bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13294: Valve Mediated Hemodynamics and Their Association With Ascending Aortic Diameter in Bicuspid Aortic Valve
Authors: Raghav Vrishank , Barker Alex J , Mangiameli Daniel , Mirabella Lucia , Markl Michael , Yoganathan Ajit
Published: April 2024

Introduction:
Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the US population. Valve-mediated hemodynamics have been postulated to contribute to the cause and progression of ascending aorta (AAo) disease.

Hypothesis:
Aortic valve morphology and hemodynamics affect distal AAo diameter in subjects with BAV disease.

Methods:
Four-dimensional flow MRI was used to evaluate the hemodynamics in the proximal AAo of 52 subjects: size-matched controls with tricuspid aortic valves (n = 24) and BAV patients with aortic dilatation (n = 14 right and left coronary cusp fusion (RL-BAV); n = 14 right and non-coronary cusp fusion (RN-BAV)). A semi-automated technique was used to systematically quantify hemodynamic metrics (flow angle, flow displacement, and jet quadrant) and valve morphology (orifice circularity) for all subjects, as illustrated in the figure. A regression analysis was conducted to develop a relationship between upstream hemodynamics and distal AAo diameter.

Results:
RN-BAV subjects displayed a stronger correlation between hemodynamic metrics in the proximal AAo with diameter in the distal AAo when compared to size-matched TAV controls and RL-BAV subjects. The distal AAo diameter was found to be strongly correlated to the flow displacement (R
2
adjusted
= 0.75) and flow angle (R
2
adjusted
= 0.66) measured at the sino-tubular junction (STJ) in RN-BAV subjects. Orifice circularity was also strongly correlated (R
2
adjusted
= 0.53) to the proximal AAo diameter in RN-BAV subjects.

Conclusions:
The findings in this work demonstrate that the hemodynamics in the STJ are significantly correlated to the distal AAo diameter in RN-BAV subjects. The hemodynamic metrics demonstrated more statistical significance than valve morphology when considering correlations to distal aortic size. These results could be used to design efficient imaging protocols for better prognosis of BAV-related aortopathy.
Abstract 13299: Cross Talk Between Hyper Permeability and Autophagy in Endothelial Cells With Persistent Inflammation
Authors: Samanta Saheli , Rajasingh Sheeja , Chen Lei , Cao Thuy , Drosos Nicholas , Dawn Buddhadeb , Rajasingh Johnson
Published: April 2024

Introduction:
Lipopolysaccharide (LPS) is known to induce endothelial dysfunction causing an increase in permeability and damage intra cellular signaling as well as known to induce autophagy. However, few studies have suggested that autophagy might interrupt cell-cell interaction through adherens junction protein, which leads to endothelial barrier dysfunction. Here we demonstrated that LPS induces autophagy, and hyper permeability of lung endothelial cells and this can be prevented by the combinatorial treatment with 5-Aza 2 deoxycytidine and Tubastatin A (HDAC6 inhibitor) (referred as Aza+TBSA).

Hypothesis:
We hypothesize that treatment with the combination of Aza+TBSA inhibits autophagy and restores vascular integrity after LPS induced vascular hyper permeability.

Methods and Results:
In this study, we have used LPS to induce hyper permeability and autophagy and mTOR inhibitor Rapamycin used as a positive control for autophagy in mouse lung endothelial cells (MLECs). Our Western analysis data showed that LPS and Rapamycin induce autophagy, which is indicated by the increased level of known autophagy markers LC3 and beclin-1, and decreased VE-cadherin expression in MLECs induced with LPS or Rapamycin. Where as treatment with Aza+TBSA significantly reduced the effect of LPS induced autophagy markers and increased VE-cadherin expression
(Fig. 1A).
Our immunofluorescence analysis also showed a decreased expression of LC3 when the LPS induced MLECs was treated with Aza+TBSA (
Fig. 1B
).

Conclusions:
These data suggest that Aza+TBSA treatment can rescue endothelial barrier dysfunction and prevent autophagy in LPS-induced MLECs, indicating that LPS-induced vascular leakage is dependent on autophagy. These results support a therapeutic potential of Aza+TBSA combination for patients with acute lung injury.
Abstract 13510: No-reflow in Reperfused Myocardium Does Not Contribute to Final Infarct Size in Pigs
Authors: Skyschally Andreas , Kleinbongard Petra , Heusch Gerd
Published: April 2024

The no-reflow phenomenon is a frequent complication in patients with reperfused acute myocardial infarction and associated with a worse prognosis. It is unclear whether cardioprotection, apart from infarct size (IS) reduction, has also a beneficial impact on the extent of no-reflow.

In an anesthetized pig model of myocardial ischemia/reperfusion, we have now used established conditioning maneuvers as a tool to distinguish damage and protection from it in the myocardium, expressed as final IS, and in the coronary microcirculation, expressed as area of no-reflow (ANR).

Myocardial ischemia was induced by transient occlusion of the left anterior descending coronary artery (LAD). Myocardial blood flow was measured with microspheres. Cardioprotection was induced by local ischemic preconditioning (IPC; n=10; 2 x 3 min LAD occlusion/2 min reperfusion 15 min prior to 60 min LAD occlusion), remote ischemic preconditioning (RIPC; n=10; 4x5 min hindlimb occlusion/reperfusion 90 min prior to 60 min LAD occlusion), or ischemic postconditioning (POCO; n=6; 4x1 min LAD re-occlusion/reperfusion at 1 min reperfusion after 60 min LAD occlusion). Pigs without protection (PLA; n=10) served as controls. After 180 min reperfusion, the ANR (intra-atrial injection of thioflavin S) and the area at risk (AAR; intra-atrial injection of blue dye with re-occluded LAD) were demarcated. IS was determined by post-mortem triphenyl-tretrazolium chloride (TTC) staining.

The AAR and myocardial blood flow during ischemia were not different among groups. IS reduction was similar with IPC, RIPC, and POCO (PLA: 37±3% of AAR; IPC*: 21±3%; RIPC*: 17±2; POCO*: 24±5%; mean±SEM; *p<0.05 vs. PLA). Only IPC and RIPC reduced the ANR (PLA: 28±4% of AAR; IPC*: 4±3%; RIPC* 9±2%), whereas POCO did not (24±5%).

All conditioning maneuvers protected the myocardium, but the microcirculation was only protected by conditioning maneuvers applied prior to LAD occlusion. POCO’s protection of myocardium, but not coronary microcirculation might be related to different time frames or to different underlying mechanisms of injury and/or protection in the two compartments. Nevertheless, the remaining no-reflow observed with POCO did not result in greater infarction.
Abstract 13513: Roles of Endothelium-Dependent Hyperpolarization in Pulmonary Microcirculation in Mice
Authors: Tanaka Shuhei , Sato Saori , Ikumi Yosuke , Ito Akiyo , Saito Hiroki , Godo Shigeo , Shimokawa Hiroaki
Published: April 2024

Background:
The endothelium modulates vascular tone by synthesizing and releasing endothelium-derived relaxing factors, including prostacycline (PGI
2
), nitric oxide (NO), and endothelium-dependent hyperpolarization (EDH). Although it is widely known that EDH plays an important role in systemic microcirculation, its role in pulmonary microcirculation remains largely unknown. Furthermore, although pulmonary hypertension (PH) is recognized as a progressive vasculopathy, the initiating mechanisms of the vasculopathy also remain to be elucidated. In this study, we thus aimed to elucidate the role of EDH in pulmonary microcirculation.

Methods and Results:
We performed experiments with isolated perfused mouse lungs. Isolated whole lungs were prepared from control mice and chronic hypoxic mice (10% O
2
for 1, 2 and 28 days). We evaluated the contribution of PGI
2
, NO, and EDH in isolated lungs by the inhibitory effect of indomethacin (Indo, 10
-5
mol/L), N
ω
-nitro-L-arginine (L-NNA, 10
-4
mol/L), and apamin (Apa, 10
-6
mol/L) plus charybdotoxin (CTx, 10
-7
mol/L), respectively. In control mice, endothelium-dependent relaxations to bradykinin (BK, 10
-5
mol/L) were resistant to Indo or L-NNA, but were highly sensitive to the combination of Apa and CTx, indicating the primary role of EDH in pulmonary microcirculation. Endothelium-dependent relaxations to BK were significantly reduced in the presence of L-NNA in mice exposed to hypoxia for one day, indicating a transition from EDH to NO in BK-mediated relaxations before developing PH. Importantly, endothelium-independent relaxations were subsequently reduced in the lungs from hypoxic mice for 2 and 28 days compared with normoxic lungs.

Conclusions:
These results indicate that EDH-mediated relaxations play primary roles in pulmonary microcirculation under physiological conditions and that hypoxia rapidly impairs EDH-mediated responses followed by vascular smooth muscle dysfunctions in pulmonary microcirculation. These findings may provide clues to elucidate the initiating mechanisms of hypoxia-induced PH.
Abstract 13796: Safety of Subcutaneous Cenderitide Co-Therapy With LVAD Support: A Phase I, Placebo Controlled Cross-Over Study for Heart Failure
Authors: Ichiki Tomoko , Schirger John A , Koenig LuAnne J , Wanek Jacqueline R , Heublien Denise M , Scott Christopher G , Joyce Lyle D , Chen Horng H , Burnett Johh C
Published: April 2024

Introduction:
While left ventricular assist devise (LVAD) support improves the prognosis of end-stage heart failure (HF) patients, the long-term outcomes remains suboptimal. Improved outcomes may occur with organ protection including reverse myocardial remodeling. Cenderitide (CDNP) is a Mayo engineered designer natriuretic peptide (NP) that co-activates particulate guanylyl cyclase A and B receptors and functions via the second messenger cGMP. We reported a NP deficient state in the heart with LVAD support which lays the rationale for NP replacement therapy with Cenderitide which has cardiorenal protective actions in experimental HF. We sought to determine if Cenderitide co-therapy would be safe and activate cGMP in patients with LVAD support.

Hypothesis:
Acute single dose of subcutaneous (SQ) Cenderitide will be safe and activate cGMP in patients with LVAD support.

Methods:
Stable HF patients with LVAD support (Heartmate II, all males) were enrolled in a cross-over design comparing SQ placebo and low (Low-C, 5 ug/kg, n=8) or high dose (High-C, 10 ug/kg, n=8) Cenderitide (Capricor Therapeutics) administration. Vital signs, plasma C(D)NP, cGMP, Aldosterone (Aldo), and NT-proBNP levels were measured before or after drug administration over 24 hours. All parameters in Cenderitide group were adjusted by those in placebo.

Results:
Both Low-C and High-C group demonstrated significantly increased plasma C(D)NP and cGMP levels for 2 hours after drug injection and those in High-C group showed more prolonged and higher increases than Low-C group. Mean arterial pressure (MAP) in Low-C did not show any changes but in High-C group tended to be lower for 18 hours but this was not significant. Plasma Aldo and NT-proBNP levels in Low-C group did not show any change but those in High-C group tended to be lower after drug injection s similar to the change in MAP. No adverse events were observed in the study.

Conclusions:
SQ Cenderitide was successfully absorbed, activated cGMP and well tolerated in patients with LVAD support. High dose Cenderitide may have cardiac unloading effects suggested by decreases in NT-proBNP. Further clinical trial for efficacy is warranted to clarify cardiorenal protective effects of Cenderitide in the LVAD population to improve outcomes.
Abstract 13835: Accuracy of Prehospital Documentation of Hypoxia Compared to Continuous Non-Invasive Monitor Data Tracking in Major Traumatic Brain Injury
Authors: Perez Octavio , Spaite Daniel W , Helfenbein Eric , Barnhart Bruce J , Babaeizadeh Saeed , Hu Chengcheng , Chikani Vatsal , Gaither Joshua B , Denninghoff Kurt R , Keim Samuel M , Viscusi Chad , Sherrill Duane , Bobrow Bentley J
Published: April 2024

Background:
It is well established that prehospital hypoxia dramatically increases mortality in Traumatic Brain Injury (TBI). Thus, in EMS TBI research, case ascertainment and risk-adjustment are highly dependent upon documentation of in-field O
2
saturation. Objective: To compare the rate of hypoxia identified by EMS personnel and documented in EMS patient care records (PCR) vs the actual rate of hypoxia recorded by continuous, non-invasive monitor in TBI.

Methods:
A subset of major TBI cases (moderate/severe) in the EPIC EMS TBI Study (NIH 1R01NS071049) were evaluated (3/30/13-6/26/15). Cases from 4 EMS agencies that report continuous monitor data (Philips MRx™) as part of EPIC were included. All monitor data available for post-hoc review were displayed and accessible to the providers during EMS care. We compared PCR documentation of hypoxia (O
2
sat <90%) to actual recorded monitor data on each patient (Fisher’s Exact Test; α=0.05).

Results:
77 cases were included [median age: 52; 65% male]. The monitors displayed and recorded 16 hypoxic cases (20.8%), but only 6 (37.5%) were documented. Thus, while the rate of actual hypoxia was 20.8%, the case ascertainment was only 7.8% (6/77) when PCR documentation alone was used (p=0.036).

Conclusion:
Among patients with major TBI, monitor-identified hypoxia occurred much more frequently (20.8%) than was documented (7.8%). Only 37.5% of cases with actual hypoxia were recorded in the PCRs. This may be explained, in part, by the fact that pulse oximetry occurs continuously. Thus, ongoing care responsibilities and scene distractions may cause providers to miss low readings as they fluctuate moment-by-moment. This has significant clinical implications as a potential hidden contributor to poor outcomes if hypoxia goes unrecognized (and untreated) rather than simply not being documented. Furthermore, these findings have important implications for case ascertainment, confounding, and risk-adjustment in EMS TBI studies. Whenever possible, quality improvement and research projects should utilize continuous non-invasive monitor data to identify and evaluate hypoxic patients in the setting of TBI. These findings may also have implications for identifying hypoxia in EMS patients with other critical conditions.
Abstract 13885: Excessive Daytime Sleepiness is Associated With Depression Scales but Not With Sleep Disordered Breathing in Patients Hospitalized With Cardiovascular Diseases
Authors: Ohashi Mikiko , Kohno Takashi , Noda Rikako , Matsuda Risa , Fukuoka Ryoma , Kohsaka Shun , Maekawa Yuichiro , Sano Motoaki , Takatsuki Seiji , Fukuda Keiichi
Published: April 2024

Background:
Excessive daytime sleepiness (EDS) is a significant public health problem, and one of its most common causes is sleep disordered breathing (SDB), which is known to be associated with the development of cardiovascular disease. However, the relationship between EDS and SDB in patients hospitalized with cardiovascular diseases is unknown. The aims of this study were to assess the prevalence of EDS in cardiovascular patients, and examine its related factors including SDB and mental status.

Methods and Results:
A total of 1783 patients (mean age, 65±15 years; 28.7% female) hospitalized for a spectrum of cardiovascular diseases in Keio University Hospital were enrolled (coronary artery disease n=564, arrhythmia n=658, heart failure n=137, valvular heart disease n=230, and other n=194). We assessed EDS using the Epworth sleepiness scale (ESS; mean 6.8±4.3), and EDS was defined as ESS>10 (n=335[18.8%]). We screened SDB using nocturnal pulse oximetry, a non-invasive method for detecting nocturnal intermittent hypoxia. The prevalence of SDB (3% oxygenation desaturation index>15/hour) did not differ between patients with EDS and those without (29% vs 29%, p=0.86). EDS was associated with younger age, alcohol use, higher eGFR, lower BNP level, and lower prevalence of hypertension, diabetics mellitus, and dyslipidemia (all p<0.05). Sex, BMI, and the prevalence of heart failure, coronary artery disease, or arrhythmia did not differ between patients with EDS and those without. The patients with EDS had significantly higher depression scales (Patient Healthcare Questionnaire [PHQ-9]; 5.2±4.6 vs 3.4±3.5, p<0.001, Hospital Anxiety and Depression Scale-Depression [HADS-D]; 5.5±4.0 vs 4.1±3.3 p<0.001). Multiple regression analysis revealed that depressive scales by PHQ-9 (OR=1.14; p=0.002; 95% CI, 1.05-1.24) and HADS-D (OR=1.16; p<0.001; 95% CI, 1.08-1.25) were independent determinants of EDS.

Conclusions:
EDS is associated with depression symptoms, but not with SDB in patients admitted with cardiovascular diseases. These findings suggest that cardiovascular patients with EDS should be thoroughly assessed for depression.
Abstract 13898: Simvastatin Inhibited Myocardial Apoptosis Undergoing Noncoronary Artery Cardiac Surgery
Authors: Ou Jingsong , Zhou Li , Liu Xiang , Wang Zhen-Qing , Ou Zhi-Jun , Xu Yin-Qi , Wang Zhi-Ping
Published: April 2024

Introduction:
We previously demonstrated that simvastatin was cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin protected myocardium were not fully understood.

Hypothesis:
Simvastatin protects myocardium is related to the inhibition of apoptosis

Methods:
35 patients undergoing noncoronary cardiac surgery such as valvular surgery, congenital heart diseases surgery, 19 from simvastatin group and 16 from untreated control group, were selected from a previous clinical trial. Simvastatin (20mg) was administered preoperatively for 5-7 days. Myocardial tissues biopsies were taken in the right atrial appendage before cross-clamping the aorta and heart beating 10 minutes after removing the aorta cross-clamp. The apoptosis in myocardium was detected by transmission electron microscope and TUNEL staining. The expression of Bcl-2 and Bak were detected by Western blot.

Results:
In the untreated controls, electron microscopic analyses revealed evidence for ischemic injury in cardiomyocytes characterized by swollen mitochondria with vacuoles, and shortened and disrupted cristae. Simvastatin significantly reduced these changes compared to the control group. TUNEL staining showed that myocardial apoptosis in simvastatin group was much less than that in the control group. Simvastatin significantly upregulated the expression of Bcl-2 and downregulated the expression of Bak after surgery.

Conclusions:
The mechanisms by which simvastatin protected myocardium undergoing noncoronary cardiac surgery is, at least in part, related to the inhibition of apoptosis, which may be related to the preservation of mitochondrial structure and function.
Abstract 13943: Psoriasis Increases Risk of New Onset Atrial Fibrillation: A Systematic Review and Meta-Analysis of Prospective Observational Studies
Authors: Upala Sikarin , Sanguankeo Anawin
Published: April 2024

Introduction:
Psoriasis is a common dermatological disease that increases risk of cardiovascular disease. Previous studies have shown possible evidence that patients with psoriasis may also have increased risk of new-onset atrial fibrillation.

Hypothesis:
We assessed a hypothesis that psoriasis increases risk of atrial fibrillation by performing a systematic review and meta-analysis of prospective observational studies.

Methods:
A comprehensive search of the databases of the MEDLINE and EMBASE was performed from inception through April 2016. The inclusion criterion was the prospective observational study that assessed risk of new-onset atrial fibrillation in adults with psoriasis. Outcome was the adjusted hazard ratio (HR) of atrial fibrillation comparing between patient with psoriasis and controls. Pooled HR and 95% confidence interval (CI) were calculated using a random-effects model.

Results:
The initial search yielded 176 articles. Fifteen articles underwent full-length review and data was extracted from 4 observational studies. All studies had prospective designs, involving totally 12,755 participants with a median follow-up time between 2.5 to 5 years. Psoriasis was identified by a medical code associated with clinic visits to a dermatologist. Incidence of atrial fibrillation was ascertained by cardiologist reviewed of electrocardiograms. There was a significant increased risk of new-onset atrial fibrillation in patients with psoriasis compared to controls with a pooled HR 1.42 (95%CI 1.22 -1.65, I
2
=68%).

Conclusions:
Our meta-analysis of prospective studies demonstrated that patient with psoriasis has increased risk of new-onset atrial fibrillation. Inflammation is likely an important factor in the pathophysiology of both atrial fibrillation and psoriasis. Future interventional studies addressing the impact of psoriasis treatment and prevention of atrial fibrillation should be performed.
Abstract 13968: Automated Pulse Detection is Achieved by Analysis of the Activity Level and Periodicity of Accelerometer Signals Acquired at the Carotid Site
Authors: Dellimore Kiran H , Wijshoff Ralph , van de Laar Jakob , Muehlsteff Jens , Russell James K , Hubner Pia , Sterz Fritz
Published: April 2024

Introduction:
Manual palpation during cardiopulmonary resuscitation (CPR) is the gold standard for pulse assessment by professional rescuers. However, this method is unreliable and time-consuming. A fast, reliable, and objective assessment of pulse presence remains an unmet need.

Hypothesis:
Automatic pulse presence detection is feasible by assessing the activity level and periodicity of accelerometer (ACC) signals acquired at the carotid site during CPR.

Methods:
A 2-step classification algorithm was developed using the activity level and periodicity of ACC signals to identify 4 categories: ‘Pulse’ (low activity and periodic), ‘No-pulse’ (low-activity and aperiodic), ‘CPR’ (high activity and periodic) or ‘Artifact’ (high activity and aperiodic). This approach uses 3 features extracted from non-overlapping 3 s windows of data: signal energy, peak prominence and rate. The algorithm analyzes the norm of the 3-axis ACC signals, computed after normalization by the gravitational constant and filtering between 0.5 and 12 Hz. The classifier was trained on data from 5 male patients (age range = 45-70 years) undergoing CPR in a hospital, with ACC signals sampled at 125 Hz. The performance was assessed by benchmarking against manual classification of artefacts, chest compressions, pulses, and pulse absence by visual inspection of all signals done by experts in the field.

Results:
Activity classification in all cases yielded sensitivity and specificity >90.3% and >88.8%, respectively (Fig. 1). For CPR classification the sensitivity and specificity was >71.9% and >71.6%, respectively, while for pulse classification the sensitivity and specificity was >51.9% and >39.5%, respectively.

Conclusions:
Automated pulse presence detection based on the activity level and periodicity of ACC signals at the carotid site is feasible with reasonable sensitivity and specificity. Automatic ACC-based pulse palpation could provide objective pulse detection support during CPR.
Abstract 13978: Response to Isoproterenol Infusion may Predict Procedural Success Following Ablation for Atrial Fibrillation
Authors: Kanda Takashi , Masuda Masaharu , Fujita Masashi , Iida Osamu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Sunaga Akihiro , Tsujimura Takuya , Okuno Shota , Matsuda Yasuhiro , Yanaka Koji , Ohashi Takuya , Kawai Hiroyuki , Tsuji Aki , Hata Yosuke , Uematsu Masaaki
Published: April 2024

Introduction:
Atrial fibrillation (AF) trigger elimination, such as pulmonary vein (PV) isolation, is one of the major procedural endpoints in AF ablation. We have previously found that the ectopies with short coupling interval (CI) more likely initiate AF, and found that %CI<40%, where %CI = CI/P-P interval of the preceding 2 beats) х100, was the best cut-off value to detect AF-trigger ectopies.

Hypothesis:
We hypothesized that patients who have AF-trigger ectopies have better procedural outcome than those without AF-trigger ectopies.

Methods:
We studied 120 consecutive patients with AF who underwent an initial ablation. Prior to ablation, AF induction was performed using isoproterenol infusion. PV isolation was performed, and non-PV trigger elimination was added if necessary. AF recurrence-free survival rates were compared between patients with the ectopies that triggered AF or had %CI <40% (identified trigger group) and those without them (unknown trigger group).

Results:
Identified trigger group comprised 39 (33%) patients. Patient characteristics were similar between the groups including age (67±10 vs. 67±8 years, p=0.83), persistent AF (42% vs. 44%, p=0.50) and left atrial diameter (38±9 vs. 39±6 mm, p=0.30). Of 276 ectopies provoked, 77(28%) triggered AF and 92(33%) demonstrated short CI without AF initiation. All of them were originated from PVs (92%) or superior vena cava (8%). At 11±2 months, 23 (20%) patients developed AF recurrence. Identified trigger group showed a significantly better AF recurrence-free survival rate than unknown trigger group (92% vs. 70%, p=0.033). In multivariate analysis, identified trigger was an independent predictor of AF recurrence-free survival (Adjusted Hazard ratio [95% CI] = 0.21 [0.05, 0.90] (p=0.036)).

Conclusions:
AF-trigger identification by isoproterenol infusion may be a useful predictor of procedural success in patients undergoing AF ablation.
Abstract 14009: Serum NMR Metabolomics Identifies Similar Associations of Lipoproteins and Lipids With Risk of Myocardial Infarction and Ischemic Stroke but Not With Hemorrhagic Stroke
Authors: Holmes Michael V , Millwood Iona Y , Kartsonaki Christiana , Hill Michael R , Boxall Ruth , Walters Robin G , Ala-Korpela Mika , Parish Sarah , Clarke Robert J , Chen Zhengming
Published: April 2024

Introduction:
In observational studies, major circulating lipids (e.g. low density lipoprotein cholesterol) are associated with risk of myocardial infarction (MI) and ischemic stroke (IS), but their relationship with hemorrhagic stroke (HS) is not reliably established. An extensive panel of lipoprotein subclasses can be analysed by serum NMR metabolomics.

Hypothesis:
Circulating concentrations of lipoprotein particles and lipid constituents show similar patterns of association with risk of MI, IS and HS.

Methods:
The prospective China Kadoorie Biobank recruited 512,891 Chinese adults from 2004-08 with 7 years follow-up for incident events from registry and health insurance records. In a nested case-control study of 938 MI, 1276 IS and 1274 HS incident cases with 1355 controls, lipoprotein and lipid-related traits were quantified in baseline samples using serum NMR metabolomics. For each outcome, logistic regression yielded adjusted odds ratios (OR) associated with individual lipoprotein and lipid traits.

Results:
Concentrations of lipoprotein particles and their lipid components showed similar patterns of association with risk of MI and IS: risk increased with higher concentrations of very-low-, intermediate- and low-density lipoproteins (Figure). By contrast, for high density lipoproteins (HDL), increases in large particle concentration or lipid components were associated with reduced risk of both MI and IS, whereas medium HDL associated with reduced risk of MI but not IS. Small HDL showed null associations with MI and a trend towards increased risk of IS. No lipoprotein or lipid-related trait showed apparent associations with HS risk.

Conclusions:
Concentrations of lipoprotein particles and their lipid constituents show similar patterns of association with risk of MI/IS, whereas no associations were identified for HS. This suggests different etiologies and casts doubt on whether lipid-related traits play a major role in the etiology of HS.
Abstract 16590: The Association Between Long-Term Changes in Cardiorespiratory Fitness and Mortality Risk
Authors: Imboden Mary , Harber Matthew P , Whaley Mitchell H , Finch W H , Bishop Derron A , Kaminsky Leonard A
Published: April 2024

Introduction:
There is a strong inverse association between cardiorespiratory fitness (CRF) and mortality outcomes. This relationship has predominantly been assessed cross-sectionally, however low CRF is a modifiable risk factor, thus assessing this association using a single baseline measure may be sub-optimal. The primary purpose of this research was to examine the association of the long-term change in CRF, measured using cardiopulmonary exercise testing (CPX) with all-cause and disease-specific mortality.

Methods:
Participants included 833 apparently healthy men and women (42.9±10.8 y) who underwent two maximal CPXs, the second CPX being ≥ 1 year following the baseline assessment. Participants were followed for 17.7 ± 11.8 years for all-cause, cardiovascular disease (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (V1) peak oxygen consumption (VO
2peak
(ml·kg
-1·
min
-1
)) - visit 2 (V2) VO
2peak
, and mortality outcomes.

Results:
During follow-up, 172 participants died. Overall, the change in CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality (p<0.05). Each 1 ml·kg
-1·
min
-1
increase was associated with a 10.8, 14.7, and 15.9% reductions in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality remained significant (p<0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO
2peak
, and age.

Conclusions:
Long-term changes in CRF were inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent examination than baseline CRF. These findings support the recent American Heart Association scientific statement advocating CRF as a clinical vital sign that should be assessed routinely in clinical practice, as well as support regular participation in physical activity to maintain adequate CRF levels across the lifespan.
Abstract 16604: Recombinant Tafazzin Enzyme Replacement Therapy Rescues Metabolic and Functional Defects in a Mouse Model of Barth Syndrome
Authors: Awata Junya , Thomas Corinne J , Dinca Ana A , Chien Wei-Ming , Blanton Robert , Aronovitz Mark , Martin Gregory L , Richey Lauren , Strathdee Douglas , Chin Michael T
Published: April 2024

Barth syndrome (BTHS) is an X-linked autosomal recessive disease caused by mutations in the tafazzin (TAZ) gene. These mutations lead to hypotonia, cyclic neutropenia, 3-methyglutaconic aciduria, and the most common cause of mortality in patients, cardiomyopathy. The TAZ gene encodes an enzyme that generates mature cardiolipin (CL) from monolysocardiolipin (MLCL)in the mitochondrial membrane, which is essential for normal mitochondrial morphology and function. Currently, there is no effective therapy for BTHS. In this study, we test an enzyme replacement therapy for BTHS in myocardial-specific TAZ conditional knockout mice which model the cardiomyopathy of BTHS. Serial echocardiograms showed that the BTHS mice developed increased septal wall thickness at 5 weeks of age. The BTHS mice were treated for 12 weeks with either vehicle or recombinant human TAZ fused to a cell penetrating peptide (hTAZ-CTP) to facilitate tissue uptake. During the treatment period, septal wall thickness in the vehicle-treated mouse continued to increase, whereas it remained stable in those treated with hTAZ-CTP . Pressure-volume (PV) loop analysis indicated that heart function was impaired in the vehicle-treated BTHS mouse while the protein-treated mice were shown to have PV loops similar to normal mice. The ratio of MLCL/CL, a direct measure of TAZ enzymatic activity, was measured in heart mitochondria isolated from BTHS and control floxed allele mice after treatment. The MLCL/CL ratio in the vehicle treated BTHS mouse was 20.4, consistent with a BTHS phenotype, whereas the MLCL/CL ratios in protein-treated and control mice were 0.01, indicating that injection of hTAZ-CTP successfully rescued the function of TAZ in BTHS mice. Histological observation of liver, spleen, kidney, and heart did not show any sign of toxicity for hTAZ-CTP injection. These results indicate that TAZ enzyme replacement therapy has great potential as a future treatment for BTHS.
Abstract 16606: Utilization of the Genome Aggregation Database, In Silico Tools, and Heterologous Expression Patch Clamp Studies to Identify and Demote Previously Published Type 2 Long QT Syndrome-Causative Variants From Pathogenic to Likely Benign
Authors: Mattivi Connor L , Ye Dan , Tester David J , Clemens Daniel J , Zhou Wei , Giudicessi John R , Ackerman Michael J
Published: April 2024

Introduction:
Loss-of-function (LOF) variants in the
KCNH2
-encoded Kv11.1 potassium channel cause type 2 long QT syndrome (LQT2). To date, hundreds of
KCNH2
missense variants (MVs) have been published as “disease-causative”. However, it has been suggested that 10% of rare LQTS variants in the literature may be "false positives”.

Objective:
To determine previously published
KCNH2
variants that are likely false positives and warrant demotion to at least likely benign status.

Methods:
A list of all case-derived LQT2-associated MVs from six large published compendia was compiled. The frequency of each MV within the Genome Aggregation Database (gnomAD, n = 141,352 individuals) was recorded. Eight
in silico
variant assessment tools were used to grade each MV. Variants (n=8) absent in gnomAD but predicted “benign” by all 8 tools were considered potential false positives, despite being ultra-rare, and were characterized functionally using whole-cell patch clamp.

Results:
Overall, 339
KCNH2
MVs were identified among LQTS cases. Of these, 13 (4%) were seen at a minor allele frequency (MAF) > 0.0004 in gnomAD. This MAF cut-off is derived from the frequency of R176W-KCNH2, a well-established albeit weakly penetrant (i.e. < 20%) LQT2-causative MV. Variants seen at MAF > R176W-KCNH2 are unlikely to be LQT2-contributing. However, 253 MVs (75%) were absent in gnomAD. Of these, 8 (4%) MVs (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, and P963T) were predicted by all 8 in silico tools to be benign and had never been characterized functionally. Patch clamp studies did not demonstrate any LOF perturbation for these 8 MVs.

Conclusion:
This study offers compelling evidence for the demotion from LQT2-causative status to likely benign status for 21 (6%) of the 339 previously published LQT2 MVs based either on i) gnomAD MAF unacceptably high for a 1:8000 disorder (LQT2) for 13 MVs or ii) ultra-rarity (never seen in gnomAD) but
in silico
variant assessment tools predicting benign impact of the amino acid substitution and
in vitro
functional validation studies devoid of LOF for 8 additional MVs. This meticulous “pruning” exercise must be conducted for all published variants previously implicated as the monogenic cause for LQTS in particular and all genetic heart diseases in general.
Abstract 16607: Shift Workers Have Higher Blood Pressure Medication Use, but Only When They Are Short Sleepers Who Prefer Mornings: A Uk Biobank Study
Authors: Daus Marguerite , Lozano Alicia , Riegel Barbara , Patterson Freda , Malone Susan , Hanlon Alexandra
Published: April 2024

Shift workers have higher blood pressure medication use, but only when they are short sleepers who prefer mornings: A UK Biobank Study

Introduction:
Poor sleep quality is a risk factor for cardiovascular disease (CVD). Shift work influences sleep patterns and duration, but this study examines how shift work and sleep influence cardiovascular health.

Methods:
Baseline (BL) and 5-year follow-up (5YFU) data from the UK Biobank cohort study (N=11,259) were used to generate separate logistic regression models of shift workers and non-shift workers to examine the moderating effects of shift work on the relationship between sleep duration (short ≤6hrs; adequate 7-8hrs; long ≥9hrs) and chronotype (morning; evening) at BL with incident blood pressure (BP) medication (med) use from BL to 5YFU. All models were adjusted for family history of CVD, depression status, insomnia, narcolepsy, and alcohol intake.

Results:
The sample was predominately female (57.6%), White (97.8%), had not attended college (50.4%) and reported a mean age of 55.2 ± 7.4 years. Most were adequate sleepers (7-8hrs) (72.1%), morning chronotype (60.4%), and currently employed (66.5%) with 8.2% identifying as shift workers at BL. Only 7.7% reported incident BP med use from BL to 5YFU. Analysis demonstrated significant moderation for both sleep duration (p=0.02) and chronotype (p=0.04) in those working shifts. Among shift workers, short sleepers (≤6hrs) had a 2-fold increased odds of incident BP med use compared to adequate sleepers (OR=2.14, 95% CI=1.24-3.67, p=0.006); those with morning chronotype had a 78% increased odds of incident BP med use compared to evening chronotype (OR=1.78, 95% CI=1.03-3.12, p=0.04). Among non-shift workers, short versus adequate sleepers and those reporting morning versus evening chronotype had only a 3% increased (OR=1.03, 95% CI=0.85-1.25, p=0.76) and a 5% decreased (OR=0.95, 95% CI=0.81-1.13, p=0.60) odds of incident BP med use, respectively.

Conclusions:
The relationship between sleep duration and chronotype with incident BP med use was significant among shift workers and not in non-shift workers. Shift workers who are short sleepers or of morning time preference have increased incident blood pressure medication use.
Abstract 16609: Characterization of Neurodevelopmental Defects Associated With a Mouse Model of Hypoplastic Left Heart Syndrome
Authors: Gabriel George C , Salamacha Nathan , Reynolds William T , Tan Tuantuan , Liu Xiaoqin , Yagi Hisato , Bais Abha , Panigrahy Ashok , Simon Dennis , Wu Yijen , Lo Cecilia W
Published: April 2024

Introduction:
Hypoplastic left heart syndrome (HLHS), a congenital heart defect involving left-sided heart structures, is associated with poor neurodevelopmental outcome, with >30% experiencing neurodevelopmental impairment. A mouse model of HLHS showed brain abnormalities, suggesting a shared genetic etiology for brain and cardiac defects in HLHS.

Hypothesis:
Mutations in
Sap130
and
Pcdha9
causing HLHS in mice may individually or together cause brain abnormalities and neurobehavioral deficits.

Methods and Results:
Confocal histopathology and MR imaging was used to analyze the brain in mutant mice that were double
Sap130/Pcdha9
homozygous, single
Pcdha9
or
Sap130
homozygous, or with forebrain targeted Emx1-Cre deletion of a floxed
Sap130
allele
. Sap130/Pcdha9
and
Sap130
mutants exhibited overlapping phenotypes with microcephaly, thin cortex, and defects in the olfactory bulb, cerebellum, corpus callosum, and hippocampus, structures commonly affected in HLHS. RNAseq of
Sap130/Pcdha9
mutant brain showed dysregulation of genes mediating learning and memory, long-term potentiation, motor coordination, feeding-processes often affected in HLHS. In the Emx1-Cre forebrain deleted
Sap130
mice, forebrain hypoplasia was associated with cortical thinning and hippocampal dysplasia (Fig1 A,B). DTI connectome analysis showed global reduction in neuronal connections. Homozygous
Pcdha9
mutant mice, which are adult viable, showed only hippocampal dysplasia, but connectome analysis also showed global reduction in neuronal connections (Fig1 C,D). In line with this, behavioral tests showed deficits in spatial memory acquisition and cued fear conditioning (Fig1 E,F).

Conclusions:
We showed HLHS associated
Pchda9
and
Sap130
mutations, individually or together, can cause brain defects with reduced neuronal connections and neurobehavioral deficits. These defects can occur independent of the cardiac lesion, indicating they are not of hemodynamic origin.
Abstract 16616: Assessment of Lipid Rich Plaque Containing Necrotic Core Using a Multi-Modality Near-Infrared Autofluorescence and Optical Coherence Tomography Imaging System
Authors: Watanabe Kohei , Gardecki Joseph A , Nishimiya Kensuke , Piao Zhonglie , Yamada Daisuke , Tearney Guillermo J
Published: April 2024

Introduction:
Optical coherence tomography (OCT) is thought to be capable of identifying lipid-rich plaque (LRP). However, several histopathological correlative studies have shown that LRP assessment by OCT alone may be indecisive for identifying advanced plaque containing a necrotic core. This study aims to investigate the feasibility of multi-modality OCT-near-infrared autofluorescence (NIRAF) imaging to identify advanced necrotic-core LRP.

Methods:
We constructed a new fully integrated multi-modality OCT-NIRAF imaging system and catheter that allows simultaneous and co-registered acquisition of OCT and NIRAF data. NIRAF excitation was 635nm and emission was collected between 690-750nm. OCT-NIRAF pullback imaging was performed with excised human cadaver coronary arteries during saline perfusion. Subsequently, H&E sections were obtained and co-registered (longitudinally and azimuthally) with corresponding OCT-NIRAF images, using the known pullback distances, and anatomic landmarks and features such as calcium nodules seen in the OCT and histopathology images. In addition, a bench top confocal microscope was used to obtain images of NIRAF on corresponding unstained, formalin-fixed, paraffin-embedded slides.

Results:
A total of 187 histopathological sections and corresponding OCT-NIRAF images from 13 cadaver coronary arteries from 5 patients were imaged and analyzed. Several LRP that were identified by histopathology in these arteries showed regions with evidence of necrotic core with hemosiderin granules that had significantly higher catheter-based NIRAF than regions without hemosiderin granules. Confocal NIRAF microscopy also showed that regions of high NIRAF were associated with accumulation of hemosiderin in corresponding histological sections.

Conclusions:
This study provides suggestive data that an integrated OCT-NIRAF imaging system and catheter may be able to be used to identify advanced LRP that contains a necrotic core with hemosiderin granules. Future investigation of NIRAF from cadaver arteries from additional patients is merited to robustly confirm these findings.
Abstract 16618: Prognostic Significance of Coronary Artery Calcium (CAC) Score among Patients on Statin Therapy: Results of Coronary Artery Calcium Consortium, a Multicenter Cohort Study
Authors: Mirbolouk Hassan , Charkhchi Paniz , Uddin S M Ifthekhar , Orimoloye Olusola A. , Shaw Leslee , Berman Daniel S. , Whelton Seamus , Dardari Zeina , Miedema Michael D , Buddof Matthew , Rumberger John A , Nasir Khurram , Blaha Michael J
Published: April 2024

Introduction:
Statins do not decrease coronary calcification, and may, in fact, increase calcification or its density. This has led some observers to question the value of coronary artery calcium (CAC) in patients taking statins. We, therefore, examined the cardiovascular prognostic significance of CAC among patients who are already on statin therapy.

Methods:
We included 6,815 patients who were taking statin at baseline from the Coronary Artery Calcium Consortium. We used Cox regression models to assess the association of CAC with cardiovascular disease (CVD) mortality using CAC as a continuous variable (1 unit increase in log-transformed CAC score) and categorical variable: CAC = 0 (reference), CAC=1-99, CAC=100-399, and CAC ≥400. Models were adjusted for age, sex, family history of CHD, smoking status, hypertension, and diabetes.

Results:
Patients (mean [SD] age 57.2 [10.4]years, 71.8% men) were followed for a median of 10.8 years. During this follow-up period, 140 participants died of CVD. One unit increase in log CAC score was associated with significantly increased risk of CVD mortality (hazard ratio (HR), 1.09; 95% CI = 1.07-1.11). Compared to CAC=0, CAC groups showed a graded increase point estimates of CVD mortality risk (P for trend <0.001)
(Table 1)
, with those with CAC score ≥400 attaining statistical significance (2.5-fold increased risk).

Conclusion:
CAC scores remain a strong predictor of CVD mortality among asymptomatic patients who are taking statin. As such, there is likely a role for CAC to guide the intensity of LDL lowering or other preventive therapies in those already taking a statin.
Abstract 16621: Holter Monitoring in Patients With Left Ventricular Noncompaction
Authors: Farwati Medhat , Vaidya Vaibhav R , Isath Ameesh , Lyle Melissa , Asirvatham Samuel J , Deshmukh Abhishek J , Foley Thomas , Michelena Hector , Connolly Heidi M , Melduni Rowlens M , Kapa Suraj
Published: April 2024

Introduction:
Multiple arrhythmias including ventricular tachycardia (VT) and atrial fibrillation (AF) have been reported in patients with left ventricular noncompaction (LVNC). We sought to determine the frequency of rhythm abnormalities on Holter monitoring, and their association with all-cause mortality, in patients with LVNC.

Methods:
Imaging databases from 2000-2016 were reviewed to identify patients with LVNC. On transthoracic echocardiography (TTE), LVNC was defined as: end systolic noncompacted: compacted (NC:C) ratio>2 and end diastolic epicardium to trough: epicardium to peak trabeculation (X:Y) ratio<0.5. Holter monitor reports from the medical record were evaluated. VT was defined as ≥3 consecutive beats of ventricular origin. All-cause mortality was obtained from a web-based research and location service (Accurint). We used a proportional hazards model to determine associations of Holter variables with all-cause mortality.

Results:
Among 340 LVNC patients, Holter reports were available for 177 patients (median age 45 years, interquartile range [IQR] 33-61; 45% females). On TTE, the median NC:C ratio was 2.7 (IQR 2.4-3.2) and X:Y ratio was 0.25 (IQR 0.20-0.28). The median ejection fraction (EF) was 48% (IQR 33-58). 48 patients (27%) had at least one episode of VT (median 4 episodes, IQR 2-4). The median longest duration of VT was 5 beats (IQR 4-9) and maximum rate was 148 beats per minute (IQR: 125-169). PVC burden >5% and 20% was present in 13% and 5% of patients respectively. Patients with EF<50% were more likely to have VT (43% vs 16%, p=0.0003) and PVC burden >5% (19% vs 7%, p=0.03). AF was infrequent (N=5, all persistent). All-cause mortality was 12% over median 6.9 years of follow up (IQR: 3.6-11.3 years). Presence of VT and PVC burden on Holter monitoring were not associated with all-cause mortality (p>0.05). Among patients with VT, the number, longest duration, and fastest rate of VT episodes were not associated with all-cause mortality.

Conclusions:
Ventricular tachycardia on Holter monitoring is common among patients with LVNC, especially those with a reduced EF. However, the clinical significance of this finding is uncertain, and presence of VT was not associated with long term all-cause mortality.