bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5096: Early versus Late Initiation of Antiretroviral Therapy and Arterial Stiffness in HIV Infection
Authors: Ho Jennifer E , Deeks Steven G , Hecht Frederick M , Xie Yu , Schnell Amanda , Martin Jeffrey N , Ganz Peter , Hsue Priscilla Y
Published: April 2024

Background:
HIV infection is associated with increased rates of cardiovascular disease. Assessment of arterial stiffness via pulse wave velocity (PWV) is strongly associated with cardiovascular risk, and prior studies have shown that HIV-infected patients have higher stiffness compared to controls. Current guidelines recommend initiation of antiretroviral therapy at a CD4 T cell count of 350 cells/ul. Whether earlier initiation of HIV therapy has any effect on cardiovascular risk as assessed by PWV is unknown.

Methods:
We conducted a cross-sectional study of 81 HIV-infected men who were antiretroviral-treated with undetectable plasma HIV RNA levels. Subjects underwent noninvasive assessment of PWV using the SphygmoCor System (AtCor Medical, Australia). A generalized linear model was used to determine the relationship between traditional cardiovascular risk factors, HIV-related predictors, and arterial stiffness as measured by PWV.

Results:
The median age was 47 years (IQR 43–54), 36% had a history of hypertension, and 46% had hypercholesterolemia. The median current CD4 T cell count was 539 cells/ul (IQR 324 –736), and nadir CD4 count was 180 cells/ul (IQR 29 –311). The median PWV was 5.3 m/s (IQR 4.9 – 6.2). In unadjusted analyses, age, diabetes, current CD4 count and nadir CD4 count <350 were predictors of PWV (all p <0.05). After adjusting for both traditional cardiovascular risk factors (age, systolic and diastolic BP, hypertension, diabetes, hypercholesterolemia, smoking) and HIV-related covariates, a nadir CD4 count <350 remained independently associated with a 0.58 m/s increase in PWV (95% CI 0.15–1.01, p<0.008). Other significant determinants of PWV in multivariate analyses included age, systolic and diastolic BP, and diabetes. Of note, neither duration of antiretroviral therapy nor exposure to protease inhibitors was associated with degree of arterial stiffness.

Conclusions:
Among treated HIV-infected individuals, higher PWV is independently associated with both traditional cardiovascular risk factors including age and diabetes, as well as low nadir CD4 count. Our data support the concept that initiation of antiretroviral therapy before low CD4 counts occur may reduce cardiovascular risk among individuals with HIV infection.
Abstract 5107: Notch3 Signaling in Macrophages Promotes Obesity and Atherosclerosis in Hypercholesterolemic Mice
Authors: Miyazaki Tetsuro , Yamazaki Hiroyuki , Morishige Kunio , Aikawa Elena , Aikawa Masanori
Published: April 2024

Background: Macrophage activation participates in the pathogenesis of atherosclerosis and obesity, major components of the cardiometabolic syndrome. The Notch signaling pathway involves four receptors (Notch1– 4) and regulates various biological processes during development. We previously demonstrated that Notch signaling induces proinflammatory responses in macrophages in vitro. However, the role of each receptor in macrophage activation remains unclear. The present study has determined the reality in vivo of our in vitro findings by exploring whether Notch3 expression in macrophages promotes cardiometabolic disorders.

Methods and Results: We established macrophage-selective transgenic mice for the Notch3 intercellular domain (a constitutively active form) under control of the scavenger receptor A promoter/enhancer (Notch3tg). In vitro studies demonstrated that peritoneal macrophages of Notch3tg mice expressed higher levels of various molecules associated with inflammation (e.g., IL-1
β
, iNOS) and arterial remodeling and calcification (MMP-8/collagenase-2, MMP-13/collagenase-3, BMP-4 and BMP-7) than wild-type macrophages (p<0.05). To assess the in vivo role of macrophage activation via Notch3 in visceral obesity and atherosclerosis, we generated compound mutant mice by crossing Notch3tg with Ldlr−/− mice, a model of atherosclerosis and the metabolic syndrome. After high fat feeding for 24 weeks, the weight of epididymal fat in Notch3tg:Ldlr−/− mice (n=10) was greater than that of Ldlr−/− littermates (n=10, p<0.05). Notch3tg:Ldlr−/− epididymal fat expressed higher RNA levels of leptin and lower levels of hormone sensitive lipase, a key regulator of lipolysis in fat tissue, consistent with visceral fat accumulation. In addition, N3tg:Ldlr−/− mice showed increased plaque size in atherosclerotic aortas (p<0.05). The aorta of N3tg:Ldlr−/− mice further exhibited more advanced calcification than Ldlr−/− mice (p<0.05) in association with higher levels of the osteogenesis inducer BMP-7 (p<0.01).

Conclusion: These data indicate that macrophage activation through Notch3 signaling promotes obesity and atherosclerosis and provide new insight into the pathogenesis of chronic inflammatory diseases.
Abstract 5108: Variation in Pial Collaterals in 15 Mouse Strains is a Major Determinant of Infarct Volume After Middle Cerebral Artery Occlusion (MCAO)
Authors: Zhang Hua , Keum Sehoon , Marchuk Douglas , Sealock Robert , Faber James
Published: April 2024

The importance of vascular, non-vascular and genetic factors in the wide variability in severity of infarct volume (IV) is unclear. We have reported previously that density and diameter of native collaterals in tissues vary widely with genetic background. The purpose of this study was to determine the contribution of genetic variation in collaterals to variation in IV in a cohort of genetic reference strains. IV was determined 1 day after MCAO. In a second set of mice, the vasculature was dilated, fixed and cast 6 days after MCAO. The number and diameter of pial collaterals were determined for the unligated left and ligated right hemispheres, as were territories of the MCA, ACA and PCA trees. Variations among strains in IV, native collateral number and diameter, and MCA, ACA and PCA territories were, respectively: 30-fold, 56-fold, and 3-fold, and 42%, 56% and 61%. IV and collateral dimensions did not correlate with brain size or PCA territory, but IV correlated highly with collateral number and diameter ((p<0.0001), and less so with MCA (p<0.05) and ACA territory (p<0.01). Arrangement of these parameters (excepting IV) into an expression of collateral conductance strongly predicted IV (p<0.0001). Prediction was improved by factoring in collateral length and hematocrit. There was no correlation between MCA territory and collateral number or diameter, suggesting genetic determinants of tree territory do not specify collateral dimensions. However, collateral dimensions were highly inter-correlated, suggesting they could arise from common genetic variants. Increase in collateral diameter on the ligated side (remodeling) varied by more than 2-fold and correlated with collateral diameter (p<0.0001) and number (p<0.01). Genome-wide haplotype and C57BL/6 × BALB/cBy F2 mapping are underway to identify potential loci harboring variants important in collateral formation. These data suggest that conductance of the pial collateral circulation is the primary determinant of stroke severity, and that polymorphisms in genes specifying formation of the native collateral circulation and its remodeling in ischemia are important determinants of stroke risk and stroke variance. These findings may generalize to heart, limb and other tissues.
Abstract 5124: Renal Function and Cardiac Structure and Function in Hypertensives With Established Diastolic Dysfunction in the VALIDD and EXCEED Trials
Authors: Shah Amil M , Uno Hajime , Hassanein Amira H , Verma Anil , Desai Akshay S , Rocha Ricardo A , Hilkert Robert , Izzo Joseph , Oparil Suzanne , Pitt Bertram , Thomas James D , Zile Michael R , Aurigemma Gerard P , Solomon Scott D
Published: April 2024

Background
: Impaired in renal function is associated with increased risk of cardiac events. The relationship between mild impairments in renal function and degree of diastolic dysfunction (DD) has not been well established.

Methods
: Estimated glomerular filtration rate (eGFR), urine albumin-to-creatine ratio (ACR) and echocardiographic measures were assessed in 597 subjects with stage 1 or 2 hypertension, no heart failure, and DD by reduced mitral annular early relaxation velocity (E′) enrolled in the VALIDD (n=381) and EXCEED (n=216) trials. Both trials tested different BP reduction strategies for improvement in DD.

Results
: eGFR was ≤60 ml/min/1.73m
2
in 80 subjects (13%), 61–75 in 130 (22%), and >75 in 387 (65%). Decreasing eGFR was significantly associated with lower E′ (p=0.0033), higher E/E′ (p=0.0252), higher LA volume index (p=0.0117), smaller LV volume (p<0.0001), and higher NT-proBNP (p=0.0042). ACR was undetectable in 149 subjects (27%), 1– 4 in 130 (24%), 5–9 in 93 (17%), 10 –30 in 104 (19%), and >30 in 75 (14%). Increasing ACR was associated with lower E′, higher LV mass, increased LV wall thickness, and higher NT-proBNP even after adjustment for age, gender, race, and differences in 7 baseline characteristics (p<0.014 for all associations). In combined analysis, both eGFR (p=0.0166) and ACR (p=0.0019) were independent predictors of baseline E′, without evidence of significant interaction.

Conclusions
: Among hypertensive subjects with DD, mild impairments of eGFR and elevated levels of albuminuria are associated with greater degrees of DD. Both eGFR and albuminuria are additive and independently associated with worse DD.
Abstract 5131: Prediction of Silent Ischemic Lesions After Carotid Artery Stenting Using Integrated Backscatter Ultrasound and Magnetic Resonance Imaging
Authors: Yamada Kiyofumi , Kawasaki Masanori , Yoshimura Shinichi , Enomoto Yukiko , Asano Takahiko , Minatoguchi Shinya , Iwama Toru
Published: April 2024

Background:
The purpose of this study was to determine whether integrated backscatter (IBS) ultrasound and black-blood magnetic resonance imaging (BB-MRI) can predict the risk of cerebral embolism after carotid artery stenting (CAS).

Methods:
We performed quantitative analysis of plaque characteristics in carotid arteries using IBS ultrasound (SONOS 7500) and BB-MRI before CAS in 50 patients. We measured IBS values and the signal intensity ratio (SIR) of carotid plaques to that of adjacent sternocleidomastoid muscle from T1-weighted images. We performed diffusion-weighted MRI of the brain before and after CAS.

Results:
In the patient group that was positive (n =19) for newly appearing ipsilateral silent ischemic lesions (NISIL), relative lipid and intra-plaque hemorrhage area (%LHA) evaluated by IBS analysis (60.2±23.4% and 35.3±19.2%, p<0.001) and SIR (1.40±0.19 and 1.18±0.25, p<0.01) in most stenotic lesions were higher than in the NISIL-negative group (n =31). From the analysis of ROC curves, 50% of the %LHA and an SIR of 1.25 were the most reliable cutoff values for predicting NISIL with the sensitivity of 68% and the specificity of 87% in the IBS analysis and 84% and 68% in the BB-MRI analysis. In multivariate logistic regression analysis, the independent predictors of NISIL were SIR (p = 0.03), the serum CRP level (p = 0.04) and the %LHA (p = 0.05).

Conclusions:
Quantitative tissue characterization of carotid plaques using IBS ultrasound and BB-MRI was useful to predict NISIL after CAS. It is recommended that plaque components be evaluated by SIR or IBS before CAS, and carotid endarterectomy should be selected to prevent distal embolism when the %LHA is > 50% or the SIR is > 1.25.
Abstract 5135: Carbon Monoxide Promotes Neovascularization After Myocardial Infarction by Modulating the Expression of Angiogenic Cytokines and Growth Factors
Authors: Lakkisto Paivi , Siren Juha-Matti , Immonen Katariina , Forsten Hanna , Kytö Ville , Segersvärd Heli , Voipio-Pulkki Liisa-Maria , Laine Mika , Pulkki Kari , Tikkanen Ilkka
Published: April 2024

Carbon monoxide is a biologically active molecule produced endogenously by heme oxygenase-1 (HO-1). Many of the beneficial properties of HO-1 are mediated by CO, but the role of CO in cardiac regeneration has not been studied earlier. Male Wistar rats were given the direct CO-donor methylene chloride (MC, 500 mg/kg, po, −3h, n=60). Control animals received no pretreatment (n=60). Rats were subjected to LAD ligation or sham-operation and sacrificed at 1 day, 3 days, 1 week and 4 weeks after ligation. Cardiac regeneration was assessed by immunohistochemistry and confocal microscopy. Stem cell and angiogenesis related gene expression was studied using real-time RT-PCR arrays. Compared to control hearts, CO significantly increased the accumulation of c-kit+/sca-1−/CD34− cells into the infarct area at weeks 1 (0.47±0.1 vs. 0.18±0.06 c-kit+ cells/mm2, p<0.05) and 4 (12.4±6.8 vs. 0.14±0.06 c-kit+ cells/mm2, p<0.001) post-MI. A substantial part of these c-kit+ cells (41%) were positive for the smooth muscle transcription factor GATA6 whereas only few Ets-1+ endothelial lineage committed cells were found. CO also increased vascular density in the infarct area at week 4 (395±24 vs. 306±25
α
-SMA+ vessels/mm2, p<0.05). Interestingly, the number of large arteries was most significantly increased (7.1±0.6 vs. 4.8±0.4
α
-SMA+ vessels/mm2, p<0.01). However, CO had no effect on capillary density. In the PCR array analysis, significantly increased expression of angiogenic cytokines and growth factors, including SDF-1, Hif-1
α
, HGF, IGF-1, IL6 and CXCL2, was found in the infarct areas of CO-donor pretreated hearts compared to control MI hearts (p<0.05). In conclusion, CO upregulates the expression of angiogenic cytokines and growth factors, thereby activating c-kit+ stem cells and promoting neovascularization in the infarcted hearts.
Abstract 5139: Critical Role of CalDAG-GEFI Signaling in Myocardial Ischemia-Reperfusion Injury
Authors: Stolla Moritz , Gao Erhe , Stefanini Lucia , Most Patrick , Force Thomas L , Bergmeier Wolfgang
Published: April 2024

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 5142: Direct Monitoring of Mitochondrial Calcium Levels in Cultured Cardiomyocytes Using a Novel Fluorescent Indicator Protein, GCaMP2-mt
Authors: Iguchi Moritake , Akao Masaharu , Nakai Junichi , Kato Masashi , Takeda Toshihiro , Matsumoto-Ida Madoka , Kimura Takeshi , Kita Toru
Published: April 2024

Background: An opening of the mitochondrial permeability transition pore (MPTP), which leads to loss of mitochondrial membrane potential (ΔΨ
m
), is the earliest event that commits the cell to death. Mitochondrial matrix calcium ([Ca
2+
]
m
) is considered a critical regulator of MPTP, but direct monitoring of [Ca
2+
]
m
has been difficult with previously reported sensors due to limited signal intensity or low targeting efficiency. We developed a novel fluorescent indicator for [Ca
2+
]
m
, GCaMP2-mt, by adding the mitochondrial targeting sequence of cytochrome oxidase to a high signal-to-noise Ca
2+
sensor protein GCaMP2, and monitored the dynamic changes in oxidant-induced cardiomyocyte death.

Methods and Results: GCaMP2-mt was transduced in neonatal rat cardiomyocytes using a recombinant adenovirus. We confirmed that GCaMP2-mt colocalized well with tetramethylrhodamine ethyl-ester, a fluorescent indicator of ΔΨ
m
. We monitored oxidant-induced response of [Ca
2+
]
m
and ΔΨ
m
using time-lapse confocal microscopy. After H
2
O
2
exposure, [Ca
2+
]
m
remained unchanged for about 20 min, followed by kinetically-distinct two-step increase; the first increase lasted for about 5 min, and the second increase was slower and persisted until cells underwent irreversible ΔΨ
m
loss. Importantly, there was a cellular heterogeneity in the second increase, and the level of [Ca
2+
]
m
overload was variable. However, ΔΨ
m
loss occurred in an all-or-none manner depending on cellular [Ca
2+
]
m
level, with a clear cut-off value. A Ca
2+
chelator BAPTA suppressed both the first and the second increase of [Ca
2+
]
m
, and protected the cells against ΔΨ
m
loss. In contrast, ruthenium red, an inhibitor of mitochondrial Ca
2+
uniporter, suppressed only the second increase of [Ca
2+
]
m
, but not the first increase. Despite the suppressed [Ca
2+
]
m
overload, ruthenium red was unable to protect against ΔΨ
m
loss; it caused earlier increase in cytosolic Ca
2+
([Ca
2+
]
c
) level which might have accelerated the MPTP opening, as measured by an indicator of [Ca
2+
]
c
, Fluo-4. These findings support the central role of [Ca
2+
]
m
as well as [Ca
2+
]
c
overload in the MPTP opening.

Conclusion: Direct monitoring of [Ca
2+
]
m
using GCaMP2-mt provides deeper insight into the mechanism of cardiomyocyte death.
Abstract 5145: Central or Ambulatory Peripheral Blood Pressure: Which Best Relates to Target-organs and Future Mortality?
Authors: Huang Chi-Ming , Wang Kang-Ling , Cheng Hao-Min , Vhuang Shao-Yuan , Ting Chih-Tai , Lakatta Edward G , Yin Frank , Chou Pesus , Chen Chen-Huan
Published: April 2024

Background: Central blood pressure (CBP) relates more to target organs and future cardiovascular mortality than peripheral blood pressure. It remains unknown whether single measurement of CBP is superior to multiple measurements of peripheral blood pressure from ambulatory blood pressure (AmBP) monitoring in the association with target organs and future mortality.

Methods: CBP by carotid tonometry and 24-hour AmBP from a community-based population of 943 participants were analyzed. Cross-sectional association of the various blood pressure variables with left ventricular mass (LVM), carotid intima-media thickness (IMT), and estimated glomerular filtration rate (eGFR), and longitudinal association with all-cause and cardiovascular mortality over a 14.9-year median follow-up were investigated.

Results: Among the 4 blood pressure variables, including the 24-hour SBP-Am and PP-Am, and SBP-C and PP-C, LVM correlated best with SBP-Am, whereas IMT and eGFR correlated best with PP-C. All 4 blood pressure variables, as well as target-organ indices predicted 14.9-year all-cause and cardiovascular mortality in the univariate analysis. With adjustment for conventional risk factors as well as LVM, IMT, and eGFR, individually entered SBP-Am, PP-Am, SBP-C or PP-C independently predicted cardiovascular mortality but not all-cause mortality. When the blood pressure variables were jointly entered into the multivariate models, only SBP-Am consistently predicted cardiovascular mortality.

Conclusion: SBP-Am and PP-C relate differently to different target-organs. SBP-Am is more powerful than SBP-C or PP-C in the prediction of cardiovascular mortality.
Abstract 5148: Coexistence of Functional Angiotensin II Type 2 Receptors Mediating Both Vasoconstriction and Vasodilation in the Human Forearm Circulation
Authors: Schinzari Francesca , Tesauro Manfredi , Rovella Valentina , Mores Nadia , Cardillo Carmine
Published: April 2024

Angiotensin (Ang) II type 2 (AT
2
) receptors have been shown to mediate vasodilation in animal models, but data to support this concept in humans have failed to clearly define AT
2
receptor-dependent effects. In this study, therefore, we investigated the hemodynamic response to modulation of AT
2
receptors under different conditions in healthy humans (n=7) by use of the forearm perfusion technique. Intra-arterial infusion of graded doses of Ang II (12.5, 25 and 50 pmol/min) led to concentration-dependent vasoconstriction (−51±4% [mean±SEM] was the maximum decrease in forearm blood flow (FBF) from baseline; P<0.001). The Ang II type 1 receptor antagonist telmisartan (30
μ
g/min) induced a mild increase in unstimulated FBF (15±5%; P=0.10) and reversed the vasoconstrictor effect of Ang II into vasodilation (15±4%; P=0.02). The AT
2
receptor antagonist PD 123,319 (10
μ
g/min) also resulted in a mild vasodilation (16±3%; P=0.08) and blunted the vasoconstrictor effect of Ang II (−8±3%; P=0.57). Most importantly, combined infusion of telmisartan and PD 123,319 was associated with a greater vasodilator effect (28±5%; P=0.02) than separate blockade of each Ang II receptor subtype; this response was unrelated to endothelial, nitric oxide (NO)-dependent mechanisms, because it was unaffected (27±5%; P=0.03) by the “NO clamp” (NO synthase inhibitor L-NMMA (4
μ
mol/min) coinfused with the NO donor sodium nitroprusside (0.2 to 0.4
μ
g/min) in order to simulate normal basal NO activity during complete inhibition of NO synthesis). By contrast, AT
2
receptor challenging with the ligand CGP 42112A (2 and 4
μ
g/min) resulted in a vasodilator response (37±5% at the highest dose; P=0.02) that was abolished by the NO clamp (3±1%; P=0.94). In conclusion, AT
2
receptors contributing to Ang II-mediated vasoconstriction, likely located on vascular smooth muscle, coexist in the human forearm circulation with functional endothelial AT
2
receptors, mediating NO-dependent vasodilation. These results suggest that imbalance between these opposing effects in conditions with endothelial dysfunction contribute to Ang II-mediated vascular damage. Our current findings might also have implications for strategies targeting Ang II for treatment of hypertension.
Abstract 5149: Ambulatory Blood Pressure in a Large Cohort of Treated Hypertensive Subjects
Authors: De La Sierra Alejandro , Banegas Jose R , Segura Julian , Gorostidi Manuel , de la Cruz Juan J , Ruilope Luis M
Published: April 2024

Aim:
To examine the concordance of blood pressure control by means of both clinic (office) measurements and ambulatory blood pressure monitoring (ABPM), in a large cohort of treated hypertensive subjects from the Spanish Ambulatory Blood Pressure Monitoring registry

Methods:
A total number of 43 499 hypertensives under antihypertensive treatment were analyzed. Office BP control was defined if the patient had BP below 140/90 mmHg. Ambulatory BP control was considered by means of 3 different criteria:

if daytime BP (based on patient’s reported activity) was below 135/85 mmHg.

if 24-hour BP was below 130/80 mmHg, and

if nighttime BP was below 120/70 mmHg.

Clinical characteristics were compared between patients with daytime BP below or above 135/85 mmHg

Results:
Table 1

shows numbers and proportions of patient having control or lack of control by means of office and ABPM (the 3 criteria used). Concordant control of BP was present in 17.4%, 15.7%, and 12.9%, by the 3 different criteria. The main source of difference between office and ABPM was the proportion of patients with isolated office resistance, the proportion of which, using the 3 aforementioned criteria was 34.5%, 29.1%, and 26.8%, respectively. When compared to patients with normal ABPM values, the presence of elevated daytime BP (higher than 135/85 mmHg) was associated (p<0.001 for all comparisons) with male gender (57.5% vs 47.7%), diabetes (25.1% vs 20.9%), smoking (17.5% vs 12.5%), left ventricular hypertrophy on EKG (11.1 vs 9.1), and chronic kidney disease (3.0% vs 2.0%).

Conclusion:
Blood pressure control in the treated hypertensive population by using ABPM is twice as observed by office measurements. The proportion of patients with isolated office resistance (white coat) is relatively large. Normal values of ABPM in treated patients are more frequent in women, nondiabetic, and nonsmokers subjects, as well as in those without organ damage.

Blood Pressure Control by means of Office and ABPM measurements
Abstract 5151: Waveform Reflections and Arterial Stiffness in the Prediction of 15.1-Year All-Cause and Cardiovascular Mortalities: A Community-Based Study
Authors: Wang Kang-Ling , Cheng Hao-Min , Chuang Shao-Yuan , Spurgeon Harold , Ting Chih-Tai , Najjar Samer , Lakatta Edward , Yin Frank , Chou Pesus , Chen Chen-Huan
Published: April 2024

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 5164: Loss of SOCS3 Expression in T Cells Reveals a Regulatory Role for Interleukin-17 in Atherosclerosis
Authors: Taleb Soraya , Romain Melissa , Ramkhelawon Bhama , Uyttenhove Catherine , Pasterkamp Gerard , Herbin Olivier , Esposito Bruno , Perez Nicolas , Yasukawa Hideo , van Snick Jacques , Yoshimura Akihiko , Tedgui Alain , Mallat Ziad
Published: April 2024

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immuno-inflammatory balance in the modulation of disease development and progression. However, the immuno-regulatory pathways that control atherosclerosis remain largely unknown. Here, we show that loss of Suppressor of Cytokine Signaling 3 (SOCS3) in T cells increases both interleukin (IL)17 and IL10 production, induces an anti-inflammatory macrophage phenotype, and leads to unexpected IL17-dependent reduction in lesion development and vascular inflammation. In vivo administration of IL17 reduces endothelial vascular cell adhesion molecule (VCAM)-1 expression, vascular T cell infiltration and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of Stat3 phosphorylation and IL17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL17 regulatory pathways in atherosclerosis and may have important implications to the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 differentiation.
Abstract 5165: Liver-x-receptor Activation Inhibits Chemokine Induced Cd4-positive Lymphocyte Migration
Authors: Walcher Daniel , Vasic Dusica , Heinz Philipp , Marx Nikolaus
Published: April 2024

Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that activation of the nuclear transcription factor Liver-X-Receptor (LXR) limits plaque formation in animal models by modulating macrophage function. Previous data demonstrated LXR alpha and beta mRNA and protein expression in human CD4-positive lymphocytes. In addition, activation of LXR limits TH1-cytokine release from CD4-positive cells, but the role of LXR in lymphocyte migration remains currently unexplored. Therefore, the present study investigated whether LXR activation might modulate chemokine-induced migration of these cells. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.5±0.8 fold increase in cell migration (p<0.05; n=12). Pretreatment of cells with the LXR activator T0901317 reduces this effect in a concentration-dependent manner to a maximal 0.9±0.4 fold induction at 1
μ
mol/L T0901317 (p<0.05 compared to SDF-1-treated cells, n=12). Similar results were received with the LXR activator GW3965. In addition, T0901317 also reduced RANTES-induced cell migration, suggesting an effect independent of the chemotactic stimulus employed. The effect of T0901317 on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, T0901317 inhibited the activation of the small GTPase Rac and the phosphorylation of the Myosin Light Chain (MLC). Pretreatment with the LXR activator also reduces f-actin formation as well as ICAM3 translocation to the uropod, both important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXR
α
/
β
siRNA abolished T0901317 inhibitory effect on MLC-phosphorylation. LXR activation by T0901317 or GW3965 inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, LXR activators may be promising tools to modulate this effect.
Abstract 5197: Arterial Remodeling Determines the Local Hemodynamic Environment and Subsequent Progression of Coronary Atherosclerotic Plaques: A Serial, Natural History Intravascular Ultrasound Study
Authors: Koskinas Konstantinos C , Chatzizisis Yiannis S , Coskun Ahment U , Jonas Michael , Baker Aaron , Edelman Elazer R , Feldman Charles L , Stone Peter H
Published: April 2024

Background

Endothelial shear stress (ESS) is a critical determinant of plaque formation and arterial remodeling. Expansive remodeling is a feature of plaque vulnerability. Our purpose was to assess the role of remodeling and ESS in plaque progression throughout the natural history of atherosclerosis.

Methods

Intravascular ultrasound (IVUS)-based 3D reconstruction of all major coronary arteries (n=15) was performed in vivo at weeks 4, 11, 16, 23 and 36 in five diabetic, hyperlipidemic pigs. Each artery was divided into 3mm-long segments (n=304). We calculated ESS in all segments at all time points using computational fluid dynamics. Remodeling was characterized at all time points as excessive expansive, compensatory or constrictive. Plaque progression between consecutive time points was assessed by change of plaque area (ΔPlaque).

Results

The remodeling response to individual plaque formation changed substantially over time. Excessive expansive remodeling persistently developed in regions of very low ESS (Fig A

), further decreased the low ESS (p<0.05), and was associated with the most marked additional plaque growth (Fig B

). Compensatory and constrictive remodeling generally resulted in increase of local ESS, and in less pronounced plaque progression (Fig A, B

).

Conclusions

This study provides new insight into the role of remodeling as a determinant of plaque progression. Excessive expansive remodeling exacerbates the pro-atherogenic low ESS environment, and promotes subsequent plaque growth. In contrast, attenuation of the low ESS stimulus occurs in lesions that elicit a compensatory, or constrictive remodeling response, leading to relative plaque quiescence.
Abstract 5218: Corrin-mediated Activation of Nitric Oxide Receptor and Its Cardiovascular Consequences
Authors: Martin Emil , Sharina Iraida G , Liang Yang Yan , Doursout Marie-Francoise
Published: April 2024

Soluble guanylyl cyclase (sGC) is the recognized receptor for nitric oxide (NO) messenger molecule. In addition to NO, several allosteric regulators, which do not produce NO, can activate sGC heme-dependently or independently. Earlier studies recognized that tetrapyrrole protoporphyrin IX can actively replace sGC heme moiety or bind to the heme-deficient sGC, resulting in a robust activation of sGC ability to produce cGMP from GTP. We investigated the effects of various tetrapyrroles on the ability of sGC to generate cGMP in vitro. Our data demonstrated that not only various protoporphyrins but some corrins can activate sGC. Pro-vitamin B12 dicyanocobinamide (CN2-Cbi) was the most efficient among tested compounds. CN2-Cbi-dependent activation of sGC was synergistically enhanced by BAY41–2272, a heme-dependent allosteric regulator of sGC. CN2-Cbi and several other corrins, including vitamin B12, induces a dose-dependent relaxation on isolated rat aorta rings. Tested corrins were equally effective in endothelium competent or endothelium denuded rings. Effective concentrations of CN2-Cbi were significantly improved with BAY41–2272, and relaxation was achieved even with micromolar CN2-Cbi. Therefore, data are consistent with direct activation of sGC by CN2-Cbi. Following ex-vivo relaxation by CN2-Cbi, we monitored blood pressure (BP) in anesthetized rats in response to CN2-Cbi. CN2-Cbi (5 mg/kg bolus) induced a modest and transient decrease in BP while 15 mg/kg showed a more marked and prolonged response. Decreased BP was associated with increased cardiac output, suggesting vascular relaxation. CN2-Cbi combined with 100
μ
g/kg BAY41–2272 induced a more profound and prolonged decrease in BP. Following U-46619, a thromboxane analogue to induce systemic and pulmonary hypertension, combined CN2-Cbi/BAY41–2272 was also effective in restoring systemic and pulmonary pressures to baseline. These data suggest that CN2-Cbi (or corrin)-mediated activation of sGC may be an alternative approach to regulate sGC activity and vascular function. Data indicate that derivatives of vitamin B12 may be used for regulation of BP in normal and hypertensive conditions as part or treatment regimens or dietary supplements.
Abstract 5252: Long-Term Administration of Thiazolidinedione Improves Vasomotion of Coronary Arteries Irrespective of Improvements in Diabetic Status for Patients Receiving an Angiotensin-II Receptor Blocker
Authors: Murakami Tatsuaki , Ohsato Kazuo
Published: April 2024

Background:
Effects of insulin sensitizing agents on coronary artery pathophysiology have marked attention, but the long-term effects remain uncertain. We previously reported clinical effects of thiazolidinedione, and adverse prognostic impacts of vasomotor dysfunction in coronary arteries. This study evaluated long-term effects of thiazolidinedione, an insulin sensitizer, on vasomotion of coronary arteries frequently affected by diabetes mellitus, in patients treated with an angiotensin-II receptor blocker, one of the best possible antiatherosclerotic therapies.

Methods:
Twenty-two type-2 diabetic patients treated with an angiotensin-II receptor blocker, were randomized where they received troglitazone (400mg/ day) or pioglitazone (30mg/day) (group-T), or they received therapy without thiazolidinedione for more than 1 year (group-C). We measured reactive changes in coronary blood flow (coronary flow reserve: CFR) or reactive endothelium-dependent dilatation (FMD) of coronary arteries to infusion of ATP (50
μ
g) into the study (normal or minimally diseased) left coronary artery. CFR (maximal hyperemic flow-baseline flow/baseline flow) was quantified by coronary angiography and intracoronary doppler-guidewire. Changes in CFR and FMD were compared between the 2 groups.

Results:
All the enrolled patients manifested good compliance to the treatment and there were improvements in some of metabolic variables in group-T (n=11). CFR increased in group-T (p=0.027) but not in group-C (p=0.102). FMD also increased in group-T (p<0.001), while it remained unchanged in group-C (p=0.768). Changes of CFR or FMD did not correlate to those of HbA1c (CFR: r=0.19, p=0.66, FMD: r=0.15, p=0.80).

Conclusion:
This study suggests that long-term thiazolidinedione use improves vasomotion of coronary arteries irrespective of glucose metabolic status, which may have beneficial potentials for management of coronary artery disease with type-2 diabetes mellitus.
Abstract 5258: Insulin Stabilizes Coronary Microvascular Endothelial Barrier via PI3K/Rac1-mediated Stabilization of cell-cell adhesions
Authors: Aslam Muhammad , Thom Johannes , Hussain Imran , Haertel Frauke V , Grebe Mathias , Erdogan Ali E , Piper Hans M , Tillmanns Harald , Noll Thomas , Guenduez Dursun
Published: April 2024

Recent findings, both in animal and clinical studies show that insulin, besides its metabolic effects, has protective effects under inflammatory conditions as well as in reducing major cardiovascular events in patients undergoing vascular surgery. Loss of endothelial barrier is one of the earliest manifestations of inflammation and atherosclerosis. The role of insulin in the regulation of endothelial barrier function is not well described. The integrity of the endothelial barrier is highly dependent on acto-myosin based endothelial contractile machinery and adherens junctions. Rho-GTPases (Rac1 and RhoA) are well described as important regulators of actin cytoskeleton and adherens junctions and maintain integrity of endothelial barrier. Here the
hypothesis
was tested whether insulin stabilizes endothelial barrier via Rac1-mediated stabilization of adherens junctions.

Methods and Results:
In cultured coronary microvascular endothelial cells from rat heart (RCEC) insulin reduced the macromolecular permeability (albumin flux) from 4.9±0.2 × 10
−6
cm
2
/s to 3.4±0.3 × 10
−6
cm
2
/s (n5, P<0.05 for all further parameters) in a concentration-dependent manner with a maximum effect with 1U/ml and caused 3-fold increase in Akt phosphorylation (Western blot). This protective effect on permeability could be blocked by HNMP(AM)3 (1
μ
M, a specific insulin receptor inhibitor), and Wortmannin (1
μ
M; PI3K inhibitor), suggesting that insulin reduces permeability via receptor-mediated activation of Akt. Furthermore, insulin induced a 3-fold activation of Rac1 (pull down assay), increased cortical actin and VE-cadherin at cell-cell adhesions (confocal microscopy). These insulin effects could be blocked by HNMP(AM)3, and wortmannin. Furthermore, inhibition of Rac1 with
NSC23766
(100
μ
M; pharmacological inhibitor of Rac1) abrogated insulin mediated barrier stabilization.

Conclusion:
We show here for the first time that insulin enhances endothelial barrier function in RCEC monolayers via PI3K/Akt-mediated activation of Rac1, which stabilizes endothelial cell adherens junctions. Further understanding of this mechanism could be beneficial in the development of therapeutic strategies for vessel protection during pathological conditions.
Abstract 5261: Myocardial Infarction Impairs Renal Function, Induces Renal Interstitial Fibrosis and Increases Kim-1 Expression: Implications for the Cardiorenal Syndrome
Authors: Lekawanvijit Suree , Kompa Andrew , Zhang Yuan , Wang Bing H , Kelly Darren J , Krum Henry
Published: April 2024

Introduction:
Accelerated progressive decline in renal function has been described as a coexistent event post-myocardial infarction (MI) (cardiorenal syndrome, CRS). We hypothesized that MI has early detrimental effects on the kidney by evaluating functional, structural and molecular changes over time.

Methods:
Male Sprague-Dawley rats were randomized to three groups: non-operated, sham and MI. Cardiac and renal function was assessed prior to sacrifice at 4, 8, 12 and 16 weeks. Tissues were assessed for injury markers and pathological changes using histological methods and real-time PCR.

Results:
Myocardial infarct size and blood pressure (BP) were the same in all groups. Percent fractional shortening was reduced in MI animals at all time points by up to 63% at 16 weeks. As expected, heart/body weight (BW) and left ventricle/BW were significantly greater in MI than sham animals. Glomerular filtration rate (GFR) was significantly decreased in MI compared to sham at 4 wks (
p
=0.016) but not at 8 and 12 wks; and deteriorated further at 16 wks (
p
=0.052). Renal cortical interstitial fibrosis and TGF-
β
bioactivity (p-smad2) were significantly greater in MI animals at all time points. The degree of fibrosis progressively increased and was maximal at 16 weeks. TGF-
β
1 gene expression in the kidney cortex trended toward an increase at 4 and 8 weeks (
p
=0.109 and 0.070, respectively). In addition, Kim-1 positive staining in the tubules was more prominent in MI animals over time.

Conclusions:
CRS occurs early post-MI and is associated with progressive renal interstitial fibrosis via activation of Smad2 signaling pathway. Kim-1 may represent an early marker of post-MI kidney injury.
Abstract 5298: Staphylococcal Superantigen-like 5 Induces Platelet Activation and Thrombosis via Binding to GPIb
α
and GPVI
Authors: Hu Houyuan , Khalil Elie , Chen Yung Chih , Straub Andreas , Li Min , Jia Fu , Bassler Nicole , Huang Dexing , Ahrens Ingo , Gardiner Elizabeth , Peter Karlheinz
Published: April 2024

Staphylococcus aureus
(S. aureus)
is a common and dangerous bacterial pathogen capable of causing life-threatening thromboembolic disease such as disseminated intravascular coagulation (DIC).
S. aureus
is known to secrete potent toxins that include Staphylococcal superantigen-like protein 5 (SSL5), which was recently shown to bind P-selectin glycoprotein ligand-1 (PSGL-1). As PSGL-1 is structurally and functionally related to the glycoprotein (GP) Ib
α
platelet receptor, this study assessed the ability of SSL5 to interact with GPIb
α
as well as other platelet glycoprotein receptors. Using flow cytometry, immunoprecipitation, surface plasmon resonance, platelet adhesion and aggregometry assays, recombinantly produced SSL5 was found to directly bind to platelet GPIb
α
via the sLacNac residues that terminate its glycan chains. SSL5 was also found to bind to the platelet collagen receptor GPVI. This binding of SSL5 to platelets causes platelet activation and aggregation as demonstrated in
in vitro
assays. SSL5 was subsequently tested for its prothrombotic effects in C57BL/6 mice. Pulmonary thrombi developed in 8 of 11 intraveneously SSL5-injected mice but were absent from 5 mice injected with a functionally-inactive SSL5 protein carrying a T175P point mutation. Further expriments using flow cytometry showed that SSL5-induced platelet activation was significantly inhibited by an anti-SSL5 monoclonal antibody designated 5E3 (10
μ
g/ml, P < 0.001), as well as sLe
x
(IC50 < 5
μ
M, P < 0.001) and sLacNac glycans (IC50 < 50
μ
M, P < 0.001). Moreover, the injection of 5E3 in SSL5-treated mice (n = 8) compared with mice only injected with SSL5 (n = 8), was found to inhibit SSL5-induced thrombus formation (P < 0.05). Taken together, our data show that SSL5 binds to GPIb
α
and GPVI and as a consequence of this activates platelets and induces thrombosis. Thus, we describe a novel pathogenic mechanism potentially active in
S. aureus
infections. Furthermore, blockade of SSL5-induced platelet activation and thrombosis by either 5E3 or inhibitory glycans defines a novel treatment strategy and identifies suitable drug candidates for prevention and treatment of thrombotic diseases associated with
S. aureus
infections.
Abstract 5302: Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis and Thrombotic Stroke
in vivo
Authors: Jin Richard C , Mahoney Christopher E , Zhang Ying-Yi , Handy Diane E , Loscalzo Joseph
Published: April 2024

Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing protein with antioxidant activity. GPx-3 plays an important role in plasma by scavenging reactive oxygen species. We have previously shown that a heritable deficiency of this enzyme is associated with platelet-dependent thrombotic stroke in patients. We recently developed a GPx-3 knockout mouse to assess platelet function and platelet-dependent thrombosis in models of vascular injury. We hypothesized that GPx-3 deficiency promotes platelet-dependent thrombus formation
in vivo
. GPx-3 (−/−) mice showed an attenuated bleeding time compared with wild-type mice (94.5±28.8 s versus 153.4±32.3, P<0.05). We also noted an increase in the plasma levels of soluble P-selectin, a marker of platelet activation and prothrombotic activity, in GPx-3 (−/−) mice compared with wild-type mice (137.8±12.3 ng/ml plasma versus 101.5±8.8, P<0.05). Using a no-flow ischemia-reperfusion stroke model, we found that GPx-3 (−/−) mice had significantly larger cerebral infarctions compared with wild-type mice (117.5±7.9 mm
3
versus 17.2±2.7, P<0.001) as well as higher neurological deficit scores (3.33±0.33 versus 1.3±0.33, P=0.02). To investigate the effect of platelet inhibition on stroke size in GPx-3 deficiency, GPx-3 deficient mice were pre-treated with clopidogrel prior to producing the stroke. We found that clopidogrel treatment reduced stroke size significantly compared with vehicle-treated controls (4.42±3.0 mm
3
versus 105.1±15.2, P=0.003) as well as lowered neurological deficit scores (0.4±0.2 versus 2.83±0.44, P=0.018). These findings demonstrate that GPx-3 deficiency promotes platelet activation resulting in a prothrombotic state. These data illustrate the importance of this plasma antioxidant enzyme in regulating platelet activity, platelet-dependent thrombosis, and vascular thrombotic propensity.