bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18476: Are Cardiac Magnetic Resonance Patterns Associated with Adverse 18-Month Outcome in Patients with Acute Myocarditis?
Authors: Sanguineti Francesca , Mana Melina , Hovasse Thomas , Louvard Yves , Unterseeh Thierry , Garot Philippe , Morice Marie-Claude , Garot Jérôme
Published: April 2024

Introduction:
Cardiac Magnetic Resonance (CMR) is a fundamental tool in the diagnosis of Acute Myocarditis (AM). However, its prognostic value is not well established.

Hypothesis:
CMR findings in patients with AM may predict functional/clinical outcome.

Methods:
We studied consecutive pts diagnosed with AM by CMR between 2008 and 2011. All pts underwent initial clinical assessment and CMR was performed at a mean of 11±12 days after acute clinical presentation. Black-blood T2-CMR was used for myocardial edema assessment and contrast-enhanced CMR was performed 3 (early gadolinium enhancement, EGE) and 10 (late gadolinium enhancement, LGE) min after gadolinium chelates. Images were analysed dividing the myocardium into 17 segments and 3 myocardial sectors (subepicardium, midwall, and subendocardium), allowing quantification of lesions extent as percent of LV myocardium. Presence of pericardial effusion and LV segmental wall motion was assessed. Adverse cardiac events including recurrence of symptoms, congestive heart failure, ventricular arrhythmias, heart transplantation, or death, were carefully recorded at clinical follow-up (FU) performed 19±8 months after indexed CMR.

Results:
The patient population comprised 203 pts (43±17 year-old, 76% males) with AM. A total of 22/203 patients (10.8% of the whole population) experienced adverse cardiac events. By univariate analysis, the extent of EGE was inversely correlated with the presence of clinical events at FU (2.2±4.1 vs. 5.1±6.0% of LV myocardial mass, for pts with and without adverse cardiac events, respectively, p=0.005). Additionally, pts with altered EF on initial CMR examination had worse myocardial function at FU. In contrast, presence of hyper-T2 signal (p=0.68), extent (p=0.72) and distribution (p=0.09) of LGE, presence of pericardial effusion p=0.18), were not associated with adverse clinical outcome. Multivariate analysis showed no CMR predictors of adverse clinical outcome.

Conclusions:
In this large cohort of patients with AM, there were no CMR predictors of adverse clinical outcome. A significant association was found between initial LV function and impaired LVEF at FU, as well as between EGE and adverse clinical events.
Abstract 18516: Common Atrial Fibrillation Susceptibility Alleles Enhance Clinical Risk Prediction Model for Postoperative Atrial fibrillation
Authors: Parvez Babar , Muhammad Raafia , Shoemaker M. Benjamin , Blair Marcia , Kor Kaylen C , Brown Nancy , Roden Dan , Bush Willian S , Darbar Dawood
Published: April 2024

Introduction:
Atrial fibrillation (AF) is a common adverse event following coronary artery bypass graft (CABG) surgery. The aim of this study was to evaluate whether single nucleotide polymorphisms (SNPs) conferring AF susceptibility identified by genome wide association (GWA) studies improve the traditional clinical risk prediction model for postoperative AF.

Methods:
Our study population consisted of 829 prospectively enrolled patients in the Vanderbilt Cardiac Surgery Registry (VCSR) undergoing CABG without concurrent valve surgery. Postoperative AF (12 months post surgery) was evaluated by review of medical records, ECGs and Holter monitors. Clinical variables in the model included age at the time of CABG, race, gender, history of AF, diabetes, hypertension, heart failure, CAD, LVEF, PR interval and use of beta-blockers, ACE inhibitors, statins, aspirin, and COX inhibitors. Thirteen AF-associated SNPs (rs13376333 and rs6666258 at 1q21; rs3903239 at 1q24; rs2200733, rs10033464 and rs6817105 at 4q25; rs3807989 at 7q31; rs10821415 at 9q22; rs10824026 at 10q22; rs1152591 at 14q23; rs7164883 at 15q24; rs2106261 and rs7193343 at 16q22) were genotyped using the Sequenom platform.

Results:
Subjects with two or more missing variables were excluded from the analysis (final cohort 444 subjects). SNP rs10033464 was not in Hardy-Weinberg equilibrium and hence removed from the analysis. Using multiple logistic regression, a model containing 12 SNPs, and all clinical covariates was fitted and found to be highly significant (P<0.001). A likelihood ratio test comparing the complete model (clinical and genetic covariates) to a reduced model containing only clinical variables was also highly significant (P<0.001), indicating an improvement in model fit with the inclusion of AF susceptibility alleles. The area under the receiver operator characteristic curve significantly improved from 0.759 (clinical variables only) to 0.816 (combined), (P<0.001).

Conclusion:
Our data show that AF susceptibility alleles enhance the clinical risk prediction model for the development of AF after cardiac surgery. Pre-procedural genotyping of AF susceptibility alleles may improve risk stratification in patients undergoing CABG surgery.
Abstract 18518: Effect of Medical Treatment for Aortic Dissection on In-Hospital Mortality and Follow-Up Aortic Expansion in Patients with and Without Marfan Syndrome; Observations from the International Registry of Acute Aortic Dissection
Authors: Suzuki Toru , Isselbacher Eric M , Eagle Kim A , Nienaber Christoph A , Sawaki Daigo , Hagan Lindsay M , Montgomery Daniel G , Froehlich James B
Published: April 2024

Background: Medical management of acute aortic dissection (AAD) is poorly understood and based mainly on personal experience, expert opinion and observational studies. Society guidelines reaffirm this lack of evidence. We sought to determine the association of specific medications on outcomes in AAD patients.

Methods: Prior analyses from the International Registry of Acute Aortic Dissection (IRAD) suggest beta blockers (BB) are associated with lower long-term mortality after AAD, and calcium channel blockers (CCB) are associated with lower long-term mortality after type B AAD. For this abstract, we analyzed factors associated with in-hospital mortality and aortic growth at follow-up, including medication use, using IRAD. We also looked at medication use and long-term survival in AAD patients with Marfan Syndrome (MFS).

Results: Among 817 patients with type B AAD, improved in-hospital survival was associated with BB use (OR 23.09, 95% CI 6.62-80.58, p<0.001), absence of mesenteric ischemia (OR 10.53, 95% CI, 1.31-84.7, p=0.03) and absence of hypotension/shock (OR 7.55, 95% CI, 1.15-49.4, p=0.04). No benefit was associated with use of angiotensin converting enzyme inhibitor (ACE). On follow-up, CCB were associated with slower aortic growth in medically treated type B patients (p=0.013), and CCB use during the first two years after AAD is associated with negative growth of the aorta ( -0.07mm/yr for patients on CCB vs. 0.42mm/yr for those not, p=0.008). Analysis of 68 MFS patients showed improved long-term survival in type A patients receiving BB (p=0.01); ACE were associated with increased mortality after 30 months (p=0.008).

Conclusions: This analysis suggests BB are associated with improved in-hospital survival in AAD patients. CCB in Type B patients are associated with improved survival and slower descending aortic growth. MFS patients also benefited from BB use. RAS inhibitors were not associated with improved in-hospital or long-term survival in patients (including MFS patients) with AAD. Whether these observed associations between treatment and outcome are due to cause-and effect cannot be determined. Optimal management needs to be confirmed in randomized controlled trials.
Abstract 18539: Atrial Fibrillation and Sleep Apnea: Modulation of Response to Drug Therapy by Common Genetic Variants
Authors: Goyal Sandeep , Wang Li , Darbar Dawood , Monahan Ken
Published: April 2024

Background:
Severe obstructive sleep apnea (OSA) is associated with a decreased response of atrial fibrillation (AF) to anti-arrhythmic drugs (AADs). Whether common AF susceptibility alleles or common single nucleotide polymorphisms (SNPs) in the β1-adrenoreceptor (ADR) modulate response to AADs in patients with OSA is unknown.

Hypothesis:
Common genetic variants associated with AF decrease the efficacy of AADs to a greater degree in severe OSA as compared to non-severe OSA.

Methods:
We analyzed 84 individuals that had polysomnography, genotyping, and a comprehensive evaluation of AF status over time. Response to AADs was defined as a decrease in AF burden score by ≥ 75% on a validated symptom scoring tool or the combination of sinus rhythm on follow-up EKGs, stable AAD therapy, AF burden below the ASSERT threshold on device diagnostics or ambulatory monitoring, and the absence of non-pharmacologic therapies (cardioversion, nodal ablation, AF ablation). Severe OSA was defined as an apnea-hypopnea index (AHI) ≥ 30 events/hour. We analyzed common AF susceptibility alleles (rs2200733 and rs10033464 at 4q25, rs7193343 in ZFHX3, rs13376333 in KCNN3) and common SNPs in the β1-ADR (rs1801252 and rs1801253 at ADRB1).

Results:
Over an average follow-up period of 9.0 ± 4.5 months, 41 participants (49%) responded to AADs and 37 (44%) had severe OSA. For the β1-ADR SNP rs1801252, the AHI was higher in those with the variant compared to wild-type (37 ± 25 vs 23 ± 20 events/hour; p = 0.03 by Mann-Whitney test). Individuals with non-severe OSA and this variant were more likely to not respond to AADs when compared to wild-type allele (OR 2.0; 95% CI 0.5-7.8;
Figure
).

Conclusions:
In a cohort receiving AAD therapy for AF, OSA severity was associated with a functional variant in the β1-ADR An unfavorable genotype may contribute to decreased response to AADs in those with AF and non-severe OSA. Genotype may play less of a role in the response to AADs in severe OSA.
Abstract 18552: The Thrombin Inhibitor Dabigatran Inhibits High Fat Diet-induced Obesity and Fatty Liver Disease in Mice
Authors: Kopec Anna K , Kassel Karen M , Sullivan Bradley P , Luyendyk James P
Published: April 2024

Inflammation associated with non-alcoholic fatty liver disease (NALFD) increases the risk of adverse cardiovascular events. NAFLD is the hepatic manifestation of obesity and the metabolic syndrome and significantly contributes to liver-related morbidity. We have shown previously that the thrombin receptor protease activated receptor-1 (PAR-1) is essential for hepatic inflammation and steatosis in mice fed a high fat diet (HFD), but PAR-1 deficiency does not affect weight gain in mice fed a HFD. To determine whether pharmacologic inhibitors of thrombin could reduce the progression of NAFLD in mice on a HFD, we utilized the direct thrombin inhibitor, dabigatran etexilate. Wild type C57Bl/6 mice were fed a HFD formulated to contain dabigatran (10 mg/g chow) or an identical HFD with starch substituted for drug for 3 months. Plasma thrombin time was significantly prolonged in mice fed HFD+dabigatran, but no adverse bleeding events were observed. Despite consuming a similar amount of chow, mice fed HFD+dabigatran gained significantly less body weight compared to mice fed HFD alone. Induction of inflammatory genes including TNFα, MCP-1, and the lipogenic genes SCD-1 and CD36, was significantly reduced in livers of mice fed HFD+dabigatran compared to mice fed HFD alone. In agreement, hepatic steatosis was dramatically reduced by dabigatran in mice fed a HFD. In summary, pharmacologic inhibition of thrombin with dabigatran reduced various features of NAFLD in mice fed a HFD. In contrast to PAR-1-deficient mice, dabigatran administration also dramatically reduced diet-induced obesity. Taken together, the results indicate that thrombin contributes to NAFLD in mice fed a HFD, and that thrombin promotes diet-induced obesity in a PAR-1-independent manner. Clinical evaluation of the potential for thrombin inhibition to reduce systemic and hepatic inflammation in obese patients taking dabigatran for another indication, such as atrial fibrillation, could reveal novel beneficial effects of oral thrombin inhibitors in metabolic disease.
Abstract 18555: Pre-operative Three-Dimensional Echocardiography Predicts Repair Failure in Ischemic Mitral Regurgitation
Authors: Levack Melissa M , McCarthy Fenton H , Takebe Manabu , Cheung Albert T , Woo Y. J , Acker Michael A , Gorman Joseph H , Gorman Robert C , Jackson Benjamin M
Published: April 2024

Objective: Early recurrence (≤ 6 months) of mitral regurgitation after ring annuloplasty for ischemic mitral regurgitation (IMR) is common. We hypothesized that the degree of pre-repair leaflet tethering as assessed by a novel three-dimensional (3D) echocardiographic based algorithm would be a sensitive predictor of repair failure within 6 months of surgery.

Methods: Real-time 3D full volume transesophegeal echocardiography loops were acquired on patients (N=12) undergoing mitral valve repair for IMR. Images were segmented using previously described methodology. Using custom algorithms, leaflets were divided into six regions for calculation of the respective degree of tethering in each leaflet region. Patients received 2D echocardiography follow-up six months after surgery to assess for recurrence of MR. Pre-operative tethering of patients who recurred were compared to those who did not recur to identify predictors of repair failure. Students’ t-tests were used to compare groups; to account for multiple dependent variables, P<.026 was considered statistically significant (Bonferroni correction).

Results: 33% of patients had moderate to severe MR at the six month follow-up. The degree of horizontal tethering for the P3 leaflet region was 13.77 ± 4.29º compared to 36.71 ± 8.04º (P<0.001) in the group which recurred. Repair failure at six months was predicted by A3 and P3 horizontal tethering angles. (Table 1) Tenting index and 2D echocardiography measurements of left ventricular size and ejection fraction were not predictive of failure.

Conclusions: Pre-operative 3D posterior leaflet tethering is predictive of mitral valve repair failure. Three-dimensional modeling may aid in determining which patients should undergo replacement rather than repair in IMR.
Abstract 18558: Characterization of Cx43-PKP2 Interaction by Direct Stochastic Optical Reconstruction Microscopy
Authors: Agullo-Pascual Esperanza , Reid Dylan , Rothenberg Eli , Delmar Mario
Published: April 2024

The cardiac intercalated disc is composed of 3 structures involved in the electrical and mechanical coupling of the cardiomyocytes: gap junctions, desmosomes and adherens junctions. Several studies suggest that these structures interact at the intercalated disc. In particular a crosstalk between the desmosomal and gap junction proteins PKP2 and Cx43 has been demonstrated. To characterize the proximity of these two proteins we used a Duolink assay. With this method, we demonstrated that Cx43 and PKP2 reside in the periphery of the adult cardiac intercalated disc at distances <40 nm. To further investigate this interaction we performed direct stochastic optical reconstruction microscopy (dSTORM) experiments. This new approach is a valuable methodology for studying the cellular architecture at the nanoscale. The dSTORM uses standard fluorescent dyes that are controlled by the laser excitation intensity and the imaging buffer conditions can be induced to switch on and off (“blink”). For these experiments, 2.000 images were recorded in a stack, each of these images showing a different subset of the fluorescent dyes active. The analysis of these images (the localization of each blink) gave a reconstructed super-resolution image with a resolution of 10nm. The images obtained in isolated neonatal cardiomyocytes showed that 43.5% of the Cx43 spots/clusters analysed (n=200 of 5 experiments) are an average of 11.38 nm apart from PKP2 (SE= 1.67), 62% of them being in contact (0nm). In conclusion, these two techniques allow us to visualize the interaction and distribution of Cx43 and PKP2 at the nanoscale in the intercalated disc and suggest that a fraction of PKP2 molecules interact directly with Cx43.
Abstract 18582: Correlation Between Reductions in LDL-cholesterol, Apolipoprotein B, and Lipoprotein(a) with Mipomersen in FH and Other Hypercholesterolemic Patients at High Risk for Coronary Disease
Authors: Santos Raul D , Raal Frederick J
Published: April 2024

Introduction:
Familial hypercholesterolemia (FH) is characterized by markedly elevated LDL-cholesterol (LDL-c) and, if untreated, premature atherosclerosis. Current treatment modalities are directed toward lowering LDL-c, although other atherogenic lipoproteins such as lipoprotein(a) [Lp(a)] are also considered independent causal risk factors for CHD. Lp(a) levels are about 2-fold higher in FH patients. However the LDL receptor is probably not the major route of Lp(a) clearance as statin therapy does not lower Lp(a). As Apo B is an integral component of Lp(a), inhibiting Apo B would be expected to reduce Lp(a) levels.

Methods
: We evaluated the relationship between the reduction in LDL-c, Apo B, and Lp(a) levels in patients with FH or hypercholesterolemia at high risk for CHD (N=256)and already receiving maximum tolerated lipid-lowering therapy, following treatment with mipomersen, an antisense Apo B synthesis inhibitor.

Results:
Table shows the absolute and percent changes in lipoprotein parameters pre/post mipomersen 200mg SC weekly for 26 weeks.Percent reductions in LDL-c and Apo B pre/post treatment were tightly correlated (r =0.95, p<0.0001). There was also a positive, but moderate, linear correlation between the percent reductions in Apo B and Lp(a) pre/post treatment (r =0.43, p<0.0001 ).

Conclusion:
Inhibiting Apo B synthesis with mipomersen reduced not only LDL-c and Apo B, but also Lp(a), and therefore represents a novel potential approach to reducing all three of these atherogenic lipid fractions. *LDL-c and Apo B results are in mean (SD) and Lp(a) in median (CI)
Abstract 18585: Purification of Cardiomyocytes from Differentiating Human Pluripotent Stem Cells Using Molecular Beacons Targeting mRNA of a Cardiomyocyte-specific Gene
Authors: Ban Kiwon , Wile Brian , Kim Sangsung , Byun Jaemin , Saafir Talib , Wagner Mary , Bao Gang , Yoon Young-sup
Published: April 2024

Background:
While various methods for generating cardiomyocytes (CMs) from pluripotent stem cells (PSCs) including both embryonic stem cells (ESCs) and recently identified induced pluripotent stem cells (iPSCs) have been reported, all available methods are only able to produce heterogeneous populations of CMs mixed with non-CM cells. Therefore, strategies to enrich pure CMs for scientific and clinical applications are urgently required. In the present study, we developed an entirely novel system in which PSC-derived CMs can be purified by cardiac-specific molecular beacons (MBs). MBs are nano-scale probes that emit a fluorescence signal when hybridized to target mRNAs. We hypothesized that MBs targeted to CM-specific mRNAs can identify CMs and allow isolation of CMs by FACS.

Method and Results:
Five MBs targeting distinct sites on mRNA of either cardiac troponin T or myosin heavy chain 6 and -7 were designed and characterized in HL-1 CMs, an immortalized mouse CM cell line and several non-CM cell types such as mouse smooth muscle cells and fibroblasts. Among five MBs in flow cytometry analysis, MHC1-MB identified up to 98% of HL-1 CMs but less than 5% of non-CM cell types, indicating that MHC1-MB is specific for identifying CMs. Subsequently, MHC1-MBs delivered into heterogeneous mouse and human PSC differentiation cultures identified 41 to 49% of the MB
+
cells. Interestingly, the rates of MB
+
cells were highly correlated with the rate of cTnT/I
+
cells, supporting their specificity for detecting PSC-derived CMs. Finally, we determined whether cell sorting with MHC1-MBs can enrich CMs from mouse and human PSC differentiating cultures and found that ∼97% of MB-based sorted CMs expressed cTnT/I. Importantly, these MB-based sorted cells continuously maintained their CM characteristics, which were verified by observation of spontaneous beating and significant expression of cardiac specific genes and proteins in qRT-PCR analysis and immunocytochemistry. Furthermore, Ca
2+
transient analysis confirmed that these enriched cells displayed functional CM characteristic.

Conclusion:
Using cardiac-specific MBs, we were able to obtain highly purified CMs. These purified CMs and this system can be highly useful for cell therapy as well as drug discovery.
Abstract 18645: Axial Integrity of Coronary Stents: Evaluation Using Intravascular Ultrasound
Authors: Dvir Danny , Kitabata Hironori , Barbash Israel M , Loh Joshua , Torguson Rebecca , Badr Salem , Sattler Lowell F , Pichard Augusto D , Waksman Ron
Published: April 2024

Background:
Longitudinal stent deformation (i.e. the axial shortening or lengthening of a stent after implantation) is increasingly reported. However, the axial integrity of stents has not been systematically studied using intravascular ultrasound (IVUS).

Methods:
Consecutive coronary artery disease patients who underwent IVUS analysis after drug-eluting stent implantation for de-novo lesions were evaluated. Stent length was studied using automatic pullback of an IVUS catheter (Boston Scientific Corp/SCIMED) and was further analyzed for change in length (IVUS - label) (mm), the absolute change in length [|IVUS - label|] (mm), and the absolute value of the relative change in length [|(IVUS -label)|/label] (%).

Results:
A total of 183 stents were included: 38.3% sirolimus-eluting stents (SES); 27.9% zotarolimus-eluting stents (ZES); 20.2% Co-Ch everolimus-eluting stents (Cc-EES); 7.1% Pl-Ch everolimus-eluting stents (Pc-EES) - the Element platform and 6.6% paclitaxel-eluting stents (PES). The change in stent length (mm) and the relative change in length (%) differed between groups: SES 0.3 ± 1.2; ZES 1.0 ± 1.3; Cc-EES 0.6 ± 1.0; Pc-EES 0.4 ± 1.1; PES -0.1 ± 1.4 (p=0.008) and SES 1.7 ± 6.0; ZES 5.7 ± 6.7; Cc-EES 3.5 ± 5.8; Pc-EES 2.3 ± 6.0; PES -2.2 ± 8.1 (p<0.001), respectively. The relative change in stent length was higher in the ZES group in comparison with SES and PES groups, (p<0.001 for both). There were no statistical differences between the Pc-EES (Element) and any other stent types. The absolute relative change in stent length (>5%) was lower in the SES group compared to the other groups: SES 34%; ZES 63%; Cc-EES 54%; Pc-EES 46%; and PES 67% (p=0.02). Significant (>15%) absolute value of the relative change in stent length was rare (3.8%) and did not differ between groups (p=0.54). Long stents (≥20 mm, n=62) had a higher absolute change in stent length when compared to other stent groups (18 mm, n=50 and ≤16 mm, n=71): 1.3 ± 1.0 vs. 1.0 ± 0.6 vs. 1.0 ± 0.6, respectively (p=0.02).

Conclusion:
IVUS analysis revealed that significant change in stent length after implantation was rare in all stent types. Stent axial integrity was influenced by stent length; longer stents displayed a higher absolute change in length than did shorter stents.
Abstract 18670: Histological Analysis of Neointimal Characteristics in Drug-eluting and Bare Metal Stents Implanted in Human Coronary Arteries: Autopsy Study
Authors: Nakano Masataka , Otsuka Fumiyuki , Finn Aloke V , Ladich Elena R , Kolodgie Frank D , Virmani Renu
Published: April 2024

Background:

The histological characteristics of neointima in DES and BMS has not been fully investigated.

Methods and Results:

From our autopsy registry, 15 coronary segments with DES showing restenosis (>75% cross-sectional narrowing within the stent) and 15 restenotic BMS lesions with matched implant duration were selected. The coronary segments were processed at 3-4 mm intervals and assessed histologically at the section with the severest narrowing. The implant duration were similar in DES (361 days) and BMS (330 days). Atherosclerotic change within stent (neoatherosclerosis) was seen in 5 of DES lesions (33%) and 1 of BMS lesions (7%). Cells in neointima around lumen mainly consisted of SMC where DES showed lower cellularity than BMS (904 vs. 1409 cells/mm
2
, p=0.014). However, α-SMA positive area were equivalent in both stent groups (DES 9.5 %, BMS 10.5 %, p=0.66), suggesting the phenotype difference of SMC with varying levels of actin expression. Percent area occupied by collagen was lower in DES (22.8%) than in BMS (33.2%) (p=0.14) with the latter showing more mature feature (Collagen score: DES 1.0 vs. BMS 1.4, p=0.022). On the contrary, % area of proteoglycan-rich ECM was predominate in DES (69.3%) as compared to BMS (48.0%) (p=0.032). Macrophage and T-lymphocyte infiltration was observed in both stent groups and frequently accompanied by microcapillaries. The number of macrophages identified in BMS (224 /mm
2
) was slightly higher than in DES (316 /mm
2
) (p=0.15). T-lymphocyte counts were significantly higher in BMS (312 /mm
2
) than in BMS (545 /mm
2
) (p=0.047). The temporal changes of parameters above are summarized in the figure.

Conclusion:

The histopathological difference of neointimal characteristics in DES and BMS might be associated with the incidence of late events attributed to neoatherosclerosis or thrombosis. Targeting for modification of SMC phenotype or ECM after stenting will be of use for newer DES to improve long-term clinical outcome.
Abstract 18690: Association Between Plasma Total Testosterone and Major Adverse Cardiovascular Events in Hypertensive Patients
Authors: Ioakeimidis Nikolaos , Vlachopoulos Charalambos , Aznaouridis Konstantinos , Terentes-Printzios Dimitrios , Aggelis Athanasios , Abdelrasoul Mahmoud , Aggelakas Aggelos , Synodinos Alexandros , Lazaros George , Stefanadis Christodoulos
Published: April 2024

Objective:
Androgen deficiency confers an independent risk for cardiovascular events and total mortality. Hypertension, a major contributory factor to the development of cardiovascular disease, has also been associated with increased prevalence of low testosterone. We investigated whether low androgen concentration predicts major adverse cardiovascular events (MACE) in middle-aged hypertensive patients without clinical atherosclerosis.

Methods:
MACE in relation to total testosterone (TT) were analyzed with proportional hazards models in 228 patients (mean age 56 years).

Results:
During a mean follow-up of 44 months, 19/228 participants (8.3%) experienced a MACE. Compared to patients who did not experience MACE, hypertensive subjects who developed MACE had lower TT concentration (3.9±0.7 ng/ml vs 4.6±1.5 ng/ml, P<0.01) and a higher prevalence of hypogonadism (36% versus 16%, P=0.025). The study population was divided into tertiles according to the TT levels (low tertile 4.9 ng/ml). TT concentration was associated with MACE and the differences between the tertiles were significant (Mantel log-rank test: 8.372; p<0.01). Subjects in the lowest TT tertile (<4.0 ng/ml) had a threefold higher risk of MACE compared to those in the highest tertile (>4.9 ng/ml, adjusted HR 3.14, P=0.035). A TT plasma level of 5.04 ng/ml was associated with a negative predictive value (ability to “rule out” MACE) of 97.2 %. Addition of TT to standard risk factors model yielded correct patient reclassification to higher or lower risk category by 38.8 % (P=0.033).

Conclusion:
Our results show that plasma testosterone is associated with increased risk for a MACE in hypertensive patients. Low endogenous androgen concentration improves risk prediction when added to standard risk factors and may represent a valuable biomarker of prediction of cardiovascular disease risk in these patients.
Abstract 18712: Adeno-associated Viral Gene Delivery of Calsequestrin 2 Protects Adult Calsequestrin 2-R33Q Knock-in Mice From Developing Ventricular Tachycardias
Authors: Denegri Marco , Avelino-Cruz José E , De Giusti Veronica C , Lodola Francesco , Curcio Antonio , Bongianino Rossana , Leccioli Valentina , Boncompagni Simona , Protasi Feliciano , Auricchio Alberto , Napolitano Carlo , Priori Silvia G
Published: April 2024

Background.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal recessive arrhythmogenic disease associated with mutations in the calsequestrin 2 (
CASQ2
) gene. We previously demonstrated that
CASQ2
gene delivery was able to rescue the arrhythmic phenotype in CASQ2 knock-out (KO) mice 5 months after the viral infection. The aim of the present study is to investigate the long-term effects of viral gene delivery in CASQ2-R33Q missense mutation mouse model.

Methods.
Newborn CPVT mice were infected with adeno-associated viral vector 9 (AAV9) containing the coding sequence of the wild type
CASQ2
co-expressed with green fluorescent protein (GFP) gene. Furthermore, we evaluated the effect at 7 and 12 months after viral infection by
in vivo
ECG analysis,
in vitro
electrophysiological and molecular assays.

Results.
Telemeter recording of ECG demonstrated
in vivo
ventricular tachycardias (VT) after epinephrine (2 mg/Kg) administration in only 17% (2 out of 12) of the infected mice, while 87% (7/8) of the control CASQ2-R33Q homozygous mice presented a clear arrhythmic phenotype (p<0.005). Additionally, electrophysiological analysis showed that delayed after depolarization (DADs) and triggered activity (TA) were almost abolished in GFP-positive cardiomyocytes (7 months: DADs: 0%, TA 0%, n=18; 12 months: DADs: 8%, TA: 8%, n=12) in comparison with their internal control (GFP-negative cells, 7 months: DADs:100%, TA: 83%, n=6; 12 months: DADs: 100%, TA: 71%, n=7; p<0.001). Finally, western blot revealed increased CASQ2 expression in the infected mice and immunofluorescence assay indicated its correct localization along the z-lines.

Conclusions.
In the present work we show that the viral expression of CASQ2 is effective for a long period of time and is able to revert the functional abnormalities of the mutant endogenous protein and to prevent life-threatening arrhythmias in the knock-in CASQ2-R33Q mice. These data suggest that despite R33Q mice, at variance with KO mice, express abnormal CASQ2, the gene replacement therapy is still able to prevent arrhythmogenic mechanisms
in vitro
and VTs
in vivo
thus suggesting that CASQ2-gene transfer may become a novel therapy for recessive CPVT.
Abstract 18714: Predictors of Incident Abdominal Aortic Aneurysm in The Elderly: Insights from the Southern Community Cohort Study
Authors: Jahangir Eiman , Lipworth Loren , Mumma Michael T , Edwards Todd L , Blot William J , Sampson Uchechukwu K
Published: April 2024

Background:
Abdominal aortic aneurysm (AAA) is a leading cause of death in the United States, with high prevalence in the elderly population. We sought additional insight into the incidence and predictors of AAA among elderly persons with documented lifestyle and socioeconomic characteristics.

Methods:
Among 11,013 elderly (≥ 65 years) participants in the Southern Community Cohort Study who were also Medicare recipients from 1999-2008, we calculated age-adjusted incidence rates (IR) of AAA. We assessed the predictors of incident AAA using Cox proportional hazards regression analysis, adjusting for demographic, lifestyle, socioeconomic factors, and medical history. Participants with prevalent AAA at baseline were excluded from this analysis.

Results:
Overall, 198 incident AAA cases were identified during the study period. Age-adjusted IR (per 100,000) were 528, 1267, 247 and 590 among black men, white men, black women and white women, respectively. After adjusting for known risk factors, women had lower risk for AAA compared with men (Hazard ratio (HR) 0.59, 95% CI 0.43-0.81; Table) and blacks had lower risk compared with whites (HR 0.42, 95% CI 0.31-0.59). Smoking remained the strongest risk factor overall (former: HR 2.14, 95% CI 1.40-3.30; current: HR 5.09, 95% CI 3.25-7.95), and this association was most pronounced among women. Hypertension and myocardial infarction or coronary artery bypass surgery were each positively associated with AAA incidence among men (respective HR 1.84, 95% CI 1.13-2.99 and 1.68, 95% CI 1.06-2.66). Interestingly, the presence of diabetes mellitus (DM) was inversely associated with incident AAA (overall HR 0.68, 95% CI 0.47-0.99).

Conclusion:
Smoking and HTN were independent predictors of increased risk of incident AAA in this cohort, while female sex, black race, and DM confers protective effects. The underlying mechanism(s) for these protective effects remain incompletely understood and warrant further evaluation.
Abstract 18780: The Impact of Anemia Severity on Angiographic and Clinical Outcomes following Percutaneous Coronary Intervention with Drug-eluting Stents in Asian Population
Authors: Park Ji Young , Rha Seung Woon , Choi Jae Woong , Ryu Sung Kee , Choi Byoung Geol , Choi Se Yeon , Im Sung Il , Kim Sun Won , Na Jin Oh , Han Seong Woo , Choi Cheol Ung , Lim Hong Euy , Kim Jin Won , Kim Eung Ju , Park Chang Gyu , Seo Hong Seog , Oh Dong Joo
Published: April 2024

Background:
The significance of anemia in patients (pts) undergoing percutaneous coronary intervention (PCI) remains controversial. The aim of this study was to evaluate the impact of the severity of anemia on the angiographic and clinical outcomes following PCI with drug eluting stent (DES).

Methods:
A total of 881 consecutive pts underwent PCI with DESs were enrolled. Anemia was defined using World Health Organization criteria with hematocrit (Hct): mild anemia (female: 29%≤Hct<36%, male:29%≤Hct<39%, A1, n=485), moderate to severe anemia (Hct<29%, A2, n=50), and no anemia (female: Hct≥36%, male: Hct≥39%, A0, n=507). Six-month angiographic and 1 year clinical outcomes were compared among the three groups.

Results:
At baseline, the rate of female gender, old age, the incidence of ST elevation myocardial infarction (STEMI), hypertension, diabetes mellitus, chronic renal disease, and congestive heart failure were highest in the Group A2. The incidence of left main and multivessel PCI was highest in the Group A2. At 6 months, the angiographic outcomes were worst in the Group A2. At 12 months, the cumulative incidence of total deaths, any myocardial infarction, and all major adverse cardiac events (MACEs) up to 2 years were highest in the Group A2 (Table). Multivariate analysis showed that anemia was an independent predictor of mortality at 2 years (Adjusted OR 3.78, CI 2.19-6.52, p<0.001).

Conclusions:
In conclusion, the severity of anemia on admission in pts undergoing PCI with DESs was associated with higher mortality and MACEs up to 2 years, suggesting special care should be exercised when a pt has moderate to severe anemia on admission.
Abstract 18789: Pharmacologically Induced Hypothermia with Cannabinoid Receptor Agonist WIN55,212-2 vs Mild Therapeutic Hypothermia in a Rat Model of Cardiac Arrest with Extracorporeal Life Support
Authors: Rungatscher Alessio , Linardi Daniele , Giacomazzi Alice , Tessari Maddalena , Menon Tiziano , Hallstroem Seth , Mazzucco Alessandro , Faggian Giuseppe
Published: April 2024

BACKGROUND:
To compare the hemodynamic, cardioprotective and metabolic effects of cannabinoid receptor agonist WIN55,212-2 with mild therapeutic hypothermia and normothermic control on post-resuscitation myocardial function in a rat model of extracorporeal life support (ECLS).

METHODS AND RESULTS:
Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32°C) and WIN55,212 intravenous infusion (1 mg/kg/h). Cooling to 32°C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. WIN55,212-2 administration produced pharmacologic hypothermia (32-34°C) and led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p<.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p<.05). LV relaxation described by Tau was preserved after WIN55,212-2 treatment but not after hypothermia or normothermia (p<.01). WIN55,212-2 and not hypothermia significantly increased phosphorylation of the kinase ERK1 and 2 (2.8+0.4 and 2.5+0.3 vs 0.5+0.2 and 0.4+0.1 -fold of baseline levels) (p<.01). Both WIN55,212-2 and hypothermia but not normothermia increased phosphorylation of Akt. This resulted in a reduced cardiomyocyte apoptotic index (TUNEL, p<.01). WIN55,212-2 but not hypothermia nor normothermia preserved high energy phosphates content and energy charge and reduced lactate plasma concentration.

CONCLUSIONS:
Pharmacologically induced hypothermia with WIN55,212-2 was more effective than mild therapeutic hypothermia in recovering myocardial function after ECLS and in improving myocardial protection through activation of the pro-survival kinases Akt and ERK1/2.
Abstract 18820: Estimating Time In Therapeutic Range Using The Percentage of Visits in International Normalized Ratio Range Among Patients with Nonvalvular Atrial Fibrillation
Authors: Choi Jiyoon , Damaraju CV , Peter Wildgoose , Schein Jeff , Nelson Winnie
Published: April 2024

OBJECTIVES:
Time in therapeutic range (TTR) has been a quality indicator for level of anticoagulation even though it is not readily available for practitioners to estimate level of anticoagulation for patients. A simpler measure that is based on the number of visits, percentage of visits in international normalized ratio (INR) range (PVIR), may estimate the anticoagulant control. This measure is examined for correlation with TTR levels achieved among patients with nonvalvular atrial fibrillation (NVAF) in a large retrospective database.

METHODS:
We analyzed longitudinal patient-level anticoagulation management records collected between 2006 and 2010 by decision support software, CoagClinic™. Adult patients with NVAF with at least 2 anticoagulation clinic visits and no gap >180 days between visits were identified. The Rosendaal method was used to calculate TTR. Anticoagulation visits with 2.0≤ INR≤3.0 was defined as visits within INR range. PVIR was calculated by dividing the number of visits within INR range by the total number of visits. PVIR was stratified by the increment of 10%, and then compared to corresponding TTR. Pearson correlation coefficient between TTR and PVIR was calculated.

RESULTS:
We identified 36,978 patients who met all inclusion criteria. The mean (±SD) age was 72.3±10.6 years, with 78.4% ≥65 years. The mean (±SD) TTR was 62.2±20.7. On average, patients had 39 visits, of which 23 were in INR range. The average PVIR was 59%. A substantial proportion of patients (79%) had PVIR ≤70%; 18% of patients had PVIR between ≤71% and ≤90%; only about 3% had PVIR ≥91%. PVIR and TTR showed a strong linear relationship (Table 1; Pearson correlation coefficient=0.87).

CONCLUSIONS:
Percentage of visits in INR range (PVIR) offers a simplified measure for daily practitioners to estimate level of anticoagulation control and help identify patients with poor control.
Abstract 18835: The Histone Deacetylase SIRT1 Modulates STAT3 Activity and Prevents De-differentiation and Proliferation of Vascular Smooth Muscle Cells
Authors: Daniel Jan-Marcus , Dutzmann Jochen , Vogel Sabina , Hamm Christian W , Sedding Daniel G
Published: April 2024

Background:
De-differentiation and proliferation of vascular smooth muscle cells (SMCs) are hallmarks of vasculo-proliferative diseases. Activation of the class III histone deacetylase SIRT1 has been shown to exert protective effects on vascular lesion progression; however, the molecular mechanisms remain incompletely understood. In this study, we tested the hypothesis that SIRT1 exerts specific effects on the differentiation and proliferation of SMCs and investigated the underlying mechanisms.

Methods and Results:
SIRT1 expression levels were significantly down-regulated in proliferating human coronary SMCs in vitro and in SMCs following wire-induced neointimal lesion formation in the mouse femoral artery in vivo. Over-expression of SIRT1 using adenoviral vector systems or activation of SIRT1 with resveratrol attenuated proliferation of cultured SMCs in a dose dependant manner. In addition, SIRT1 activation induced a more differentiated phenotype of SMCs, which was accompanied by higher expression levels of multiple cytoskeletal and contractile proteins, as determined by proteomic analysis (MALDI-TOF) and subsequent immune blotting as well as qPCR. In a mouse model of wire-induced injury, over-expression of wild type-SIRT1 but not a deacetylase inactive SIRT1-H355A mutant prevented neointimal formation and significantly reduced SMC proliferation at 3 weeks after dilation (neointima/media ratio: pAd control: 1.94 ± 0.31, pAd-SIRT1-H355A 2.04 ± 0.24, pAd-SIRT1-WT 0.56 ± 0.49, n=8, P<0.05). A gene microarray analysis identified STAT3 dependent target genes to be strongly regulated in response to changes in SIRT1 expression levels and SIRT1 activity. Using immunoprecipitation analysis, we confirmed a direct interaction of SIRT1 with the transcription factor STAT3. Mechanistically, deacetylation of STAT3 by SIRT1 significantly prevented transcription of cyclinD1 and survivin in activated SMCs.

Conclusion:
These data provide evidence that activation of SIRT1 prevents STAT3 signaling in SMCs and holds promise as an excellent therapeutic strategy to target vasculo-proliferative diseases.
Abstract 18845: PPARalpha/Sirt1 Complex is Involved in the Deterioration of Fatty Acid Metabolism During the Pathological Development of Heart Failure
Authors: Oka Shinichi , Zhai Peiyong , Yamamoto Takanobu , Sadoshima Junichi
Published: April 2024

The major substrate shifts from fatty acid to glucose during the pathological development of heart failure, which may promote left ventricular (LV) dysfunction through energetic shortage. PPARα transcribes fatty acid oxidation (FAO) genes through the PPAR response element /direct repeat 1 (DR1), which is composed of two units of AGGTCA-like sequences that directionally align, separated by a single spacer. In addition to activating transcription through DR1, PPARα, in complex with Sirt1, suppresses transcription through an isolated single hexad element which is not configured into a DR1. Since many PPREs have imperfect DR1s in which one AGGTCA sequence is conserved but the other is not, we hypothesized that the PPARα/Sirt1 complex suppresses a subset of PPAR target genes harboring the imperfect DR1 under pressure overload (PO) conditions. Both PPARα and Sirt1 are upregulated in the heart during PO, and PO-induced cardiac systolic dysfunctions are attenuated in PPARα+/- (LV ejection fraction (EF) (%), WT 51, PPARα+/- 68*, p<0.05 vs WT), and Sirt1+/- (LV EF (%), WT 40, Sirt1+/- 62*, p<0.05 vs WT) mice. PO-induced downregulation of a subset of PPAR target genes harboring imperfect DR1s, such as Cpt2 and Mcad, was partly normalized in PPARα+/- (relative mRNA vs Wild type (WT) sham, Cpt2: WT TAC 0.7, PPARα+/- sham 1.1, PPARα+/- TAC 1.05*, Mcad: WT TAC 0.49, PPARα+/- sham 1.1, PPARα+/- TAC 0.77* p<0.05 vs WT TAC) and Sirt1+/- (relative mRNA vs WT sham, Cpt2: WT TAC 0.37, Sirt1+/- sham 1.1, Sirt1+/- TAC 0.78*, Mcad: WT TAC 0.49, Sirt1+/- sham 1.2, Sirt1+/- TAC 0.73* p<0.05 vs WT TAC) mice. Forced expression of PPARα resulted in increased occupancies of PPARα and Sirt1 on the proximal regions of the imperfect DR1s of the Cpt2 and Mcad promoters in the heart, indicating that PPARα recruits Sirt1 to the imperfect DR1. FAO activity was impaired by PO, but was partly normalized in PPARα+/- mice (relative FAO activity vs WT sham, WT TAC 0.50, PPARα+/- Sham 0.88, PPARα+/- TAC 0.89*, * p<0.05 vs WT TAC). PPARα and Sirt1 cooperatively suppressed reporter gene activity driven by the imperfect DR1 in the Mcad promoter. These results suggest that PPARα and Sirt1 play a role in the impaired FAO in the failing heart though transcriptional suppression of imperfect DR1s.
Abstract 18876: Increased Tricuspid Regurgitation after Cardiac Resynchronization Therapy Device Implantation is Associated with Reduced Likelihood of Left Ventricular Reverse Remodeling
Authors: Shin John H , Metzl Mark D , Hansen James C , Lazar Sorin , Tsai Kevin , Rich Jonathan D , Lang Roberto M , Beshai John F , Nayak Hemal M , Burke Martin C , Moss Joshua D
Published: April 2024

Background:
Increased tricuspid regurgitation (TR) is a potential consequence of pacemaker and defibrillator lead insertion. We examined the association between increased TR following cardiac resynchronization therapy (CRT) device implantation and left ventricular (LV) reverse remodeling.

Methods:
Patients who underwent de-novo CRT-D device implantation at our institution from 2003 to 2011 with available baseline and follow-up echocardiograms were included in this retrospective analysis. Pre- and post-operative echocardiograms were evaluated for change in degree of TR and evidence of LV reverse remodeling. TR was graded as absent (0), minimal (0.5), mild (1), mild-moderate (1.5), moderate (2), moderate-severe (2.5), or severe (3), and the numeric change in TR grade pre- and post-CRT implantation was determined. LV reverse remodeling was defined as an absolute improvement in LV ejection fraction (EF) ≥5%, a relative reduction in LV end diastolic dimension ≥10%, or improvement in mitral regurgitation ≥1 full grade.

Results:
A total of 101 patients were included. Median time to post-operative echocardiogram was 8.5 months, with an interquartile range of 4.7-15.1 months. Seventeen patients (17%) developed ≥1 full grade increase in TR post CRT-D. Only four of the 17 (24%) with ≥1 full grade increase in TR had evidence of LV reverse remodeling, compared with 46 of 84 (55%) with <1 full grade increase (p = 0.031). In multivariate analysis, increase in TR post-device implant by ≥ 1 grade, baseline EF ≥ 35%, absence of baseline left bundle branch block, and male gender were independently associated with reduced likelihood of LV reverse remodeling.

Conclusions:
In patients undergoing de-novo CRT-D implantation for standard indications, increased TR of ≥ 1 full grade after device implantation is independently associated with a reduced likelihood of LV reverse remodeling. Prospective studies are needed to determine if lead-related TR adversely impacts response to CRT.
Abstract 18884: Coronary Flow Velocity Pattern After Primary Percutaneous Coronary Intervention as a Predictor of Transmural Extent of Infarction in Patients with St-segment Elevation Acute Myocardial Infarction
Authors: Imamura Sari , Hirata Kumiko , Kubo T , Orii M , Ishibashi K , Yamano T , Tanimoto T , Ino Y , Yamaguchi T , Imanishi T , Akasaka T
Published: April 2024

Purpose:
The purpose of this study was to investigate whether coronary flow velocity pattern after primary percutaneous coronary intervention (PCI) can predict the transmural extent of infarction (TEI) defined by contrast-enhanced cardiac magnetic resonance (ce-CMR) in patients with acute myocardial infarction (MI).

Methods:
In 91 patients after successful PCI for first acute MI, deceleration time of diastolic coronary flow velocity (DDT) were measured by transthoracic echocardiography. Ce-MRI were performed 7 days after onset of AMI. TEI was graded from 1 to 4 based on the transmural extent of hyperenhanced tissue (grade 1: 0-25% of left ventricular wall thickness, 2: 26-50%, 3: 51-75%, and 4: 76-100%). Infarct size by ce-CMR was also calculated.

Results:
Adequate recording of DDT were obtained in 87 of 91 patients (96%). Infarct size by ce-CMR and peak creatine kinase-myocardial band values were significantly correlated with DDT (r=0.54, p <0.0001 and (r=0.40, p=0.006, respectively). Moreover, decreased DDT was significantly related to increased TEI-grade (p< 0.0001) (figure) and existence of microvascular obstruction (p<0.0001).

Conclusion:
DDT measured after primary PCI is a useful predictor for the TEI in patients with acute MI.