bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 578: Urotensin-II Upregulation in Human Heart Failure: Direct Effects on Contractility and Sarcoplasmic Reticulum Calcium Load
Authors: Quaile Michael P , Margulies Kenneth B
Published: April 2024

While studies have reported that Urotensin II (UII) is upregulated in failing (F) hearts, the pathophysiologic implications of increased UII on cardiac function is incompletely understood. We investigated the direct effects of exogenous UII on in vitro contractile performance and sarcoplasmic reticulum (SR) Ca
2+
load in F and non failing (NF) human myocardium.

Methods:
Isometric force was measured in F (n=11) and NF (n=6) right ventricular trabeculae (0.5 Hz, 37°C) before and after bath application of UII (UII; 0.1, 1.0, 10, 100, 1000 nM). Single and paired rapid cooling contractures (RCCs) were employed to define SR Ca
2+
load and the balance between SERCA and the NCX.

Results:
UII induced increases in developed tension (DT) in NF trabeculae and dose-dependent decreases in DT in F trabeculae. UII did not alter resting tension in either group. RCC amplitude increased during graded increases in UII in NF trabeculae, suggesting increases in SR calcium load, but remained stable in F trabeculae. In NF trabeculae, UII did not alter the RCC2/RCC1 ratio at any concentration, but in F trabeculae the RCC2/RCC1 ratio increased at 0.1 nM UII then exhibited dose-dependent decreases at higher concentrations.

Conclusion:
In contrast to the positive inotropic response elicited in NF hearts, UII is a negative inotrope in ventricular trabeculae obtained from F human hearts. Based on the RCC data, UII has little effect on SR Ca
2+
load in F myocardium suggesting that negative inotropic responses reflect decreases in myofilament Ca
2+
sensitivity. The paired RCC data suggests that U-II also affects the functional competition between SERCA and NCX differently in F and NF human hearts.
Abstract 600: Inhibition of G Protein-Coupled Receptor Kinase-3 (GRK3) Rescues Cardiac Dysfunction after Pressure Overload
Authors: Gravning Jørgen A , von Lueder Thomas G , Edvardsen Thor , How Ole J , Aasum Ellen , Ahmed Mohammad S , Vinge Leif E , Mikkelsen Birthe V , Larsen Terje S , Smiseth Otto A , Attramadal Havard
Published: April 2024

Background:
Previous studies of transgenic mice with cardiac-restricted inhibition of G protein-coupled receptor kinase-3 (GRK3) have disclosed phenotype consistent with α
1
- adrenergic receptor (α
1
-AR) hyperresponsiveness. As opposed to GRK2 (β-ARK1), an isoenzyme with selectivity for β-AR, the pathophysiologic role of GRK3 in heart failure has not been investigated. Accordingly, the functional role of GRK3 during evolving cardiac dysfunction after pressure overload was dissected in this study.

Methods and results:
GRK3ct transgenic mice (Tg-GRK3ct) with α-MHC promoter-driven expression of mini-gene encoding the carboxyl-terminal membrane targeting domain of GRK3 were employed. Inhibition of endogenous GRK3 was confirmed by enhanced α
1
-AR mediated activation of ERK 1/2 in cardiac myocytes from Tg-GRK3ct as compared to non-transgenic littermates controls (NLC). Tg-GRK3ct mice characteristically displayed myocardial hypercontractility despite unaltered cardiac mass, compared to NLC. Pressure overload was induced by abdominal aortic banding (AB) in weight matched male Tg-GRK3ct (GRK3ct-AB) and NLC (NLC-AB) mice and compared with sham-operated Tg-GRK3ct (GRK3ct-SH) and NLC (NLC-SH) mice. Echocardiography disclosed similar baseline cardiac dimensions among all groups. Eight and twelve weeks after AB significant increases of cardiac mass were found in AB mice compared to sham, but no differences between GRK3ct-AB and NLC-AB were discerned. Eight weeks after AB, analysis of electrically paced,
ex vivo
perfused hearts at increasing filling pressures revealed preserved end-diastolic and end-systolic pressure-volume (PV) relations in GRK3ct-AB (n=10), with substantially higher cardiac output and dP/dt
max
compared to NLC-AB (n=10). Twelve weeks after AB, simultaneous
in vivo
PV-analysis revealed elevated end-diastolic pressure (10.6±3.1 mmHg vs. 2.7±2.2, p<0.05) and lower cardiac output (7379±738 μL/min vs. 9847±785, p<0.05) in NLC-AB (n=11) compared to GRK3ct-AB (n=16). Consistently, myocardial mRNA level of B-type natriuretic peptide was substantially elevated in NLC-AB compared to GRK3ct-AB (p<0.05).

Conclusion:
Inhibition of cardiac GRK3 in mice rescues cardiac dysfunction and heart failure after pressure overload.
Abstract 601: Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice
Authors: Blum Shany , Asaf Roy , Guetta Julia , Miller-Lotan Rachel , Asleh Rabea , Kremer Ran , Levy Nina S , Aronson Doron , Fu Xiaoming , Zhang Renliang , Hazen Stanley L , Levy Andrew P
Published: April 2024

Objectives.
We sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM).

Background.
Two common alleles (1 and 2) exist at the Hp locus in man. The haptoglobin (Hp) 2 allele is associated with increased MI size in individuals with DM. Enhanced oxidative stress resulting in increased production of reactive oxygen species has been shown to play a critical role in the generation of myocardial ischemia-reperfusion injury (IR). Redox active labile plasma iron (LPI) and the anti-inflammatory cytokine interleukin-10 (Il-10) are known to play major roles in determining the extent of myocardial injury after myocardial IR. In vitro the Hp 2 protein is associated with increased generation of oxidatively active iron while the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin-10 (Il-10).

Methods.
MI was produced by myocardial ischemia-reperfusion (IR) using an occlusion of the left anterior descending artery followed by reperfusion in DM C57Bl/6 mice carrying the Hp 1 or Hp 2 allele. Myocardial oxidative stress after IR was assessed using electrospray ionization mass spectrometry. Redox active iron and Il-10 were measured in the serum after IR.

Results.
MI size was significantly larger in Hp 2 mice as compared to Hp 1 mice (44.3±9.3% vs. 21.0±4.0%, p=0.03) and these larger infarctions were associated with a significant increase in a panel of hydroxyl-eicosatetraenoic acids (HETEs). Redox active iron was greater in Hp 2 mice (0.45±0.11uM vs. 0.14uM±0.05uM, p=0.02) while Il-10 was greater in Hp 1 mice (4170±646 pg/ml vs. 2115±541 pg/ml, p=0.03) after IR. Administration of an antioxidant (glutathione peroxidase mimic BXT-51072) to Hp 2 mice reduced myocardial injury after IR by over 80% (44.3±9.3 % vs. 7.0±3.1%, p=0.003). but no myocardial protection was provided by the antioxidant to Hp 1 mice.

Conclusions.
The increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress. We suggest that strategies which will be designed to decrease this oxidative stress may provide significant myocardial protection.
Abstract 609: Erythropoietin-Mediated Protection Against Hypoxia/Reoxygenation Injury in Human Muscle is via Phosphatidylinositol-3-Kinase and P42/44 Kinase Activation
Authors: Mudalagiri Naveen R , Yellon Derek M
Published: April 2024

The renal cytokine Erythropoietin (EPO) has in animal studies demonstrated myocardial protection, this being linked to the activation of pro-survival signalling cascades, phosphatidylinositol-3-kinase (PI3K) and p42/44 extra-cellular signal-regulated kinases. This protection and the mechanisms associated with it have to date not been observed in human myocardium. We investigated the ability of EPO to protect human atrial trabeculae obtained from patients undergoing coronary artery bypass surgery. Since PI3K has been shown to be down regulated in diabetic animal studies we also examined the ability of EPO to protect human muscle from type 2 diabetic patients. Isolated human atrial trabeculae were suspended in an organ bath and exposed to 90 minutes of hypoxia followed by 120 minutes of reoxygenation. EPO (50ng/ml) was administered throughout reoxygenation following simulated ischemia. Cardiac function was assessed by measuring the developed force of contraction which was calculated as a percentage of baseline force of contraction. EPO improved force of contraction when administered at reoxygenation (46.7% +/− 1.7 vs. 30.2% +/− 2.2 for control, p< 0.001). These effects were abrogated by the PI3K inhibitor, LY294002 (29.4% +/− 2.5 vs. 30.2% +/−2.2 for control) and P42/44 inhibitor, UO126 (31.5% +/− 2.5 vs. 30.2% +/− 2.2 for control). EPO and preconditioning (as a positive control) offered similar degrees of protection (46.7% +/− 1.8 vs. 51.2% +/− 1.4 for preconditioning). In the diabetic group, EPO improved force of contraction (38.3% +/− 1.4 vs. 30.2% +/− 2.2 for control, p<0.05). However, the degree of cardioprotection was less than that observed in the non diabetic group (38.3% +/− 1.4 vs. 46.7% +/− 1.7 for non diabetic EPO group, p<0.005). EPO administered at reoxygenation protects the human muscle via the PI3K and P42/44 dependent pathways. Inhibiton of either pro-survival kinase results in loss of cardiac protection. EPO cardioprotection was also observed in the diabetic group, although still significant, was not of the same magnitude as observed in the non diabetic group. This data supports the potential use of EPO as a novel cardioprotective strategy when used alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.
2006 Russell Ross Memorial Lectureship in Vascular Biology—Tissue Factor as a Mediator and Marker of Cardiovascular Disease: New Roles for an Old Molecule
Authors: Taubman Mark
Published: April 2024

Tissue factor (TF) is a transmembrane glycoprotein that initiates coagulation and plays a critical role in hemostasis and thrombosis. TF expression is linked to inflammatory and proliferative responses, in part through the generation of thrombin, an important mediator of growth and inflammation. Recent data have implicated TF as an important mediator of angiogenesis, intimal hyperplasia, ischemia-reperfusion injury, and cardiac fibrosis. Our data also suggest that TF may mediate the intimal and proliferative responses in a rat model of pulmonary arterial hypertension. It is likely that the effects of TF on these processes are particularly related to its role in mediating inflammation. Although TF was once thought to act exclusively as a cell-associated molecule, TF is present in several forms in the circulation. The predominant form is in microparticles (MPs) that presumably bud from the surface of many cell types, such as endothelium, macrophages, and smooth muscle cells, as a part of normal cellular homeostasis or are released during cell death or injury. TF-containing MPs have been found in association with naturally occurring and experimental thrombi. In addition to MPs, there is a naturally occurring, soluble form of human TF generated by alternative splicing. This splice variant has a novel C-terminus, lacks a transmembrane domain, and is present in blood. There are conflicting data as to the role of TF-containing MPs in mediating thrombosis. However, recent studies have found that blood TF is elevated in a variety of cardiovascular diseases, and blood TF levels may have predictive value for secondary events in patients with previous myocardial infarction and for venous thromboembolism.
2006 Dickinson W. Richards Memorial Lecture—Wading in the Genomic Pool for Insights Into Lung Vascular Pathobiology
Authors: Garcia Joe G.N.
Published: April 2024

The completion of the Human Genome Project enabled rapid, high-throughput genotyping and gene expression profiling, thereby ushering in the era of genomic medicine. The promise of molecular/ genomic medicine is that we may rapidly ascertain a patient’s genetic and molecular profile and thus target highly individualized therapies appropriate to that patient with little risk and high likelihood of success. In this lecture, we present currently available approaches to investigate potential genetic susceptibility factors that have led to the identification of several genes that impact susceptibility, protection, or severity in enigmatic and complex pulmonary syndromes such as acute lung injury (ALI). We highlight the utility of combining advanced bioinformatic techniques with multispecies gene expression profiling as a way to broaden our net for ALI-related genes. This genome-wise approach is the ideal complement to more traditional, hypothesis-based testing of candidate genes. We anticipate that the genome-wide approach will fuel additional analysis of new candidates while allowing for a wide-angle view of key biological processes such as inflammation, coagulation, and cell proliferation. It remains challenging to determine exactly which environmental and genetic factors are relevant within well-phenotyped populations of patients with complex lung disease (such as ALI/ARDS), and we continue to be constrained by our incomplete current understanding of how various factors interact. Nevertheless, with the dawn of the genomic era, the study of lung pathobiology and the elucidation of the molecular basis of complex lung disorders remains a lofty but achievable goal.
2006 Robert Levy Memorial Lecture—Physical Activity in the Prevention and Treatment of Cardiovascular Disease
Authors: Blair Steven
Published: April 2024

Much of the evidence linking a sedentary way of life to cardiovascular disease (CVD) has been derived from relatively healthy populations, but there are data on the effects of physical activity in individuals with health problems or with risk factors for chronic disease. Clinicians, and often the general public, frequently consider the primary value of physical activity as the contribution it makes to control of these other risk factors. This approach underestimates the value of physical activity in the prevention and treatment of CVD. There is a steep inverse gradient of CVD and all-cause mortality across categories of cardiorespiratory fitness and physical activity in all subgroups—women and men who are middle-aged or older, obese or normal weight, or healthy or unhealthy. The overall death rates vary by these subgroups (older individuals obviously have higher death rates than younger persons), but the pattern of association of fitness or activity to mortality is comparable for the various population subgroups. In fact, fit individuals with another risk factor often have lower death rates than unfit individuals without the risk factor. Regular physical activity and moderate to high levels of cardiorespiratory fitness provide protection against CVD and all-cause mortality, and these items should be given increased attention by physicians and other healthcare professionals. These findings are supported by both observational studies and randomized trials.
Gene Deletion Screen for Cardiomyopathy in Adult Drosophila Identifies Weary (Wry), a New Notch Ligand
Authors: Kim Il-Man
Published: April 2024

Abstract #3057

Il-Man Kim, Matthew J. Wolf, Howard A. Rockman, Duke Univ Medical Ctr, Durham, NC

Il-Man Kim, 2009 Finalist and Presenting Author
Delivery of SOD With Polyketal Particles Protects Rats From Acute Myocardial Infarction
Authors: Davis Michael E
Published: April 2024

Abstract #3086

Michael E Davis, Gokulakrishnan Seshadri, Sergey Dikalov, Milton Brown, Emory Univ Sch of Med, Atlanta, GA; Niren Murthy, Georgia Inst of Technology, Atlanta, GA

Michael E Davis, 2009 Finalist and Presenting Author
Running on Exhaustion: Pathogen Burden, Immune Dysregulation, and Endothelial Activation After Coronary Artery Bypass Graft Surgery
Authors: Miller Pamela S.
Published: April 2024

Abstract #906

Pamela S. Miller, Lorraine S. Evangelista, Joyce Newman Giger, Otoniel Martinez-Maza, Univ of California, Los Angeles, Los Angeles, CA; Teresita Corvera-Tindel, VA Greater Los Angeles Health Care System, Los Angeles, CA; Fardad Esmailian, Lynn V. Doering, Univ of California, Los Angeles, Los Angeles, CA

Pamela S. Miller, 2009 Finalist and Presenting Author
Clinical Implications of JUPITER in a United States Population: Insights From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Yang Eric Y
Published: April 2024

Abstract #896

Eric Y Yang, Vijay Nambi, Baylor Coll of Med, Houston, TX; Zhengzheng Tang, Univ of North Carolina, Chapel Hill, NC; Salim S. Virani, Baylor Coll of Med, Houston, TX; Eric Boerwinkle, Univ of Texas-Houston Sch of Public Health, Houston, TX; Ron C Hoogeveen, Baylor Coll of Med, Houston, TX; Brad C Astor, John Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Thomas H Mosley, Univ of Mississippi Medical Ctr, Jackson, MS; Josef Coresh, John Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Lloyd Chambless, Univ of North Carolina, Chapel Hill, NC; Christie M Ballantyne, Baylor Coll of Med, Houston, TX

Eric Y Yang, 2009 Finalist and Presenting Author
Superbowl Syncope in a 21-Year-Old College Linebacker
Authors: Udell Jacob A.
Published: April 2024

Abstract #3081

Jacob A. Udell, Brigham and Womens Hosp, Boston, MA

Jacob A. Udell, 2009 Finalist and Presenting Author
Cardiac Arrest in a 22 Year Old Postpartum Female With Carnitine Deficiency
Authors: Tadros Thomas M
Published: April 2024

Abstract #3082

Thomas M Tadros, Michael J Mazzini, Michael D Klein, Boston Univ Medical Cent, Boston, MA

Thomas M Tadros, 2009 Finalist and Presenting Author
Metabolic Homeostasis Is Maintained in Myocardial Hibernation by Adaptive Changes in the Transcriptome and Proteome
Authors: Mayr Manuel
Published: April 2024

Abstract #1810

Manuel Mayr, Kings Coll London, London, United Kingdom; Dalit May, The Hebrew Univ-Hadassah Univ Hosp, Jerusalem, Israel; Basetti Madhu, John Griffiths, Cancer Res UK, Cambridge, United Kingdom; Anton Horrevoets, VU Univ Medical Ctr, Amsterdam, Netherlands; Eli Keshet, The Hebrew Univ-Hadassah Univ Hosp, Jerusalem, Israel

Manuel Mayr, 2009 Finalist and Presenting Author
Abstract 4844: Influence of Early Stage Chronic Kidney Disease on Coronary Spastic Angina
Authors: Koga Seiji , Ikeda Satoshi , Yasunaga Tomohiko , Nakata Tomoo , Takeno Masayoshi , Koide Yuji , Maemura Koji
Published: April 2024

Background:
Chronic kidney disease (CKD) is associated with the morbidity and mortality of cardiovascular disease through atherosclerotic processes. However, the relationship between CKD and coronary artery spasm has not been elucidated. The aim of this study was to investigate whether CKD is associated with coronary spastic angina (CSA).

Methods:
We evaluated 127 patients (mean age 60 ± 12 years) who underwent coronary angiography with intracoronary acetylcholine or ergonovine provocation test. CSA was defined as total or subtotal coronary vasoconstriction with chest pain and ischemic ST segment changes on electrocardiography after provocation that were resolved by an intracoronary injection of isosorbide dinitrate, and the absence of organic coronary stenosis. Kidney function was determined by the estimated glomerular filtration rate (eGFR). Patients with eGFR ≤ 29 mL/min/1.73 m
2
were excluded.

Results:
There were 53 and 74 patients with and without CSA, respectively. Age and proportion of smokers, hypertension, diabetes mellitus, and obesity were similar between the two groups. The proportion of male gender and dyslipidemia was higher among the patients with, than without CSA (72 vs. 46 %, P = 0.004, and 49 vs. 31 %, P = 0.040). As compared with patients without CSA, patients with CSA had significantly lower eGFR value (70.4 ± 14.8 vs. 79.2 ± 17.2 mL/min/1.73 m
2
, P = 0.003) and higher proportion of eGFR category ≤ 59 mL/min/1.73 m
2
(25 vs. 11 %, P = 0.040). Prevalence of CSA was 56 % in the lowest eGFR quartile (< 63.9 mL/min/1.73 m
2
) and 55% in second lower quartile (63.9 – 75.0 mL/min/1.73 m
2
), which was significantly increased compared to 23 % in highest quartile (≥ 85.3 mL/min/1.73 m
2
) (P = 0.006 and P = 0.009, respectively). No significant difference was observed between highest and second highest quartile (75.0 – 85.3 mL/min/1.73 m
2
). Logistic regression analysis showed that independent factors associated with CSA were male gender (OR, 3.938; 95%CI, 1.725 to 8.988) and eGFR (OR, 0.658; 95%CI, 0.506 to 0.857).

Conclusions:
Mildly and moderately decreased eGFR is associated with a higher prevalence of CSA, suggesting that early stage CKD is related to a relatively initial stage of atherosclerosis. Management for CKD might lower the incidence of CSA.
Abstract 4846: Rab5a-mediated Localization at Cell-cell Contacts of a Tight Junction Protein Claudin-1 is Regulated by Proteasome in Endothelial Cells
Authors: Asaka Machiko , Hirase Tetsuaki , Hashimoto-Komatsu Aiko , Node Koichi
Published: April 2024

Increased endothelial permeability induced by inflammatory stimuli promotes atherosclerosis. Tight junction that is composed of transmembrane proteins, including claudin, and peripheral membrane proteins is a major barrier of endothelial permeability, whereas roles of claudin in the regulation of endothelial TJ permeability are not yet clear. We demonstrate that claudin-1 is dominantly expressed in cultured human endothelial cells by immonofluorescence and immunoblotting. To elucidate the physiological roles of claudin-1 in endothelial permeability, we depleted claudin-1 by RNA interference in endothelial cells. Depletion of claudin-1 protein expression significantly increased TJ permeability measured by transendothelial electrical resistance compared to control cells, indicating that claudin-1 is a crucial regulator of TJ permeability in endothelial cells. Ubiquitin-proteasome system has been implicated in the regulation of degradation and intracellular localization of proteins. We show that ubiquitin-proteasome system regulates claudin-1 localization from plasma membrane to cytoplasm using a proteasome inhibitor N-acetyl-Leu-Leu-Nle-CHO (ALLN) in endothelial cells. On the other hand, members of the small GTPase Rab protein family play important roles in intracellular vesicle transport and localization of membrane proteins. We examined colocalization of claudin-1 and Rab5a by confocal microscopy and studied the involvement of proteasome in the localization and the Rab-mediated transport of claudin-1 in endothelial cells. In control cells, claudin-1 was localized at cell-cell contact sites. In contrast, caludin-1 localization was observed at perinuclear regions in cytoplasm in association with Rab5a and EEA-1, a marker of early endosome, in ALLN-treated cells. Depletion of Rab5a by RNA interference reversed the localization of claudin-1 in ALLN-treated cells. These data suggest that Rab5a in early endosome is implicated in proteasome-mediated localization at cell-cell contacts of claudin-1 in endothelial cells. Rab5a-mediated intracellular transport of claudin-1 that is regulated by proteasome may play a role in the regulation of tight junction permeability in endothelial cells.
Abstract 4853: Spironolactone Therapy is Associated With Rapid Improvements in Blood Pressure Control and Cardiac Remodeling in Patients With Resistant Hypertension
Authors: Ahmed Mustafa I , Gaddam Krishna K , Gladden James D , Desai Ravi V , Lloyd Steven G , Gupta Himanshu , Denney Thomas S , Oparil Suzanne , Dell’Italia Louis J , Calhoun David A
Published: April 2024

Background: The addition of spironolactone to a multidrug regimen is emerging as an effective antihypertensive strategy in patients with resistant hypertension independent of underlying aldosterone status. The effect of spironolactone on cardiac remodeling in these patients is not clear however.

Aims: In the current prospective study we used 3D-magnetic resonance imaging (MRI) to accurately evaluate the effects of spironolactone therapy on cardiac remodeling in patients with resistant hypertension.

Methods and Results: Twenty-two resistant hypertension patients were evaluated by MRI, prior to, and then 3 and 6 months following addition of spironolactone to a multidrug regime (all were taking at least 3 antihypertensives including a diuretic). Patients had a mean age of 54±2 years, 27% were female, 27% were African American and mean left ventricular (LV) ejection fraction was 70±1%. At three-months following spironolactone therapy, systolic and diastolic blood pressures were significantly improved (141±3 vs. 122±2, p<0.001 and 85±3 vs. 77±2, p=0.002, respectively). Furthermore significant reductions were noted in LV mass index (86±3 vs. 72±3, p<0.001), LA volume index (46±3 vs. 39±2, p=0.003) and BNP levels (44±9 vs. 17±5, p=0.009). Reductions in blood pressures, LV mass index and LA volumes remained significant independent of underlying aldosterone status. At six-months, there were no significant further reductions in any of these parameters.

Conclusions: In addition to a marked antihypertensive effect, addition of spironolactone to a multidrug regimen is associated with rapid regression of LV hypertrophy and reductions in LA volumes and BNP, all of which are important prognostic indicators. These findings demonstrate the broad cardiovascular benefits associated with spironolactone therapy in patients with resistant hypertension.
Abstract 4856: Nighttime Sodium Excretion Following Acute Sodium Loading Predicts Blood Pressure Dipping and Aortic Augmentation Index
Authors: Hummel Scott L , Weder Alan B
Published: April 2024

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 < .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 4861: Prolonged QRS Duration is a Strong Predictor of Adverse Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Kosuge Masami , Kimura Kazuo , Morita Satoshi , Ishikawa Toshiyuki , Ebina Toshiaki , Hibi Kiyoshi , Okuda Jyun , Iwahashi Noriaki , Tsukahara Kengo , Uchino Kazuaki , Umemura Satoshi
Published: April 2024

Background:
Although ECG assessment of myocardial ischemia is usually based on ST-segment changes, prolonged QRS duration (QRSd) has been shown to be more sensitive than ST-segment change for the detection of ischemia. However, the implication of QRSd in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) is not known.

Methods:
We studied 501 patients with NSTE-ACS who underwent coronary angiography during hospitalization. Patients with bundle branch block, left ventricular hypertrophy, and paced rhythm were excluded. Maximal QRSd and ST-segment deviation were measured on admission 12-lead ECG. Patients were divided into the 4 groups according to QRSd: ≤80 ms (n=153, G-A); 81–90 ms (n=214, G-B); 91–100 ms (n=86, G-C); and ≥101 ms (n=48, G-D). Troponin T (TnT), brain natriuretic peptide (BNP), and high-sensitivity C-reactive protein (hsCRP) were measured on admission.

Results:
There were no differences in sex or coronary risk factors except for diabetes mellitus in the 4 groups. In G-A, G-B, G-C, and G-D, age was 64±12, 67±11, 68±11, and 69±11 years; the rates of diabetes mellitus were 23%, 33%, 49%, and 50%; Killip class ≥2 was 3%, 6%, 11%, and 31%; positive TnT was 16%, 36%, 44%, and 56%; the levels of BNP were 105±259, 158±235, 306±355, and 391±390 pg/ml; hsCRP was 0.180±0.233, 0.400±0.748, 0.417±0.530, and 0.716±1.230 mg/dl; the degrees of summed ST-segment depression in all leads except aVR were 1.8±2.8, 2.8±3.6, 5.4±5.1, and 8.7±6.0 mm; ST-segment elevation in lead aVR was 0.1±0.2, 0.1±0.3, 0.5±0.6, and 0.8±0.6 mm; the frequencies of left main or 3-vessel disease (LM/3VD) were 1%, 5%, 49%, and 88%; and major adverse events (death, [re]infarction, or urgent revascularization) at 30 days were 5%, 13%, 24%, and 67%, respectively (all p<0.01). Multivariate analysis showed that QRSd was the strongest predictor of 30-day adverse events (OR 2.40, 95%CI 1.54 –3.24, p<0.001), followed by the degree of ST-segment elevation in lead aVR (OR 1.97, 95%CI 1.20 –5.82, p=0.039) and positive TnT (OR 1.60, 95%CI 1.10 –3.17, p=0.048).

Conclusions:
In patients with NSTE-ACS, prolonged QRSd on admission ECG is strongly associated with LM/3VD and predicts adverse outcomes, even after adjusting for ST-segment changes, biomarker profiles and traditional risk factors.
Abstract 4865: Detection of Basal and Transient Myocardial Ischemia-Induced Cardiac Troponin Release Into Coronary Circulation by Highly Sensitive Assay
Authors: Konishi Masaaki , Sugiyama Seigo , Akiyama Eichi , Ohba Keisuke , Nozaki Toshimitsu , Sakamoto Kenji , Sumida Hitoshi , Ogawa Hisao
Published: April 2024

Background:
Cardiac troponin is well established as a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes but not in angina pectoris. However, troponin release from coronary circulation during transient ischemic attack by angina remains to be determined because of lower sensitivity of traditional troponin assay. We assessed the basal and angina-induced occurrence of troponin release using highly sensitive troponin T (TnT) assay before and after acetylcholine-induced coronary spasm.

Methods and Results:
Serum cardiac TnT levels sampled from peripheral vein (PV), aortic root (Ao), and coronary sinus (CS) were measured by highly sensitive assay in 108 consecutive patients (57% men, 67±10 years) suspected of stable coronary artery disease (CAD). TnT in PV was detectable in 91.4% of the patients [9.8 (7.1, 14.7) pg/mL for median (25
th
, 75
th
percentile)]. At the baseline condition, there was significant increase in TnT levels from Ao [9.6 (6.9, 14.3) pg/mL] to CS [10.9 (7.9, 17.3) pg/mL, p<0.001] in 92.5% of patients and the difference was 1.2 (0.6, 2.5) pg/mL, which reflects basal transcardiac release of TnT. The cardiac release of TnT positively correlated with PV levels (r=0.21, p<0.05). In univariate logistic regression analysis, male gender (odds ratio [OR]; 3.65, 95% confidence interval [CI]; 1.58 – 8.47, p<0.01), presence of heart failure (OR; 3.18, 95% CI; 1.11–9.15, p<0.05), and presence of organic CAD (OR; 2.40, 95% CI; 1.05–5.47, p<0.05) were significantly correlated with elevated transcardiac TnT release (above median). Furthermore, there was significant increase in transcardiac TnT release after acetyocholine provocation test in patients with positive result of coronary spasm [7.2 (−1.8, 11.5) pg/mL, p<0.05] but not in 19 patients with negative result [0.0 (−0.5, 0.5) pg/mL, p=0.95].

Conclusions:
Basal TnT release in coronary circulation was observed in most of patients suspected of CAD and the transcardiac TnT values were significantly correlated with the peripheral levels. Presence of heart failure or CAD significantly contributed to the elevated TnT release in stable states. This sensitive assay detected angina like transient myocardial ischemia-induced significant increase in transcardiac troponin release.
Abstract 4869: Association Between Admission Neutrophil to Lymphocyte Ratio and Angiographical Findings in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes
Authors: Nakachi Tatsuya , Kosuge Masami , Hibi Kiyoshi , Ebina Toshiaki , Tsukahara Kengo , Okuda Jun , Iwahashi Noriaki , Tahara Yoshio , Umemura Satoshi , Kimura Kazuo
Published: April 2024

Background:
Recently, neutrophil to lymphocyte ratio (NLR) was found to be an independent predictor of adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS); however, its underlying mechanism remains unknown.

Methods:
We examined the relation between NLR and coronary artery disease (CAD) progression in 290 patients with NSTE-ACS who underwent percutaneous coronary intervention, followed by planned coronary angiography 8 months later. The counts of white blood cell, neutrophils, and lymphocytes, high-sensitivity C-reactive protein (hsCRP) level, troponin T, estimated glomerular filtration rate (eGFR) and lipid profiles were measured on initial admission. Patients were divided into the 2 groups according to NLR at initial admission: G-H [NLR ≥2.53 (upper tertile), n=97] and G-L [NLR <2.53 (low and middle tertiles), n=193]. Rapid progression was defined as ≥10% diameter reduction of a pre-existing stenosis ≥50%, ≥30% diameter reduction of a stenosis <50% on follow-up coronary angiography.

Results:
There were no differences in sex, hypertension, diabetes mellitus, smoking, troponin T, lipid profiles, medications, multivessel disease, and restenosis rate between the 2 groups. G-H patients were older (67±10 vs 65±9 years, p<0.05) and had less frequently hyperlipidemia (44% vs 59%, p=0.02), higher hsCRP level (0.233 vs 0.125 mg/dl, p=0.02), white blood cell count (8235±3205 vs 7004±2190/
μ
l, p=0.009), and lower eGFR (65±17 vs 71±18 ml/min/1.73m
2
, p=0.02). G-H patients had more frequently culprit lesion with complex morphology (76% vs 61%, p=0.02), multiple complex lesion (57% vs 43%, p=0.007), rapid progression of non-culprit lesion (31% vs 15%, p=0.002), and adverse events (death, [re] infarction, or urgent revascularization) at 24 months (14% vs 5%, p=0.007). Multivariate analysis revealed that upper tertile of NLR (odds ratio 2.41, p=0.01) and upper tertile of hsCRP (odds ratio 2.29, p=0.01) were independently associated with rapid progression, but white blood cell count was not.

Conclusions:
High NLR is associated with not only plaque vulnerability but also rapid CAD progression in patients with NSTE-ACS. These findings may partly explain adverse outcomes in patients with high NLR.
Abstract 4872: Beta Blockers and Acute Release of ET-1 in Response to Anger Recall Stress in Patients With CAD
Authors: Jain Hitender , Burg Matthew M , Fernandez Antonio B , White Margueritte , Collins Dorothea , Soufer Robert
Published: April 2024

Acute anger is associated with triggered AMI and transient myocardial ischemia. Anger provoked ischemia differs from demand related ischemia with regard to differential epicardial vs. microvascular processes. Use of beta-blockers is standard of care for patients with CAD. Endothelin-1 plays a central role in vascular regulation and homeostasis, particularly in diseased coronary segments, and has been linked to endothelial dysfunction during laboratory emotional stress. Beta-blockade has been reported to reduce plasma levels of ET-1 in patients with marked LV dysfunction/CHF and to inhibit the synthesis and release of ET-1 in cellular preparations. We studied the relationship of beta-blockade use on laboratory anger stress-provoked levels of ET-1 in patients with CAD without marked LV dysfunction/CHF.

Methods and results:
104 patients with history of stable CAD underwent sequential 10-min resting baseline (BL) and 6 minute anger-recall stress (AR). Blood samples drawn at the end of rest and stress were assayed for ET-1 by ELISA (fmo/mL) and change from BL to AR calculated. As expected, the hemodynamic response to anger stress was significantly lower (p=0.015) among patients taking beta-blockers (n=81) than those not taking these agents (n=23). These two groups did not differ in ET-1 at BL (2.27±3.77 vs. 1.24±1.89, p = 0.98). Those not taking beta-blockers however, showed a significantly greater % increase in ET-1 from BL to AR (16.12%±29.09% vs. 2.14%±23.85%, p <0.036); this relationship persisted after adjusting for rate pressure product, age, diabetes, HTN, and statin use (p=0.03).

Comments:
Beta-blocker use was associated with a significantly less anger-stress provoked increase in ET-1. This may be one of the mechanisms behind beneficial effects longitudinally of beta-blocker use on incident coronary events in patients with CAD.
Abstract 4874: Vascular Endothelial Barrier Compromise in Advanced Atherosclerosis: Novel in vivo Animal Models and Nanoparticle Characterization Methods
Authors: Wickline Samuel A , Zhang Huiying , Chen Junjie , Zhang Lei , Bibee Kristin , Allen John , Lanza Gregory
Published: April 2024

To elucidate the functional consequences of advanced atherosclerosis on the vascular endothelial barrier, 8 NZW rabbits were fed a high fat diet for 9 –12 months (cholesterol: 1200 –1700 mg/dl). Control animals comprised 3 month-old rabbits on high fat or normal chow diets. Fluorescent perfluorocarbon-core nanoparticles (NP: ~250 nm) were given i.v. (2 ml/kg) and circulated for 1, 12, or 24 hours in selected animals. The aorta was then excised, imaged ex
vivo
with 12T MRI (
1
H and
19
F) and whole mount fluorescence scanning, then fixed for histological and TEM/SEM analysis.

Results:
6/8 of the older atherosclerotic rabbits exhibited massive penetration and persistence of NP into the intimal plaques extending upwards toward the IM junction. Most NP situated in the extracellular matrix in regions that co-stained for glycosaminoglycans and smooth muscle cell actin. Fewer NP penetrated plaques after 1 hour

as compared with 12

or 24 hours, and even larger NP could be observed intact at high power

Spin-dried SEM samples revealed extensive cholesterol crystal deposition

penetrating the plaque endothelium.

19
F MRI/MRS revealed the presence of fluorinated NP core elements confirming the presence of
intact
NP. The 3 month fed animals exhibited far less NP penetration.

Conclusion:
These data suggest that disruption of the endothelial barrier in older atherosclerotic rabbits is a consequence of rapid (<1 hr) passive (non receptor-mediated) diffusion and trapping of
19
F-detectable NP in plaque interstitium. If demonstrable in humans, this previously unrecognized mechanism for blood-intima communication could contribute to plaque vulnerability and disruption.
Abstract 4877: Circadian Variation of Blood Pressure is Correlated to Vascular Endothelial Function in Nondiabetic Essential Hypertensives
Authors: Huang Chin-Chou , Leu Hsin-Bang , Wu Tao-Cheng , Lin Shing-Jong , Chen Jaw-Wen
Published: April 2024

Background:
Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension has been described. We assessed the hypothesis that there was relationship between the circadian rhythm of blood pressure and endothelial function in patients with essential hypertension.

Methods:
Non-diabetic patients with either treated or untreated essential hypertension were evaluated if their office systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg. Serial studies including 24-hour ambulatory blood pressure monitoring, serum biomarkers, and brachial artery ultrasound were arranged.

Results:
Thirty-nine patients were enrolled into the study. They were subclassified by their nocturnal DBP fall (25 dippers, with nocturnal DBP fall ≥10%; and 14 non-dippers, with nocturnal DBP fall <10%). The baseline characteristics and serum biomarkers including adiponectin, asymmetric dimethylargine, oxidized low-density lipoprotein, monocyte chemoattractant protein-1, high-sensitivity C-reactive protein, insulin, and nitrate and nitrite were similar between the 2 groups. The flow-mediated dilation (FMD) of brachial artery was greater in the dippers than in the non-dippers (6.1±3.1% vs. 4.1±2.6%,
p
=0.04) while the nitroglycerin-mediated dilation of brachial artery was similar between the two groups (14.3±5.5% vs. 13.7±6.0%,
p
=0.746). In all patients, sleep DBP (r=−0.379,
p
=0.017), nocturnal change of SBP (r=0.344,
p
=0.032) and DBP (r=0.420,
p
=0.008), and the use of calcium channel blockers (r=−0.394,
p
=0.013) were correlated to FMD. In multivariate analysis, only nocturnal change of DBP was the independent predictor for FMD (
β
=0.175,
p
=0.008).

Conclusions:
In non-diabetic hypertensive patients, the dippers had better endothelial function than the non-dippers. Nocturnal change of DBP was the major predictor for endothelial function.
Abstract 4887: The Thiazolidinedione Pioglitazone up-regulates Vascular Telomere Regulating Proteins and Prevents Cellular Senescence in Mice
Authors: Werner Christian , Pöss Janine , Gensch Christoph , Böhm Michael , Laufs Ulrich
Published: April 2024

Background:
PPAR-
γ
agonists (thiazolidinediones, TZDs) are used for the treatment of diabetes mellitus. Experimental and clinical data implicate that TZDs may mediate vascular effects in addition to the lowering of blood glucose. Aging is the predominant risk factor for the development of cardiovascular disease. Telomeres and telomere-associated proteins affect cellular aging, senescence and survival. We hypothesized that TZDs may regulate vascular telomere biology.

Methods and Results:
C57/Bl6 mice (Age 12 weeks, male) were subjected to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks. Telomere repeat amplification protocol (TRAP) assays showed a marked increase in aortic telomerase activity in the pioglitazone group to 319±30% vs. vehicle. Western blots demonstrated an increased protein levels of telomere-repeat binding factor 2 (367±20%) and reduced expression of the senescence- and apoptosis-related factors p16 (65±11%) and p53 (53±28%). Similar observations were made in mononuclear cells isolated from the spleen. Additionally, the number of spleen-derived endothelial progenitor cells was up-regulated in TZD-treated mice (550±36%). The physiologic significance of these findings was tested by induction of vascular oxidative stress
in-vivo
by injection of lipopolysaccharide (LPS, 125mg, i.p.). Endothelial apoptosis in the thoracic aorta was quantitated by hairpin oligonucleotid assays. LPS increased apotosis to 576±16 % of vehicle which was potently prevented in TZD-treated animals (Pio+LPS 241±12 %). All reported effects were significant with p<0.05, n = 6 –12 per group.

Conclusions:
TZD treatment up-regulates telomerase activity, telomere-capping proteins and induces anti-senescent effects in the vascular wall. The reduction of LPS-induced endothelial apoptosis indicates that the observed effects are physiologically relevant in mice. Our data improve the molecular understanding of the vascular effects of TZDs.
Abstract 4895: Competing Effects of Hypokalemia and Hydrochlorothiazide Treatment on Regression of Cornell Product Left Ventricular Hypertrophy in Hypertensive Patients: Implications for Development of Potassium-Sparing Diuretics
Authors: Okin Peter M , Kjeldsen Sverre , Lindholm Lars H , Dahlöf Björn , Devereux Richard B
Published: April 2024

Background:
Hydrochlorothiazide (HCTZ) treatment is associated with blood pressure reduction and regression of left ventricular hypertrophy (LVH). HCTZ is also associated with hypokalemia (hypoK), which increases blood pressure and is associated with a greater likelihood and severity of electrocardiographic (ECG) LVH. However, the competing effects of HCTZ use and concomitant hypoK on LVH regression have not been examined.

Methods:
Baseline and yearly Cornell product (CP) ECG LVH levels were examined in relation to hypoK (serum K ≤ 3.90, the lowest quartile) and HCTZ use in 7816 patients in the LIFE study with baseline and year-1 K levels. Patients were randomized to losartan vs atenolol-based treatment and additional HCTZ as needed.

Results:
Patients on HCTZ had lower serum K levels at year 1 (4.05 ± 0.38 vs 4.24 ± 0.38), year 2 (4.04 ± 0.38 vs 4.25 ± 0.38), year 3 (4.04 ± 0.39 vs 4.27 ± 0.39) and year 4 (4.05 ± 0.41 vs 4.26 ± 0.38) of the study (all p < 0.001). In 2-way analysis of covariance adjusting for age, sex, race, prior and randomized treatment, yearly body mass index, serum glucose and creatinine, and for baseline and change in diastolic and systolic pressure, hypoK was associated with less mean reduction of CP LVH whereas HCTZ use was associated with greater regression of CP LVH between baseline and years 1 to 4. Multivariate logistic regression analyses with the same covariates revealed that hypoK was associated with a statistically significant 15 to 19% lower likelihood of ≥ median (236 mm·ms) reduction in CP LVH while HCTZ use was associated with an 18 to 33% greater likelihood of CP LVH regression of ≥ 236 mm·ms between baseline and years 1 to 4.

Conclusions:
HCTZ therapy is independently associated with a greater likelihood and magnitude of LVH regression whereas concomitant hypoK is associated with a competing lower likelihood and magnitude of LVH regression during antihypertensive therapy. These findings suggest that hypoK may blunt regression of LVH during treatment.

Regression of Cornell Product LVH in Relation to HCTZ Use and Hypokalemia
Abstract 4901: Morning Hypertension is the Strong Predictor of Left Ventricular Remodeling in Never-Medicated Hypertensives
Authors: Matsui Yoshio , Eguchi Kazuo , Shibasaki Seiichi , Shimada Kazuyuki , Kario Kazuomi
Published: April 2024

We aimed this study to investigate the association between morning hypertension and left ventricular (LV) remodeling. This cross-sectional study enrolled consecutive 356 never-medicated hypertensives, and measured the LV mass and relative wall thickness using echocardiography. Home blood pressure (BP) was measured in the morning and evening for 14 consecutive days with a memory-equipped device. We divided all subjects into 4 groups according to the morning-evening difference in self-measured systolic BP (MEdif) and the average of morning and evening systolic BP (MEave): home normotension (MEave <135 mmHg and MEdif <15 mmHg), morning riser (MEave <135 mmHg and MEdif ≥15 mmHg), sustained hypertension (MEave ≥ 135 mmHg and MEdif <15 mmHg) and morning hypertension (MEave ≥ 135 mmHg and MEdif <15 mmHg). Morning hypertensives was significantly older than normotensives (70 years vs. 64 years, P<0.001). We compared distributions of LV remodeling patterns among the 4 groups (
Figure

). Concentric hypertrophy was more prevalent in morning hypertensives (48.6%) than in normotensives (7.8%, P<0.001), morning risers (20.0%, P = 0.007), and sustained hypertensives (30.0%, P = 0.003). Morning risers had higher percentage of concentric hypertrophy and concentric remodeling than normotensives (20% vs. 7.8%, P = 0.039; 32.5% vs. 14.7%, P = 0.017) despite similar MEave between the 2 groups. The association observed here between morning hypertension and concentric hypertrophy may be related to the mechanism of increased cardiovascular risk of morning hypertension.