Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Acute kidney disease and acute kidney injury biomarkers in coronary care unit patients.

BACKGROUND: Acute kidney disease (AKD) describes acute or subacute damage and/or loss of kidney function for a duration of between 7 and 90 days after exposure to an acute kidney injury (AKI) initiating event. This study investigated the predictive ability of AKI biomarkers in predicting AKD in coronary care unit (CCU) patients. METHODS: A total of 269 (mean age: 64 years; 202 (75%) men and 67 (25%) women) patients admitted to the CCU of a tertiary care teaching hospital from November 2009 to September 2014 were enrolled. Information considered necessary to evaluate 31 demographic, clinical and laboratory variables (including AKI biomarkers) was prospectively recorded on the first day of CCU admission for post hoc analysis as predictors of AKD. Blood and urinary samples of the enrolled patients were tested for neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and interleukin-18 (IL-18). RESULTS: The overall hospital mortality rate was 4.8%. Of the 269 patients, 128 (47.6%) had AKD. Multivariate logistic regression analysis revealed that age, hemoglobin, ejection fraction and serum IL-18 were independent predictors of AKD. Cumulative survival rates at 5 years of follow-up after hospital discharge differed significantly (p < 0.001) between subgroups of patients diagnosed with AKD (stage 0A, 0C, 1, 2 and 3). The overall 5-year survival rate was 81.8% (220/269). Multivariate Cox proportional hazard analysis revealed that urine NGAL, body weight and hemoglobin level were independent risk factors for 5-year mortality. CONCLUSIONS: This investigation confirmed that AKI biomarkers can predict AKD in CCU patients. Age, hemoglobin, ejection fraction and serum IL-18 were independently associated with developing AKD in the CCU patients, and urine NGAL, body weight and hemoglobin level could predict 5-year survival in these patients.

2019 Focused Update of the Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure.

Heart failure is a growing epidemic, especially in Taiwan because of the aging population. The 2016 Taiwan Society of Cardiology - Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry showed that the guideline-recommended therapies were prescribed suboptimally both at the time of hospital discharge and during follow-up. We, therefore, conducted this 2019 focused update of the guidelines of the Taiwan Society of Cardiology for the diagnosis and treatment of heart failure to reinforce the importance of new diagnostic and therapeutic modalities of heart failure. The 2019 focused update discusses new diagnostic criteria, pharmacotherapy, non-pharmacological management, and certain co-morbidities of heart failure. Angiotensin receptor neprilysin inhibitor and If channel inhibitor is introduced as new and recommended medical therapies. Latest criteria of cardiac resynchronization therapy, implantable cardioverter-defibrillator, heart transplantation, and ventricular assist device therapy are reviewed in the non-pharmacological management chapter. Co-morbidities in heart failure are discussed including chronic kidney disease, diabetes, chronic obstructive pulmonary disease, and sleep-disordered breathing. We also explain the adequate use of oxygen therapy and non-invasive ventilation in heart failure management. A particular chapter for chemotherapy-induced cardiac toxicity is incorporated in the focused update to emphasize the importance of its recognition and management. Lastly, implications from the TSOC-HFrEF registry and post-acute care of heart failure are discussed to highlight the importance of guideline-directed medical therapy and the benefits of multidisciplinary disease management programs. With guideline recommendations, we hope that the management of heart failure can be improved in our society.

Clinical outcomes of second-generation limus-eluting stents compared to paclitaxel-eluting stents for acute myocardial infarction with cardiogenic shock.

OBJECTIVE: Whether the cardiovascular (CV) outcomes of second-generation limus-eluting stents (LESs) differ from those of paclitaxel-eluting stents (PESs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) is still unclear. METHODS: We used the Taiwan National Health Insurance Research Database to analyse data of 516 patients with AMI and CS diagnosed from January 2007 to December 2011. We used propensity score matching to adjust for the imbalance in covariate baseline values between these two groups. We evaluated clinical outcomes by comparing 197 subjects who used second-generation LESs to 319 matched subjects who used PESs. RESULTS: The risk of the primary composite outcomes (i.e., myocardial infarction, coronary revascularisation or CV death) was significantly lower in the second-generation LES group than in the PES group [37.3% vs. 51.8%; hazard ratio (HR), 0.73; 95% CI: 0.56-0.95] at the 12-month follow-up. The patients who received second-generation LESs had a lower risk of coronary revascularisation (HR 0.62; 95% CI: 0.41-0.93) than those who used PESs. However, the risks of myocardial infarction (HR 0.56; 95% CI: 0.26-1.24), ischemic stroke (HR 0.73; 95% CI: 0.23-2.35), or CV death (HR 0.90; 95% CI: 0.63-1.28) were not significantly different between the two groups. CONCLUSIONS: Among patients with CS-complicating AMI, second-generation LES implantation significantly reduced the risk of coronary revascularisation and composite CV events compared to PES implantation at the 12-month follow-up.

Predictors of long-term survival prior to permanent pacemaker implantation in octogenarians or older.

BACKGROUND: There is an increased need for permanent pacemaker (PPM) implantation for older patients with multiple comorbidities. The current guidelines recommend that, before implanting PPM, clinicians should discuss life expectancy with patients and their families as part of the decision-making process. However, estimating individual life expectancy is always a challenge. AIMS: We investigated predictors of long-term survival prior to PPM implantation in patients aged 80 or older. METHODS AND RESULTS: From September 2004 to September 2015, 100 patients aged ≥ 80 years who received PPM implantation were included for retrospective survival analysis. The end point was all-cause mortality. Follow-up duration was 4.0 ± 2.7 years. By the end of the study, 54 patients (54%) had died. Of the 54 who died, 40 patients (74.1%) died of non-cardiac causes. Their survival rates at 1, 2, 3, 5, and 7 years were 90%, 76%, 54%, 32%, and 16%, respectively. Patients with a longer length of hospital stay before PPM implantation (LOS-B) [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.02-1.05, p < 0.001], estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 (HR 4.07, 95% CI 1.95-8.52, p < 0.001), body mass index (BMI) < 21 kg/m2 (HR 2.50, 95% CI 1.16-5.39, p = 0.02), and dyspnea as the major presenting symptom (HR 2.88, 95% CI 1.27-6.55, p = 0.01) were associated with lower cumulative survival. CONCLUSIONS: Longer LOS-B, lower eGFR and BMI, and dyspnea as the major presenting symptom are pre-PPM implantation predictors of long-term survival in patients aged 80 or older.

Metastatic cardiac tumor presenting as atrial fibrillation in a previously healthy woman: A case report.

RATIONALE: Metastatic cardiac tumor (MCT) is rare in clinical practice. MCT presenting initially as atrial fibrillation (AF) is even rarer. PATIENT CONCERNS: We report a 47-year-old woman with no previous medical history presented with intermittent palpitation for 3 days. DIAGNOSES: The electrocardiography showed AF with rapid ventricular rate. The transthoracic echocardiography showed a 4 × 4 cm mass occupying the left atrium (LA). The contrast enhanced computed tomography (CT) showed a left lower lung mass with invasion to the LA and left upper pulmonary vein (PV). The chest CT guided biopsy revealed poorly differentiated squamous cell carcinoma. Further workup including bone scan showed no significant findings. The diagnosis of lung squamous cell carcinoma with cardiac invasion was made. INTERVENTIONS: She went on to received palliative chemotherapy. OUTCOMES: She is being followed up regularly at the outpatient department. LESSONS: Tumor invasion of the LA and PV was thought to be the cause of the AF. This condition is rare, but clinically important. Physicians should be alert that MCT could be an important differential diagnosis in patients presenting with unexplained AF.

Decreased Hemolysis and Improved Hemodynamic Performance of Synchronized Bileaflet Mechanical Valve.

PURPOSE: This study compared the performance of a newly patented synchronized valve (SV) with that of a commercially available (CAV) bileaflet mechanical heart valve. DESCRIPTION: A high-speed camera was used to record the leaflet kinematics of the SV vs the CAV along the flow channel. Transvalvular energy loss, effective orifice area, and hemolysis ratios were obtained using a mock circulatory system at two fixed pulse rates and at various cardiac outputs with a fixed aortic pressure. EVALUATION: The rotational radius and inertia of the SV was lower than that of the CAV during valve closure. For heart rates and at cardiac outputs of 7, 5, and 4 L/min, the ratio of total energy loss to effective energy of the SV was significantly less than the CAV, whereas the effective orifice area of the SV was significantly larger than that of CAV. The hemolysis ratio after 4 hours was significantly higher in the CAV than in the SV for both pulse rates. CONCLUSIONS: The synchronized leaflet motion mitigated leaflet rebound and regurgitation during valve closure, which could decrease energy loss, increase the effective orifice area, and reduce hemolysis.

c-Src-dependent MAPKs/AP-1 activation is involved in TNF-α-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells.

TNF-α plays a critical mediator in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-α in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-α-induced MMP-9 expression are largely unclear in the heart cells. Here, we demonstrated that in rat embryonic-heart derived H9c2 cells, TNF-α could induce MMP-9 mRNA expression associated with an increase in the secretion of MMP-9, determined by real-time PCR, zymography, and promoter activity assays. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of c-Src, EGFR, PDGFR, p110, Akt, or c-Jun. TNF-α stimulated c-Src, PDGFR, and EGFR phosphorylation, which were reduced by PP1. In addition, TNF-α-stimulated Akt phosphorylation was inhibited by PP1, AG1478, AG1296, or LY294002. We further demonstrated that TNF-α markedly stimulated p38 MAPK, p42/p44 MAPK, and JNK1/2 phosphorylation via a c-Src/EGFR, PDGFR/PI3K/Akt pathway. Finally, we showed that, in H9c2 cells, TNF-α-stimulated AP-1 promoter activity, c-Jun mRNA expression, and c-Jun phosphorylation were attenuated by PP1, AG1478, AG1296, LY294002, SB202190, SP600125, or U0126. These results suggested that TNF-α-induced MMP-9 expression is mediated through a c-Src/EGFR, PDGFR/PI3K/Akt/MAPKs/AP-1 cascade in H9c2 cells. Consequently, MMP-9 induction may contribute to cell migration and cardiovascular inflammation.

ATP stimulates PGE(2)/cyclin D1-dependent VSMCs proliferation via STAT3 activation: role of PKCs-dependent NADPH oxidase/ROS generation.

Vascular smooth muscle cells (VSMCs) that function as synthetic units play important roles in cardiovascular diseases. Extracellular nucleotides, such as ATP, have been shown to act via activation of P2 purinoceptors implicated in various inflammatory diseases, we hypothesized that extracellular nucleotides contribute to vascular diseases via up-regulation of inflammatory proteins, including cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) in VSMCs. However, the mechanisms of ATP-induced cPLA2 and COX-2 expression and PGE2 synthesis remain largely unclear. We showed that pretreatment with the inhibitors of STAT3 (CBE), NADPH oxidase [diphenyleneiodonium chloride (DPI) or apocynin (APO)], ROS [N-acetyl-l-cysteine (NAC)], and PKC (Ro-318220, Gö6983, or Rottlerin) or transfection with siRNAs of STAT3 and p47(phox) markedly inhibited ATPγS-induced cPLA2 and COX-2 mRNA/protein expression and promoter activity and PGE2 secretion. ATPγS further stimulated PKC, p47(phox), and STAT3 translocation. Moreover, ATPγS-induced STAT3 phosphorylation and translocation was inhibited by pretreatment with the inhibitors of PKC, NADPH oxidase, and ROS. ATPγS enhanced NADPH oxidase activity and ROS generation in VSMCs, which were reduced by pretreatment with Ro-318220, Gö6983, or Rottlerin. Finally, we found that ATPγS significantly induced cyclin D1 expression and VSMCs proliferation, which were inhibited by pretreatment with NAC, APO, DPI, Ro-318220, Gö6983, Rottlerin, or CBE or transfection with siRNAs of COX-2 and cyclin D1. We also demonstrated that ATPγS induced cyclin D1 expression via a PGE2-dependent pathway. These results suggested that ATPγS-induced cPLA2/COX-2 expression and PGE2 secretion is mediated through a PKC/NADPH oxidase/ROS/STAT3-dependent pathway in VSMCs.

Differentiation profile of peripheral blood-derived vascular progenitor cell predicts intimal hyperplasia after coronary stenting.

In-stent restenosis is largely due to intimal hyperplasia (IH). The number of vascular progenitor cells (VPCs) mobilized at the acute phase after stenting is associated with IH. This study sought to determine whether the differentiation profile of VPC predicts the development of IH. Peripheral blood was collected in 58 patients after bare-metal stenting to culture VPCs. Intravascular ultrasound was performed to estimate the area of IH 6 months after stenting. VPC differentiation was determined using flow cytometry. VE-cadherin (VE-Cad) and α-smooth muscle actin (α-SMA) were used to identify endothelial and smooth muscle cell lineages, respectively. After culturing, VPCs differentiated into four different phenotypes (α-SMA(-)VE-Cad(+), α-SMA(+)VE-cad(high), α-SMA(+)VE-cad(low), and α-SMA(+)VE-Cad(-)). IH was correlated with gender (P = 0.04), smoking status (P = 0.04), reference diameter (P = 0.03), minimal lumen diameter (P = 0.03), stent area (P < 0.0001), and parameters in the VPC differentiation profile (P < 0.05). Multivariate analysis controlling for stent area, smoking status, and gender revealed that IH was positively and independently associated with the number of differentiated α-SMA(+)VE-Cad (low/-) VPCs (P < 0.0001), and the ratio of α-SMA(+)VE-Cad (low/-) VPCs to α-SMA(-)VE-Cad(+) VPCs (P = 0.001). These parameters in the VPC differentiation profile independently predicted the IH and provided additive information to traditional risk factors. In conclusion, the profile of VPC differentiation predicts the severity of post-stent IH and may be a potential tool in the future for clinicians to identify patients at risk of post-stent restenosis.

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury--beyond the direct renin inhibition.

Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, P<0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, P<0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

VE-Cadherin(low)α-smooth muscle actin+ component of vascular progenitor cells correlates with the coronary artery Gensini score.

BACKGROUND: Vascular progenitor cells (VPCs) are a heterogeneous population, containing a subpopulation co-expressing both endothelial and smooth muscle phenotypes. This study sought to determine whether the level of this subpopulation correlated with the coronary Gensini score. METHODS AND RESULTS: VPCs were cultivated in 50 patients undergoing coronary angiography. A subpopulation of VPCs expressed both endothelial (VE-cadherin [VE-Cad]) and smooth-muscle phenotypes (α-smooth muscle actin [α-SMA]). Correlations of the VE-Cad(low)α-SMA(+) VPC level and adhesion molecule expression by VPCs with the Gensini score were investigated. The association between the amount of this subpopulation and the development of intimal hyperplasia (IH) was also estimated in a vascular injury animal model. Both the number of VE-Cad(low)α-SMA(+) VPCs (P = 0.002) and the expression level of intracellular adhesion molecule (ICAM)-1 by VPCs (P = 0.008) correlated with the Gensini score. However, only the number of VE-Cad(low)α-SMA(+) VPCs (P = 0.004) and the blood level of low-density lipoprotein cholesterol (P = 0.016) were parameters independently associated with the Gensini score in multivariate analysis. Furthermore, in an animal model of injecting VPCs into SCID mice after femoral artery wire injury, a higher number of VE-Cad(low)α-SMA(+) VPCs correlated with greater IH (r = 0.69, P<0.0001). CONCLUSIONS: The level of VE-Cad(low)α-SMA(+) VPCs was associated with the severity of coronary atherosclerosis as quantified by the Gensini score. Manipulating this subpopulation may provide a way of attenuating atherosclerosis in the future.

Assessment of mouse hind limb endothelial function by measuring femoral artery blood flow responses.

OBJECTIVE: Substantial progress has been made in cell therapy strategies and in gene- and cytokine-introduced angiogenesis using a variety of mouse models, such as hind limb ischemia models. Endothelial function is an important target in evaluating the effects and outcomes of these potential therapies. Although animal models have been established for estimating endothelium-dependent function by measuring the blood flow responses in carotid and renal arteries and the abdominal aorta, a model specific for an indicated hind limb by measuring femoral artery blood flow (FABF) has not yet been established. METHODS: A 2-day protocol was designed, including exploration of the segmental femoral artery on the first day, and evaluation of endothelium-dependent vasodilatation function the next day. By placing a transonic flow probe around the left femoral artery, the FABF in response to endothelium-dependent and endothelium-independent vasodilatory stimulations was reproducibly measured. Hemodynamic measurements, including the left FABF and mean arterial pressure, were recorded. RESULTS: In normal controls, the baseline left FABF averaged 0.12 ± 0.01 mL/min. Acetylcholine increased the FABF up to 0.41 ± 0.02 mL/min. Rose bengal-associated photochemical injury was titrated to cause endothelial dysfunction but without disturbing the integrity of the endothelial layer. The response to acetylcholine significantly decreased 10 minutes after photochemical injury and was further impaired after 1 and 24 hours. However, the response to nitroprusside was preserved. A femoral and iliac artery wire-injury model was also introduced to cause endothelial and smooth muscle cell injury. One day after the wire injury, the responses to acetylcholine and nitroprusside injections were both remarkably attenuated. CONCLUSIONS: This model can be widely used to analyze the in vivo endothelium-dependent vasodilatation function before and after a variety of therapeutic interventions on a mouse hind limb.

Factors associated with purity, biological function, and activation potential of endothelial colony-forming cells.

Endothelial colony-forming cells (ECFCs) are undergoing extensive investigations to tackle certain deliberating cardiovascular diseases. However, the success of this approach depends on a thorough understanding of ECFC biology. This study sought to determine the factors associated with the purity, biological function, and activation potential of ex vivo expanded ECFCs. Seventy-three patients with newly diagnosed coronary artery disease (CAD) and 24 controls were studied. ECFCs were cultured for up to 10 passages to investigate changes in and the impact of coronary risk factors on ECFC biological functions and the atherogenic potential. Passages 3-5 of ECFCs exhibited higher endothelial phenotype expression and better biological functions, in terms of nitric oxide secretion and tubular formation, but lower activation potentials compared with later passages (P <0.05). Studies on passage 3 showed that endothelial phenotype expression and biological functions were impaired, and the activation potentials of the ECFCs were significantly upregulated in subjects with coronary risk factors and especially those with CAD (P < 0.05). Furthermore, ECFCs were already activated before inflammatory stimulation in subjects with diabetes mellitus, hypertension, and CAD. Atorvastatin upregulated the endothelial nitric oxide synthase expression of ECFCs in CAD patients (P < 0.01), although not up to the baseline level of controls. In conclusion, the passage number and a variety of coronary risk factors were associated with the purity, biological function, and activation potential of ex vivo-expanded ECFCs. Functional assessments and manipulations of ECFCs have to be pursued in patients with extensive risk factors.

Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm.

BACKGROUND: Coronary vasospasm (CVsp) has been reported to be an inflammatory disease, reflected by elevated high-sensitivity C-reactive protein (hs-CRP). We investigated the interactions among gender, age, hypertension and hs-CRP in patients with CVsp. MATERIALS AND METHODS: We retrospectively examined 722 Taiwanese patients with or without CVsp during an 8-year period. None of the patients had obstructive coronary artery disease. Serum hs-CRP levels were examined in a subset of 375 patients to evaluate the interactions of hs-CRP with gender, age, smoking and hypertension in the development of CVsp. RESULTS: In women, only the highest hs-CRP tertile (> 3 mg L⁻¹) was independently associated with CVsp. In men, age > 58 years and the highest hs-CRP tertile were independently associated with CVsp. In women, elevated risk was only demonstrated in patients ≤ 58 years of age with hs-CRP levels in the highest tertile. In men, a positively monotonic trend was demonstrated between hs-CRP levels and CVsp in those > 58 years of age. The odds ratios of CVsp in both women and men with hs-CRP in the highest tertile reduced from 6·01 to 1·48 and 6·35-2·69 respectively, if they had hypertension. CONCLUSION: The relationship between hs-CRP and CVsp differed between men and women. Our findings that there is a non-threshold model in men and a threshold model in women provide evidence that more smokers in men (life-style) and age (induction time) contribute to the natural history of CVsp development. The negative effect of hypertension on CVsp suggests that the pathogenesis of CVsp differs from that of coronary atherosclerosis.

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells.

OBJECTIVE: We hypothesized a possible mechanism for atherosclerosis in which interleukin-6 (IL-6) might affect the endothelial nitric oxide synthase (eNOS)-caveolin-1 interaction and result in decreased nitric oxide bioavailability in the setting of low-grade inflammation. METHODS: Because eNOS and caveolin-1 are crucial for vascular tone control, we studied the effects of IL-6 on the expression and activation of eNOS and caveolin-1 in human vascular endothelial cells. RESULTS: IL-6 inhibited the phosphorylation of eNOS at Ser1177 and the bradykinin-stimulated nitric oxide production; however, eNOS protein expression was not changed. In addition, IL-6 inhibited bradykinin-stimulated Akt phosphorylation at Ser473 and Thr 308 without affecting the Akt protein expression. IL-6 did not alter the mRNA level of caveolin-1; however, the caveolin-1 protein level was significantly increased dose-dependently. The binding of eNOS and caveolin-1 in endothelial cells, as demonstrated by coimmunoprecipitation assay, was increased by IL-6 treatment. IL-6 treatment was found to stabilize caveolin-1 protein and its half-life was estimated to prolong from 7.5 h to longer than 12 h. Furthermore, treatment with PD98059 and short interference RNA of extracellular signal-regulated kinase gene reversed the effects of IL-6 on eNOS and caveolin-1. CONCLUSION: In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

Interaction between cigarette smoking and high-sensitivity C-reactive protein in the development of coronary vasospasm in patients without hemodynamically significant coronary artery disease.

BACKGROUND: Interaction between 2 major risk factors, cigarette smoking and high-sensitivity C-reactive protein (hs-CRP), has not been evaluated in patients with coronary vasospasm (CV) without hemodynamically significant coronary artery disease. METHODS: From 1999 to 2005, patients undergoing diagnostic coronary angiography with or without proven CV and without coronary stenosis >50% were evaluated. A total of 621 subjects (335 and 286 with and without CV, respectively) were enrolled in the study. The levels of hs-CRP, measured immediately before coronary angiography, were examined in a subset of 314 patients. RESULTS: Subjects with CV were likely to be older, men, current smokers, and have high hs-CRP levels. The most significant factors for CV were smoking and hs-CRP. In the nonsmoker group, elevated risk of developing CV was only demonstrated in patients with the highest hs-CRP tertile (>5.01 mg/L, P = 0.012). In the smoker group, however, a positively monotonic trend of association was demonstrated between hs-CRP tertile and CV risk, with multivariate-adjusted odds ratios of 1.11, 3.09 (P = 0.012), and 4.12 by the hs-CRP tertiles, suggesting that smokers developed CV at a lower hs-CRP level than nonsmokers and there was a positive interaction between smoking and hs-CRP. CONCLUSIONS: The smokers developed CV at a lower hs-CRP level compared with the nonsmokers. A positive interaction between smoking and hs-CRP was demonstrated for this disease in our study population.

Late reperfusion of a totally occluded infarct-related artery increases granulocyte-colony stimulation factor and reduces stroma-derived factor-1alpha blood levels in patients with ongoing ischemia after acute myocardial infarction.

After acute myocardial infarction (AMI), reopening of a totally occluded infarct-related artery (IRA) at a subacute stage is still controversial in symptom-free patients. However, in patients with persistent ischemic symptoms and inadequate collaterals to the infarct area, recanalization is thought to provide beneficial effects. In addition to augmenting myocardial perfusion, we hypothesized that the benefit of recanalization involves the manipulation of circulating stem cell-mobilizing cytokines. This study included 30 patients with a totally occluded IRA and ongoing ischemic symptoms (the study group) and 30 patients with a partially occluded IRA (the control group). All patients underwent successful angioplasty and/or stenting. Before and immediately after the coronary intervention, blood granulocyte-colony-stimulating factor (G-CSF), stem-cell factor (SCF), vascular endothelial growth factor (VEGF), and stroma-derived factor-1 (SDF-1alpha) were measured. After recanalization, G-CSF levels significantly increased in the study group compared to the control group (P=0.03). SDF-1alpha levels in the study group decreased relative to the controls (P=0.02). However, no significant changes in VEGF or SCF levels between the two groups were found. In the multivariate analysis, reopening of a totally occluded IRA was independently and significantly associated with changes in G-CSF and SDF-1alpha levels after recanalization. In conclusion, our data suggest that the benefits of late reperfusion of a totally occluded IRA in patients with ongoing myocardial ischemia may involve mechanisms associated with stem cell-mobilizing and plaque-stabilizing cytokines. This study provides the rationale to investigate serial changes in cytokines and the numbers of circulating progenitors after reperfusion in the future.

High body mass index is not associated with coronary artery disease in angina patients with chronic kidney disease: a coronary angiography study.

BACKGROUND: High body mass index (BMI) is an established risk factor for coronary artery disease (CAD) in the general population. This relationship is less clear in CAD patients with different stages of chronic kidney disease (CKD) because many complications of CKD can cause malnutrition and low BMI. We studied the association of BMI and angiography-confirmed CAD in CKD patients. METHODS: Thousand one hundred thirty-three patients admitted for coronary angiography was stratified by CKD classification. Demographic, clinical, hemodynamic, and angiographic findings were assessed. CKD patients (n = 980) were divided into angiographic CAD and non-CAD groups to compare traditional CAD risk factors. Patients with angiography-confirmed CAD (n = 496) were further analyzed for the association between BMI and CAD risk at different stages of CKD patients. RESULTS: Mean BMI was 27.4 +/- 4.1, 27.7 +/- 4.0, 25.9 +/- 3.5, 24.2 +/- 3.8, 23.2 +/- 3.0 and 23.8 +/- 4.2 kg/m for normal renal function, stage I, II, III, IV, and V CKD patients, respectively. Male, old age, presence of CKD, diabetes, hypertension, smoking, and higher cholesterol had significant association with angiographic CAD in the CKD sub-cohort. Obesity was not related to CAD in the CKD sub-cohort. Using WHO category for obesity, mild CKD patients were more likely to be overweight (62.8%) and obese (72%); meanwhile, most moderate and severe CKD patients were not obese (P < 0.05). Only 17.6% and 18.8% of moderate and severe CKD patients were obese (P < 0.05), by Taiwan classification. CONCLUSION: High BMI was not associated with angiographic CAD in CKD patients with angina.

Serum interleukin-6 levels, not genotype, correlate with coronary plaque complexity.

An increased serum interleukin-6 (IL-6) level is associated with an increased risk of cardiovascular events in healthy subjects. However, it is unknown whether the level of serum IL-6 or genetic IL-6 polymorphism is correlated with the complexity of coronary plaque in patients with stable coronary artery disease (CAD). Patients with stable CAD (n = 135) were divided into 3 groups: insignificant coronary plaque (n = 77), simple coronary plaque (n = 15), and complex coronary plaque (n = 43). IL-6-174G > C polymorphism and serum levels of IL-6 and C-reactive protein (CRP) were investigated. No significant difference in the distribution of IL-6 genotypes was found among the groups. The presence of complex coronary plaque was associated with higher serum concentrations of IL-6 (P = 0.026) and CRP (P < 0.0001). To predict the presence of complex lesions, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L had sensitivities of 86% and 74%, and specificities of 61% and 62%, respectively. By multivariate analysis, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were independently related to the presence of complex coronary plaque (P = 0.0002 and 0.004, respectively). IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were associated with a 4.5-fold increase in the odds of having complex coronary plaque (P < 0.005). A simple measurement of the serum IL-6 level in patients with CAD can potentially identify subjects with complex coronary lesions and provide the option of aggressive medical strategies in a clinical setting.