Naritaka Kimura

Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis

The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.

Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents

Valvular heart disease (VHD) is the term given to any disease process involving one or more of the heart valves. The condition can be congenital or acquired, for example as a result of atherosclerosis or rheumatic fever. Despite its clinical importance, the molecular mechanisms underlying VHD remain unknown. We investigated the pathophysiologic role and molecular mechanism of periostin, a protein that plays critical roles in cardiac valve development, in degenerative VHD. Unexpectedly, we found that periostin levels were drastically increased in infiltrated inflammatory cells and myofibroblasts in areas of angiogenesis in human atherosclerotic and rheumatic VHD, whereas periostin was localized to the subendothelial layer in normal valves. The expression patterns of periostin and chondromodulin I, an angioinhibitory factor that maintains cardiac valvular function, were mutually exclusive. In WT mice, a high-fat diet markedly increased aortic valve thickening, annular fibrosis, and MMP-2 and MMP-13 expression levels, concomitant with increased periostin expression; these changes were attenuated in periostin-knockout mice. In vitro and ex vivo studies revealed that periostin promoted tube formation and mobilization of ECs. Furthermore, periostin prominently increased MMP secretion from cultured valvular interstitial cells, ECs, and macrophages in a cell type-specific manner. These findings indicate that, in contrast to chondromodulin I, periostin plays an essential role in the progression of cardiac valve complex degeneration by inducing angiogenesis and MMP production.

Molecular mechanisms underlying the onset of degenerative aortic valve disease

Morbidity from degenerative aortic valve disease is increasing worldwide, concomitant with the ageing of the general population and the habitual consumption of diets high in calories and cholesterol. Immunohistologic studies have suggested that the molecular mechanism occurring in the degenerate aortic valve resembles that of atherosclerosis, prompting the testing of HMG CoA reductase inhibitors (statins) for the prevention of progression of native and bioprosthetic aortic valve degeneration. However, the effects of these therapies remain controversial. Although the molecular mechanisms underlying the onset of aortic valve degeneration are largely unknown, research in this area is advancing rapidly. The signaling components involved in embryonic valvulogenesis, such as Wnt, TGF-β1, BMP, and Notch, are also involved in the onset of aortic valve degeneration. Furthermore, investigations into extracellular matrix remodeling, angiogenesis, and osteogenesis in the aortic valve have been reported. Having noted avascularity of normal cardiac valves, we recently identified chondromodulin-I (chm-I) as a crucial anti-angiogenic factor. The expression of chm-I is restricted to cardiac valves from late embryogenesis to adulthood in the mouse, rat, and human. In human degenerate atherosclerotic valves, the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases and angiogenesis is observed in the area of chm-I downregulation. Gene targeting of chm-I resulted in VEGF expression, angiogenesis, and calcification in the aortic valves of aged mice, and aortic stenosis is detected by echocardiography, indicating that chm-I is a crucial factor for maintaining normal cardiac valvular function by preventing angiogenesis. The present review focuses on the animal models of aortic valve degeneration and recent studies on the molecular mechanisms underlying the onset of degenerative aortic valve disease.

Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis

Background— Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture. Methods and Results— We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner. Conclusions— These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.

A Simple Method of Prevention for Systolic Anterior Motion in Mitral Valve Repair by Loop Technique Method

The loop technique is commonly adopted as a surgical procedure in mitral valve repair to secure the effective valve area of the valve leaflet, and to preserve, as much as possible, the physiological movement of the valve leaflet or annulus. On the other hand, the prolapsed valve leaflet is very high in some patients. In this case, the redundant valve leaflet may increase the risk of development of postoperative systolic anterior motion because the valve leaflet is not surgically removed at all. In this article, we describe a simple procedure for preventing systolic anterior motion after mitral valve repair using the loop technique.

Risk factor analysis for acute type A aortic dissection after aortic valve replacement

PurposePrevious aortic valve replacement (AVR) is considered to be an independent risk factor for late acute type A aortic dissection (AAAD). However, the predictors of late AAAD at the time of AVR have not been characterized.MethodsA total of 285 patients who underwent isolated AVR were followed for 7.6 ± 8.1 years (mean ± SD). These 285 patients were divided into two groups. Group A consisted of 275 patients who did not develop late aortic complications after AVR, and group B consisted of 10 patients (3.5%) who developed late AAAD after AVR.ResultsThe mean time interval between initial AVR and developing late AAAD was 6.1 ± 5.2 years. The diameter of the ascending aorta at the time of AVR was significantly greater in group B than those of group A (47.7 ± 4.6 vs. 35.6 ± 6.3 mm; P < 0.001). Univariate analysis identified other predictors as well: aortic regurgitation (P = 0.029), systemic hypertension (P < 0.001), thinning or fragility of the aortic wall (P < 0.001), and male sex (P = 0.039).ConclusionAortic regurgitation combined with systemic hypertension, male sex, and thinned or fragile aortic walls in patients with ascending aortic dilatation (≥45 mm diameter) at the time of AVR may be predisposing factors for postsurgical aortic complications. These patients should be considered for concomitant replacement of the ascending aorta unless the patient has a high operative risk or older age.

Examination of mitral valve repair with port-access method-Aiming at early and less invasive mitral valve repair

ObjectiveWe reviewed the results of mitral valvuloplasty by port-access minimally invasive cardiac surgery to examine the validity of operating during an early phase.MethodsFrom 1988 through March 2007, a total of 126 patients requiring mitral valvuloplasty were treated with port-access minimally invasive cardiac surgery. Their mean age was 51 ± 13 years, and 88 were male. The operative procedures were resection-suture in 51 cases, artificial chordal replacement in 5 cases, chordal translocation in 3 cases, leaflet plication in 3 cases, and artificial chordal reconstruction by the loop technique in 64 cases.ResultsThere was one hospital death, and two patients required reoperation at 1 and 21 postoperative days because of hemolysis and intractable systolic anterior motion, respectively. Except for the two patients undergoing reoperation, the duration of the postoperative hospital stay was 9.7 ± 3 days. The results of the other cases were satisfactory during each follow-up period.ConclusionComplete valvuloplasty with port-access MIS is thought to be an increasingly important procedure for treating mitral regurgitation.

Comparison of aortic arch repair using the endovascular technique, total arch replacement and staged surgery

OBJECTIVES We evaluated the operative and long-term outcomes of various approaches for aortic arch repair. METHODS A total of 436 consecutive patients who underwent aortic arch repair from January 2001 to March 2016 in our centre were evaluated. Of these, 276 underwent conventional total arch replacement (TAR), and 118 underwent thoracic endovascular repair (TEVAR). The remaining 42 patients underwent staged thoracic endovascular repair (STEVAR). A total of 72 patients in the TEVAR group were matched to 72 patients who underwent open surgery including TAR or STEVAR by using propensity score analysis. RESULTS Surgical outcomes showed shorter ICU and hospital stay in the TEVAR group ( P  < 0.001 and P  < 0.001, respectively). The 30-day mortality and neurologic dysfunction showed no significant difference among the three groups (2.8 and 5.4% in TAR group, 1.7 and 8.5% in TEVAR group and 0 and 2.4% in STEVAR group; P  = 0.500 and P  = 0.297, respectively). Long-term survival was not significantly different among the three groups (78% in TAR group, 67% in TEVAR group and 81% in STEVAR group at 5 years; P  = 0.123). Freedom from aortic reintervention was lower in the TEVAR group than in other groups (98% in TAR, 92% in TEVAR and 97% in STEVAR at 5 years, P  = 0.040). CONCLUSIONS Operative outcomes showed no significant differences between the groups except for early recovery after TEVAR. Long-term survival was similar between groups; however, TEVAR had inferior reintervention free rate.

Chronic Occlusion of an Abdominal Aortic Aneurysm

A 67-year-old woman with peripheral arterial occlusive disease in both lower extremities, secondary to an abdominal aortic aneurysm, developed chronic total occlusion of the abdominal aortic aneurysm during the 3-year follow-up period. She suffered from sudden onset of paraplegia 3 months after palliative axillobifemoral bypass grafting and died of pneumonia. The paraplegia was considered to have been caused by thrombosis of lumbar arteries that might have served as an important collateral pathway in the distal spinal cord, due to proximally propagated infrarenal aortic thrombosis. It is necessary to recognize that chronically thrombosed abdominal aortic aneurysm (AAA) still has a risk of causing serious complications with a high mortality rate, especially in cases treated medically or with palliative operations.

A case report of surgical correction for congenital mitral regurgitation with subvalvular apparatus abnormality

We report a successful complex mitral valve plasty using port access minimally invasive cardiac surgery for congenital mitral regurgitation that presented as an abnormality of the subvalvular apparatus. A 16-year-old male patient received a diagnosis of mitral regurgitation resulting from tethering of the anterior mitral leaflet and posterior mitral leaflet caused by an abnormality in papillary muscle insertion and a hypoplastic chordae tendineae. The posterior leaflet was closely tethered to the tips of the papillary muscle with essentially no chordae tendineae. The flexibility of the leaflet was restored by surgically removing the abnormal chordae, and reconstruction of chordae tendinae of the anterior leaflet was carried out using three loops and of the posterior leaflet using one loop with a loop technique method. As an additional procedure for persistent regurgitation, an edge-to-edge technique to the posterior commissure side was performed, after which the mitral regurgitation disappeared.