bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12033: PCI De Lucs: A Prehospital Pathway Direct to the Cath Lab for Patients Suffering From Out-of Hospital Cardiac Arrest
Authors: Axelsson Christer , Jimenez-Herrera Maria , Herlitz Johan , Holmen Johan
Published: April 2024

Purpose:
In Sweden, the ambulance response time from call to arrival is 11 minutes in patients with an out-of-hospital cardiac arrest (OHCA). However, there is a small group of OHCA patients (20%) in whom this delay is minimized, namely those that occur minutes before or after the arrival of the ambulance. Despite CPR and/or defibrillation within one minute, only 20% survive to hospital discharge. The objective was therefore to determine whether a pathway with direct transportation to the cath lab, using mechanical chest compression (LUCAS), could improve survival in this selected group.

Aim:
To describe characteristics, feasibility and outcome among a selected group of OHCA patients transported directly to the cath lab by the ambulance in a new pathway

Method:
A prospective observational study from November 2013 to November 2015

Inclusion criteria:
1. Crew-witnessed cardiac arrest (CA) of cardiac origin or CA immediately defibrillated to return of spontaneous circulation (ROSC) by public access. 2. CA occurring two to three minutes before ambulance arrival where the patient had immediate bystander CPR of high quality. 4. CA occurring two to three minutes before ambulance arrival where the patient was still breathing at ambulance arrival.

Exclusion criteria:
Non-cardiac origin CA or high physiologic age (hospice patients)

Result:
Sixty-four patients fulfilled the inclusion criteria and 14 were excluded. Of the remaining 50 patients, 25 were transported with mechanical CPR to the cath lab. The time from CA to hospital was a median of 38 minutes. Survival to 30 days was 38% among all patients, 47% among VF (N=34) and 12% (N=25) among those who were transported with mechanical CPR.

Conclusion:
The pathway appears safe and feasible, but the inclusion criteria need to be less complex. The vast majority of survivors were found in the VF population. There were survivors (12%) among patients transported with ongoing CPR (N=25) directly to the cath lab by the ambulance.
Abstract 12038: A Family-focused and Literacy-sensitive Intervention to Improve Medication Adherence in Patients With Heart Failure
Authors: Wu Jia-rong , Mark Barbara
Published: April 2024

Background:
Medication nonadherence contributes to rehospitalization and death in heart failure (HF) patients, yet there is no intervention that improves and sustains adherence after intervention completion.

Objective:
To address the need for a more effective intervention, we combined a literacy sensitive approach that also incorporated family support in an educational counseling intervention. The purpose of the study was to pilot-test the effects of a
fam
ily-focused,
lit
eracy-sensitive (
FamLit
) intervention on improving and sustaining medication adherence in HF patients.

Methods:
A randomized controlled pilot trial was conducted on 43 HF patients and their family members (dyads) who were assigned to the FamLit intervention group or usual care attention-control group. All dyads had an in-person session at baseline and received bi-weekly phone booster calls for the 3 month intervention. The Medication Event Monitoring System (MEMS) was used to measure medication adherence continuously for 6 months (from baseline). Repeated measures analysis of variance (ANOVA) was used to analyze the data.

Results:
No differences on demographic and clinical factors between groups at baseline. After the intervention, patients in the FamLit group (n=24) had better medication adherence compared to the control group (n=19) as measured by the MEMS (84.96% vs. 79.9%). Repeated measures ANOVA showed that there was a significant group by time interaction (F=7.158, p=.011). Improvement of medication adherence was sustained from 3 to 6 months in the intervention group (84.96% to 84.67%, Figure) while medication adherence decreased in the control group (79.9% to 69.96%), reflecting the natural trajectory of medication adherence.

Conclusion:
Incorporating family support and providing easy-to-read educational material to both HF patients and their caregivers enhances medication adherence during the intervention and sustains adherence 3 months after intervention completion.
Abstract 12050: Cardiomyocyte Specific Deletion of Sirt1 Gene Alters Substrate Metabolism and Sensitizes Myocardium to Ischemia and Reperfusion Injury
Authors: Wang Lin , Quan Nanhu , Chu Dongyang , Chen Xu , Zhao Xuezhong , Li Ji
Published: April 2024

Introduction:
A longevity gene, sirtuin 1 (SIRT1) is a conserved NAD
+
-dependent protein deacetylase. AMP-activated protein kinase (AMPK) is an energy sensor. AMPK and SIRT1 signaling pathways have common activators such as caloric restriction, oxidative stress and exercise.

Hypothesis:
Aging-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults are due to a decreased SIRT1 levels in aging.

Methods:
Mice were subjected to ligation of left anterior descending coronary artery for
in vivo
ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system.

Results:
The cardiac functions by echocardiography show no difference in young (SIRT1

flox/flox

), aged (SIRT1

flox/flox

) and young inducible cardiomyocyte specific SIRT1 knockout (icSIRT1 KO) mice under physiological conditions, but after 45 mins ischemia and 24 hours reperfusion, the ejection fraction of aged and icSIRT1 KO mice were impaired. The aged and icSIRT1 KO hearts versus young hearts also show an impaired post-ischemic contractile function in Langendorff perfusion system. The infarct size of aged and icSIRT1 KO hearts was larger than that of young hearts (p<0.05). The immunoblotting data demonstrated that aged and icSIRT1 KO hearts versus young hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged and icSIRT1 KO hearts that could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impair substrate metabolism in the hearts, fatty acid oxidation is augmented and glucose oxidation is blunted during ischemia and reperfusion. Aged and icSIRT1 KO hearts versus young hearts demonstrated significant cardiac fibrosis and macrophage infiltration during ischemia and reperfusion. Furthermore, AMPK agonist A769662 treatment can rescue the tolerance of aged heart but not icSIRT1 KO hearts to ischemic insults.

Conclusions:
Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation during ischemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.
Abstract 12052: Non-complement-Binding Donor Specific Antibodies and Cardiac-Allograft Vasculopathy in Pediatric Heart Transplant Recipients
Authors: Das Bibhuti , Lacelle Chantale , Zhang Song , Fixler David
Published: April 2024

Aim:
We hypothesized that the non-complement binding of de novo donor specific antibodies (DSA) detected after heart transplant (HT) confer a lower risk for acute rejections and coronary artery vasculopathy (CAV). The purpose of this study was to compare the clinical outcomes between pediatric HT recipients with C1q+ and C1q- fixing de novo DSA

Methods:
127 patients from January 2005 to December 2014 were analyzed in this study to evaluate the outcomes including acute rejections and CAV of pediatric HT recipients who had C1q+ DSA compared to those with C1q- DSA. Serum samples from patients with circulating DSA were analyzed for C1q fixing according to the manufacturer’s protocol (C1qScreen, One Lambda).

Results:
Out of 127 patients transplanted between 2005 and 2014, 59 (46.4%) patients developed de novo DSA, of those 37 (62.7%) had C1q+ DSA. No difference in baseline characteristics: age at HT, gender, pre-HT diagnosis of CHD, ischemic time, number of HLA mismatch and pre-HT PRA >10. We found that DSA strength is significantly associated with C1q+ (C-statistics 0.89 and p <0.05) and at cut off 7000 MFI has 80% sensitivity and 80% specificity. C1q positive rate varied according to DSA class type: Class I (25% C1q+), class II (66% C1q +) and Class I and II (67% C1q+). C1q+ DSA patients had 2.4 times higher rate of acute rejection episodes compared to those with C1q- DSA. C1q+ DSA patients had significantly higher rates of CAV at 10-yr post-HT compared to C1q- DSA patients (72% vs 28%) (Figure) (P<0.001). C1q+ DSA patients had a trend towards poor allograft survival at 10-yr post-HT compared to C1q-DSA patients (70% vs 52%) (p =0.15).

Conclusions:
De novo DSA which are C1q+ have significantly greater deleterious effect on long-term allograft outcome in pediatric heart transplant recipients. Thus, measuring DSA and determining their complement binding capacity is helpful in assessing the risk of cardiac allograft vasculopathy. Figure:
Abstract 12057: Improving Hypertension Control and Patient Engagement Using Digital Tools
Authors: Milani Richard V , Lavie Carl J , Bober Robert M , Milani Alexander R , Ventura Hector O
Published: April 2024

Introduction:
Hypertension (HTN) is present in 30% of the adult US population and is a major contributor to heart and vascular disease. The current office-based approach yields only 50% control rates and low levels of patient activation. Current home technology now provides accurate, reliable data that can be transmitted to the electronic medical record (EMR).

Purpose:
To evaluate the feasibility and impact of a home blood pressure (BP) monitoring program on BP control and patient activation in patients with uncontrolled HTN (unHTN).

Methods:
We enrolled 125 patients with unHTN (last 3 readings > 140/90) into a home-based digital monitoring program (digital) and compared them to 400 patients (matched to age, gender, BMI and BP) with unHTN in a usual care (UC) group after 6 months. Digital patients completed questionnaires on-line, were asked to submit ≥1 BP reading/week, and received medication management and lifestyle recommendations via a clinical pharmacist and a health coach. BP units were commercially available, that transmitted data to the EMR (Epic).

Results:
There were no significant differences at baseline between Digital and UC patients. Digital patients averaged 4.2 BP readings per week. At 6-months 67% of Digital patients versus 32% of UC patients had achieved BP control. Mean drop in systolic/diastolic BP was 15/6 mmHg in Digital versus 7/3 mmHg in UC. Excess sodium consumption decreased from 54% to 41% in the Digital group. Mean patient activation increased from 42.3 to 44.0 (p<0.05) and the percentage of patients with low patient activation decreased from 15.8% to 10.7% (p<0.05).
Limitations
• Non-randomized trial • Single site

Conclusions:
A digital HTN program is feasible and associated with significant improvement in BP control rates and lifestyle change. Utilization of a virtual health intervention using connected devices improves patient activation and is well accepted by patients.
Abstract 12136: Bag-mask Ventilation Without Lung Inflation is Common During Out-of-Hospital 30:2 Cardiopulmonary Resuscitation
Authors: Fredericks Andrew , Lu Yuanzheng , Schroeder Lindsay , Cooper Thomas , Floyd Lawson , Chang Mary , Idris Ahamed H
Published: April 2024

Introduction:
American Heart Association guidelines for cardiopulmonary resuscitation (CPR) recommend recurring cycles of 30 chest compressions interrupted by a pause for two ventilations when an advanced airway device has not been placed. Few studies have measured lung inflation during pauses for ventilation in 30:2 CPR for out-of-hospital cardiac arrest (OOHCA).

Objective:
To determine the number of ventilation pauses with measureable lung inflation during 30:2 CPR for OOHCA.

Methods:
This is an observational, retrospective analysis of non-traumatic, OOHCA in patients ≥18 years old who received 30:2 CPR by emergency medical service (EMS) rescuers. Data is from the Dallas-Fort Worth site of the Resuscitation Outcomes Consortium cardiac arrest registry. Ventilation data are derived from defibrillator electronic recordings during the first six minutes of CPR when rescuers used a bag-mask device for ventilation. The recordings display thoracic bioimpedance waveforms of chest compressions and lung inflations. An interruption for ventilation is defined as a pause in chest compressions of 3 to 15 seconds. We assessed the presence of lung inflation waveforms during the pause for ventilation. Lung inflation was defined as a waveform with at least 2 mm (0.4 ohm) amplitude and at least 1-second duration.

Results:
We analyzed 200 patients with OOHCA who received 30:2 CPR cycles by EMS from February 2012 to June 2014. A total of 1,590 ventilation pauses were analyzed; of the 1,590 ventilation pauses, 57% did not have any measurable lung inflation waveforms (Table). Twenty-five (12.5%) patients had no lung inflation during the first six minutes of CPR. Return of spontaneous circulation occurred in 21%.

Conclusions:
The majority of patients did not receive lung inflation during 50% or more of each 30:2 CPR episode. This could be a factor in explaining why ventilation has not been shown to improve survival outcomes. Further studies should evaluate this topic in greater detail.
Abstract 12140: Effect of Hypothermia on the Peripheral and Cerebral Microcirculation in a Rat Model of Cardiac Arrest
Authors: Tang Ziren , Wang Jiangang , Yin Lu , Zhao Shen , Yu Haifang , Wu Xiaobo , Peberdy Mary A , Ornato Joseph P , Tang Wanchun
Published: April 2024

Introduction:
Therapeutic hypothermia improves outcomes after cardiac arrest (CA) and is a standard therapy for comatose patients after successful initial resuscitation. Post-resuscitation functional vital organ recovery is largely dependent on microcirculatory function. The effects of hypothermia on the peripheral and cerebral microcirculation following CA are not fully understood.

Hypothesis:
Hypothermia reduces the peripheral microcirculatory flow. However, the microcirculatory flow of cerebral cortex is preserved during hypothermia in a rat model of CPR.

Methods:
Twenty-one male Sprague-Dawley rats were randomized into three groups: hypothermic (HT, n=8), normothermic (NT, n=8) or sham-operated group (SO, n=5). Ventricular fibrillation was induced electrically and untreated for 8 mins, followed by 8 mins of precordial compressions and mechanical ventilations. The core temperature was reduced to 33±0.2°C at 5 mins following successful resuscitation and maintained for 8 hrs in the HT group. Normothermic animals were maintained at 37±0.2°C for 8 hrs. Sublingual and cerebral cortex microcirculation was measured by a sidestream dark-field imaging device at baseline, 1, 2, 3, 4, 6 and 8 hrs post-resuscitation.

Results:
All animals were resuscitated successfully. The sublingual microcirculatory flow index (MFI) was decreased significantly compared to the cerebral cortex MFI in the HT group following resuscitation (P< 0.05) (Figure 1). However, sublingual and cerebral microcirculation were impaired equally in the NT group after resuscitation.(Figure 2)

Conclusions:
A similar reduction in both sublingual and cerebral cortex microcirculatory flow was observed following resuscitation under conditions of normothermia. Hypothermia preserved the cerebral cortex microcirculation, but not the peripheral microcirculation, after resuscitation.
Abstract 12162: Changes in Renal Function Following Left Ventricular Assist Device Placement in Pediatric Patients: A PediMACS Analysis
Authors: Friedland-Little Joshua M , Hong Borah J , Gossett Jeffrey G , Deshpande Shriprasad R , Law Sabrina , Hollifield Kathryn A , Cantor Ryan S , Kindel Steven J , Turrentine Mark W , Davies Ryan R
Published: April 2024

Introduction:
Renal dysfunction (RD) is prevalent among pediatric patients with advanced heart failure. Data are limited regarding changes in renal function following left ventricular assist device (LVAD) placement in this population.

Hypothesis:
Renal function will improve following pediatric LVAD placement, but degree and durability of improvement may vary based upon patient and device characteristics.

Methods:
Pediatric LVAD recipients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) between September 19, 2012 and December 31, 2015 were included. The Schwartz equation was used to calculate eGFR and longitudinal changes in renal function were analyzed for the entire cohort as well as subgroups stratified by patient and device characteristics.

Results:
Data from 218 patients from 39 centers were analyzed. Mean age at implant was 9.2 years and total follow up time was 768 patient-months. There were 117 (54%) durable continuous flow LVADs, 60 (27%) durable pulsatile flow LVADs, and 41 (19%) temporary LVADs. The underlying diagnosis was cardiomyopathy in 162 (74%) patients and congenital heart disease in 47 (22%) patients. Baseline RD (eGFR < 90 mL/min/1.73 m
2
) was present in 140 (64%) patients. Overall, eGFR improved post-LVAD, peaking at 1 month post-implant (Figure 1). There was an inverse relationship between baseline eGFR and the degree of improvement at 1 month (mean increase in eGFR of 45 +/- 16 for patients with baseline RD vs. mean increase of 16 +/- 58 for patients with normal eGFR pre-LVAD, p=0.001). Degree of improvement in eGFR at 1 month did not appear impacted by device type, age, or diagnosis. There was a downward trend in eGFR after 1 month, although eGFR remained over baseline for patients with pre-implant RD.

Conclusions:
Renal function improves post-LVAD placement in pediatric patients regardless of age, diagnosis or device type, with improvement most pronounced in patients with baseline RD.
Abstract 12164: Inhibition of NOTCH3 Cleavage Effectively Reverses Pulmonary Hypertension in Rat and Mouse Models of Disease
Authors: Gower Jonathan R , Zhang Yu , Singh Martanday , Louie Mikaela , Nyugen Marie , Peterson Kirk , Thistlethwaite Patricia
Published: April 2024

Background:
NOTCH3 signaling is required for the proliferation of vascular smooth muscle cells. NOTCH3 signaling has been implicated in the development of pulmonary arterial hypertension (PAH) as reflected by increased levels of cleaved NOTCH3 and its downstream effector, HES-5 in small pulmonary artery smooth muscle cells (PASMCS) of PAH patients. Gamma-secretase inhibitor drugs that block NOTCH cleavage are effective in treating pulmonary hypertension (PH) in rodents, but they are associated with toxic side effects.

Hypothesis:
We hypothesize that a monoclonal antibody that specifically blocks NOTCH3 cleavage will effectively reverse PH in rodent models of disease, with an acceptable safety profile.

Methods/Results:
A monoclonal antibody specific to rodent and human NOTCH3 (Anti-NOTCH3 Ab) was made and shown to block Jagged-1/Delta-like 4-mediated NOTCH3 cleavage in PASMCs
in vitro
. We tested Anti-NOTCH3 Ab for its ability to reverse PH in mouse hypoxia and rat Sugen models. After 4 weeks of hypoxia, mice treated with Anti-NOTCH3 Ab for 6 weeks demonstrated normalization of right ventricular systolic pressure (mean 17 mmHg), compared to RVSP in control mice (mean 35mmHg). Treated mice demonstrated reversal of small vessel remodeling and had angiograms consistent with normal vasculature. In the Sugen model, rats treated with Anti-NOTCH3 Ab for 10 weeks showed reversal of established disease. This included normalization of RVSPs (mean 18 mmHg - treated group vs. 70 mmHg - control group), normalization of TAPSE values (mean 3.7 mm - treated group vs. 2.4 mm - control group) and normalization of PAAT values (mean 42 msec - treated group vs. 17 msec - control group). The lungs of Anti-NOTCH3 Ab-treated rats had reversal of small vessel remodeling with loss of medial hypertrophy. Western blot analysis showed significantly decreased cleavage of NOTCH3 in the treated group vs. control group. Anti-NOTCH3 Ab-treated rodents did not manifest clinical side effects and had normal organ histology of brain, liver, kidney, intestine, skin, ovary, and heart.

Conclusion:
Inhibition of cleavage of NOTCH3 by a monoclonal Anti-NOTCH3 Ab effectively treats PH in mouse hypoxia and rat Sugen models. Anti-NOTCH3 Ab treatment was associated with an acceptable safety profile.
Abstract 12173: A Randomized Controlled Trial Comparing Self-instruction and Traditional Instruction in Training of Bystander Cardiopulmonary Resuscitation
Authors: Hsieh Ming-Ju , Yang Chih-Wei , Lin Hao-Yang , Hsu Shu-Hsien , Chiang Wen-Chu , Sun Jen-Tang , Chong Kah-Meng , Ma Matthew Huei-Ming
Published: April 2024

Introduction:
Self-instruction of learning cardiopulmonary resuscitation (CPR) saves manpower and may be applied in large-scale public training, but its effect comparing to traditional instruction remains unclear.

Hypothesis:
In bystander CPR training, self-instruction compared to traditional instruction, has different post-training performances.

Methods:
In this randomized controlled study, administrative clerks and other non-health care providers were randomly allocated into 2 groups: self-instruction group and traditional instruction group. Both groups watched a 27-minute standardized teaching video. Participants in the self-instruction group then performed a 30-minute hands-on practice on Resusci Anne® QCPR (Laerdal company, Norway) with automated feedback, while participants in the traditional instruction group performed the same duration of practice on manikins with feedback by the instructors aside. Both groups had to receive skill tests before and after practice. Blinded evaluators used checklists to decide whether participants passed the tests by reviewing the videos of the skill tests. Data of skill performance was also collected using SkillReporter® software. The primary outcome was the pass rate. The secondary outcomes were items of individual skill performances.

Results:
Totally sixty-four participants were randomly allocated. All participants completed the protocol. The baseline characteristics of 2 groups were no different. In the primary outcome, the pass rates were the same between 2 groups (94% vs 94%, p=1.00). In the secondary outcomes, the self-instruction group performed better in mean compression depth (48.4 vs 42.0 mm, p=0.002), mean percentage of full chest recoils (77.7% vs 56.4%, p=0.014) and mean percentage of correct ventilation volume (96.5% vs 75.1%, p=0.013), but performed worse in confirming environmental safety (47% vs 78%, p=0.010) and checking normal breathing (26% vs 97%, p<0.001).

Conclusions:
Bystander CPR training using self-instruction was no different from traditional instruction in pass rate, and even better in some skill performances, but confirmation of environmental safety and check of normal breathing before starting CPR should be emphasized in self-instruction training.
Abstract 12175: Microsurgical Technique in Coronary Surgery Improves Long-term Outcomes
Authors: Shiryaev Andrey , Lepilin Michael , Galyautdinov Damir , Vasilyev Vladislav , Cherkashin Dmitriy , Akchurin Renat
Published: April 2024

Introduction:
The operating microscope is widely used in surgical practice, but there is no common opinion on the benefits of its use in coronary surgery.

Objectives:
The aim of this study was to compare the long-term outcomes of coronary artery bypass grafting with microsurgical technique and conventional technique.

Methods:
We have studied 270 patients operated on for coronary artery disease by the same surgical team in 2004. We included observations of 3-vessel disease in which at least 1 bypassed vessel was type C according to Coronary Artery Surgery Study protocol or had the diameter at the anastomotic site of less than 1.5 mm. Patients were randomly assigned to 2 groups: microsurgical group (n=128); patients were operated on using a microsurgical technique (8-12х magnification, 8-0 polypropylene sutures with a 3/8, 6.5 mm needle for distal anastomoses) and nonmicrosurgical group (n=142); patients were operated on with a magnifying loupes (3.5х magnification, 8-0 polypropylene sutures with a 3/8, 8.0 mm needle). The mean number of distal anastomoses in microsurgical group was 4.1±0.8 vs 3.9±0.9 (p=ns) in nonmicrosurgical group, the number of anastomoses to arteries of less than 1.5 mm - 254 vs 121 (p=<0.001) and patients with endarterectomies - 3 vs 44 (p=<0.001), respectively. In all cases the left internal thoracic artery was anastomosed to the left anterior descending coronary artery. Follow-up was complete in 95% (258 patients). Survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test.

Results:
Ten-year survival rates in groups of patients operated on with and without the use of microsurgical technique were 82.7% vs 72.0% (p=0.03), incidence of non-fatal myocardial infarction - 9.8% vs 16.1% (p=0.14), recurrence of angina - 14.7% vs 22.7% (p=0.11), repeat interventions - 8.1% vs 17.6% (p=0.02), all cardiac events - 34.4% vs 58.8% (p=0.0001), respectively.

Conclusions:
The use of the microsurgery compared with the conventional technique yields superior clinical results in coronary surgery during a 10-year follow-up.
Abstract 12206: Altered Cardiomyocyte Inotropic Response to Chymase/Ang-(1-12) Pathway Activation in Heart Failure
Authors: Li Tiankai , Zhang Xiaowei , Ahmad Sarfaraz , Varagic Jasmina , Cheng Heng-Jie , Zhang Zhi , Groban Leanne , Ferrario Carlos M , Cheng Che Ping
Published: April 2024

Background:
Angiotensin-(1-12) [Ang-(1-12)], a new member of the renin-angiotensin system (RAS) has been identified as a chymase-dependent source for Angiotensin II (Ang II) inotropic activity. Recent observations suggest that activation of this non-canonical chymase/Ang-(1-12) pathway may modulate cardiac function bypassing the inhibitory effects of RAS blockade with ACEI and ARBs in heart failure (HF). However, the direct cardiac effects of Ang-(1-12) and Ang II are unclear. Moreover, whether and how HF alters Ang-(1-12) and Ang II cardiac responses are undefined. We assessed the hypothesis that HF is associated with a reduced action of Ang-(1-12) on myocyte contractility and [Ca
2+
]
i
regulation.

Methods:
We compared LV myocyte contractile and calcium transient ([Ca
2+
]
iT
) responses to angiotensin peptides in 12 SD rats with isoproterenol induced HF (2 months after isoproterenol 170 mg/kg sq for 2 days) and 16 age-matched controls.

Results:
In normal myocytes, versus baseline, Ang II (10
-6
M) superfusion significantly increased myocyte contraction (dL/dt
max
)

(40%, 184.6 vs 132.1 μm/s), relaxation (dR/dt
max
) (34%, 141.3 vs 107.0 μm/s) and [Ca
2+
]
iT
(29%, 0.31 vs 0.24). Superfusion of Ang-(1-12) (4x10
-6
M) caused similar increases in dL/dt
max
(34%) dR/dt
max
(25%) and [Ca
2+
]
iT
(25%). Compared with the changes in normal myocytes, in HF myocytes, Ang II and Ang-(1-12) caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dt
max
, dR/dt
max
and [Ca
2+
]
iT
. The Ang-(1-12)-mediated effects were abolished by prior exposure of myocytes to chymostatin in both normal and HF. The Ang II-induced inotropic effects were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (10
–4
M 2 h) in both normal and HF myocytes, but were further augmented only in HF after the incubation of myocytes with the G
i
inhibitor, pertussis toxin (PTX, 2 μg/ml, 36°C, 5h).

Conclusions:
Ang-(1-12) stimulates LV myocyte contractile function and [Ca
2+
]
iT
in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes is mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.
Abstract 12208: Mode of Death in Heart Failure With Preserved Ejection Fraction: A Systematic Review
Authors: Patel Ravi B , Vaduganathan Muthiah , Michel Alexander , Shah Sanjiv J , Senni Michele , Gheorghiade Mihai , Butler Javed
Published: April 2024

Introduction:
Despite its tremendous clinical and economic impact, remarkably little is known about the specific modes of death (MOD) in patients with heart failure with preserved ejection fraction (HFpEF).

Methods:
We conducted a systematic review of published HFpEF clinical trials and epidemiological studies from January 1
st
, 1985 to December 31
st
, 2015 using the PubMed and EMBASE databases. Two independent investigators manually screened 1,608 articles in duplicate, selected studies, and extracted relevant data. The systematic search yielded 8 major randomized controlled trials and 24 epidemiological studies that reported MOD data.

Results:
Definitions of cardiovascular (CV), sudden, heart failure (HF), and non-CV deaths in HFpEF trials were similar to those used in contemporary trials of HF with reduced ejection fraction (HFrEF). CV causes accounted for ~60-70% of total deaths in HFpEF clinical trials (Figure), while this proportion was more variable (14-83%) in epidemiological studies. Only 4 (50%) trials and 5 (20.8%) epidemiological studies reported data on sudden death (SD). SD accounted for ~40% of the CV deaths in clinical trials, but only 20-28% in epidemiological studies. Proportions of HF deaths were consistent across clinical trials (20-30% of CV deaths) but varied in epidemiological studies (17-60%). Cancer was the most frequently reported non-CV MOD (~30-40% of non-CV deaths), followed by infection/sepsis, which accounted for a quarter of non-CV deaths.

Conclusions:
Cause-specific mortality is infrequently reported, informed by <1,000 events (in trials) and <500 events (in epidemiological studies), and when it is, event definitions are directly applied from HFrEF studies. The definition of SD is non-specific and suboptimal in the majority of studies; therefore, it is unclear whether these truly represent arrhythmic deaths. Reporting and definitions of MOD must be standardized and tailored to the HFpEF population.
Abstract 12507: Spatial Gradients in Wall Shear Stress Promote Collective Human Lymphatic Microvascular Endothelial Cell Migration and Alignment Through Sphingosine 1-phosphate Receptor 1
Authors: Surya Vinay N , Michalaki Eleftheria , Huang Eva Y , Fuller Gerald G , Dunn Alexander R
Published: April 2024

Introduction:
Spatial variations in fluid flow are thought to help trigger the formation of valves within the blood and lymphatic circulatory systems during embryonic development. However, how the physical stimulus drives the collective cell movements and changes in gene expression that underlie valve formation is not known. This knowledge gap is of considerable importance since valve failure within the lymphatic and venous vessels is significant in a wide variety of cardiovascular disease states.

Methods:
In this study, we developed
in vitro
fluid flow devices that allow us to replicate key aspects of the fluid flow environment found in the vicinity of developing valves within the lymphatic and venous vasculatures. We developed an impinging flow chamber as a model for vessel bifurcations, applying a spatial gradient in wall shear stress (WSS). We have also developed a device which applies flow through a constriction such as is commonly found at sites of valve initiation.

Results:
Using these devices, we examined the migration of human lymphatic microvascular ECs (MVECs) subjected to spatial gradients in WSS. We found that lymphatic MVECs subjected to a variety of WSS ranges from 0 to 9, 33, or 72 dynes/cm
2
align and collectively migrate against the flow direction over the course of 20 hours. When subjected to flow through a constriction, lymphatic MVECs turned perpendicular to the flow direction at regions near the site of maximum constriction. We determined that the G-Protein Coupled Receptor, Sphingosine 1-Phosphate Receptor 1 (S1PR1) was required for both lymphatic MVEC alignment and collective migration: a 70%
S1PR1
mRNA knockdown relative to scrambled siRNA control was sufficient to prevent the collective migration and perpendicular alignment phenotypes we observed in our
in vitro
flow devices. In addition, these shear stress gradients resulted in higher nuclear levels of Prospero Homeobox Protein 1, a transcription factor known to be required for valvulogenesis, relative to cells in the absence of flow (Impinging Flow; 9.8 +/- 2.2 fold, Constriction; 5.1 +/- 0.8 fold).

Conclusions:
Our observations implicate S1PR1 as a key component in both the phenotypic and transcriptional responses of LECs to gradients in WSS, such as those at sites of valve formation.
Abstract 12513: Comparison of Global Myocardial Function With 2 Types of Pressure-Overload Left Ventricular Hypertrophy Using Two-Dimentional Speckle-Tracking Echocardiography
Authors: Ohara Yoshikazu , Tsuda Yuki , Fukuoka Yohko , Furukawa Atsuko , Hosogi Shingo , Yamamoto Katsuhito
Published: April 2024

Introduction:
Left ventricular hypertrophy (LVH) secondary to hypertension and aortic stenosis (AS) are often considered together to be pressure overload hypertrophy. Comparisons of myocardial function by the 2 most common causes of LVH are limited. The global LV afterload that may be assessed by valvuloarterial impedance plays a detrimental effect on LV systolic function.

Hypothesis:
We hypothesized that important differences may exist in the myocardial function with these 2 origins of pressure-overload LVH.

Methods:
Global LV longitudinal strain (GLS) were measured using speckle-tracking echocardiography in 38 hypertensive LVH (H-LVH) patients and 36 patients with severe AS and preserved LV ejection fraction. To estimate the global LV afterload, we calculated the valvuloarterial impedance (Z
va
) as the sum of the systolic arterial pressure and the mean transvalvular pressure gradient divided by the stroke volume index.

Results:
The patients were divided into two groups according to the level of Z
va
: low Z
va
(Z
va
<3mmHg ml/m
2
, n=25) and high Z
va
(Z
va
≥3mmHg ml/m
2
, n=49). GLS was reduced in the high Z
va
group (p<0.05). The patients in the high Z
va
group were divided into two subgroups: AS group (n=28) and H-LVH group (n=21). Systolic blood pressure was higher in the H-LVH group than in the AS group (p<0.0001). However, LV mass index and LV ejection fraction were not significantly differences. GLS was significantly reduced in the AS group (p<0.0001). In the AS group, GLS was significantly correlated with Zva (r=0.44). However, there was no correlation between GLS and mean transaortic pressure gradient.

Conclusions:
Despite of similar global LV afterload and LV hypertrophy, myocardial LV longitudinal systolic function is impaired in patients with severe AS compared with H-LVH patients. However, there is no correlation between AS severity and LV longitudinal deformation. The magnitude of the global LV afterload as reflected by Z
va
is a powerful determinant of altered LV longitudinal deformation in severe AS patinets with preserved LV ejection fraction.
Abstract 12569: Relationship Between Neurodevelopmental Outcomes at 2 Years and 4 Years in Children With Congenital Heart Disease After Surgical Palliation
Authors: Brosig Cheryl L , Bear Laurel , Allen Sydney , Hoffmann Raymond G , Pan Amy , Frommelt Michele , Mussatto Kathleen A
Published: April 2024

Introduction:
Children with congenital heart disease (CHD) are at risk for neurodevelopmental (ND) delays. The American Heart Association (AHA) recommends serial ND evaluation for children with CHD. This study compares the ND testing results of children with CHD at 2 and 4 years of age.

Methods:
Children with CHD meeting the AHA high-risk criteria for ND delay were seen for longitudinal developmental evaluation. Testing included the Bayley Scales of Infant Development - III (BSID-III) at 2 years (±3 months) of age, and standardized neuropsychological measures at 4 years. Scores were compared to test norms and were classified as: average (within one SD of test mean); at risk (1-2 SDs from the test mean); and impaired (>2SD from test mean). Spearman correlations and McNemar’s exact tests were performed to determine the relationship between test scores at the two times of assessment.

Results:
Of the 102 patients evaluated at 4 years of age, 73% (n=75) had a previous evaluation using the BSID-III; 48 (47%) completed the BSID-III at 24±3 months of age. Median age at first cardiac operation was 13 days. Patients had the following characteristics: single ventricle anatomy 33%; male 63%; prenatal diagnosis 53%; premature 18%; non-white/Hispanic race 13%; and comorbidities: medical 25%, genetic 17%. BSID-III cognitive, language, and motor scores were correlated with preschool IQ, language, and motor scores, r = 0.49 to 0.75, all p<0.01. Of the patients who had average or above BSID-III cognitive scores at age 2, 29.7% scored in the at risk or delayed range on the preschool IQ test.

Conclusion:
BSID-III scores at 2 years are significantly associated with ND outcomes at 4 years. However, even though scores were related, many patients who scored in the average range at age 2 showed some deficits at age 4. Therefore, longitudinal ND assessment is recommended.
Abstract 12604: Potassium-dependence of Arrhythmias due to the
SCN5A
Variant R222Q
Authors: Daniel Laura , Yang Tao , Roden Dan
Published: April 2024

Background:
R222Q is a charge-neutralizing mutation in domain I/S4 voltage sensor of the cardiac sodium channel. Mutation carriers display very frequent ectopy and dilated cardiomyopathy (DCM). To probe mechanisms for the ectopy, DCM, and the relationship between the two, we have generated mice carrying humanized wild-type (H) or mutant (RQ) channels.

Methods and results:
RQ/RQ pups are viable but typically die by 7 days postnatally, so the data reported here compare RQ/H and H/H. Consistent with previous heterologous expression studies, RQ/H myocytes displayed hyperpolarizing shifts in both inactivation (V
1/2
: -107.1±1.2 mV vs -94.7±1.3, p<0.01) and activation (V
1/2
: -70.1±1.3 mV vs -53.8±1.6, p<0.01) resulting in increased window current. RQ/H myocytes also displayed accelerated I
Na
fast inactivation (1.5±0.1 ms vs 2.1±0.2 at -40 mV, p<0.01), recovery from inactivation, and unusually short action potential duration (APD
90
: 12.6±1.3 ms vs 29.1±1, p<0.01). However, at 3 and 6 months RQ/H mice exhibited only infrequent ectopy. Surface ECGs and echocardiograms were normal. Previous reports have identified an outward pore current with DCM-associated
SCN5A
voltage sensor domain mutations, and in analogous
SCN4A
mutations associated with hypokalemic periodic paralysis. Decreasing [K
+
]
o
from 4 to 2 mM increased R222Q-associated pore current from 11.9±2.0 pA/pF to 19.1±2.1 at +40 mV (p<0.05); there was minimal pore current in H/H myocytes at either potassium concentration. Decreasing [K
+
]
o
also elicited afterdepolarizations in 9/14 RQ/H myocytes compared to 0/10 H/H. With Langendorff perfusion of 2 mM [K
+
]
o
, ectopy was present in 0.2±0.6% of beats in H/H hearts but was markedly enhanced to 24.3±9.6% in RQ/H (n=6-9; P<0.05).

Conclusion:
Despite striking I
Na
dysfunction, RQ/H mice displayed minimal ectopy. The lack of DCM in the absence of frequent ectopy supports the hypothesis that frequent ectopy causes the DCM in human mutation carriers. Hypokalemia increased pore current in R222Q myocytes, and was highly arrhythmogenic
in vitro
and
ex vivo
. We speculate that frequent ectopy in human mutation carriers could be responsive to potassium supplements, and this in turn could prevent or ameliorate the DCM phenotype.
Abstract 12605: Brain Metabolic Activity Within Regions Involved in Stress Perception Associates Directly With Arterial Inflammation and Inversely With Aortic Distensibility in Psoriasis
Authors: Aberra Tsion M , Chaturvedi Abhishek , Lerman Joseph B , Dey Amit K , Shukla Parag , Joshi Aditya A , Rodante Justin A , Silverman Joanna I , Ng Qimin , Teague Heather L , Ahlman Mark A , Bluemke David A , Playford Martin P , Tawakol Ahmed A , Mehta Nehal N
Published: April 2024

Introduction:
Psychological stress and depression are linked to increased cardiovascular (CV) events in the general population and in psoriasis (PSO), a chronic inflammatory disease that increases CV risk. 18-FDG-PET/CT enables quantification of metabolic activity of the amygdala, a neural tissue critically involved in the pathobiology of stress and depression. In individuals without chronic inflammatory diseases, amygdalar activity (AmygAct) associates with greater vascular inflammation (VI) and CV events. However, it is not known whether PSO maintains this relationship with VI and whether AmygAct associates with other measures of subclinical CVD.

Hypothesis:
In PSO, AmygAct: 1) is higher in individuals who report depression/anxiety, and 2) associates with greater VI and decreased aortic distensibility.

Methods:
Subjects with PSO (n=82) completed a questionnaire at baseline, reporting psychiatric history and were placed into two groups accordingly: patients with depression/anxiety and age and sex matched controls with no psychiatric diagnoses. AmygAct was quantified using 18-FDG PET/CT by an analyst blinded to clinical data. Mean standardized uptake values (SUV) for the left amygdala were corrected for background brain activity. VI was quantified as a ratio of aortic to blood background SUV. Aortic distensibility was measured using phase contrast MRI.

Results:
Subjects had a mean age of 49.2 years, were 49% males, and had a median Framingham risk score of 3. Patients with a history of depression and/or anxiety had significantly higher AmygAct than those without (mean±SEM 0.85±0.01 vs. 0.81±0.01; p=0.01). AmygAct correlated with VI (β= 0.26, p=0.02) as well as aortic distensibility (β= -0.50, p<0.001). Moreover, AmygAct remained associated with aortic distensibility after adjustment for Framingham risk score and hypertension (β= -0.37, p=0.007).

Conclusions:
Metabolic activity within neural tissues involved in stress perception significantly associates with indices of atherosclerotic disease in PSO. Future studies should further evaluate the mechanisms linking neural and atherosclerotic tissues in chronic inflammatory conditions such as PSO, and probe whether perturbing this mechanism may reduce the burden of atherosclerosis.
Abstract 12622: Gut-microbiota-derived Trimethylamine-N-oxide levels and Risk of Major Adverse Cardiovascular Events: A Systematic Review and Meta-analysis of Prospective Cohort Studies
Authors: Heianza Yoriko , Ma Wenjie , Qi Lu
Published: April 2024

Introduction:
Gut microbial metabolite trimethylamine-N-oxide (TMAO) has been implicated as a novel risk factor for cardiovascular events. The strength and consistency of the association between blood levels of the gut microbiota-related risk factor and cardiovascular events or deaths remain unclear.

Hypothesis:
We performed a systematic review and meta-analysis of prospective cohort studies to quantify the association of blood levels of TMAO and the risk of major adverse cardiovascular events (MACE).

Methods:
PubMed and Embase databases were searched up to 3 May 2016 and prospective studies with either quantitative estimates of the association of blood TMAO levels with incident MACE were included. MACE was indicated by myocardial infarction, stroke, heart transplant, heart failure, other ischemic cardiovascular events or death (either cardiovascular or all-cause). Two reviewers independently extracted data and assessed study quality. Generalized least-squares trend estimation was used to assess dose-response relationships. Summary relative risk (RR) for higher TMAO levels as compared to lower levels was calculated using only prospective cohort studies.

Results:
A total of 12 cohorts were included in the meta-analysis. High circulating TMAO levels were associated with an increased risk of MACE with a pooled RR of 1.76 (95% confidence interval: 1.50, 2.07; heterogeneity p = 0.22; I-squared = 22.8%) compared with low TMAO levels. Elevated TMAO levels were consistently associated with an increased risk of MACE regardless of older ages, high prevalence of diabetes, histories of cardiovascular diseases or renal failure at the baseline across studies. Pooled adjusted RR (95% confidence interval) of MACE was 1.02 (1.01, 1.04) per 1 μM (n=6 cohorts) or 1.22 (1.12, 1.32) per log-transformed 1 SD (n=4) increment in TMAO levels.

Conclusions:
Higher blood TMAO levels were consistently and dose-dependently associated with the development of MACE across diverse populations, independently of traditional risk factors.
Abstract 12623: Complementary Role of Exercise Performance and Right Heart Metrics to the Validated MAGGIC score: Insights From a Network Analysis
Authors: Moneghetti Kegan J , Giraldeau Genevieve , Kobayashi Yukari , Ariyama Miyuki , Boulate David , Kouznestsova Tatiana , Schnittger Ingela , Wheeler Matthew , Wu Joseph C , Ashley Euan , Myers Jonathan , Haddad Francois
Published: April 2024

Background:
Risk stratification in heart failure can be completed with established risk scores. However, right heart metrics, deformation imaging and the cardiopulmonary response to exercise have not been routinely incorporated. We investigated the interaction and incremental prognostic value of novel echocardiographic metrics and exercise performance in a consecutive cohort of patients with dilated cardiomyopathy (DCM).

Methods:
The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score was applied to 208 ambulatory patients with DCM (age 47 ± 13 years) who had undergone echocardiography in conjunction with cardiopulmonary exercise testing. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation and hospitalization for acute heart failure. Partial correlation network analysis was used to assess interaction between variables. Cox proportional hazard models identified independent predictors of outcome.

Results:
Mean LVEF and LV GLS were 33 ± 13 % and -10.6 ± 4.4 % respectively. Among echocardiographic variables, LVEF and LV GLS and LV strain rate were strongly related (r = -0.89, and -0.86, respectively, p < 0.01). Age, sex, BMI, LV GLS and RV GLS explained 56% of the variance in peak VO
2
. Over a median follow up of 5.3 years, 60 events occurred including 16 deaths. MAGGIC scores were normally distributed (Figure 1, left) and log rank testing showed significant differences in survival. Cox proportional hazards identified MAGGIC score (1.78 [1.27-2.50], p <0.01), peak VO
2
(HR 0.40 [0.24-0.84], p<0.01) and right atrial volume indexed (RAVI) (HR 1.10 [1.02-1.19], p = 0.01) as independently associated with outcome. In combination these variables were incremental in prognostic value compared to MAGGIC score alone (
x
2
= 65 vs 42, p <0.01, Figure 1, right).

Conclusion:
In patients with DCM exercise performance and RAVI provide incremental prognostic value when combined with the validated MAGGIC score.