in the calcified regions than the non-calcified ones. The osteogenic proteins also formed key connections between the biological signaling pathways in the network model. In conclusion, this proteomic analysis demonstrated the involvement of multiple signaling pathways in CAVD. The interconnectedness of these pathways provides new insights for the treatment of this disease.

Surgery for Ventricular Tachycardia.

The treatment of drug-refractory chronic ventricular tachycardia (VT) has undergone a revolution over the last 50 years. We now have automatic implantable cardioverter defibrillator therapy with pace-terminating capabilities, and catheter ablation of VT has refined mapping and improved methods of lesion generation. Between 1980 and 1993, Houston Methodist Hospital became a leader in the diagnosis and surgical ablation of VT and other arrhythmias. This is a brief account of that period and some of the experiences and lessons that have led to significant advances used today.

Mitral Valve Remodeling and Strain in Secondary Mitral Regurgitation: Comparison With Primary Regurgitation and Normal Valves.

OBJECTIVES: The aim of this study was to assess mitral valve (MV) remodeling and strain in patients with secondary mitral regurgitation (SMR) compared with primary MR (PMR) and normal valves. BACKGROUND: A paucity of data exists on MV strain during the cardiac cycle in humans. Real-time 3-dimensional (3D) echocardiography allows for dynamic MV imaging, enabling computerized modeling of MV function in normal and disease states. METHODS: Three-dimensional transesophageal echocardiography (TEE) was performed in a total of 106 subjects: 36 with SMR, 38 with PMR, and 32 with normal valves; MR severity was at least moderate in both MR groups. Valve geometric parameters were quantitated and patient-specific 3D MV models generated in systole using a dedicated software. Global and regional peak systolic MV strain was computed using a proprietary software. RESULTS: MV annular area was larger in both the SMR and PMR groups (12.7 ± 0.7 and 13.3 ± 0.7 cm2, respectively) compared with normal subjects (9.9 ± 0.3 cm2; p < 0.05). The leaflets also had significant remodeling, with total MV leaflet area larger in both SMR (16.2 ± 0.9 cm2) and PMR (15.6 ± 0.8 cm2) versus normal subjects (11.6 ± 0.4 cm2). Leaflets in SMR were thicker than those in normal subjects but slightly less than those with PMR posteriorly. Posterior leaflet strain was significantly higher than anterior leaflet strain in all 3 groups. Despite MV remodeling, strain in SMR (8.8 ± 0.3%) was overall similar to normal subjects (8.5 ± 0.2%), and both were lower than in PMR (12 ± 0.4%; p < 0.0001). Valve thickness, severity of MR, and primary etiology of MR were correlates of strain, with leaflet thickness being the multivariable parameter significantly associated with MV strain. In patients with less severe MR, anterior leaflet strain in SMR was lower than normal, whereas strain in PMR remained higher than normal. CONCLUSIONS: The MV in secondary MR remodels significantly and similarly to PMR with a resultant larger annular area, leaflet surface area, and leaflet thickness compared with that of normal subjects. Despite these changes, MV strain remains close to or in some instances lower than normal and is significantly lower than that of PMR. Strain determination has the potential to improve characterization of MV mechano-biologic properties in humans and to evaluate its prognostic impact in patients with MR, with or without valve interventions.

Valve Strain Quantitation in Normal Mitral Valves and Mitral Prolapse With Variable Degrees of Regurgitation.

OBJECTIVES: The aim of this study was to quantitate patient-specific mitral valve (MV) strain in normal valves and in patients with mitral valve prolapse with and without significant mitral regurgitation (MR) and assess the determinants of MV strain. BACKGROUND: Few data exist on MV deformation during systole in humans. Three-dimensional echocardiography allows for dynamic MV imaging, enabling digital modeling of MV function in health and disease. METHODS: Three-dimensional transesophageal echocardiography was performed in 82 patients, 32 with normal MV and 50 with mitral valve prolapse (MVP): 12 with mild mitral regurgitation or less (MVP - MR) and 38 with moderate MR or greater (MVP + MR). Three-dimensional MV models were generated, and the peak systolic strain of MV leaflets was computed on proprietary software. RESULTS: Left ventricular ejection fraction was normal in all groups. MV annular dimensions were largest in MVP + MR (annular area: 13.8 ± 0.7 cm2) and comparable in MVP - MR (10.6 ± 1 cm2) and normal valves (10.5 ± 0.3 cm2; analysis of variance: p < 0.001). Similarly, MV leaflet areas were largest in MVP + MR, particularly the posterior leaflet (8.7 ± 0.5 cm2); intermediate in MVP - MR (6.5 ± 0.7 cm2); and smallest in normal valves (5.5 ± 0.2 cm2; p < 0.0001). Strain was overall highest in MVP + MR and lowest in normal valves. Patients with MVP - MR had intermediate strain values that were higher than normal valves in the posterior leaflet (p = 0.001). On multivariable analysis, after adjustment for clinical and MV geometric parameters, leaflet thickness was the only parameter that was retained as being significantly correlated with mean MV strain (r = 0.34; p = 0.008). CONCLUSIONS: MVs that exhibit prolapse have higher strain compared to normal valves, particularly in the posterior leaflet. Although higher strain is observed with worsening MR and larger valves and annuli, mitral valve leaflet thickness-and, thus, underlying MV pathology-is the most significant independent determinant of valve deformation. Future studies are needed to assess the impact of MV strain determination on clinical outcome.

Extracellular Volume in Primary Mitral Regurgitation.

OBJECTIVES: This study used cardiovascular magnetic resonance (CMR) to evaluate whether elevated extracellular volume (ECV) was associated with mitral valve prolapse (MVP) or if elevated ECV was a consequence of remodeling independent of primary mitral regurgitation (MR) etiology. BACKGROUND: Replacement fibrosis in primary MR is more prevalent in MVP; however, data on ECV as a surrogate for diffuse interstitial fibrosis in primary MR are limited. METHODS: Patients with chronic primary MR underwent comprehensive CMR phenotyping and were stratified into an MVP cohort (>2 mm leaflet displacement on a 3-chamber cine CMR) and a non-MVP cohort. Factors associated with ECV and replacement fibrosis were assessed. The association of ECV and symptoms related to MR and clinical events (mitral surgery and cardiovascular death) was ascertained. RESULTS: A total of 424 patients with primary MR (229 with MVP and 195 non-MVP) were enrolled. Replacement fibrosis was more prevalent in the MVP cohort (34.1% vs. 6.7%; p < 0.001), with bi-leaflet MVP having the strongest association with replacement fibrosis (odds ratio: 10.5; p < 0.001). ECV increased with MR severity in a similar fashion for both MVP and non-MVP cohorts and was associated with MR severity but not MVP on multivariable analysis. Elevated ECV was independently associated with symptoms related to MR and clinical events. CONCLUSIONS: Although replacement fibrosis was more prevalent in MVP, diffuse interstitial fibrosis as inferred by ECV was associated with MR severity, regardless of primary MR etiology. ECV was independently associated with symptoms related to MR and clinical events. (DeBakey Cardiovascular Magnetic Resonance Study [DEBAKEY-CMR]; NCT04281823).

Resolving the Disproportionate Left Ventricular Enlargement in Mitral Valve Prolapse Due to Barlow Disease: Insights From Cardiovascular Magnetic Resonance.

OBJECTIVES: This study hypothesized that left ventricular (LV) enlargement in Barlow disease can be explained by accounting for the total volume load that consists of transvalvular mitral regurgitation (MR) and the prolapse volume. BACKGROUND: Barlow disease is characterized by long prolapsing mitral leaflets that can harbor a significant amount of blood-the prolapse volume-at end-systole. The LV in Barlow disease can be disproportionately enlarged relative to MR severity, leading to speculation of Barlow cardiomyopathy. METHODS: Cardiac magnetic resonance (CMR) was used to compare MR, prolapse volume, and heart chambers remodeling in patients with Barlow disease (bileaflet prolapse [BLP]) and in single leaflet prolapse (SLP). RESULTS: A total of 157 patients (81 with BLP, 76 with SLP) were included. Patients with SLP were older and more had hypertension. Patients with BLP had more heart failure. Indexed LV end-diastolic volume was larger in BLP despite similar transvalvular MR. However, the prolapse volume was larger in BLP, which led to larger total volume load compared with SLP. Increasing tertiles of prolapse volume and MR both led to an incremental increase in LV end-diastolic volume in BLP. Using the total volume load improved the correlation with indexed LV end-diastolic volume in the BLP group, which closely matched that of SLP. A multivariable model that incorporated the prolapse volume explained left heart chamber enlargement better than a MR-based model, independent of prolapse category. CONCLUSIONS: The prolapse volume is part of the total volume load exerted on the LV during the cardiac cycle and could help explain the disproportionate LV enlargement relative to MR severity noted in Barlow disease.

Surgical treatment of mitral regurgitation.

PURPOSE OF REVIEW: Mitral repair is the best treatment for degenerative mitral regurgitation. Many patients are referred too late for optimal outcomes. The US repair vs. replacement rate is only 60-80%, at a time when the inferiority of replacement has been established. Therefore, widely used traditional techniques of repair are being reappraised. RECENT FINDINGS: Identification of risk factors predictive of poor early and late outcome have improved timing for surgical referral. Composite risk scores have been developed. Novel echocardiographic, cardiac MRI, and molecular level risk factors could improve timing. Analysis of factors contributing to low repair rates is also of critical importance. The role of institutional and surgeon volumes have been identified. More detailed data on the importance of dynamic function of the mitral valve have led to improved repair techniques such as intraoperative simulation of end diastole and early systole, use of expanded polytetrafluoroethylene neochords instead of leaflet resection, and dynamic instead of rigid annuloplasty. SUMMARY: Our perception of mitral regurgitation has changed from a seemingly simple condition to one of considerable complexity at multiple levels. National guidelines should be studied and followed.

Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse.

BACKGROUND: Recent studies reported left ventricular (LV) fibrosis in patients with primary mitral regurgitation (MR) thought to be principally due to mitral valve prolapse (MVP). OBJECTIVES: This study sought to evaluate the prevalence, characteristics, and prognostic implications of LV fibrosis in a large cohort of primary MR patients with and without MVP using cardiovascular magnetic resonance (CMR). METHODS: Patients referred for contrast CMR assessment of chronic primary MR were enrolled and underwent comprehensive assessment of cardiac remodeling, severity of MR, and LV replacement fibrosis. Primary MR patients were stratified into: an MVP group if there was >2 mm mitral leaflet displacement on cine-CMR, or a non-MVP group. Patients were followed for arrhythmic events (sudden cardiac death, aborted sudden cardiac arrest, and sustained or inducible ventricular arrhythmia). RESULTS: A total of 356 primary MR patients (177 MVP and 179 non-MVP) were enrolled. LV fibrosis was more prevalent in the MVP group than the non-MVP group (36.7% vs. 6.7%; p < 0.001). The presence of MVP had the strongest association (odds ratio: 6.82; p < 0.001) with LV fibrosis even after adjustment for clinical variables, measures of cardiac remodeling, and MR severity. During follow-up (median 1,354 days), MVP patients with LV fibrosis had the highest event rate for arrhythmic events. CONCLUSIONS: In primary MR patients, LV fibrosis is more prevalent in MVP than non-MVP, suggesting a unique pathophysiology beyond volume overload in MVP. LV fibrosis in primary MR may represent a risk marker of arrhythmic events.

Early Trifecta valve failure: Report of a cluster of cases from a tertiary care referral center.

BACKGROUND: The Trifecta valve (St Jude Medical, Inc, St Paul, Minn) was approved for commercial use by the US Food and Drug Administration in 2011. Several isolated cases have been reported since then, describing early structural valve deterioration. We report a case series of 8 Trifecta valve failures, describing patients' clinical substrate and management, and the pathologic characteristics of the explanted valves. METHODS: Trifecta valve failure occurred in 7 patients (8 valves) receiving 19-mm (n = 2), 21-mm (n = 3), 23-mm (n = 1), and 25-mm (n = 2) valves. The mean duration of valve durability was 32 ± 21 months, and the most common lesion was prosthetic regurgitation. The mean Society of Thoracic Surgeons risk score for perioperative mortality at the time of reintervention was 9.75% ± 8.1%. Heart failure exacerbation was the most common presenting symptom. RESULTS: Five patients underwent surgical aortic valve replacement, 2 patients received valve-in-valve transcatheter aortic valve replacement, and 1 patient died of cardiogenic shock before reintervention. The most common pathologic finding in the explanted valves was a tan-yellow fibrofatty circumferential pannus adherent to the inflow portion of the Trifecta valve. CONCLUSIONS: Our findings provide further insights into the pathologic mechanisms leading to early Trifecta valve failure. In addition to tear of the noncoronary cusp of the Trifecta prosthesis described as the most common mechanism in the literature for its failure, circumferential pannus formation composed of fibrofatty tissue in the inflow portion and leaflet calcification concentrated around the posts in the outflow portion are important mechanisms contributing toward early Trifecta valve failure.

Morphometric analysis of calcification and fibrous layer thickness in carotid endarterectomy tissues.

BACKGROUND: Advanced atherosclerotic lesions are commonly characterized by the presence of calcification. Several studies indicate that extensive calcification is associated with plaque stability, yet recent studies suggest that calcification morphology and location may adversely affect the mechanical stability of atherosclerotic plaques. The underlying cause of atherosclerotic calcification and the importance of intra-plaque calcium distribution remains poorly understood. METHOD: The goal of this study was the characterization of calcification morphology based on histological features in 20 human carotid endarterectomy (CEA) specimens. Representative frozen sections (10µm thick) were cut from the common, bulb, internal and external segments of CEA tissues and stained with von Kossa׳s reagent for calcium phosphate. The morphology of calcification (calcified patches) and fibrous layer thickness were quantified in 135 histological sections. RESULTS: Intra-plaque calcification was distributed heterogeneously (calcification %-area: bulb segment: 14.2±2.1%; internal segment: 12.9±2.8%; common segment: 4.6±1.1%; p=0.001). Calcified patches were found in 20 CEAs (patch size: <0.1mm(2) to >1.0mm(2)). Calcified patches were most abundant in the bulb and least in the common segment (bulb n=7.30±1.08; internal n=4.81±1.17; common n=2.56±0.56; p=0.0007). Calcified patch circularity decreased with increasing size (<0.1mm(2): 0.77±0.01, 0.1-1mm(2): 0.62±0.01, >1.0mm(2): 0.51±0.02; p=0.0001). A reduced fibrous layer thickness was associated with increased calcium patch size (p<0.0001). CONCLUSIONS: In advanced carotid atherosclerosis, calcification appears to be a heterogeneous and dynamic atherosclerotic plaque component, as indicated by the simultaneous presence of few large stabilizing calcified patches and numerous small calcific patches. Future studies are needed to elucidate the associations of intra-plaque calcification size and distribution with atherothrombotic events.