bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9898: Weight Loss Decreases High Sensitivity C-Reactive Protein Irrespective of Dietary Composition
Authors: Nicklas Jacinda M , Sacks Frank M , Smith Steven R , Bray George A , LeBoff Meryl S , Ridker Paul M
Published: April 2024

Introduction:
Randomized trials indicate that statins reduce the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) by 20-40%. Although not as widely publicized, diet-induced weight loss also reduces hsCRP. However, the magnitude of this effect in overweight individuals is uncertain and little is known about how diets differing in fat, protein, or carbohydrate composition modify this effect.

Hypothesis:
Weight loss will decrease hsCRP in overweight individuals, and diets lower in carbohydrate will be most effective.

Methods:
POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST was a 2 year trial of overweight and obese adults randomly allocated to 1 of 4 weight loss diets with targeted percentages of energy derived from fat, protein, and carbohydrates (20, 15, 65%; 20, 25, 55%; 40, 15, 45%; 40, 25, 35%, respectively). hsCRP was measured at baseline, 6, and 24 months among 710 participants, and data on adiposity as measured by dual X-ray absorptiometry (N=340) or abdominal computed tomography (N=126) were also evaluated as potential correlates of hsCRP change.

Results:
At 6 months, hsCRP was reduced in all trial participants by a median 25% (IQR +7%, -50%), weight by 7% (IQR -3%, -11%), and waist circumference by 6% (IQR -3%, -10%) (all P<.002) with no significant differences observed according to randomized dietary composition. Irrespective of diet composition, the percent change in hsCRP at 6 and 24 months correlated modestly with change in weight, waist circumference, fasting insulin, fasting glucose, HOMA, and most lipid levels. Reductions in hsCRP persisted throughout the study period despite an approximate 50% regain of weight by 24 months. In imaging studies, the percent change in hsCRP at 24 months significantly correlated with changes in percent total body fat (r=0.42), as well as absolute changes in total abdominal adiposity (r=0.52), subcutaneous abdominal adiposity (r=0.52), and visceral adiposity (r=0.47) (all P<.001).

Conclusion:
Weight loss, regardless of dietary composition, reduces hsCRP with a magnitude of effect similar to statin therapy. As is recommended for individuals with elevated LDL cholesterol, the first intervention for those with elevated hsCRP should be weight loss via caloric restriction.
Abstract 9911: Circulating miR-499-5p and -21 are Sensitive and Specific Biomarkers of NSTEMI in Geriatric Patients with Borderline cTnT Elevation
Authors: D Alessandra Yuri , Olivieri Fabiola , Antonicelli Roberto , Lorenzi Maria , Spazzafumo Liana , Lisa Rosamaria , La Sala Lucia , Galeazzi Roberta , Recchioni Rina , Testa Roberto , Pompilio Giulio , Capogrossi Maurizio C , Procopio Antonio Domenico
Published: April 2024

Background:
Geriatric patients with NSTEMI often present atypical symptoms, uninterpretable electrocardiogram and borderline cTnT elevation; therefore, these patients can be misdiagnosed and inappropriately treated. Some circulating miRNAs have emerged as novel biomarkers of MI. Our objective was to establish whether selected circulating microRNAs (miRNAs) are biomarkers of non-ST elevation myocardial infarction (NSTEMI) in geriatric patients and, eventually, whether miRNAs exhibit higher sensitivity and specificity than cardiac troponin T (cTnT) in patients with borderline cTnT elevation.

Methods and Results:
Elderly individuals (81.4 ± 7.1 years old) were enrolled; 61 patients presented with acute NSTEMI complicated by congestive heart failure (CHF) in 85 % of cases; 47 patients presented with acute CHF without MI. Blood samples were collected 4-9 hours after the onset of symptoms. A third group comprised 46 age-matched healthy control subjects (CTR). Plasma levels of miR-1, -21, -133a, -146a, -208, -423-5p and -499-5p were analysed. NSTEMI was associated with a ∼80-fold and ∼6-fold increase in miR-499-5p and -21, respectively, whereas CHF caused a ∼20-fold increase in miR-423-5p vs CTR. Moreover, miR-499-5p and -21 exhibited the highest sensitivity and specificity in differentiating between NSTEMI and CHF. Interestingly, among subjects with borderline cTnT elevation (0.03-0.10 ng/ml), NSTEMI (n=27) and CHF (n=21) patients were differentiated by miR-499-5p (AUC=0.90), miR-21 (AUC=0.89) and their combination (AUC=0.92), more effectively than by cTnT (AUC =0.61).

Conclusions:
Circulating miR-499-5p and -21 are sensitive and specific biomarkers of NSTEMI in the geriatric population; in patients with borderline increase in cTnT, these miRNAs are more accurate that cTnT in discriminating NSTEMI vs. CHF patients.
Abstract 9922: Pentraxin 3 is a Local Inflammatory Marker in Atrial Fibrillation
Authors: Soeki Takeshi , Bando Sachiko , Niki Toshiyuki , Yamazaki Hiromu , Takashima Akira , Ogasawara Kozue , Bando Mika , Ise Takayuki , Takeuchi Hidekazu , Tomita Noriko , Ueda Yuka , Kusunose Kenya , Yamaguchi Koji , Taketani Yoshio , Iwase Takashi , Yamada Hirotsugu , Wakatsuki Tetsuzo , Sata Masataka
Published: April 2024

Objectives:
Increasing evidence indicates that inflammation contributes to the pathogenesis of atrial fibrillation (AF), but their role remains poorly defined. Pentraxin 3 (PTX3), which has C-terminal sequence homology with the classic pentraxin C-reactive protein (CRP), is produced abundantly from local inflammatory lesion while CRP is mainly produced in the liver. In this study, we investigated whether the local level of PTX3 might be a sensitive marker for the local inflammation of AF.

Methods:
Sampling of blood in periphery and left atrial appendage (LAA) was performed in 18 patients with AF undergoing pulmonary vein isolation and 10 control subjects with atrial septal defect or WPW syndrome. We measured the concentrations of CRP, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and PTX3 in plasma of periphery and LAA.

Results:
Plasma PTX3 concentrations both in periphery and LAA were higher in patients with AF than control subjects. PTX3 concentration was significantly higher in LAA than periphery in patients with AF (3.3±0.7 vs 2.8±0.5 ng/ml, p<0.01) but not in control subjects (2.4±0.5 vs 2.4±0.5 ng/ml, NS). On the other hand, there was no significant difference of CRP, IL-6, and TNF-alpha concentrations in periphery and LAA between AF patients and control subjects. Plasma PTX3 concentartion did not differ between patients with paroxysmal AF and persistent AF. However, there was a significantly positive correlation between plasma concentration of PTX3 in LAA and left atrial diameter (r=0.47, p<0.05).

Conclusion:
Local production of PTX3 in left atrium might reflect the local inflammation of AF. In addition, PTX3 might be superior to other inflammatory markers which are reported to be elevated in AF.
Abstract 9943: Prevention and Reversal of Hypertrophy Through a Novel Drug-Like Compound That Inhibits Local Calcium Oscillations in a Pmca4/calcineurin Microdomain
Authors: Mohamed Tamer M , Oceandy Delvac , Abou-Leisa Riham , Zi Min , prehar Sukhpal , Baudoin-Stanley Florence , Cartwright Elizabeth J , Neyses Ludwig
Published: April 2024

In pathological hypertrophy, the calcium/calmodulin dependent phosphatase calcineurin has been shown to transmit upstream calcium signals through dephosphorylation of the transcription factor NFAT which subsequently translocates to the nucleus and initiates a hypertrophic gene programme. We have previously shown that plasma membrane calcium ATPase isoform 4 (PMCA4) binds to calcineurin when overexpressed in HEK293 cells. We here investigated whether targeting PMCA4 by genetic or pharmacological strategies provides novel opportunities for the reduction of cardiac hypertrophy through modulation of calcineurin. Germline PMCA4 ablation resulted in the attenuation of pathological hypertrophy in response to pressure overload (Heart weight /tibia length ratio after transverse aortic constriction (TAC), PMCA4-/-: 6.74 ± 0.33 mg/mm vs WT: 8.34 ± 0.88 mg/mm, P10). Mechanistically, PMCA4 ablation led to a significant reduction in calcineurin at the sarcolemma as shown by Western blot and electron microscopy. We then developed a specific pharmacological inhibitor of PMCA4, which had not previously been available. Using a modified colorimetric ATPase assay we screened a library of medically optimized drug-like molecules and identified AP2 which has an IC50 of 150 nM for PMCA4. Injection of AP2 in mice (5 mg/kg body weight/day ip) significantly reduced cardiac hypertrophy following TAC for 2 weeks by 50% (n=10 each group, p<0.01). Moreover, AP2 reversed pre-established TAC-induced hypertrophy (HW/TL (mg/mm): sham, 5.7+0.3, TAC+vehicle, 9.1+0.7, TAC+AP2, 7.6+0.6, n=4-6 each group, P<0.05). Using a novel fluorescent Ca2+ sensor (GCaMP2) attached to the N-terminus of PMCA4 we found that AP2 reduced calcium oscillations in the microdomain around PMCA4 by 45% leading to reduced calcineurin activation. Furthermore, AP2 inhibited the NFAT pathway as shown by expression of the bona fide calcineurin target RCAN 1.4 and NFAT phosphorylation levels. Overall, our results demonstrated that specific inhibition of PMCA4 prevents and reverses pressure-overload hypertrophy, likely through regulation of local calcium oscillations around calcineurin making the plasma membrane calcium pump a potential target for the treatment of cardiac hypertrophy.
Abstract 9946: Serum Immunoglobulin G4 Levels Are Increased in Patients with Coronary Artery Disease but Not in Atherosclerotic Aortic Aneurysm
Authors: Sakamoto Aiko , Ishizaka Nobukazu , Imai Yasushi , Nagai Ryozo
Published: April 2024

Objectives:
Immunoglobulin G4 (IgG4)-related sclerosing disease may manifest as cardiovascular disorders, such as inflammatory abdominal aortic aneurysm and lymphoplasmacytic aortitis. Immune inflammatory process is recognized to underlie the pathogenesis of atherosclerosis, thus we investigated the serum levels of IgG4.

Methods:
Serum levels of IgG4 and soluble interleukin-2 receptor (sIL-2R), another marker for lymphocytic activation, were measured in 571 patients (424 males) who underwent coronary angiography. Among the 571 patients enrolled, 409 patients had angiographically-proven coronary artery disease (CAD). In addition, 86 patients had aortic aneurysm: abdominal aortic aneurysm alone, 49; thoracic aortic aneurysm alone, 21, and both abdominal and thoracic aortic aneurysm, 16.

Results:
The mean age of the 571 patients was 66.9 ± 10.3 years. In patients with CAD, the medians of serum levels of IgG4 (34.1 mg/dL) and sIL-2R (396 U/mL) were significantly higher than in those without CAD (IgG4, 30.5 mg/dL, P=0.045; sIL-2R, 322 U/mL, P<0.001). Age and gender-adjusted logistic regression analysis showed that the first (151-292 U/mL), second (293-378 U/mL), third (379-509 U/mL), and fourth (510-3180 U/mL) quartiles of sIL-2R levels had the graded association with CAD with the odds ratio of 1 (reference), 2.21 (95% CI 1.32-3.71), 2.25 (95% CI 1.32-3.85), and 2.50 (95% CI 1.45-4.30), respectively. The fourth quartiles of IgG4 (≥ 57.1 mg/dL) and sIL-2R (≥ 510 U/mL) were also predictive of CAD with an odds ratio of 2.21 and 2.13, respectively, compared with the lowest quartiles among 371 subjects without PCI/CABG history. The medians of IgG4 and sIL-2R levels in patients with aortic aneurysm were 36.6 mg/dL and 384 U/mL, respectively, and these did not significantly differ from those without aortic aneurysm (IgG4, 32.5 mg/dL; sIL-2R, 374 U/mL).

Conclusions:
Serum levels of IgG4, as well as sIL-2R, were significantly higher in patients with CAD than in those without CAD among subjects without previous coronary interventions, suggesting that IgG4-related immune inflammation may play a role in the coronary atherogenesis. On the other hand, values of these markers did not significantly differ according to the presence or absence of the aortic aneurysm.
Abstract 9955: Cooperative Operation of PGD
2
/FP and 15d-PGJ
2
/nrf2 Pathway in the L-PGDS-Mediated Cardioprotection
Authors: Katsumata Yoshinori , Sano Motoaki , Shinmura Ken , Matsuhashi Tomohiro , Tohyama Shugo , Endo Jin , Anzai Atsushi , Yan Cardex , Fukuda Keiishi
Published: April 2024

Background
Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed in adult cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD2-dominated activation of prostanoid biosynthesis via induction of phospholipase A2 and cyclooxygenase-2, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD2-dominated activation of prostanoid biosynthesis.

Methods and Results
(1) In cultured neonatal rat cardiomyocytes, PGD2 strongly activated ERK in a dose-dependent manner, although canonical PGD2 receptors, including DP (PGD2 receptor) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors, were hardly expressed on cardiomyocytes. (2) Interestingly, PGD2 bound to FP receptor (the canonical PGF2α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor was abundantly expressed in cardiomyocytes. (3) PGD2-induced ERK activation was completely blocked by FP antagonist or siRNA-mediated knockdown of the FP, but not by DP and CRTH2 antagonist and siRNA-mediated knockdown of DP and CRTH2. (4) PGD2 activated ERK in Langendorff perfused DP-knock-out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while it did not activate ERK in FP-KO hearts. (5) Dexamethasone protected hearts against ischemia-reperfusion injury in L-PGDS-dependent manner. The dexamethasone-mediated cardioprotection was partially cancelled in FP-KO mice. (6) Gene-chip and Q-PCR analysis revealed that dexamethasone induced Nrf2-dependent antioxidant gene expression in wild-type mice, but not in L-PGDS KO mice. Dexamethasone-mediated cardioprotection against ischemia-reperfusion injury was partially attenuated in Nrf-2 KO mice. (7) In cultured cardiomyocytes, PGD2 had little effect on Nrf2 activation, while 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which is formed from PGD2, strongly activated Nrf2.

Conclusion
PGD2 and 15d-PGJ2 are cooperatively involved in the L-PGDS-mediated cardioprotection against ischemia-reperfusion injury via FP receptor and Nrf-2 activation, respectively.
Abstract 9965: Low-Intensity Pulsed Ultrasound Stimulation Restored the Neovascularization Capacity of Endothelial Progenitor Cells in Mice
Authors: Toyama Yasuyuki , Sasaki Ken-ichiro , Tachibana Katsuro , Ueno Takafumi , Kajimoto Hidemi , Ohtsuka Masanori , Koiwaya Hiroshi , Nakayoshi Takaharu , Yokoyama Shinji , Mitsutake Yoshiaki , Chibana Hidetoshi , Itaya Naoki , Imaizumi Tsutomu
Published: April 2024

Background
Endothelial progenitor cells (EPCs) have been used for therapeutic angiogenesis to rescue the tissue with critical ischemia. However, the effects are unsatisfactory. The cause may be use of EPCs with impaired neovascularization capacity caused by risk factors of arteriosclerosis. Ultrasound stimulation provides cells with several biological effects. Accordingly, we assessed the hypothesis that ultrasound stimulation can restore the impaired neovascularization capacity of EPCs.

Methods and Results
We cultured peripheral blood-derived mononuclear cells obtained from healthy volunteers or patients with >two risk factors of arteriosclerosis for four days to achieve EPCs. During the culture, we daily stimulated the cells with a 1.011 MHz pulsed ultrasound through a gas permeable membrane film from the base of the culture plate. In healthy volunteers-derived EPCs, the low-intensity pulsed ultrasound stimulation (LIPUS) of 100 mW cm
-2
intensity and 240 sec exposure time generated the greatest number of EPCs with maintained cell viability and augmented migration capacity in the modified Boyden-chamber assay. LIPUS to cultured EPCs significantly increased the concentration of angiopoietin 2 in the culture medium, suggesting the augmented secretion capacity. LIPUS increased expressions of phosphorylated-Akt and endothelial nitric oxide synthetase in the EPCs on the western blotting with the increased concentration of nitrogen oxides in the medium. The intramuscular injection of the atherosclerotic patients-derived EPCs in the hind-limb ischemia mouse model showed lower ischemic/non-ischemic hind-limb blood flow ratio after 14 days than the injection of healthy volunteers-derived EPCs (0.59±0.02 vs. 0.68±0.03; p<0.05, n=7, each), indicating impaired neovascularization capacity of the atherosclerotic patients-derived EPCs. LIPUS to the atherosclerotic patients-derived EPCs significantly increased the ratio from 0.59±0.02 to 0.7±0.04 (p<0.05, n=7, each), indicating restoration of the impaired neovascularization capacities.

Conclusion
In conclusion, LIPUS to the atherosclerotic patients-derived EPCs may be a new strategy to enhance clinical effects of therapeutic angiogenesis.
Abstract 9970: Combined Clenbuterol and Metoprolol Therapy Improves Cardiac Function and Calcium Handling in a Rodent Model of Heart Failure, but Does Not Prevent Myocardial Atrophy or Enhance Myocyte Recovery Associated with Mechanical Unloading
Authors: Navaratnarajah Manoraj , van Doorn Carin , Siedlecka Urszula , Ibrahim Michael , Shah Adarsh , Gandhi Ajay , Dias Priyanthi , Yacoub Magdi , Terracciano Cesare
Published: April 2024

Clenbuterol (CL) a β
2
-AR agonist has been successfully employed alongside β
1
-AR blockade in combination with left ventricular assist devices (LVAD) to prevent myocardial atrophy, and promote myocardial recovery in patients with severe heart failure (HF). CL is known to have beneficial effects on excitation contraction (EC) coupling in HF and during mechanical unloading (MU) in animal models. However, CL-induced cardiac hypertrophy and tachycardia have discouraged its use in clinical HF therapy. We compared the chronic effects (4 wks) of CL (2mg/kg/day) and metoprolol (M) (200mg/kg/day) alone and in combination with MU (heterotopic abdominal transplantation) on heart/cardiomyocyte size, function and cellular EC coupling in a rat model of HF (LAD ligation). CL improved ejection fraction compared to untreated HF group, an effect further augmented by M (EF (%): HF 36.2 ± 2.3, p<0.01 vs CL 40.78 ± 2.1, p<0.001 vs M+CL 44.3 ± 2.3 (all groups n=8). CL caused a rise in heart rate (HR) but, when combined with M, HR was reduced (both groups p<0.01 vs HF). CL caused cardiac hypertrophy whereas combined M+CL did not (heart weight:body weight ratio (g/g x 1000)): HF 3.6 ± 0.28, p< 0.05 vs CL 4.2 ± 0.38, Μ+CL 3.6 ± 0.24, p>0.05 vs HF (all groups n=8). Both groups failed to prevent MU-induced myocyte atrophy, but myocyte size was greater in MU+CL group compared with MU+M+CL (cell volume measured by di-8-ANNEPS staining and confocal microscopy (µm3)): MU+ CL 30025 ± 8562, p<0.001 vs MU + M+CL 18750 ± 7500, (both groups n= 50). Myocyte Ca
2+
cycling was studied using the fluorescent dye Indo-1 AM. Ca
2+
transient amplitude was elevated in M+CL group but was not affected by CL (ratio units): HF 0.14 ± 0.06, p<0.001 vs M+CL 0.19 ± 0.09 (both groups n=26). CL alone and M + CL augmented sarcoplasmic reticulum Ca2
+
content equally (ratio units): CL 0.20 ± 0.04, M + CL 0.22 ± 0.06, both groups p<0.01 vs HF, (all groups n=20). MU alone normalised HF cardiomyocyte EC parameters with no additional benefit derived by M+CL therapy. We show that combination of CL and M enhances whole heart function and cellular EC coupling in HF without increase in heart size or HR, but does not affect the consequences of MU on cell size and function. Whether such effects can be exploited in the treatment of HF patients requires further studies.
Abstract 9971: Rock2 is the Predominant Rho Kinase Involved in Thrombin Receptor-Mediated Vascular Permeability
Authors: Beckers Cora M , Knezevic Nebosja , Tauseef Mohammad , Krishnan Ramaswamy , Rajendran Kavitha , Aman Jurjan , van Bezu Jan , W. Victor , Mehta Dolly , Van Nieuw Amerongen Geerten P
Published: April 2024

Objective
Endothelial barrier function is critically regulated by Rho kinase. Basal Rho kinase activity is essential for barrier maintenance, but its enhanced activity induced by vascular permeability factors such as thrombin causes barrier dysfunction involving acto-myosin contractility. Here, we investigated the isoform-specific roles of Rho kinase (ROCK1 and ROCK2) in regulating endothelial (hyper-)permeability.

Methods
Endothelial hyperpermeability was induced in vitro by thrombin and was assessed by the passage of a tracer or by Electrical Cell-substrate Impedance Sensing (ECIS). In the intact lungs of untreated and ROCK1/2 siRNA-transducing mice vascular permeability was induced by TFLLRN, an agonist of the thrombin receptor PAR1 and was assessed by lung Evans blue dye extravasation and wet-dry weight ratios of isolated lungs. Contractile forces were mapped by traction force microscopy.

Results
Downregulation of ROCK2, but not ROCK1 expression attenuated PAR1-mediated hyperpermeability of endothelial monolayers and the pulmonary microvasculature. Simultaneous downregulation of both Rho kinase isoforms further reduced the hyperpermeability. Surprisingly, inhibition of ROCK2 did not affect the net thrombin-induced contractile force enhancements and the formation of thrombin-induced F-actin stress fibers, but lowered basal traction forces, enforcing the basal barrier function of the endothelium.

Conclusions
These data show that ROCK2, but not ROCK1 is the critical Rho kinase for thrombin-induced endothelial barrier disruption. Rather than mediating the evoked contractile force enhancements through the formation of stress fibers, ROCK2 activity is of vital importance for the basal isometric tone of the endothelium. Thus, selective pharmacological inhibition of basal traction forces could provide a novel approach to stabilize the endothelial barrier, and limit vascular leak during derailed inflammatory episodes.
Abstract 9981: Systolic Heart Failure is Associated with Decreased Mitochondrial Respiration in Biopsies From Human Left Ventricle
Authors: Stride Nis , Larsen Steen , Hey-Mogensen Martin , Hansen Christina N , Køber Lars , Steinbrüchel Daniel , Dela Flemming
Published: April 2024

Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization (metabolic remodeling) and reduced ATP and phosphocreatine (PCr) content. We hypothesized that these changes could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) and reduced mitochondrial creatine kinase (miCK) capacity. Myocardial biopsies were obtained from left ventricle of patients undergoing cardiac valve- and left ventricular assist device (LVAD), surgery. The patients were stratified in two groups according to left ventricular ejection fraction (LVEF): Controls (LVEF= 55±2%, n=14) and LVSD (LVEF= 17±3%, n=12). Mitochondrial respiration was measured in permeabilized muscle fibers during successive additions of Krebs cycle substrates. In a separate experiment we assessed the oxidation of octanoyl-L-carnitine, a medium chain fatty-acid (MCFA). The kinetics of miCK was determined from APD titrations in the presence or absence of creatine, revealing the
in situ
enzyme capacity (Vmax) and sensitivity (C50). Octanoyl-L-carnitine elicited 41 % lower respiration in LVSD than in controls (10±2 vs. 17±2 ρmol sec
-1
mg
-1
, respectively, figure 1,
P
<0.05), whereas the sensitivity (C50) for octanoyl-L-carnitine was the same in both groups. Maximal respiratory capacity with dual electron input through complex I and II (malate, glutamate, succinate) was lower in the LVSD group compared with controls (76±8 vs. 104 ±7 pmol sec
-1
mg
-1
, respectively,
P
<0.05). Addition of creatine increased ADP sensitivity significantly in both groups (62 % vs 42 % reduction C50 respectively,
P
<0.05), but revealed no significant differences in Vmax. The novel finding of this study is that human LVSD is associated with a markedly diminished OXPHOS capacity, particularly in the oxidation of MCFA. This offers a candidate mechanism for decreased reliance on fatty-acid utilization in HF and for decreased myocardial ATP and PCr content.
Abstract 18248: Should We Refrain to Perform TAVI Procedures in Patients with a Mitral Regurgitation? Insights from the FRANCE 2 Registry
Authors: van belle Eric , Juthier Francis , Vincentelli Andre , Iung Bernard , Eltchaninoff Helene , Laskar Marc , Fajadet Jean , Leguerrier Alain , Gilard Martine , Banfi Carlo , Leprince Pascal , Prat Alain , Teiger Emmanuel ,   France 2 investigators
Published: April 2024

Background: The presence of mitral regurgitation (MR) is an independent predictor of mortality after conventional aortic valve replacement for aortic stenosis. The predictive value of pre-procedural MR on clinical outcome after TAVI is unknown.

Methods: 3,195 consecutive patients were enrolled between January 2010 and October 2011 in 33 centres. MR was graded according to pre-procedural transthoracic echocardiography (TTE) as none/trivial (=0), mild (=1), moderate (=2), moderate-to-severe (=3), or severe (=4). The mean age was 82±7 years; 49% were female and mean logistic EuroSCORE was 21.9±14.3. Balloon (BE) and self-expendable (SE) devices were implanted in 66.9% and 33.1% of patients, respectively. Approaches were transarterial (transfemoral: 74.6%; subclavian: 5.8%), transapical (17.8%), and transaortic (1.8%).

Results: Pre-procedural TTE showed no MR in 32% of cases, a grade 1 MR in 46% of cases, a grade 2 MR in 20% of cases and a grade 3-4 in 2% of cases. Procedural success rate was 96.9%. Actuarial 1 year mortality was 19.5%. By univariate analysis, pre-procedural MR grade≥2, MR Grade=1 and MR Grade=0 were associated with a 1 year mortality rate of 24.0%, 20.1% and 15.8%, respectively (p=0.002). By multivariate analysis, 4 independent baseline characteristics were associated with preprocedural MR: a higer Logistic EuroSCORE (p=0.0001), a lower ejection fraction (p=0.0002), a higher NYHA class (p=0.0007), and female gender (p=0.001). By multivariate Cox analysis, independent predictors of one-year mortality were: logistic EuroSCORE (p=0.0001), NYHA class (p=0.0001) and transapical approach (p=0.0005). The presence of preprocedural MR was not significantly associated with 1-year mortality (p=0.31). Results did not differ when analyses were restricted only to BE or only to SE devices.

Conclusion: A mild (grade1) or a moderate (grade 2) MR preprocedural is associated with a higher 1-year mortality after TAVI. However, since preprocedural MR is associated with a higher NYHA class or a higher logistic Euroscore, pre-procedural MR is not an independent predictor of mortality. These findings suggest that, in itself, the presence of a mild or a moderate MR should not refrain from performing TAVI and should not impact the type of valve to be used
Abstract 18269: Invasive Treatment of ST-Elevation Acute Coronary Syndrome in Russian Hospitals is Predominantly Used in Lower Risk Patients
Authors: Erlikh Alexey D , Gratsiansky Nikolay A ,   Participants of Regisries RECORD and RECORD-2
Published: April 2024

Introduction
. Inhospital mortality of patients with ST-elevation (STE) acute coronary syndrome (ACS) in Russia is generally very high while it is reported to be low in patients subjected to primary percutaneous coronary interventions (pPCI) in invasive institutions.

Hypothesis
. Low mortality in STEMI patients treated with pPCI is at least partially explained by selection of patients with lower risk.

Methods
. To test this hypothesis we studied data from two independent Russian prospective ACS registries which were organized upon initiative of their participants - RECORD (2007-2008 years, 18 hospitals from 13 cities) and RECORD-2 (2009-2011 years, 7 hospitals from 7 cities).

Results
. There were 967 STEACS patients included in both registries (≥ 65 years - 41%, Killip class ≥ II - 21%). Hospitals with ability to apply invasive treatment (invasive hospitals) recruited 79% of patients. The rate of pPCI was 36% (in invasive hospitals - 46%). Rates of pPCI in invasive hospitals in patients aged ≥ 65 and < 65 years were 33% and 54%, respectively (p<0.0001); in patients with Killip class ≥ II and I - 34% and 49%, respectively (p=0.002); in patients with high and non-high risk of inhospital death according to GRACE score - 35% and 51%, respectively (p<0.0001). Overall inhospital mortality was 11%. Rates of death in patients aged ≥ 65 and < 65 years were 21% and 5%, respectively (p<0.0001), in patients with Killip class ≥ II and I - 32% and 6%, respectively (p<0.0001). Among patients aged 65 years and older inhospital mortality was significantly lower in those treated with pPCI than in patients treated without pPCI (11% and 23%, respectively, p=0.01). Among patients aged < 65 years there was no significant difference in hospital mortality between patients subjected and not subjected to pPCI (5% in both groups, p=0.8).

Conclusions
. Data from limited size independent Russian ACS registries RECORD and RECORD-2 show that in high risk patients with STEACS (≥ 65 years old, Killip ≥ II, high risk by GRACE score) rate of pPCI was significantly lower than in non-high risk patients. However association of pPCI with lower hospital mortality was found only in patients aged ≥ 65 years.
Abstract 18286: Left Atrial Spontaneous Echocardiographic Contrast is a Predictor of Cardiovascular Events (Death, Stroke, Heart Failure) Beyond the CHA2DS2VASc Score at Long-term Follow-up in a Single-Center Cohort of Patients with Non Valvular Atrial Fibrillation
Authors: Boyer-Chatenet Louise , Lang Sylvie , Ederhy Stéphane , Fleury Guillaune , Haddour Nabila , Meuleman Catherine , Adavane Saroumadi , Di Angelantonio Emanuele , Boccara Franck , Cohen Ariel
Published: April 2024

Background:
The CHA
2
DS
2
VASc score has been proposed as an additional tool in thromboembolic (TE) risk stratification, beyond the CHADS
2
score, in patients with non-valvular atrial fibrillation (NVAF). The role of additional TE risk markers, i.e. derived from echocardiography, has not been yet fully evaluated. We aimed to evaluate in a multivariate model the role of clinical
versus
TEE parameters in predicting cardiovascular (CV) events at long-term follow-up.

Methods:
In 763 consecutive patients hospitalized for NVAF, TEE was systematically performed within 24h after admission. All patients were followed-up (mean 5.8 ± 4.1 years) and cardiovascular (CV) events (stroke, death, or heart failure) defining a composite endpoint were recorded.

Results:
Two hundred and five patients (26.9%) had a CHADS
2
=0, 228 (29.9%) a CHADS
2
=1, and 330 (43.3%) a CHADS
2
≥2. The corresponding figures for the CHA
2
DS
2
VASc score were 92 (12.1%), 115 (15.1) and 556 (72.9%), respectively. Left atrial spontaneous contrast (LASEC) was present in 358 (46.9%), described as mild in 212 (27.8%), moderate in 111 (14.6%) and severe in 35 (4.6%). LA thrombus was found in 17 patients (2.2%) and protruding aortic atheroma ≥4 mm in 116 (15.2%). Six hundred thirty three patients (83%) were prescribed warfarin and 158 (27%) aspirin at discharge. At follow-up, death occurred in 253 patients (33.2%), stroke in 29 (3.8%) and heart failure in 100 (13.1%). The Kaplan-Meier curves showed that a CHA
2
DS
2
VASc score >3 was associated with a higher risk of CV events. In the multivariate analysis, non paroxysmal AF (HR 1.54, 95%CI 1.17-2.01), CHA
2
DS
2
VASc score (HR 1.47, 95%CI 1.38-1.57) and LASEC (presence/absence, HR 1.42 95%CI 1.11-1.82) were predictors of CV events. Warfarin treatment at discharge was protective (HR 0.65, 95%CI 0.48-0.87).

Conclusions:
TEE-detected LA spontaneous echocardiographic contrast in NVAF patients is associated with a higher risk of CV events, beyond the CHA
2
DS
2
VASc score and the type of AF.
Abstract 18304: Identification of MicroRNAs Dysregulated in a Porcine Model of Coronary In-stent Restenosis
Authors: Robertson Keith E , McDonald Robert A , Oldroyd Keith G , Kennedy Simon , Baker Andrew H
Published: April 2024

Introduction
Vascular injury following stent delivery results in proliferation and migration of smooth muscle cells (SMC) leading to in-stent restenosis. MicroRNAs (miRs) are short, non-coding ribonucleic acids that act to control gene expression at a posttranscriptional level. MiR-21 and -221 positively regulate SMC proliferation through modulation of cell-cycle regulators. MiR-143 and -145 are important in the maintenance of vascular SMC in the differentiated state.

Hypothesis
We hypothesised that expression patterns of these key regulatory miRs in the vasculature would alter in response to stent-induced injury.

Methods
Pigs received standardized bare-metal (cobalt alloy) or drug-eluting (zotarolimus) stents (n=4/group), over-expanded to induce vessel injury, and were euthanized at 0, 7 or 28 days (BMS) and 28 days (DES). Total RNA was extracted from stented tissue. MiR expression levels were determined by quantitative real-time polymerase chain reaction and normalized to miR-199a-3p, a suitable endogenous control with mean cycle threshold + SD 25.70 + 0.84 across all samples. All comparisons made against control vessels (unstented arteries).

Results
MiR-21 levels were upregulated at 7 and 28 days in both stent types. No differences were seen between BMS and DES at 28 days. MiR-221 levels were elevated at Day 7 in the BMS group, returning to baseline at 28 days. MiR-145 levels showed immediate downregulation (Day 0) and stayed significantly low in all groups. MiR-143 levels did not show this immediate change, but were otherwise similar to miR-145. Levels of miR-145 only were significantly lower in arteries receiving DES compared with BMS at 28 days (75% vs. 48% downregulation).

Conclusions
In conclusion, vascular miRs show altered expression following stent insertion. MiR-145 levels were lower in arteries with DES, in comparison to BMS, at 28 days. This provides potentially important information for future manipulation of miRs in the vessel wall.
Abstract 18330: Asymmetric Dimethylarginine, a Biomarker for the Effects of Drug Therapy in Pulmonary Hypertension
Authors: Skoro-Sajer Nika , Aschauer Stefan , Hlavin Gerald , Wolzt Michael , Sadushi-Kolici Roela , Lang Irene
Published: April 2024

Rationale:
Pulmonary hypertension (PH) is characterized by high morbidity and mortality, requiring aggressive treatment. Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase inhibitor, is increased in PH, and associated with unfavorable outcome. We hypothesized that ADMA may serve as a biomarker to monitor disease progression under pulmonary arterial hypertension (PAH)-specific treatment.

Methods:
ADMA plasma levels were measured at baseline and at least after 24 weeks of treatment in consecutive patients (pts) under PAH-targeted treatments (endothelin receptor antagonists (bosentan, ambrisentan), phosophodiesterase-V inhibitors (sildenafil), high dose calcium channel blockers (diltiazem) and prostanoids (subcutaneous treprostinil)). Therapy “responders” were defined by decrease of pulmonary vascular resistance (PVR) of at least 200dynes.cm-1.s-5, 6-minute walking distance >380m, and improvement of WHO by one class and were compared with “non-responders”.

Results:
51 consecutive patients (44 pts with PAH; 23 pts with idiopathic PAH, 8 pts with PAH associated (APAH) with congenital heart disease (CHD), 2 APAH pts with HIV, 4 APAH pts with connective tissue diseases (CTD), 5 pts with portopulmonary hypertension, 2 PAH patient with hepatitis C) and 7 patients with PH due to lung disease/hypoxia) were enrolled in this study. According to our definition; there were 16 non-responders, and 23 responders to treatments. 11 patients showed no change. ADMA plasma levels did not change significantly under treatment in the whole group. However, there was a significant drop of ADMA in responder group (p<0.0001), Furthermore, ADMA change in “responders” and “non-responders” was significantly different (p=0.003). The decrease of ADMA correlated with the decrease of PVR (r=0.56, p<0.0001), and with the decrease of mean pulmonary arterial pressure (r=0.44, p=0.001). Furthermore, the difference of ADMA correlated with the increase of cardiac index (r=-0.38, p=0.005) and mixed venous saturation (r=-0.3, p=0.03).

Conclusions:
ADMA parallels the hemodynamic benefit of PAH-specific treatment in patients with PH of various etiologies. ADMA can serve as a biomarker for the effect of PAH-specific treatments.
Abstract 18334: Electrocardiographic Alterations After Alcohol Septal Ablation Demonstrate 1-Year Lasting Reverse Remodeling Effect
Authors: Matsuda Junya , Kitamura Mitsunobu , Takayama Morimasa , Kubota Yoshiaki , Nakamura Shunichi , Murata Hiroshige , Takagi Gen , Takano Hitoshi , Asai Kuniya , Mizuno Kyoichi
Published: April 2024

Background: Alcohol septal ablation (ASA) is a treatment option in patients with hypertrophic obstructive cardiomyopathy (HOCM) and its refractory symptoms in spite of optimal medical therapy. The improvements of the related symptoms were derived from the acute reduction of left ventricular pressure gradieint (LVPG) and the chronic reverse remodeling. In many patients, the reverse remodeling effects have been observed for several months over.

Methods: From 1998 through 2011, we performed 174 ASA procedures for drug-refractory symptomatic patients. We investigated clinical 2-years follow up and analyzed electrocardiogram (ECG) alternations from 1 month to 6months, 1 year and 2 years, to confirm the chronic effects. .

Results: Out of 174 prosedures treated by ASA, excluding right bundle branch block (RBBB) and DDD or ICD therapy after ASA, total 23 patients in which we could complete 2-years follow-up were assigned to this study. Immediately after ASA, LVPG significantly improved from 68±39 to 25±28 mmHg (p<0.001), associated with symptomatic improvement (NYHA class from 2.5±0.6 to 1.2±0.5, p<0.001). From ECG findings, Sokolow-Lyon index reduced until 1 year later (5.0±0.4 to 4.8±0.4, p=0.005) and QRS duration significantly reduced until 6 months later (100±11 to 96±13msec, p=0.038).

Conclusions: ASA improved not only the obstructive property but also the electrical abnormality in drug-refractory HOCM patients. The reduction of Sokolow-Lyon index and QRS duration suggested the reverse remodeling effects sustained 6 months to 1 year after ASA. Therefore, the effects should be monitored until 1 year from the ASA procedure.
Abstract 18445: Potential Contribution of RANKL System in Adipose Tissue Inflammation and Insulin Resistance
Authors: Osako Mariana K , Nakagami Futoshi , Nakagami Hironori , Morishita Ryuichi
Published: April 2024

Hypertension and obesity are related to adipose tissue inflammation and insulin resistance, and both are important factors for the development of type II Diabetes mellitus. High serum osteoprotegerin (OPG) level has been reported in diabetic patients, and is considered a marker for future cardiovascular events. OPG is a decoy receptor of RANKL, and inhibits its binding to the receptor RANK. The RANKL system has been reported in bone, mammary gland development, immune cells communication, and we have previously reported its role in vascular calcification and potential cross-talk with Renin-angiotensin II system via ERK phosphorylation pathway. In this study, we examined the role of RANKL system in adipose tissue. High fat diet significantly increased the RANK-RANKL, ACE, AT1R as well as TNF alpha and MCP-1 mRNA expression in C57/BL6 and db/db mice adipose tissue. In vitro studies showed that RANKL expression increases following human pre adipocyte differentiation, and is further increased in the presence of Angiotensin II. We have found that PMA-activated monocytes (THP1) express higher level of RANK compared to non-stimulated monocytes, and that RANKL stimulation induces inflammatory cytokines expression in the presence of anti-OPG neutralizing antibody. Also, RANKL induced macrophage migration in boyden chamber assay dose dependently. OPG-/- mice under high fat diet presented increased number of crown-like structures in adipose tissue compared to wild type. Interestingly the deletion of AT1R in OPG-/-mice significantly decreased that macrophage infiltration, and inhibited the expression of inflammatory cytokines and RANKL system in adipose tissue. OPG-/- mice, known as the model of continuous activation of RANKL system, showed higher insulin level and insulin resistance compared to WT and AT1R-/-/OPG-/- mice. Overall, we propose that RANKL is activated in adipose tissue under high fat diet, and may contribute to insulin resistance by inducing macrophage recruitment and adipose tissue inflammation. Moreover, blockade of local renin-angiotensin II activation can also inhibit RANKL system activation in adipose tissue.
Abstract 18528: Knocking out of E2F4 Aggravates Cardiac Function During Pressure Overload
Authors: Yamamoto Takanubo , Zhai Peiyong , Sadoshima Junichi
Published: April 2024

Background:
The E2F family constitutes a family of transcription factors involved in the cell cycle. E2F4 is considered to be a repressive E2F due to its lacking the N-terminal domain characteristic of the activating E2Fs, including E2F1, E2F2, and E2F3a. The activating E2Fs are known not only as cell cycle regulators but also as pro-apoptotic factors. Cardiac specific ablation of Rb, a negative regulator of the activating E2Fs, enhances cardiac hypertrophy and failure in response to transverse aortic constriction (TAC). Currently, however, the function of the repressive E2Fs in cardiac hypertrophy and failure is unknown.

Methods:
To evaluate the role of E2F4 in regulating cardiac hypertrophy and function during pressure overload (PO), E2F4 knockout (E2F4-/-) and wild type (WT) mice were subjected to TAC for 4 weeks.

Results:
In the sham operation group, there was no significant difference in left ventricular (LV) weight/ tibial length (TL) or ejection fraction (EF) between E2F4-/- and WT (LV weight/ TL: E2F4-/-= 5.5±0.2 mg, WT= 5.7±0.3 mg/mm, n.s.; EF: E2F4-/-= 70.3±3.3%, WT= 71.6±2.9%, n.s.; n=5-8). In the TAC group (4 weeks), there was no significant difference in LV weight/ TL between E2F4-/- and WT (E2F4-/-= 8.6±1.1, WT= 8.9±0.6 mg/mm, n.s.; n=4-7), whereas the EF was significantly lower in E2F4-/- than in WT (E2F4-/-= 48.0±2.9%, WT= 64.6±3.4%, p<0.01; n=4-7). In histological analyses, although the cell size of cardiomyocytes in E2F4-/- was not different from that in WT (E2F4-/-= 690±13 μ m
2
, WT= 637±64 μ m
2
, n.s.; n-3-4), fibrosis and the number of TdT-mediated dUTP nick-end labeling (TUNEL) positive cells were significantly greater in E2F4-/- than in WT (fibrosis: E2F4-/-= 5.2±1.3%, WT= 0.8±0.6%, p<0.05; TUNEL: E2F4-/-= 0.50±0.06%, WT= 0.07±0.03%, p<0.01; n=3-4). RT-PCR showed that mRNA expression of E2F1 and its target genes that are involved in apoptosis were increased in E2F4-/- compared to in WT (E2F1: 2.5-fold, p<0.05; caspase-8: 2.6-fold, p<0.05), indicating upregulation of the pro-apoptotic mechanism in E2F4-/-.

Conclusions:
These results suggest that E2F4 plays an essential role in maintaining cardiac function during pressure overload by negatively regulating the pro-apoptotic mechanisms and suppressing cardiac fibrosis.
Abstract 18590: The Underutilization of Guideline Recommended Antihypertensive Agents is Associated with a High Prevalence of Uncontrolled Hypertension in Urban Community Dwelling Older Adults
Authors: Sethi Sanjum S , Bordowitz Richard , Morland Kimberly B , Granieri Evelyn , Farkouh Michael E
Published: April 2024

Background:
Hypertension (HTN) is a major risk factor for cardiovascular disease. Despite numerous medication options and clear clinical practice guidelines (JNC 7), uncontrolled HTN disproportionately affects the elderly population.

Hypothesis:
We hypothesized that blood pressure (BP) control in adult seniors may be affected by their prescribed antihypertensive medication regimen.

Methods:
Adults 59-99 years old from two New York City boroughs were enrolled in the NHLBI-funded Cardiovascular Health of Seniors and the Built Environment Study from 2009 to 2011 (n=1,453). At the baseline visit, participants brought their medications and had three BP measurements performed. The average of the 2
nd
and 3
rd
measurements was recorded. Uncontrolled HTN was defined as a measured BP greater than 140/90 mmHg. Medications were grouped by class including thiazide diuretics, beta blockers (BB), calcium channel blockers (CCB), angiotensin II converting enzyme inhibitors (ACEI), and angiotensin II receptor blockers (ARB). All other agents were grouped together.

Results:
The prevalence of hypertension was 68.7%. Hypertension increased with age, affected more women (71%) compared to men (61%); and was higher among African Americans (75%) compared to Whites (63%) or Hispanics (63%). Nearly 70% of the hypertensive participants were treated with at least one medication, but in those with uncontrolled BPs (41%), only 65% were prescribed an antihypertensive agent. CCBs were prescribed most frequently (23%) followed by BBs (21%), ACEIs (17%), ARBs (17%), thiazide diuretics (14%), and second line agents (7%). Thiazide diuretics remained the least prescribed first line drug class regardless of underlying comorbidities (diabetes, heart disease, renal disease) or BP control.

Conclusions:
Despite longstanding consensus recommendations, more than a third of participants with uncontrolled HTN in our cohort were not prescribed any antihypertensive medication. Further, thiazide diuretics were prescribed less often than any other first line agent, contrary to the JNC 7 guidelines. Increased attention to the guideline recommended prescription of antihypertensives may have a beneficial population level effect on uncontrolled hypertension.
Abstract 18656: A Decade of Follow-up with Excellent Transmural Atrial Lead Performance in Complex Congenital Heart Patients
Authors: Perry James C , Shepard Suzanne M , Boramanand Nicole K , Williams Matthew R , Lamberti John J
Published: April 2024

Background:
Many patients (pts) with postoperative congenital heart disease require permanent pacing for rhythm management and cannot undergo transvenous atrial leads. Extensive epicardial scar can prohibit adequate acute and chronic pacing and sensing thresholds. We described transmural atrial lead (TMA, epicardial to endocardial) pacing previously and now report long-term lead performance.

Methods:
A bipolar, steroid eluting transvenous lead is placed from the epicardial surface via purse-string and affixed to position the lead against the atrial endocardium. 52 patients underwent TMA placement between 1998 and 2004. Records were reviewed for lead characteristics and acute and long term performance. Follow up data was available for 51 patients. TMAs were placed in the right atrial appendage, the lateral right atrial wall, left atrium, and dome of the left atrium. Medtronic 5072 (n=43), Guidant 4469 (n=6) or other (n=3) leads were used.

Results:
52 pts underwent TMA at an avg age of 13.4 yrs; 19 to replace existing leads and 36 as part of a larger surgery. Pre-op, 25 pts had atrial tachycardia (AT). 22 pts had Fontan/revision. Acute TMA pace threshold was 0.87V @ 0.5msec. 43/52 leads remain active at an avg follow-up of 10.2 yrs. Chronic pace threshold avg is 0.96V @ 0.3-0.5msec; atrial electrogram is 2.97mV in 30/43 pts with intrinsic P waves. Atrial overdrive of AT using TMA was successful in 8/9 pts. No clots were oberved in any pt in follow-up. 3 pts died (one awaiting transplant, one sudden, one stroke (TMA on Fontan side, no fenestration). There were 2 TMA fractures, 3 removed for non-TMA reasons.

Conclusions:
TMAs show excellent late functional properties as an alternative to epicardial leads in complex pts, maintaining low atrial pacing thresholds, consistent sensing and the benefit of effective overdrive pacing of ATs. TMAs exhibit superior long term performance in complex Fontan and atrial switch patients.