Prognostic impact of pulse pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction.

Data regarding relationship between pulse pressure (PP) at admission and in-hospital outcome in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are still lacking. A total of 1413 primary PCI-treated AMI patients were classified into quintiles based on admission PP (<40, n = 280; 40-48, n = 276; 49-57, n = 288; 58-70, n = 288; and ≥71 mmHg, n = 281). The patients with PP < 40 mmHg tended to have higher prevalence of male, smoking, and Killip class ≥3 at admission; right coronary artery, left main trunk (LMT), or multivessels as culprit lesions; larger number of diseased vessels; lower Thrombolysis in Myocardial Infarction (TIMI) grade in the infarct-related artery before/after primary PCI; and higher value of peak creatine phosphokinase concentration. Patients with PP < 40 mmHg had highest mortality, while patients with PP 49-57 mmHg had the lowest: 11.8 % (<40), 7.2 % (40-48), 2.8 % (49-57), 5.9 % (58-70), and 6.0 % (≥71 mmHg). On multivariate analysis, Killip class ≥3 at admission, LMT or multivessels as culprit lesions, chronic kidney disease, and age were the independent positive predictors of the in-hospital mortality, whereas admission PP 49-57 mmHg, hypercholesterolemia, and TIMI 3 flow before/after PCI were the negative ones, but admission PP < 40 mmHg was not. These results suggest that admission PP 49-57 mmHg might be correlated with better in-hospital prognosis in Japanese AMI patients undergoing primary PCI.

Zilver stent implantation through 4.5 French guiding sheath in iliac vein compression syndrome complicated with acute deep vein thrombosis.

BACKGROUND: Downsized devices for less invasive endovascular treatment are gaining more attention. CASE REPORT: An 82-year-old woman was admitted to our hospital with pain and swelling in left lower extremity. Ultrasonography showed much thrombus at the left common femoral, superficial femoral, and popliteal veins, confirming a diagnosis of acute deep vein thrombosis (DVT). For lack of therapeutic effect of systemically administered anticoagulative and thrombolytic agents, we performed catheter intervention against DVT. After insertion of a 4.5 French guiding sheath (Parent Plus, Medikit, Tokyo, Japan) into left popliteal vein, venography showed a total occlusion of the common femoral vein. Even after thrombectomy by aspiration catheter, balloon dilation, and catheter-induced thrombolysis, severe stenosis at the proximal site of the left common iliac vein remained. After confirming the presence of iliac vein compression syndrome (IVCS) by intravascular ultrasound imaging, we successfully implanted a Zilver® stent (Cook Inc., Bloomington, IN, USA) in the common-external iliac vein through a 4.5 French guiding sheath, leading to an optimal venous-return flow. CONCLUSIONS: The present case suggests that in addition to thrombus aspiration, Zilver stent implantation using a 4.5 French guiding sheath has the potential to serve as a minimally invasive strategy for the treatment of IVCS complicated with iliofemoral DVT..

WITHDRAWN: Cardio-cerebrovascular protective effects of valsartan in high-risk hypertensive patients with overweight/obesity: A post-hoc analysis of the KYOTO HEART Study.

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Prognostic impact of systolic blood pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: Data regarding the relationship between systolic blood pressure (SBP) at admission and in-hospital outcome in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are still lacking in Japan. METHODS AND RESULTS: A total of 1475 primary PCI-treated AMI patients were classified into quintiles based on admission SBP (<105 mmHg, n=300; 105-125 mmHg, n=294; 126-140 mmHg, n=306; 141-158 mmHg, n=286; and ≥159 mmHg n=289). The patients with SBP<105 mmHg tended to have higher age, previous myocardial infarction, chronic kidney disease (CKD), Killip class≥3 at admission, right coronary artery, left main trunk (LMT), or multivessels as culprit lesions, larger number of diseased vessels, lower Thrombolysis In Myocardial Infarction (TIMI) grade in the infarct-related artery before primary PCI, and higher value of peak creatine phosphokinase concentration. Patients with SBP<105 mmHg had a significantly higher mortality, while mortality was not significantly different among the other quintiles: 24.3% (<105 mmHg), 4.8% (105-125 mmHg), 4.9% (126-140 mmHg), 2.8% (141-158 mmHg), and 5.2% (≥159 mmHg) (p<0.001). On multivariate analysis, Killip class≥3 at admission, LMT or multivessels as culprit lesions, admission SBP<105 mmHg, CKD, and age were the independent positive predictors of in-hospital mortality, whereas admission SBP 141-158 mmHg and TIMI 3 flow after PCI were the negative ones, but admission SBP 105-125 mmHg, admission SBP 126-140 mmHg, and admission SBP≥159 mmHg were not. CONCLUSIONS: These results suggest that admission SBP 141-158 mmHg might be correlated with better in-hospital prognosis, whereas admission SBP<105 mmHg was associated with in-hospital death in Japanese AMI patients undergoing primary PCI.

Primary percutaneous coronary intervention and intravascular ultrasound imaging for coronary thrombosis after cisplatin-based chemotherapy.

Although cisplatin is indispensable for the chemotherapy treatment of many malignancies, cisplatin-associated thrombosis is attracting increasing attention. However, experience of primary percutaneous coronary intervention (PCI) and intravascular ultrasound imaging (IVUS) for coronary thrombosis, possibly due to cisplatin-based chemotherapy, has been limited. Case 1 with postoperative gastric cancer developed acute myocardial infarction (AMI) on the sixth day of the second chemotherapy course with conventional doses of cisplatin and tegafur gimeracil oteracil potassium. Emergency coronary angiography (CAG) showed a filling defect in the proximal left anterior descending coronary artery (LAD) concomitant with no reflow in the distal LAD. Case 2 with advanced lung cancer and brain metastasis suffered AMI on the fifth day of the first chemotherapy course with conventional doses of cisplatin and gemcitabine. Emergency CAG delineated a total occlusion in the proximal right coronary artery. In both cases, thrombectomy using aspiration catheter alone obtained optimal angiographic results and subsequent IVUS revealed no definite atherosclerotic plaque, while slow flow still remained even after selective intra-coronary infusion of vasodilator in the case 1. These cases suggest that primary PCI using thrombus-aspiration catheter might be safe and effective for coronary thrombosis due to cisplatin-based chemotherapy.

Systolic blood pressure at admission, clinical manifestations, and in-hospital outcomes in patients with acute myocardial infarction.

BACKGROUND: Several clinical studies have demonstrated an inverse relationship between systolic blood pressure (SBP) at admission and in-hospital mortality in patients hospitalized for acute myocardial infarction (AMI). However, data on the relation between admission SBP and in-hospital prognosis in AMI patients are still lacking in Japan. METHODS AND RESULTS: A total of 1211 AMI patients were classified into quintiles based on SBP at hospital admission (<106 mmHg, n = 241; 106-125 mmHg, n = 239; 126-140 mmHg, n = 244; 141-159 mmHg, n = 238; and ≥ 160 mmHg, n = 249). The patients with SBP < 106 mmHg tended to have higher age, Killip class ≥ 3 at admission, right coronary artery, left main trunk, or multivessels as culprit lesions, larger number of diseased vessels, lower Thrombolysis In Myocardial Infarction grade in the infarct-related artery before primary percutaneous coronary intervention (PCI), and higher value of peak creatine phosphokinase concentration. Patients with SBP <106 mmHg had a significantly higher mortality, while mortality was not significantly different among the other quintiles: 25.7% (<106 mmHg), 5.4% (106-125 mmHg), 5.7% (126-140 mmHg), 2.5% (141-159 mmHg), and 5.6% (≥ 160 mmHg) (p<0.001). On multivariate analysis, Killip class ≥ 3 at admission, admission SBP <106 mmHg, and age were the independent positive predictors of in-hospital mortality, whereas admission SBP 141-159 mmHg and primary PCI were the negative ones, but admission SBP 106-125 mmHg, admission SBP 126-140 mmHg, and admission SBP ≥ 160 mmHg were not. CONCLUSIONS: These results suggest that admission SBP 141-159 mmHg might be correlated with better in-hospital prognosis, whereas admission SBP <106 mmHg was associated with in-hospital death in Japanese patients hospitalized for AMI.

Long-term angiographic outcomes of post-sirolimus-eluting stent restenosis in Japanese patients.

Though restenosis after drug-eluting stent implantation is still observed, the factors affecting post-sirolimus-eluting stent restenosis (re-restenosis) have not been fully determined. We evaluated the long-term angiographic outcomes and examined background factors affecting re-restenosis. We enrolled 51 patients with 68 sirolimus-eluting stent (SES) restenosis lesions who underwent target lesion revascularization (TLR) and angiographic follow-up studies. Re-restenosis was observed in 29 of 68 restenosis lesions, and the rate was 42.6%. Study subjects were divided into two groups: a re-restenosis (Re-R) group (20 patients) with 29 lesions and a restenosis (R) group (31 patients) with 39 lesions with no re-restenosis. There were no differences in age, sex, coronary risk factors, past history, or medications between the two groups. Re-restenosis was observed more frequently in the right coronary artery (Re-R group vs. R group; 65.5 vs. 33.3%, P = 0.009). The incidence of stent fracture was higher in the Re-R group (Re-R group vs. R group; 48.3 vs. 12.8%, P = 0.003). QCA results showed that the initial lesion length at the time of first coronary intervention was significantly longer in the Re-R group (Re-R group vs. R group; 21.6 ± 3.37 vs. 12.6 ± 4.98 mm, P = 0.049). The rate of re-restenosis was 47.1% when treated with POBA alone, while it was 36.7% with SES treatment. In multivariate analysis, the initial lesion length at the time of first coronary intervention (odds ratio = 1.64, 95% CI 1.29-2.06, P < 0.001) and stent fracture (odds ratio = 12.42, 95% CI 1.89-81.4, P = 0.009) were independent predictors of re-restenosis. This study demonstrates that recurrent restenosis with SES treatment is associated with lesion length and stent fracture, a finding that is beneficial in the management of restenosis after SES implantation.

Erythropoietin in patients with acute coronary syndrome and its cardioprotective action after percutaneous coronary intervention.

BACKGROUND: Erythropoietin (EPO) has been shown to have effects beyond hematopoiesis, such as prevention of cardiac apoptosis. The purpose of the current study is to examine the influence of the time-course change in the serum concentration of endogenous EPO on cardiac functions in the chronic phase in patients with acute coronary syndrome, who successfully achieved reperfusion by primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: The prospective study included 34 patients with angiographically documented coronary artery disease, including 24 patients with acute myocardial infarction (AMI) and 10 patients with unstable angina pectoris (UAP) who underwent successful PCI within 24 h from the onset. Serum EPO concentration significantly increased at Day 3 and Day 7 compared with that at Day 1 in the AMI group, and the level at Day 3 was significantly higher in the AMI group than in the UAP group. There were significant correlations between DeltaEPO and Delta left ventricular ejection fraction (LVEF) or Delta left ventricular end-diastolic volume index and between peak EPO concentration and DeltaLVEF. CONCLUSIONS: These data showed the time-dependent increase of serum EPO in AMI patients after primary PCI, indicating its possible contribution to cardioprotective effect in the chronic phase.

HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis.

BACKGROUND: The klotho gene and its protein product are mainly expressed in the kidney. The klotho protein induces suppression of multiple aging-related phenotypes, and homozygous klotho gene mutant mice display various senescent morbidity. Chronic inhibition of nitric oxide synthase (NOS) induces arteriosclerosis, while HMG-CoA reductase inhibitors (statins) have pleiotropic vascular protective effects besides cholesterol lowering. Therefore, the present studies were performed to determine whether chronic NOS blockade would affect anti-ageing klotho protein expression. In addition, the effects of statins on klotho protein expression and arteriosclerosis in these rats were investigated. METHODS: Forty-two rats were divided into 6 groups as follows: (1) control, (2) NOS blockade, (3) atorvastatin (10 mg/kg/day), (4) pitavastatin (3 mg/kg/day), (5) NOS blockade+atorvastatin, (6) NOS blockade+pitavastatin. To induce arteriosclerosis further, a cuff was placed around the left femoral artery in each rat. After 4 weeks observation, rats were killed and renal klotho expression and the level of arteriosclerosis were examined. RESULTS: The rats of chronic NOS inhibition developed hypertension, while statin treatment did not affect blood pressure in the rats with or without NOS blockade. Despite statin treatment, plasma levels of lipids did not differ among 6 groups. Immunohistochemical staining revealed that klotho protein was localized in the renal tubules. Chronic NOS inhibition markedly reduced renal klotho protein expression, while treatment with atorvastatin or pitavastatin completely prevented the reduction of klotho expression induced by NOS inhibition. In addition, statin treatment significantly improved arteriosclerotic lesions induced by NOS inhibition and cuff placement. CONCLUSION: Since statin treatment did not alter blood pressure or serum lipid profiles, a novel vascular protective effect of statins via enhancing anti-aging klotho protein expression is suggested.

Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction.

BACKGROUND: Transplantation of non-expanded peripheral blood mononuclear cells (PBMNCs) enhances neovessel formation in ischemic myocardium and limbs by releasing angiogenic factors. This study was designed to examine whether intracoronary transplantation of PBMNCs improves cardiac function after acute myocardial infarction (AMI). METHODS AND RESULTS: After successful percutaneous coronary intervention (PCI) for a ST-elevation AMI with occlusion of proximal left anterior descending coronary artery within 24 h, patients received an intracoronary infusion of PBMNCs within 5 days after PCI (PBMNC group). PBMNCs were obtained from patients by COBE spectra-apheresis and concentrated to 10 ml, 3.3 ml of which was infused via over-the-wire catheter. The global left ventricular ejection fraction (LVEF) change from baseline to 6 months followup in th ePBMNC group that underwent standard PCI for similar AMI [corrected]. The primary endpoint was the global left ventricular ejection fraction (LVEF) change from baseline to 6 months' follow-up. The data showed that the absolute increase in LVEF was 7.4% in the control group and 13.4% (p=0.037 vs control) in the PBMNC group. Cell therapy resulted in a greater tendency of DeltaRegional ejection fraction (EF) or significant improvement in the wall motion score index and Tc-99m-tetrofosmin perfusion defect score associated with the infarct area, compared with controls. Moreover, intracoronary administration of PBMNCs did not exacerbate either left ventricular (LV) end-diastolic and end-systolic volume expansion or high-risk arrhythmia, without any adverse clinical events. CONCLUSION: Intracoronary infusion of non-expanded PBMNCs promotes improvement of LV systolic function. This less invasive and more feasible approach to collecting endothelial progenitor cells may provide a novel therapeutic option for improving cardiac function after AMI.

[Coronary artery plaque assessment using Volcano Therapeutics' Virtual Histology intravascular ultrasound and temperature guide wire].

OBJECTIVES: This study investigated the tissue characterization of human coronary artery plaque using Virtual Histology intravascular ultrasound (VH-IVUS) and temperature guide wire. METHODS AND RESULTS: Between August 2005 and December 2005, VH-IVUS examination and guide wire based measurement of coronary temperature were performed in 66 patients: 39 with stable angina pectoris (SAP), and 27 with unstable angina pectoris(UAP). Patients in the acute myocardial infarction with necrotic tissue and thrombus were excluded. After measurement of distal coronary pressure and coronary temperature, the following tissue types of atherosclerotic plaque were evaluated by VH-IVUS: fibrotic, fibro-fatty, dense calcium and necrotic core. Occurrence of fibro-fatty tissue was significantly higher in UAP patients than in SAP patients (17.4 +/- 7.0% vs 11.2 +/- 5.2%, p = 0.04), and coronary temperature was significantly higher in UAP patients than in SAP patients (0.08 +/- 0.05 vs 0.03 +/- 0.02 degrees C, p = 0.01). CONCLUSIONS: These results suggest that the combination of VH-IVUS analysis and measurement of coronary temperature may be able to predict the progression of lesions.

[Clinical usefulness of 201Tl/99mTc-PYP dual myocardial quantitative gated SPECT program using low-dose dobutamine loading in assessment of myocardial viability in patient with acute myocardial infarction--a case report].

An 86-year-old man with chest pain was admitted to our hospital. Coronary angiography revealed 99% stenosis of the mid segment of the left anterior descending coronary artery, therefore, a coronary stent was implanted. Immediately after the stent implantation, 99% stenosis occurred at the proximal site of the 1st diagonal artery because of stent jeal. On the 4th hospital day, ECG-gated 201TL/99mTc-PYP dual myocardial quantitative gated SPECT was performed at rest and during low-dose dobutamine loading. The 201Tl scintigraphy revealed moderately reduced uptake in the anterior, septal and apical walls, and 99mTc-PYP uptake was observed in the mid-anterior wall. A three-dimensional surface display of gated 201Tl SPECT images showed severe hypokinesis in the anterior, septal and apical walls at rest. On the other hand, during low-dose dobutamine loading, improved wall motion was observed in the basal anterior and septal walls, while no change was observed in the midanterior and apical wall movements. Three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images revealed similar patterns of wall motion as those of gated 201Tl SPECT images at rest. During low-dose dobutamine loading, on the other hand, a three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images revealed improved wall motion in the basal anterior, septal and apical walls, but worsened wall motion of the mid-anterior wall. After 6 months, a follow-up coronary angiography revealed no re-stenosis of the stent, but 99% stenosis at the proximal aspect of the 1st diagonal artery. Left ventriculography revealed improved wall motion in the apex and akinesis of the mid-anterior wall. These wall motion findings were similar to those visualized in the three-dimensional surface display of gated 201Tl/99mTc-PYP dual SPECT images during low-dose dobutamine loading in the acute phase. These results suggest that 201Tl/99mTc-PYP dual myocardial quantitative gated SPECT using low-dose dobutamine loading could be useful for the assessment of myocardial viability after reperfusion therapy in patients with acute myocardial infarction.

[A case of takotsubo cardiomyopathy provoked by taking a new quinolone antibiotic drug and a non-steroidal anti-inflammatory drug].

A 97-year-old woman was provoked a convulsion after taking a new quinolone antibiotic drug Levofloxacin and a non-steroidal anti-inflammatory drug Loxoprofen. At a later time, she was suffered from severe chest pain. An electrocardiogram showed ST segment elevation in leads II, III and aVF, and T-wave inversion in leads V1 to V4. Coronary angiography demonstrated no organic stenosis, however biventriculography revealed apical ballooning akinesis and basal hyperkinesis. Positron emission tomography was also performed to assess the uptake of 18F-fluorodeoxyglucose (FDG) after 75 g oral glucose loading for evaluating myocardial glucose metabolism at 10th day. Severely reduced uptake of FDG was observed in the apical ballooning region. Left ventriculography showed normal wall motion at 19th day. Thallium-201 myocardial single-photon emission computed tomography (SPECT) to determine the status of myocardial perfusion at the 20th hospital day showed normal perfusion. Iodine-123-beta-methyl-p-iodophenyl penta-decanoic acid myocardial SPECT to evaluate myocardial fatty acid metabolism at the 23rd day revealed severely reduced uptake in the apical ballooning region. These findings suggested that the coronary microcirculation was impaired in the apical ballooning region.

[Clinical usefulness of 1231I-BMIPP myocardial SPECT in patient with microvascular spasm: a case report].

This patient was a 64-year-old man with chest pain at rest. An electrocardiogram showed depression of the ST segment in V2-V5 leads during chest pain. 123I-BMIPP myocardial SPECT revealed reduced uptake in the apex. Coronary angiographies revealed severely delayed filling of contrast medium without narrowing of epicardial coronary arteries. An intracoronary infusion of isosorbide dinitrate did not improve the delayed filling of contrast medium or the ST segment depression. After an intracoronary infusion of nicorandil, coronary arterial flows were remarkably improved, chest symptoms disappeared, and electrocardiographic findings were improved. Left ventriculography showed severe hypokinesis in the apex. After the medication with nicorandil, reduced 123I-BMIPP myocardial uptake and reduced wall motion on echocardiography were improved. These findings suggest that myocardial ischemia in this case might be explained as having been caused by microcirculation disturbance.

[Assessment of microcirculation disturbance in patients with coronary ectasia by ATP-loading 99mTc-tetrofosmin myocardial SPECT].

UNLABELLED: Patients with coronary ectasia often develop chest pain and reveal ischemic changes on electrocardiograms and reduced left ventricular wall motion on left ventriculography, in the absence of epicardial coronary artery stenotic regions. We examined the disturbances in the coronary microcirculation in patients with coronary ectasia using left ventriculography and ATP loading 99mTc-tetrofosmin myocardial single photon emission computed tomography (SPECT) before and after administration of a coronary vasodilator and antiplatelet agents. METHODS: Twenty patients in whom coronary angiography revealed diffuse coronary artery ectasia but no stenotic regions were enrolled in this study. Left ventriculography and ATP loading 99mTc-tetrofosmin myocardial SPECT were performed before and after administration of the coronary vasodilator, nicorandil, as well as that of the antiplatelet agents, aspirin and ticlopidine. RESULTS: (1) The ejection fraction in left ventriculography was 48.3 +/- 17.4% before, and 56.6 +/- 18.3% after the drug administration, the ejection fraction was improved after the drug administration (p < 0.05). (2) Before the drug administration, the total defect scores on 99mTc-tetrofosmin myocardial SPECT were 5.9 +/- 3.1 and 8.8 +/- 2.7 in the ATP-loading and rest images, respectively (p < 0.05), and the corresponding scores after the drug administration were 4.1 +/- 3.0 and 5.4 +/- 3.1, respectively (N.S.). Thus, the total defect scores in the ATP-loading and rest images improved after the drug administration (p < 0.05). CONCLUSION: Myocardial damage in patients with coronary ectasia might be induced by microthrombotic embolism and microcirculation disturbance.

Analysis of circulating apoptosis mediators and proinflammatory cytokines in patients with idiopathic hypertrophic cardiomyopathy: comparison between nonobstructive and dilated-phase hypertrophic cardiomyopathy.

We examined the plasma levels of soluble Fas (sFas) or Fas ligand (sFas-L), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in patients with idiopathic nonobstructive (HNCM) and dilated-phase (DHCM) hypertrophic cardiomyopathy. Patients with idiopathic hypertrophic cardiomyopathy (HCM) may deteriorate to DHCM and the pathogenesis is unknown. The levels of these plasma cytokines were measured by ELISA and echocardiography was performed in 38 HNCM and 11 DHCM patients, and 10 normal subjects. The follow-up period was three years. In HNCM, TNF-alpha (43.3 +/- 45.2 versus 16.9 +/- 4.3 pg/mL) and IL-6 (65.1 +/- 86.4 versus 4.0 +/- 2.1 pg/mL) were slightly higher compared to normal subjects and sFas (3.7 +/- 1.2 versus 2.1 +/- 0.7 ng/mL) increased significantly. sFas (3.9 +/- 1.8), TNF-alpha (79.3 +/- 72.4), and IL-6 (234.1 +/- 135.2) in DHCM were significantly increased and only IL-6 was significantly different from HNCM. sFas-L (0.18 +/- 0.08 versus 0.25 +/- 0.05 ng/mL) in HNCM was significantly decreased, and the decrease was marked in DHCM (0.05 +/- 0.02). In HNCM, TNF-alpha was negatively correlated with fractional shortening (r = -0.432, P = 0.0062) or positively with IL-6 (r = 0.665, P < 0.0001), while sFas-L was negatively correlated with IL-6 (r = -0.580, P < 0.0001). DHCM with high sFas had significantly higher cumulative incidences of worsening heart failure. The Fas/Fas-L system and proinflammatory cytokines may play an important role in the status of HCM and its progression to DHCM.

Carbon dioxide-rich water bathing enhances collateral blood flow in ischemic hindlimb via mobilization of endothelial progenitor cells and activation of NO-cGMP system.

BACKGROUND: Carbon dioxide-rich water bathing has the effect of vasodilatation, whereas it remains undetermined whether this therapy exerts an angiogenic action associated with new vessel formation. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced by resecting the femoral arteries of C57BL/J mice. Lower limbs were immersed in CO2-enriched water (CO2 concentration, 1000 to 1200 mg/L) or freshwater (control) at 37 degrees C for 10 minutes once a day. Laser Doppler imaging revealed increased blood perfusion in ischemic limbs of CO2 bathing (38% increase at day 28, P<0.001), whereas N(G)-nitro-L-arginine methyl ester treatment abolished this effect. Angiography or immunohistochemistry revealed that collateral vessel formation and capillary densities were increased (4.1-fold and 3.7-fold, P<0.001, respectively). Plasma vascular endothelial growth factor (VEGF) levels were elevated at day 14 (18%, P<0.05). VEGF mRNA levels, phosphorylation of NO synthase, and cGMP accumulation in the CO2-bathed hindlimb muscles were increased (2.7-fold, 2.4-fold, and 3.4-fold, respectively) but not in forelimb muscles. The number of circulating Lin-/Flk-1+/CD34- endothelial-lineage progenitor cells was markedly increased by CO2 bathing (24-fold at day 14, P<0.001). The Lin-/Flk-1+/CD34- cells express other endothelial antigens (endoglin and VE-cadherin) and incorporated acetylated LDL. CONCLUSIONS: Our present study demonstrates that CO2 bathing of ischemic hindlimb causes the induction of local VEGF synthesis, resulting in an NO-dependent neocapillary formation associated with mobilization of endothelial progenitor cells.

HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells.

OBJECTIVE: Klotho is thought to play a critical role in the development of age-related disorders including arteriosclerosis. Statins may exert vascular protective effects, independent of the lowering of plasma cholesterol levels. We investigated the impact of statins on mRNA expression of the age-suppressor gene, klotho in mIMCD3 cells. METHODS AND RESULTS: Klotho mRNA levels were evaluated with real-time RT-PCR. Atorvastatin and pitavastatin increased the expression of klotho mRNA in a dose-dependent manner. This stimulatory effect was abolished by the addition of mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment, stimulation with angiotensin II down-regulated klotho mRNA expression without obvious morphological changes. Furthermore, pretreatment with atorvastatin blunted the angiotensin II-induced response and ameliorated the decrease in klotho mRNA expression towards basal levels. RhoA activity was further evaluated by detection of its translocation. Angiotensin II activated RhoA, whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II. CONCLUSION: Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection.