tbuckley/cabot-search huggingface dataset:
Abstract 5046: Nitric Oxide and Superoxide Dismutase Modulate Endothelial Progenitor Cell Function in Type 2 Diabetes Mellitus
Authors: Saher Hamed, Benjamin Brenner, Ariel Roguin
Journal: Circulation (2009)

Objectives: To investigate the roles of NO and SOD in glucose-stressed endothelial progenitor cells (EPCs). Background: The function of EPCs, which are key cells in vascular repair, is impaired in diabetes mellitus (DM). Nitric oxide (NO) and reactive oxygen species can regulate EPC functions. EPCs tolerate oxidative stress by upregulating superoxide dismutase (SOD), the enzyme that neutralizes superoxide anion (O 2 − ). Methods: The functions of circulating EPCs from patients with type 2 DM were compared to those from healthy individuals. Healthy EPCs were glucose-stressed, and then treated with insulin and/or SOD. We assessed O 2 − generation, NO production, SOD activity, and their ability to form colonies. Results: EPCs from DM patients generated more O 2 − , had higher SOD activity, but lower NO bioavailability, than those from the healthy individuals. Serum fasting glucose and HbA1c levels in the DM patients were correlated negatively with the NO production from their EPCs. SOD treatment of glucose-stressed EPCs attenuated O 2 − generation, restored NO production, and partially restored their ability to form colonies. Insulin treatment of glucose-stressed EPCs increased NO production, but did not change O 2 − generation and their ability to form colonies. However, their ability to produce NO and to form colonies was fully restored after combined SOD and insulin treatment. Conclusions: Our data provide evidence that SOD may play an essential role in EPCs, and emphasize the important role of antioxidant therapy in type 2 DM patients.
Abstract 4856: Nighttime Sodium Excretion Following Acute Sodium Loading Predicts Blood Pressure Dipping and Aortic Augmentation Index
Authors: Scott L Hummel, Alan B Weder
Journal: Circulation (2009)

Background: In subjects who are in sodium (Na) balance, chronically increased night:day urinary Na excretion ratio is associated with arterial stiffening and nocturnal blood pressure non-dipping; less is known about these relationships following acute Na loading. Methods: We studied 11 young (24±5 yrs, 8 male/3 female), non obese, otherwise healthy prehypertensives over 6 days. Subjects ate a 20 mMol Na diet for 4 days. On day 5, they received 2 liters of 0.9% saline (308 mMol Na) over 2 hours, then an additional 130 mMol Na over 2 meals. Between days 4 and 6, subjects performed complete urine collections and ambulatory blood pressure monitoring, and underwent SphygmoCor assessment of aortic augmentation index (AIx75; in %, standardized to heart rate 75) on days 4 and 6. We defined the increase in nighttime urinary Na excretion following Na loading as: Nighttime-Na Excretion Ratio (NNER) = mMol Na/hr (rate night 5, post-Na load)/mMol Na/hr (rate night 4, pre-Na load). We also defined the change in nocturnal blood pressure dipping between night 4 (pre-Na load) and night 5 (post-Na load) as: ChgDip = nocturnal decrease in mean arterial pressure [mmHg, night 4] - nocturnal decrease in mean arterial pressure [mmHg, night 5] We then explored how the NNER related to ChgDip and AIx75 post-Na loading with linear regression. Results: The nighttime Na excretion rate increased following Na loading (.9±.9 to 8±4 mMol/hr, p &lt; .001); the mean NNER was 13±9. After stepwise regression including age, gender, body mass index, daytime Na excretion, post-Na mean arterial pressure, and pre-Na blood pressure dip, higher NNER predicted less effect of Na loading on ChgDip ( β = −0.4, p = .005). In a stepwise regression model including age, gender, height, mean arterial pressure, left ventricular mass, aortic augmentation index in low-Na balance, and daytime Na excretion, the NNER was the only significant predictor of post-Na loading AIx75 ( β = −1.3, p= .009). Blood pressure dipping and AIx75 did not correlate with daytime Na excretion. Conclusions : Following an acute Na load, prehypertensive subjects who increase their nighttime Na excretion rate the most preserve nocturnal blood pressure dipping and have lower aortic augmentation index.
Abstract 4905: High Density Lipoprotein is Dysfunctional in Primary Antiphospholipid Syndrome and is Associated With Impaired Vascular Function
Authors: Marietta Charakida, Christian Besler, Joanna Batuca, Shirish Sangle, José Alves, David D’Cruz, Dimitris Tousoulis, Charles Mackworth-Young, Thomas Lüscher, John Deanfield
Journal: Circulation (2009)

Objectives: Antiphospholipid syndrome is characterised by increased thrombogenicity and/or pregnancy morbidity in the presence of raised levels of antiphospholipid antibodies (aPL). Increased oxidative properties of HDL (decreased activity of paraoxonase (PON) and accelerated atherosclerosis have been described in this syndrome. In this study, we assessed the functional properties of HDL and evaluated its impact on the vasculature in aPL positive patients and matched controls. Methods: We studied 77 women with positive aPL (APL) aged 46.6 ± 1.2 yrs (mean ± SE) and matched Controls of 77 women aged 47.5 ± 1.2 yrs. In all subjects, carotid intima media thickness (IMT), flow mediated dilatation (FMD) and pulse wave velocity (PWV) were measured. PON activity was assessed by measuring p-nitrophenol formation. HDL was isolated in APL (N = 6) and Controls (N = 6). The impact of HDL on human aortic endothelial cell (HAEC) nitric oxide (NO) and superoxide production were determined. Anti-inflammatory properties of HDL were examined by analyzing the effect of HDL on endothelial cell VCAM-1 expression and monocyte adhesion to activated HAEC. Results: APL had significantly increased IMT and PWV compared to Controls (0.75 ± 0.02mm vs 0.65 ± 0.01mm, p &lt; 0.001 and 9.14 ± 0.18 m/s vs 8.56 ± 0.21m/s, p &lt; 0.05 respectively) and decreased FMD (6.2 ± 0.5% vs 9.6 ± 0.5%, p &lt; 0.001). PON activity was significantly reduced in APL compared to Controls (p = 0.006). PON activity was inversely associated with cIMT and PWV in APL (p &lt; 0.05 for both) but not in Controls. HDL from Controls increased endothelial cell NO production, whereas in marked contrast HDL from APL reduced NO production by 20% (p &lt; 0.0001). The beneficial effect of HDL on endothelial VCAM-1 expression, superoxide production and monocyte adhesion was diminished in APL (p &lt; 0.05 for all). Conclusions: APL is associated with impaired vascular function and structure. PON activity is decreased in APL and is inversely associated with IMT and PWV. HDL in APL is associated with decreased endothelial NO production and has impaired anti-inflammatory and anti-oxidant properties. These findings suggest that HDL is dysfunctional in APL and support its role in promoting early vascular changes in antiphospholipid syndrome.
Abstract 5139: Critical Role of CalDAG-GEFI Signaling in Myocardial Ischemia-Reperfusion Injury
Authors: Moritz Stolla, Erhe Gao, Lucia Stefanini, Patrick Most, Thomas L Force, Wolfgang Bergmeier
Journal: Circulation (2009)

Background: Myocardial infarction (MI) is a national health concern, with an occurrence of over 1 million cases per year. An event central to MI is reperfusion injury, i.e. the damage to tissue caused when blood supply returns to the tissue after the period of ischemia. An important role for both leukocytes and platelets in the development of reperfusion injury has been described. Our recent studies demonstrated that the signaling molecule CalDAG-GEFI (Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I) is predominantly expressed in neutrophils and platelets, where it plays a critical role for integrin activation and cell adhesion. Objective: We evaluated if CalDAG-GEFI is a potential target for intervention with reperfusion injury. Methods/Results: Myocardial ischemia was induced for 30 minutes in wild-type (WT) and CalDAG-GEFI−/− mice by a minimally invasive operative procedure. After 24 hours of reperfusion, the mice were sacrificed and the hearts were extracted for further analysis. CalDAG-GEFI-deficient mice showed an approximately 40% reduction in infarct size compared to WT mice (48% vs. 30% in WT and CalDAG-GEFI−/− respectively). In order to rule out that CalDAG-GEFI affects mI/R injury due to its role in endothelial cell and/or cardiomyocyte function, we first studied its expression in these cell types. Compared to the strong expression in both platelets and neutrophils, only trace amounts of CalDAG-GEFI expression were observed in cardiomyocytes or endothelial cells. In a next step, mI/R injury was studied in lethally irradiated CalDAG-GEFI−/− mice reconstituted with bone marrow isolated from WT (KO/WT) or CalDAG-GEFI−/− (KO/KO) mice. As expected, the infarct size in KO/WT chimeras was similar to that observed in WT mice and significantly larger than that of KO/KO chimeras, strongly suggesting that CalDAG-GEFI is critical for the development of mI/R injury due to its role in platelet and/or neutrophil function. Interestingly, CalDAG-GEFI−/− mice showed a stronger protection from mI/R injury than neutrophil-depleted WT mice. Conclusion: Our studies identify CalDAG-GEFI as a novel and promising intracellular therapeutic target for the reduction of myocardial reperfusion injury.
Abstract 5268: A Critical Role of Bradykinin in the Murine Model of Contrast Media-Induced Nephropathy
Authors: Jun-ichi Suzuki, Masahito Ogawa, Yasunobu Hirata, Ryozo Nagai, Mitsuaki Isobe
Journal: Circulation (2009)

Background: Iodinated contrast media (CM) has been broadly used for diagnostic procedures; CM-induced nephropathy (CIN) affects morbidity and mortality of patients. Although CIN is known to be mediated by several factors, including the renin-angiotensin system (RAS), little is known about the evidence obtained from experimental models. Thus, we developed a murine CIN model to evaluate the mechanism. Methods: We performed 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol, 500 μ l/25 g mice) intravenously into the mice 4 weeks after NTX. We administered an angiotensin converting enzyme inhibitor (ACEI, imidapril, 1 mg/kg/day, n=6), an angiotensin II receptor blocker (ARB, TA606, 1 mg/kg/day, n=4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, 0.25 mg/kg, n=5) into the mice daily. Results: Serum creatinine levels on day 28 were significantly elevated in the NTX group (0.26±0.01 mg/dl) compared to those in the non-NTX group (0.13±0.01 mg/dl). A day after CM injection, creatinine levels were significantly elevated in the non-treated group (0.41±0.01 mg/dl). While ACEI treatment significantly suppressed the increase in creatinine levels (0.34±0.04 mg/dl, p&lt;0.05 vs. CIN group), ARB treatment did not suppress (0.47±0.06 mg/dl). A bradykinin antagoninst Hoe-140 negated (0.43±0.07 mg/dl, p&lt;0.05 vs. CIN+ACEI) ACEI’s ability to suppress renal damage. We examined renal AT1R, COX-2, MCP-1 and MMP-9 mRNA levels using quantitative RT-PCR. AT1R mRNA levels were enhanced in the NTX and CIN groups compared to those in the native group. COX-2, MCP-1 and MMP-9 mRNA levels were enhanced in the CIN+ACEI group compared to the native and CIN groups. ACEI+Hoe-140 treatment suppressed the mRNA expression. Both treatments did not reduce their blood pressure compared to those of the vehicle treatment, statistically. Conclusion: ACEI treatment is useful for the prevention of CM-induced nephropathycompared to that of ARB treatment in the murine model of CIN because bradykinin pathway is critical in regulating CIN development.
2006 Donald Seldin Lecture—Molecular Genetics of Cardiovascular Risks: The Kidney as the Cause of Hypertension
Authors: Richard Lifton
Journal: Circulation (2006)

Hypertension affects 1 billion people worldwide and is a major contributor to death from myocardial infarction, stroke, congestive heart failure, and kidney failure. Its pathogenesis has been unknown because of the complexity of blood pressure regulation, and only a minority of patients is adequately treated. To identify key pathways involved in long-term determination of blood pressure, we have investigated rare families from around the world in which hypertension or hypotension show evidence of transmission via the effects of a single gene. Using molecular genetic analysis, we have identified the specific genes and mutations that cause these disorders and have determined their biochemical mechanisms of action. These include mutations in 9 genes that cause hypertension and 8 that cause hypotension. These genes converge on a final common pathway that regulates renal salt homeostasis; mutations that cause increased renal salt reabsorption raise blood pressure, whereas those that reduce salt reabsorption lower blood pressure. Mutated genes include those encoding ion channels and transporters that mediate or regulate salt reabsorption, enzymes and receptors that regulate production of aldosterone and transduction of its signal, and a novel family of serine-threonine kinases that regulate diverse flux pathways to coordinate the balance between renal salt reabsorption and K + secretion. These studies demonstrate the key role of renal salt handling in determination of blood pressure and identify promising new targets for therapeutic intervention. Moreover, they underscore the importance of reduction of salt balance in the treatment of hypertension in the general population while revealing limitations of single-agent diuretic therapies.
Abstract 5150: The Difference in Awake Ambulatory Blood Pressure and Office Blood Pressure: A Meta-analysis
Authors: Joji Ishikawa, Yukiko Ishikawa, Joseph E Schwartz, Thomas G Pickering
Journal: Circulation (2009)

Background : Masked hypertension is associated with an increased risk of cardiovascular events, while white coat hypertension is considered to be a relatively lower risk condition; both are defined by the difference between awake ambulatory blood pressure (ABP) and office blood pressure (OBP). We review evidence on the relationship of this difference to age. Method : We performed a systematic review of papers in PubMed using the combination of terms “office and ambulatory or home blood pressure (HBP),” and selected articles in which the OBP and awake ABP (or HBP) were presented. A random effects model was used for the meta-analyses. Results : In the 18 studies of adults (N=8779), OBP was higher than awake ABP (the difference; 2.0±0.04/1.0±0.03 mmHg, both P&lt;0.001); however, in the 5 studies of children and youth (N=1829), awake ABP was higher than OBP (7.9±0.12/7.9±0.10 mmHg, both P&lt;0.001). In studies of general populations, OBP became higher than awake ABP after age 49.1/43.0 in women (N=5893) and age 44.7/44.8 in men (N=6776). In the studies comparing OBP and HBP (N=8079), OBP was higher than HBP at all ages. In the studies in which OBP, awake ABP, and HBP were all available, HBP was lower than awake ABP, and became similar to awake ABP around 65.2 years old (Figure ). Conclusion : Awake ABP tends to exceed OBP at younger ages while the reverse is true after age 50; in contrast OBP tends to exceed HBP at all ages. This suggests that the prevalence of masked hypertension will be lower, while that of white coat hypertension will be greater when defined by HBP instead of ABP. The determinants of the age-related differences between ABP (or HBP) and OBP merit further investigation.
Abstract 5151: Waveform Reflections and Arterial Stiffness in the Prediction of 15.1-Year All-Cause and Cardiovascular Mortalities: A Community-Based Study
Authors: Kang-Ling Wang, Hao-Min Cheng, Shao-Yuan Chuang, Harold Spurgeon, Chih-Tai Ting, Samer Najjar, Edward Lakatta, Frank Yin, Pesus Chou, Chen-Huan Chen
Journal: Circulation (2009)

Background- The role of arterial wave reflection, usually assessed by the transit-time dependent augmentation index (AI) and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit-time independent measurements of reflected wave magnitude predict cardiovascular outcomes independently of arterial stiffness indexed by carotid-femoral pulse wave velocity (PWV). Method- A total of 1272 participants (47.0% women) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed to generate forward wave amplitude (Pf), backward wave amplitude (Pb), and reflection index (RI, = [Pb/(Pf+Pb)]), in addition to AI, Pa, and reflected wave transit time (RWTT). Results During a median follow-up of 15.1 years, 225 deaths occurred, including 64 cardiovascular origins. In univariate Cox proportional hazards regression analysis, PWV, Pa and Pb predicted all-cause and cardiovascular mortalities in both men and women whereas AI, RWTT and RI were predictive only in men. In multi-variate Cox analysis accounting for age, height, and heart rate, Pb predicted all-cause mortality in women and cardiovascular mortality in both men and women, whereas Pa only predicted cardiovascular mortality in men but not in women. When PWV and Pb were jointly entered into the multivariate model accounting for age, sex, height, heart rate, and brachial mean blood pressure, Pb (hazard ratio 1.066, 95% confidence interval 1.023–1.110) but not PWV (1.086, 0.993–1.189), independently predicted cardiovascular mortality. Conclusion- Pb, a transit-time independent measurement of reflected wave magnitude, predicted long term cardiovascular mortality in men and women independently of PWV.
Abstract 4860: A Simple Electrocardiographic Criterion for Differentiating Tako-tsubo Cardiomyopathy From Anterior Acute Myocardial Infarction
Authors: Masami Kosuge, Toshiaki Ebina, Kiyoshi Hibi, Satoshi Morita, Noriaki Iwahashi, Jyun Okuda, Kengo Tsukahara, Kazuaki Uchino, Toshiyuki Ishikawa, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2009)

Background: Because clinical and ECG findings of Tako-tsubo cardiomyopathy (TC) mimic those of anterior acute myocardial infarction (ant AMI), differential diagnosis is crucial for deciding whether reperfusion therapy is required. Methods: We compared admission ECGs between 33 patients (pts) with TC and 342 with a first ant AMI due to the left anterior descending coronary artery occlusion as documented by emergency coronary angiography. All pts were admitted within 6 h after symptom onset. ST-segment deviation was considered present if deviation was &gt;0.5 mm in limb leads and &gt;1.0 mm in precordial leads. Results: Pts with TC were older (70±11 vs 61±11 yrs, p&lt;0.01), more likely to be women (75 vs 15%, p&lt;0.01), and had a lower initial left ventricular ejection fraction (39±11 vs 46±11%, p=0.08) than those with ant AMI. On admission ECG, TC was more frequently associated with the absence of abnormal Q waves (42 vs 26%, p&lt;0.05) and of inferior ST-segment depression (ST↓) (94 vs 51%, p&lt;0.01), and lesser maximal ST-segment elevation (ST ↑) (5±5 vs 7±3 mm, p&lt;0.01). Distribution of ST↑ is shown in Figure , using the Cabrera sequence for display of limb leads. In pts with TC, ST↑ most frequently occurred in lead -aVR, but was rare in lead V1. ST↑ in lead -aVR and no ST↑ in lead V1 was observed in 91% of pts with TC, as compared with only 4% of those with ant AMI (p&lt;0.001). This finding identified TC with 91% sensitivity, 96% specificity, and 95% predictive accuracy, which were higher than those of other ECG variables. Conclusions: The presence of ST↑ in lead -aVR (i.e, ST↓ in lead aVR) and the absence of ST↑ in lead V1 strongly suggests TC. This ECG finding allows TC to be simply but accurately differentiated from ant AMI.
Abstract 5159: Arterial Wall Expression of Tumor Necrosis Factor Receptor-2 Attenuates Atherosclerosis by Reducing Recruitment of Monocyte/Macrophages
Authors: Lisheng Zhang, Leigh Brian, Neil J Freedman
Journal: Circulation (2009)

Deficiency of tumor necrosis factor receptor-2 (TNFR2) increases TNF-induced endothelial cell apoptosis, decreases the rate of vein graft re-endothelialization, and consequently increases vein graft neointimal hyperplasia. We therefore tested the hypothesis that TNFR2 expression in the arterial wall protects against atherogenesis, by placing common carotid arterial interposition isografts from tnfr2 −/− or congenic wild type (WT) mice into the common carotid arteries of congenic apolipoprotein E −/− mice fed normal chow. We used a procedure we previously demonstrated engenders typical atherosclerosis, but in an accelerated time frame. Grafts were harvested 7 weeks post-op, perfusion-fixed, paraffin-embedded, sectioned at 4 μ m, and stained for collagen and elastin. Computerized morphometry was performed by observers blinded to specimen identity. Eccentric lesions with fibrous caps and necrotic cores developed, and demonstrated up to 85% luminal stenosis. Compared with WT carotid grafts (n=6), tnfr2 KO carotid grafts (n=5) demonstrated significantly more atherosclerosis, with 33% greater neointimal area (0.16±0.03 vs. 0.12±0.01 mm 2 , p&lt;0.01). However, medial area was equivalent in WT and tnfr2 KO arteries (0.12±0.02 vs. 0.10±0.04 mm 2 ). Outward remodeling tended to be greater in tnfr2 KO arteries (external diameter was 14±1% greater); consequently, luminal stenosis was comparable between tnfr2 KO and WT arteries (89±8% vs. 86±14%). Tnfr2 KO arteries not only developed larger neointimal lesions but also showed evidence for more unstable plaque composition: macrophage prevalence was 80±10% higher (p&lt;0.05), and SMC prevalence was 43±5% lower in tnfr2 KO than in WT arteries (p&lt;0.05), as assessed by quantitative immunofluorescence microscopy for F4/80 (macrophages) and SMC α -actin (normalized to Hoechst 33342-stained nuclear fluorescence). Concordantly, immunofluorescence of vascular cell adhesion molecule-1 per cell was 70±20% greater in tnfr2 KO carotid grafts (p&lt;0.05). We conclude that TNFR2 expression in arterial wall cells protects against atherogenesis, by mechanisms that reduce monocyte/macrophage recruitment to the atheroma.