Yuji Ikari

Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease

Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD). Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94±0.34, 1.04±0.38, 1.19±0.38, and 1.44±0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0]. Conclusions—Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.

Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment

OBJECTIVES The goal of this study was to evaluate the cellular and extracellular composition of human coronary arterial in-stent restenosis after various periods of time following stent deployment. BACKGROUND Neointimal in-growth rather than stent recoil is thought to be important for coronary arterial in-stent restenosis. There is only limited data on the cellular and extracellular composition changes with time after stent deployment. METHODS We analyzed 29 coronary arterial in-stent restenotic tissue samples (14 left anterior descending coronary artery, 10 right coronary artery, and 5 left circumflex artery) retrieved by using directional coronary atherectomy from 25 patients at 0.5 to 23 (mean, 5.7) months after deployment of Palmaz-Schatz stents employing histochemical and immunocytochemical techniques. RESULTS Cell proliferation was low (0% to 4%). Myxoid tissue containing extracellular matrix (ECM) enriched with proteoglycans was found in 69% of cases and decreased over time after stenting. Cell-depleted areas were found in 57% of cases and increased with time after stenting. Versican, biglycan, perlecan, and hyaluronan were present with varying individual distributions in all samples. Positive transforming growth factor-beta1 staining was found in 80% of cases. Immunostaining with alpha-smooth muscle actin identified the majority of cells as smooth muscle cells with occasional macrophages present (< or =12 cells per section). CONCLUSIONS These data suggest that enhanced ECM accumulation rather than cell proliferation contribute to later stages of in-stent restenosis. Balloon angioplasty of in-stent restenosis may, therefore, fail due to ECM changes during: 1) additional stent expansion, 2) tissue extrusion out of the stent, or 3) tissue compression.

Vascular calcification in chronic kidney disease.

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as α-actin and SM-22α, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, putative calcification inhibitory molecules have been identified using mouse mutational analyses, including MGP, β-glucosidase, fetuin-A, and osteoprotegerin. Mutant mice deficient in these molecules present with enhanced cardiovascular calcification, demonstrating that specific molecules are normally important in suppressing vascular calcification. These findings suggest that the balance of inducers, such as phosphate, and inhibitors, such as MGP, fetuin-A, and others, are likely to control whether or not calcification occurs under pathological conditions.

Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

Matrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hyper-tension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 +/- 20.3, 104.9 +/- 19.2, 95.2 +/- 15.2 and 82.2 +/- 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.

Upfront thrombus aspiration in primary coronary intervention for patients with ST-segment elevation acute myocardial infarction: report of the VAMPIRE (VAcuuM asPIration thrombus REmoval) trial.

OBJECTIVES This study evaluated safety and efficacy of upfront thrombus aspiration during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Distal embolization during primary PCI results in reduced myocardial perfusion and poor clinical outcomes. METHODS The VAMPIRE (VAcuuM asPIration thrombus REmoval) study was a prospective, randomized, controlled multicenter trial conducted in 23 institutions. Patients (N = 355) presenting within 24 h of STEMI symptoms onset were randomized to primary PCI with (n = 180) or without (n = 175) upfront thrombus aspiration using Nipros TransVascular Aspiration Catheter (Osaka, Japan). RESULTS The TransVascular Aspiration Catheter reached the lesion in 100% of cases. It successfully crossed the target obstruction in 86% without any delay in procedure time or time to reperfusion; whereas macroscopic thrombi were removed in 75% of the cases. Procedure success was similar between groups (98.9% vs. 98.3%). There was a trend toward lower incidence of slow or no reflow (primary end point-defined as a Thrombolysis In Myocardial Infarction flow grade <3) in patients treated with aspiration versus conventional primary PCI (12.4% vs. 19.4%, p = 0.07). Rate of myocardial blush grade 3 was higher in the aspiration group (46.0% vs. 20.5%, p < 0.001). Aspiration was most effective in patients presenting after 6 h of symptoms onset (slow flow rate: 8.1% vs. 37.6%, p = 0.01). CONCLUSIONS This study suggested the safety of primary PCI with upfront thrombectomy using a novel device in patients with STEMI. The study showed a trend toward improved myocardial perfusion and lower clinical events in patients treated with aspiration. Patients presenting late after STEMI appear to benefit the most from thrombectomy.

Effects of competitive blood flow on arterial graft patency and diameter: Medium-term postoperative follow-up

To identify predictors of arterial graft patency, we followed up 30 internal thoracic arterial grafts and 23 right gastroepiploic arterial grafts in situ with patency documented during postoperative angiography. After 24 months of follow-up on average, repeat angiography detected that one internal thoracic artery and two gastroepiploic arteries were anatomically occluded and that the other three gastroepiploic arteries were nonfunctioning. The logistic regression model identified a relationship between graft patency and competitive flow, which was detected as stenosis in the recipient coronary arteries (coefficients, p < 0.05; model, Hosmer-Lemeshow chi2 statistic 3.59, p = 0.89). The linear regression model demonstrated that changes in graft luminal diameter correlated with competitive flow (p < 0.01), smoking history (p < 0.05), and type of arterial grafts (p < 0.001) (R2 = 0.40, adjusted R2 = 0.36). The findings suggest a temporal relationship between competitive flow and prognosis of arterial graft.

Prevalence of Carotid Artery Stenosis in Patients With Coronary Artery Disease in Japanese Population

Background and Purpose— Prevalence of carotid artery stenosis in patients with coronary artery disease (CAD) is unknown in Japanese population. Methods— The study populations consisted of 632 consecutive patients who underwent coronary angiography because of suspicion of CAD. All patients underwent carotid ultrasonography to screen carotid artery stenosis before coronary angiography. We defined echographic carotid stenosis as area stenosis of >50% or peak systolic velocity of >200 cm/s. Results— Echographic carotid stenosis was observed in 124 patients (19.6%). Coronary angiography revealed 433 patients had CAD. Prevalence of echographic carotid artery stenosis was 14 of 199 (7.0%), 18 of 124 (14.5%), 28 of 131 (21.4%), and 64 of 178 (36.0%) in patients with 0-, 1-, 2-, and 3-vessel CAD, respectively (P<0.0001). The prevalence rate with carotid stenosis and CAD was 25.4%. Multivariate stepwise logistic regression analysis showed that age and the extent of CAD were independently related to the presence of carotid stenosis (P=0.0002 and <0.0001, respectively). Conclusions— Prevalence of carotid stenosis in patients with CAD is high in Japan as well as in Western countries. Screening of carotid artery stenosis is recommended especially in older patients with multivessel CAD.

Luminal loss and site of restenosis after Palmaz-Schatz coronary stent implantation

Restenosis has frequently been observed at the articulation of the Palmaz-Schatz stent. However, the precise mechanism for this remains poorly understood. We measured the luminal diameter in 5 segments within the stent in 67 lesions of 63 patients with successful stenting. Luminal diameter at all 5 sites was significantly reduced 6 months after stent implantation (3.2 +/- 0.5 vs 2.4 +/- 0.7 mm, p < 0.05). Angiographic restenosis rate was 18%. Restenosis involving the articulation was found in 75% of the lesions, and that involving the articulation or edges in 83%. The diameter at the articulation was significantly smaller both immediately (3.0 +/- 0.5 mm vs 3.3 +/- 0.5 mm, p < 0.05) and 6 months after (2.1 +/- 0.8 mm vs 2.5 +/- 0.7 mm, p < 0.05) stenting than the diameter of other stent segments. The loss index was significantly greater at the proximal and distal edges than at the bodies of the stent (0.98 vs 0.60, p < 0.05). The edges of the Palmaz-Schatz stent tend to dilate more than the body of the stent during normal inflation. Although this anchoring system protects against dislodgment or migration of the stent, it may cause more injury. The articulation has 2 anchoring edges within only a 1 mm diameter. Thus, restenosis at the articulation may be ascribed to residual stenosis, increased intimal proliferation due to more severe injury, and delayed late vessel remodeling from lack of mechanical support. These characteristics may be attributed to stent design, and design improvement of the articulation may lead to more favorable results after stent implantation.

A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drug-eluting stent restenosis

BACKGROUND The aim of this study was to investigate the efficacy and safety of paclitaxel-coated balloon (PCB) for the treatment of the bare-metal stent restenosis (BMS-ISR) and drug-eluting stent restenosis (DES-ISR). METHODS This study was a prospective, multicenter, randomized (2:1) trial conducted in 208 patients with 213 in-stent restenosis lesions (BMS-ISR: 123 lesions, DES-ISR: 90 lesions) at 13 centers in Japan. Patients were randomly assigned to a PCB group (137 patients with 142 lesions) or a conventional balloon angioplasty (BA) group (71 patients with 71 lesions). The primary end point was target vessel failure at 6-month follow-up. RESULTS Clinical and angiographic follow-up 6 months after intervention was performed in 207 patients (99.5%) with 208 lesions (97.7%). Target vessel failure was noted in 6.6% of the PCB group and 31.0% of the BA group (P < .001). Recurrent restenosis occurred in 4.3% of the PCB group and 31.9% of the BA group (P < .001). Late lumen loss was lower in the PCB group than in the BA group (0.11 ± 0.33 mm vs 0.49 ± 0.50 mm, P < .001). In PCB-treated lesions, recurrent restenosis occurred in 1.1% of patients with BMS-ISR and in 9.1% of patients with DES-ISR (P = .04). Late lumen loss was lower in patients with BMS-ISR than in patients with DES-ISR (0.05 ± 0.28 mm vs 0.18 ± 0.38 mm, P = .03). CONCLUSIONS This randomized clinical study suggested that PCB provided much better clinical and angiographic outcomes than did conventional BA in patients with BMS-ISR and DES-ISR. Drug-eluting stent restenosis was associated with poorer outcomes compared with BMS-ISR after treatment with PCB.

Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of α-galactosidase A

A new variant form of Fabry disease with hypertrophic cardiomyopathy of late onset is reported. Two unrelated male hemizygotes of this disease first presented with signs and symptoms of cardiomyopathy after 50 years of age. Cultured lymphoblastoid cells showed significantly higher residual αgalactosidase A activities than in the patients with classical phenotypic expressions.