Masahiro Yasutake

Therapeutic angiogenesis by autologous bone marrow cell implantation for refractory chronic peripheral arterial disease using assessment of neovascularization by 99mTc-tetrofosmin (TF) perfusion scintigraphy.

We investigated efficacy and safety of implantation of autologous bone marrow mononuclear cells plus platelets, including endothelial progenitor cells (EPCs), for recovering refractory chronic peripheral arterial disease (PAD) using visual and quantitative analyses by 99mTc-tetrofosmin (TF) perfusion scintigraphy, and also investigated various quantitative assessments objectively. We performed 12 consecutive cases and 19 limbs and hands with severe chronic PAD that were almost Fontaine class IV (11/12 cases, about 92%) in this trial. This treatment was very effective in relieving severe pain of PAD, especially for Buergers disease. We used a visual analog scale (VAS) for measurement of pain level. The maximum pain level before implantation was 66.5 ± 5.0 mm, and it decreased to 12.1 ± 2.2 mm after implantation (p < 0.001). Rest pain in legs and fingers was resolved in 11 cases (11/12 cases, 92%). All patients could measure pain-free walking time on a treadmill, which improved remarkably (140 ± 53 s before implantation vs. 451 ± 74 s after implantation, p = 0.034). Resting ankle brachial pressure index (ABI) in legs implanted with bone marrow mononuclear cells was also improved (0.65 ± 0.08 before implantation vs. 0.73 ± 0.07 after implantation, p = 0.055). According to 99mTc-TF perfusion scintigraphy, the proximal area (region from knee to ankle) was 1.32 ± 0.10 before implantation versus 1.56 ± 0.11 after implantation (p = 0.007). 99mTc-TF perfusion scintigraphy in the distal area (region from ankle to end of toes, or from wrist to end of fingers) was 0.79 ± 0.06 before implantation versus 0.83 ± 0.06 after implantation (p = 0.29). Ischemic legs and hands that were injected showed increased perfusion blood flow. 99mTc-TF perfusion scintigraphy was effective to estimate visual and quantitative analysis of collateral vessels in neovascularization. We were successful with this new treatment for the most severe, chronic PAD that was not curable by any of the current treatments. Thus, this therapeutic angiogenesis could be a new strategy for saving severe ischemic limbs and hands.

Clinical significance of increased plasma concentration of macrophage colony–stimulating factor in patients with angina pectoris

OBJECTIVES To determine the effect of macrophage colony-stimulating factor (MCSF) on atherogenesis in patients with coronary artery disease (CAD), we assessed the relation between the plasma concentration of MCSF and the incidence of acute coronary events in patients with CAD. BACKGROUND Cytokines such as MCSF play a central role in inflammatory and proliferative responses in patients with acute coronary syndromes. However, the effect of MCSF on the clinical course in patients with CAD is still not known. METHODS We measured the plasma MCSF concentration in 142 patients with documented CAD (62 +/- 9 years) and followed up for a mean period of 14 +/- 6 months. The study included 97 patients with stable angina (SA), 45 patients with unstable angina (UA) and 22 age-matched control subjects. The predictors of coronary events were analyzed by using a Cox proportional hazards model. RESULTS The mean plasma MCSF concentration in patients with UA was significantly higher than that in patients with SA and in control subjects (981 +/- 277 vs. 693 +/- 223 vs. 680 +/- 158 pg/ml, p < 0.001). The mean plasma MCSF concentration in the 20 patients with coronary events was significantly higher than that in patients without coronary events (1,192 +/- 232 vs. 690 +/- 213 pg/ml, p < 0.001). The predictors of unfavorable outcome were an increased MCSF concentration, the presence of CAD and a low ejection fraction. CONCLUSIONS These findings suggest that an increased circulating MCSF concentration reflects atherosclerotic progression in patients with CAD and predicts future cardiac events.

Controlled-Release Basic Fibroblast Growth Factor for Peripheral Artery Disease: Comparison with Autologous Bone Marrow-Derived Stem Cell Transfer

OBJECTIVE We examined the safety and efficacy of controlled-release basic fibroblast growth factor (b-FGF) for peripheral artery disease (PAD), compared with autologous bone marrow mononuclear cell implantation (BMCI). BACKGROUND We recently developed a b-FGF-incorporated biodegradable hydrogel that enables slow-releasing drug delivery system. METHODS PAD patients were divided into a b-FGF group (n=10) and BMCI group (n=15). Injection of gelatin hydrogel containing 600 μg b-FGF or BMCI (0.4-5.1×10(10) cell) was performed. Visual analog pain scale (VAS), (99m)technetium-tetrofosmin (Tc-TF) scintigraphy, transcutaneous oxygen tension (TcPO(2)), and ankle-brachial index (ABI) were evaluated before and 4 weeks after each treatment, and 2-year prognosis was determined. RESULTS VAS (b-FGF 67±15 to 4±5, p<0.01, BMCI 67±42 to 5±9 mm, p<0.01) and TcPO(2) (b-FGF 16±14 to 47±17, p<0.01, BMCI 13±13 to 37±21 mmHg, p<0.01) were significantly improved in both groups. Tc-TF and ABI were not changed. Prognosis was similar between the groups (b-FGF 91%, BMCI 80%, NS). CONCLUSION Controlled-release b-FGF is as safe as BMCI, and its efficacy appears to be comparable. Thus, this therapy may be an alternative to BMCI.

SNPs on chromosome 5p15.3 associated with myocardial infarction in Japanese population

Myocardial infarction (MI) occurs as the result of complex interactions of multiple genetic and environmental factors. By conducting a genome wide association study in a Japanese population using 210 785 single nucleotide polymorphism (SNP) markers, we identified a novel susceptible locus for MI on chromosome 5p15.3. An SNP (rs11748327) in this locus showed significant association in several independent cohorts (combined P=5.3 × 10−13, odds ratio=0.80, comparison of allele frequency). Association study using tag SNPs in the same linkage disequilibrium block revealed that two additional SNPs (rs490556 and rs521660) conferred risk of MI. These findings indicate that the SNPs on chromosome 5p15.3 are novel protective genetic factors against MI.

Effects of long-term treatment for obstructive sleep apnea on pulse wave velocity.

Continuous positive airway pressure (CPAP) treatment improves endothelial function and sympathetic activity in patients with obstructive sleep apnea (OSA). However, the long-term effects of CPAP on pulse wave velocity (PWV), which reflects arterial stiffness that is associated with cardiovascular events, have not been evaluated in OSA patients with or without hypertension (HT). In this study, 212 male OSA patients who had been receiving CPAP treatment for 2 years and were divided into two groups, those with HT (n=114) and those without (n=98), were studied. In both HT and normotensive (NT) patients, PWV decreased significantly over the first 6 months of treatment (P=0.005 and 0.010, respectively), before increasing gradually from 6 to 24 months. Body mass index (BMI), body weight, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels decreased significantly in the HT group over the 2 years of CPAP treatment (P<0.001 for all). In contrast, only HR decreased significantly in the NT group over the 2 years of treatment (P<0.001). Multivariate regression analysis revealed that age (P=0.008), decreases in DBP (P<0.001) and HR (P<0.001) and higher initial levels of serum high-density lipoprotein–cholesterol (P=0.040) were independent factors related to changes in PWV over the 2 years of CPAP treatment in all patients. In conclusion, we found a significant decrease in PWV in both NT and HT patients after 6 months of CPAP treatment. In HT patients, long-term CPAP treatment significantly decreases blood pressure, which may contribute to explain the PWV improvement.

Elevated peripheral blood mononuclear cell count is an independent predictor of left ventricular remodeling in patients with acute myocardial infarction

OBJECTIVES Peripheral blood mononuclear cells (PBMCs) increase after acute myocardial infarction (AMI) and infiltrate to the infarct region. However, its impact on left ventricular (LV) remodeling remains unclear. The purpose of the present study was to clarify whether elevated PBMC count contributed to LV remodeling in patients with AMI. SUBJECTS AND METHODS A total of 131 patients with AMI were recruited. White blood cell (WBC), monocyte, and lymphocyte counts were measured at presentation and every 24h for five days after presentation. The correlation between PBMC count and LV remodeling was evaluated. LV remodeling was defined as an increase of LV end-diastolic volume index ≥ 10% at the 6-month follow-up left ventriculography. RESULTS Forty-eight patients had LV remodeling. Peak WBC (p=0.008), peak monocyte (p=0.001), and peak PBMC (p<0.001) counts were significantly greater in patients with LV remodeling than those without remodeling. Multivariate analysis revealed the peak PBMC count ≥ 3600/mm(3) was an independent predictor of LV remodeling [relative risk (RR) 3.243, p=0.011]. CONCLUSION Increased PBMC count is significantly correlated with LV remodeling, thus suggesting that PBMCs play a pivotal role for the development of LV remodeling after AMI.

Optical coherence tomography after new scoring balloon angioplasty for in-stent restenosis and de novo coronary lesions.

The AngioSculpt scoring balloon catheter (AngioScore, Inc., Fremont, California) has recently been developed for percutaneous intervention in coronary and peripheral arteries. This device is composed of two major components, a minimally compliant balloon and three nitinol wore. The three wires encapsulate the low-compliant balloon in a spiral configuration. The concept is for the spiral wires to score the lumen surface during balloon expansion. However, the precise mechanisms and efficacy of this scoring technology in humans had not yet to be determined. In this case, both a de novo coronary lesion and an in-stent restenosis lesion were treated with the scoring balloon and were subsequently observed via optical coherence tomography (OCT) with high-resolution images ( approximately 15 microm). OCT clearly demonstrated the effects of this device on plaque and neointimal hyperplasia scoring, as well as its ability to achieve sufficient lumen sizes after coronary artery dilatation.

Therapeutic Angiogenesis by Controlled-Release Fibroblast Growth Factor in a Patient With Churg-Strauss Syndrome Complicated by an Intractable Ischemic Leg Ulcer

Churg-Strauss syndrome (CSS) causes necrotizing vasculitis affecting small- to medium-sized arteries, mainly in the lungs, gastrointestinal system, heart, kidneys, and skin. Skin lesions sometimes ulcerate because of severe ischemia and become intractable when complicated by bacterial infection. We report a rare case of CSS, characterized by a nonhealing ischemic skin ulcer of the right calf with bacterial infection resistant to antibiotics. After sterile maggot debridement therapy, 2 skin autografts failed. Subsequently, a slow-release formula of basic fibroblast growth factor incorporated in biodegradable gelatin hydrogel was administered into the calf muscles to induce vascular regeneration. The ulcer eventually healed with no recurrence. This report describes the use of controlled-release basic fibroblast growth factor for an ischemic leg ulcer in a patient with CSS, suggesting a possible therapeutic role of this novel neovascularization therapy in treating severe skin lesions complicating autoimmune vasculitis syndromes.

Usefulness of rosuvastatin to prevent periprocedural myocardial injury in patients undergoing elective coronary intervention.

The aim of the present study was to investigate whether percutaneous coronary intervention-related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention-related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins.

A new strategy for the reduction of acute myocardial infarction in variant angina

To study the effects of stepwise early treatment in variant angina pectoris, frequencies of cardiac events and complications were examined after three different types of treatment. The subjects of the study consisted of 159 consecutive patients with variant angina pectoris, who were in need of hospitalization. The three treatment modalities were the introduction of calcium antagonists, nicorandil and nitroglycerin infusion, and percutaneous transluminal coronary angioplasty (PTCA), respectively. The cardiac event rate for this series of patients was 16% (25 of 159). The cumulative cardiac event rate was 22% at 1 year and 23% at 3 years in the first treatment period; 11% at the same intervals in the second treatment period; and 6% at the same intervals in the third treatment period. Our results suggest that it is important in the treatment of variant angina pectoris not only to prevent anginal attacks by the use of fast-acting coronary vasodilators, but also to initiate early revascularization.