bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16560: Impact of Assuming a Circular Orifice on Flow Error Through Elliptical Regurgitant Orifices: A Computational Fluid Dynamics (CFD) Analysis
Authors: Mitter Sumeet S , Wagner Gregory J , Barker Alex J , Markl Michael , Thomas James D
Published: July 2021

Introduction:
Hydrodynamic theory predicts fluid approaches a point orifice with accelerating velocity in hemispheric shells, forming the basis for the proximal isovelocity surface area (PISA) method to quantify valve regurgitation. Previous CFD and in vitro work has shown that with a finite, non-point orifice, there is a small, systematic underestimation of flow that is approximately the ratio of contour velocity (va) to maximal orifice velocity (vo), e.g., roughly an 8% error if a 40 cm/s contour is used with a 5 m/s jet. The PISA method is further questioned in the setting of noncircular orifices, with concerns of further underestimation. We sought to quantify this impact with CFD.

Hypothesis:
Application of standard PISA analysis to an elliptical orifice leads to further flow underestimation, but the magnitude is negligible.

Methods:
Mathematical modeling of flow through a finite elliptical orifice was computed using the open-source incompressible flow solver Nalu. Forty-five permutations of valve flow were characterized by varying valve orifice area (0.1, 0.3 and 0.5 cm^2), ellipse axis ratios (1:1, 2:1, 3:1, 5:1, and 10:1), and max velocity (400, 500 and 600 cm/s). Computed hemispherical flow contours scaled to true orifice flow (Qc/Qo) and scaled computed area to true orifice area (Ac/Ao) were plotted against distance from the orifice scaled to a circular orifice with equivalent orifice area.

Results:
Qc/Qo and Ac/Ao for each ellipse axis ratio when plotted against normalized orifice distance produced the same curves for each permutation of valve orifice area and max velocity. Plotting Qc/Qo (or Ac/Ao) against va/vo reveals marginal underestimation of flow with physiologic elliptical axis ratios of 2:1 and 3:1 against a circular orifice with axis ratios of 1:1 (Figure 1).

Conclusions:
The added error in using PISA to approximate flow through an elliptical mitral valve orifice area is minimal compared to traditional assumptions of a circular mitral valve orifice.
Abstract 16563: Outcomes of Acute Ischemic Mitral Regurgitation in Anterior versus Inferior ST Elevation Myocardial Infarction
Authors: Mentias Amgad , Raza Mohammad Qasim , Barakat Amr F , Krishnaswamy Amar , Desai Milind Y , Griffin Brian P , Ellis Stephen , Menon Venu , Tuzcu E. Murat , Kapadia Samir R
Published: July 2021

Background:
Acute ischemic mitral regurgitation (MR) is a detrimental complication of ST elevation myocardial infarction (STEMI). We studied a) patient characteristics in acute ischemic MR in anterior versus inferior STEMI and b) its impact on outcomes.

Methods:
We retrospectively studied all patients presenting with STEMI complicated by acute ischemic MR to our center from 1994-2014. Patients were divided into two groups: anterior and inferior STEMI. Endpoints were 30-day and 1-year mortality. All cases with new development of > 2+ MR on baseline echo within 3 days of index MI were analyzed.

Results:
Out of 4005 STEMI patients, there were 221 patients (52.5% males) with acute MR at an incidence of 5.5% [74/1666 (4.4%) in anterior vs 147/2306 (6.4%) in inferior STEMI, p=0.02]. At baseline, there were no significant differences between anterior vs. inferior STEMI in age, co-morbidities or degree of MR (Table). Mean ejection fraction (EF) was 31±14 vs 45±13% (p<0.01). Median length of hospital stay was 6 vs 4 days (p<0.01). Overall 30-day mortality was 20 with anterior vs 10% (p=0.03) with inferior while 1-year mortality was 43 vs 24% (p<0.01) respectively. Overall 30-day mortality in 2+, 3+ and 4+ MR was 9, 19 and 29% while 1-year mortality was 23, 39 and 41% (p<0.01). Factors associated with 1-year mortality were older age (Hazards Ratio or (HR) 1.5, 95% CI 1.3-1.9, p<0.01), EF (HR 0.96, 95% CI 0.94-0.97, p<0.01), higher degree of MR (HR 4.6, 95% CI 1.6-11.7, p<0.01), DM (HR 2.4, 95% CI 1.4-3.9, p<0.01), shock on presentation (HR 2.3, 9% CI 1.3-4, p<0.01) and blood transfusion (HR 2.4, 95% CI 1.5-4, p<0.01). Kaplan-Meier survival curves for both groups and across grades of MR are shown in figure 1a and b.

Conclusion:
Acute ischemic MR is seen more commonly with inferior yet has worse outcomes in anterior STEMI with increased short and long term mortality. Further, old age, low EF, higher degree of MR, shock on presentation, and need for blood transfusion are associated with worse outcomes.
Abstract 16571: The Potential Impact of Expanding Cardiac Rehabilitation Coverage in Heart Failure: Insights From Get With the Guidelines Heart Failure
Authors: Kelly Jacob P , Hammill Brad G , Doll Jacob A , Felker G. Michael , Heidenreich Paul A , Yancy Clyde W , Bhatt Deepak L , Fonarow Greg C , Hernandez Adrian F
Published: July 2021

Background:
In February 2014, coverage for cardiac rehabilitation (CR) was expanded by Centers for Medicare & Medicaid to include patients with chronic symptomatic heart failure (HF) on optimal medical therapy with ejection fraction <35%. Thus, we sought to characterize the patient population newly eligible for CR based on the expanded criteria and their associated outcomes.

Methods:
We analyzed the Get With The Guidelines-HF registry linked to Medicare claims data from 2008-2012 to assess three groups of patients age 65 or older: previously eligible (due to prior MI, CABG, stable angina, heart valve surgery, or PCI in the previous 12 months), newly eligible, and ineligible for CR. Ineligible patients met neither criteria. Incidence rate was calculated with Kaplan-Meier estimates and Cox proportional hazard models were used to determine the association of events.

Results:
Among 51,665 HF patients discharged alive, 27.2% (n=14,053) were newly eligible and 14.5% were previously eligible for CR (n=7477). Newly eligible patients were more likely to be black, have atrial fibrillation and EF < 35%, while having fewer previous hospitalizations than patients previously eligible for CR. Newly eligible and ineligible patients had similar risk for 1-year mortality compared with those previously eligible (adjusted Hazard Ratio [HR] 0.95, 95% Confidence Interval [CI] 0.88-1.02, p-value=0.13 and [HR] 1.05, 95% [CI] 0.98-1.13, p-value=0.17, respectively). However, newly eligible and ineligible patients had lower risk for 1-year readmission compared with those previously eligible (adjusted [HR] 0.89, 95% [CI] 0.85-0.93, p-value<0.001 and [HR] 0.94, 95% [CI] 0.90- 0.98, p-value<0.001).

Conclusions:
The extension of coverage for cardiac rehabilitation has tripled the potentially eligible HF population. As these newly eligible patients are at high risk for adverse outcomes, cardiac rehabilitation should be considered.
Abstract 16663: Premature Ventricular Contractions and Incident Heart Failure: Identifying Risk Factors via Interaction Analyses
Authors: Agarwal Vratika , Vittinghoff Eric , Whitman Isaac R , Dewland Thomas A , Dukes Jonathan , Marcus Gregory M
Published: July 2021

Introduction:
Premature ventricular contraction (PVC)-induced cardiomyopathy is a potentially reversible cause of heart failure (HF). The association between PVCs and HF has been limited to case reports and small observational studies. Our objective was to leverage a large population-based database to examine interactions that might prove clinically useful in risk stratification.

Methods:
We included adult patients free of structural heart disease in the California Healthcare Cost and Utilization Project (HCUP) database from 2005-2009. After excluding patients with prevalent cardiomyopathy or heart failure, we identified patients with a diagnosis of PVCs. The primary outcome was incident systolic HF.

Results:
Among 16.8 million patients experiencing 48.1 million hospitalizations, 35,817 (0.2%) had a PVC diagnosis, and 198,818 (1.2%) developed systolic HF during study follow-up. After adjustment for age, sex, race, income & known HF risk factors, PVCs were an independent predictor of systolic HF [Hazard Ratio (HR) 1.57, 95% CI 1.51-1.63, p-value<0.001]. Interaction analyses revealed that relationship between PVCs and incident systolic HF was especially strong among younger patients and in those without coronary artery disease (CAD), hypertension (HTN), diabetes mellitus (DM) or atrial fibrillation (AF) [Table 1]. In patients <65 years without HTN, DM, CAD or AF, a PVC diagnosis was associated with an over 6-fold increase in incident HF risk (HR 6.5, 95% CI 5.5-7.7, p<0.001).

Conclusion:
Using a large population-based database, we found that a diagnosis of PVCs predicts incident systolic HF even after adjusting for conventional risk factors. This effect is most pronounced in younger patients, and those without HTN, DM, CAD or AF, suggesting that PVCs impart the greatest risk for heart failure when other cardiac comorbidities are absent.
Abstract 16745: It Would be Possible to Rescue Traumatic Hemorrhagic Shock Patients Who Failed to Fluid Resuscitation (Fluid Non-responder) but Succeed in REBOA Resuscitation (REBOA/IABO Responder)
Authors: Orita Tomohiko , Funabiki Tomohiro , Yamazaki Motoyasu , Shimizu Masayuki , Sato Tomohiro , Akashi Taku , Kobayashi Yousuke , Yoshida Kousuke , Nakamichi Yoshimi , Kurata Saori , Kitano Mitsuhide
Published: July 2021

Introduction:
Fluid resuscitation (FR) and massive transfusion protocol (MTP) are important initial strategies for traumatic hemorrhagic shock cases. But poor responded patients to them are difficult to rescue. In such cases, open aortic cross clamping or intra-aortic balloon occlusion (IABO) would be performed as a temporary hemostasis treatment. Recently, IABO for severe trauma has been named resuscitative endovascular balloon occlusion of the aorta (REBOA). But it is still unclear which case can be rescued with REBOA. So we studied the relationship between the responsiveness to FR and REBOA.

Methods:
Consecutive 46 traumatic hemorrhagic shock patients underwent REBOA at our ER for last 86 months were included. All of their FAST were positive and done FR and MTP as a first-line resuscitation. 10Fr or 7Fr IABO devices were inserted at supraphrenic level (zone I) and underwent fundamental hemostasis by operative management (OM) and/or transcatheter arterial embolization (TAE). They were sorted into responded group or non-responded group for REBOA. The primary end point was a recovery rate from the shock state within 48 hours. Secondary end points were a survival rate in 30th days and a rate of complications.

Results:
26 transient or non-responded patients (Fluid Non-responder) responded for REBOA (REBOA Responder group). 20 Fluid Non-responders did not respond for REBOA (REBOA Non-responder group). There were no significant differences in ISS (REBOA Responder vs. Non-responder: 45.8+/-15.2 vs. 54.8+/-22.3), amount of total fluid (7187+/-5782ml vs. 6772+/-4851) and total blood transfusion (4816+/-3006ml vs. 5080+/-3330), required time to occlude after arriving ER (25.3+/-12.6min vs. 19.4+/-9.8) and total occlusion time (76.4+/-66.5min vs. 92.7+/-34.4). There was significant difference in the changes of systolic blood pressure before and after of REBOA (59.3+/-25.7mmHg vs. 38.3+/-39.4, p=0.04). A recovery rate from shock state was 65%(12/26) vs. 0%(0/20) (p<0.01) and a survival rate was 14/26(54%) vs. 0/20(0%) (p<0.01). One complication occurred in REBOA Responder group but was not lethal.

Conclusions:
It would be necessary to recognize that Fluid Non-responder but REBOA Responder with traumatic hemorrhagic shock could be possible to rescue.
Abstract 16763: Unchanged Central Aortic Blood Pressure and Increased Myocardial Perfusion in Patients With Stable Coronary Artery Disease Receiving Ivabradine
Authors: Levy Bernard I. , Dillinger Jean-Guillaume , Henry Patrick , Logeart Damien , Manzo Silberman Stephane , Allee Guillaume , Maher Vincent , Vitale Cristiana
Published: July 2021

Background:
Treatment of hypertensive patients with beta-blockers reduces heart rate (HR) and increases central blood pressure, implying that the decrease in HR could explain reported increases in cardiovascular risk with beta-blocker. This analysis from a randomized, double-blind study explores whether HR reduction with the
I
f
inhibitor ivabradine had an impact on central blood pressure and coronary perfusion.

Methods and results:
We included 12 normotensive patients with stable CAD, HR ≥70 bpm (sinus rhythm), and stable background beta-blocker therapy. Patients received ivabradine 7.5 mg bid or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting HR after 3 weeks versus no change with placebo (-15.8±7.7 versus +0.3±5.8 bpm, p=0.0010). There was no relevant between-group difference in change in central aortic SBP (-4.0±9.6 versus +2.4±12.0 mm Hg, p=0.13) or augmentation index (-0.8±10.0% versus +0.3±7.6%, p=0.87). Treatment with ivabradine was associated with prolongation of diastolic perfusion time by 41% from baseline to 3 weeks (+215.6±105.3 versus -3.0±55.8 ms with placebo, p=0.0005) (Figure) and with a pronounced increase in an index of myocardial viability (Buckberg index, +39.3±27.6% versus -2.5±13.5% with placebo, p=0.0015). There were no safety issues during the study.

Conclusion:
Heart rate reduction with ivabradine does not modify central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion.
Abstract 16814: Does Small Size Matter With Continuous Flow Devices: Analysis of the INTERMACS Database of Adults With BSA ≤1.5m2
Authors: Zafar Farhan , Morales David L , Villa Chet S , Blume Elizabeth D , Rosenthal David N , Kirklin James K , Khan Muhammad S , Lorts Angela
Published: July 2021

Introduction:
Favorable outcomes with continuous flow devices (CFD) have enticed clinicians to implant CFD in patients smaller than the suggested body surface area (BSA) criteria of >1.5 m
2
. Despite limited data, the VAD community is using CFD in patients down to a BSA of 0.7m
2
. For this reason, we sought to examine the use of CFD in adults with BSA ≤1.5 m
2
and compare outcomes to adult patients with BSA >1.5m
2
.

Methods:
CFD implants in adults (>18 years) from 04/2008 to 09/2014 were identified using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. Patients were divided into two cohorts based on BSA. Patient characteristics and post implant outcomes including mortality, transplant, and adverse events were compared between the two cohorts.

Results:
Of adults (11142) undergoing CFD implants 2% (239) had BSA of ≤1.5m
2
; BSA median 1.4m
2
[0.76 – 1.5 m
2
]. One patient had BSA <1.0m
2
, 6% (15) 1.0-1.2m
2
and 93% (223) >1.2-1.5m
2
. Pre-implant patient characteristics were similar between the two groups except gender and INTERMACS profile [Table]. Overall survival (p=0.8) and favorable outcomes at 1-year were similar between the two groups; however, fewer patients with BSA ≤1.5m
2
were transplanted (p<0.01) [Figure]. There were more bleeding events and infection; however, less renal dysfunction and right heart failure in patients with BSA ≤1.5m
2
[Table].

Conclusion:
CFDs can be safely used in smaller adult patients. The outcomes are favorable but clinicians must be mindful that the adverse event profile is different in smaller patients. These results are reassuring for the recent trend in the VAD community for placing CFDs in smaller patients.
Abstract 16827: Double-chambered Right Ventricle Diagnosed in Late Adulthood by Multi-modality Imaging. Report of Two Cases With Associated Aortopathy
Authors: Duarte Valeria E , Yousefzai Rayan , Paterick Timothy , Tajik Jamil
Published: July 2021

Introduction:
Double-chambered right ventricle (DCRV) is a rare congenital disorder. The right ventricle (RV) is divided into two: a high-pressure inlet and a low-pressure outlet by an abnormal muscle bundle. Rarely diagnosed in adulthood, it is associated with other congenital defects. Association with aortopathy is not described.

Patient 1:
67 year-old male with dyspnea:
PE:
grade 4 harsh systolic murmur radiating to the base.
Echo:
DCRV with obstruction -peak gradient (PG) 75mmHg (Fig 1-C), hypertrophied/dilated RV, decreased function; small perimembranous VSD, small right-to-left shunt. Ascending aorta aneurysm: 49 mm (Fig 1-D). Normal aortic valve.
MRI:
DCRV with muscle bundle causing RVOT obstruction. RV with delayed gadolinium enhancement (Fig 2).
Heart cath:
severe RV obstruction (PG 105 mmHg).
Surgery:
Resection of the muscular bundle, VSD closure and grafting of ascending aorta.
Follow-up:
significant improvement.

Patient 2:
56 year-old female with VSD.
PE:
4/6 holosystolic murmur at left sternal border.
Echo:
DCRV: Mean gradient (MG) 30 mmHg (Fig 1-B), small perimembranous VSD. Ascending aorta: 39 mm. Functionally bicuspid aortic valve, mild AR.
Exercise echo:
sub-pulmonary resting MG 35, stress MG 52 and PG 90 mmHg.
MRI:
DCRV with a membrane causing RVOT stenosis.
Gene testing
for TAAD/Marfan negative.
Surgery:
VSD closure and resection of RV membrane.
Follow up:
asymptomatic.

Conclusion:
DCRV should be considered with an elevated RV systolic pressure and intracavitary gradient. Comprehensive echocardiographic examination of the RV is essential. CMR is useful providing anatomic detail. Surgical correction has successful short and long term outcomes.
Abstract 16861: Liposomal Prednisolone Aggravates Atherosclerosis by Promoting Lipotoxicity in Macrophages
Authors: van der Valk Fleur , Schulte Dominik , de Winther Menno , Lutgens Esther , Metselaar Josbert , Stroes Erik , Hamers Anouk
Published: July 2021

Background:
Whereas liposomal nanoparticles loaded with prednisolone phosphate (LN-PLP) reduced arterial wall inflammation in an atherosclerotic rabbit model, an unanticipated increase in arterial wall inflammation was observed in patients with atherosclerosis following LN-PLP infusions, despite proof of local accumulation in plaque macrophages. We hypothesized that this apparent discrepancy relates to the lipid-rich environment, and aimed to unravel the effect of LN-PLP upon local accumulation in lipid-laden macrophages.

Methods & Results:
LN-PLP administration for two weeks (10mg/kg biweekly) in LDLR-/- mice on a high fat diet (n=15/group) resulted in increased influx of CD11b+ monocytes (11±6%) in the plaque, compared to empty LN and PBS (<6%, p<0.01), assessed with flow cytometry. Monocyte staining (ER-MP58) was also increased in the plaque (24±11%) after LN-PLP, whereas monocyte number in plasma decreased. After six weeks of LN-PLP administration, plaque stages progressed more rapidly (40% of plaques in stage V) in LDLR-/- mice (n=15/group) compared to free PLP, empty LN and PBS (for all <10% of plaques in stage V). Immunohistochemical staining showed an increased macrophage content after LN-PLP (25±13% positivity for MAC3) compared to free PLP, empty LN or PBS (14%, p<0.01). Necrotic core area was also higher after LN-PLP (68±4%) compared to free PLP, empty LN and PBS (<50±3%, p2.00%, p<0.01), (ii) increased expression of ER stress (e.g. PERK 2.5±0.2 after LN-PLP versus <0.7±0.01 after empty LN or control, p<0.05), and (iii) 23% of macrophages underwent apoptosis compared to <3% of the macrophages in control conditions.

Conclusion:
Prednisolone, delivered locally in lipid-rich plaque macrophages, elicits a pro-atherogenic, lipotoxic effect, leading to more unstable plaques with larger necrotic core area and augmented macrophage apoptosis. These data bear direct consequences for future drug candidates aiming to target plaque macrophages; these require multifaceted screening taking the lipid-rich atherosclerotic milieu into account.
Abstract 16896: Exercise Pulmonary Capillary Wedge Pressure Patterns in Patients With Normal Resting Left-sided Filling Pressures Predict Heart Failure Outcomes
Authors: Eisman Aaron S , Shah Ravi V , Dhakal Bishnu P , Meller Stephanie M , Pappagianopoulos Paul P , Dress Ashley E , Malhotra Rajeev , Weiner Rory B , Baggish Aaron L , Lewis Gregory D
Published: July 2021

Introduction:
Serial measurements of pulmonary capillary wedge pressure (PCWP) during exercise testing may help to improve hemodynamic (HD) classification of heart failure with preserved ejection fraction (HFpEF). However, the physiologic and prognostic significance of exercise PCWP patterns is largely unknown.

Hypothesis:
An elevated PCWP increment relative to cardiac output (CO) augmentation during exercise will independently predict exercise capacity and outcomes in patients with dyspnea on exertion and normal resting PCWP (DOE-nlrW).

Methods:
In a single center cohort of 175 patients referred for cardiopulmonary exercise testing (CPET) with invasive HD monitoring (n = 33 normal controls, n = 32 HFpEF with resting PCWP ≥ 15, and n = 110 consecutive patients with DOE-nlrW and LVEF > 0.45) 1,929 PCWP-CO points during exercise were measured. Median follow-up was 3.2 years and events consisted of HF hospitalization, CV death, or future RHC with resting PCWP ≥ 15 mmHg.

Results:
PCWP-CO slope of 1.2±0.4 mmHg/L/min in controls was used to establish the upper limit (mean + 2SDev) of normal of 2mmHg/L/min. HFpEF patients had a PCWP-CO slope of 3.6±1.8 mmHg/L/min. In the DOE-nlrW cohort, patients achieved a mean peak VO2 of 17±6 ml/kg/min (74±19 % predicted), mean PCWP-CO was 2.1±1.3 mmHg/L/min (Figure) with 45 of 110 patients having elevated PCWP-CO. PCWP-CO but not resting PCWP was related to peak VO2 in univariable (rho = -0.51, p < 0.01) and multi-variable linear regression adjusted for age, sex, hypertension, beta blocker use, diabetes, and resting PCWP (ß = -0.17, p = 0.03). Increased PCWP-CO also predicted worse event-free survival in univariable Cox regression (HR 1.67, p < 0.01) and after adjustment for age, sex, BMI, and resting PCWP (HR 1.56, p = 0.03).

Conclusions:
Elevated PCWP-CO during exercise ( > 2mmHg/L/min) is common in DOE-nlrW and predicts exercise capacity as well as outcomes, suggesting that assessment of exercise HD may help to refine early HFpEF diagnosis.
Abstract 16915: Mortality And Safety Outcomes of Various Catheter-based Treatment Modalities in Patients With High-risk Pulmonary Embolism: A Meta-analysis
Authors: Bajaj Navkaranbir S , Kalra Rajat , Ather Sameer , Guichard Jason , Lancaster William J , Raman Fabio , Arora Pankaj , Clark Trey , McGiffin David C , Ahmed Mustafa I
Published: July 2021

Background:
Catheter-based treatments (CBTs) are diverse set of techniques aimed at relieving pulmonary arterial obstruction in patients with high-risk pulmonary embolism. Multiple modalities are currently available. The mortality and safety outcomes have not been studied among these different modalities.

Hypothesis:
We conducted this investigation to determine the mortality and safety of individual modalities.

Methods:
We searched SCOPUS since inception to November 2014 using predefined criteria. Studies including massive PE or a combination of massive and submassive PE, as defined by the American Heart Association, were included. In-hospital mortality rates and pooled safety complication rate (defined as a composite of peri- and post-procedural cardiac arrest, minor access site bleeding, major access site bleeding, and bleeding at other sites) were estimated using standard meta-analytic methods and compared among six different groups namely aspiration thrombectomy, intrapulmonary thrombolysis (IP), mechanical fragmentation (MF), rheolytic thrombectomy (RT), ultrasound-accelerated thrombolysis (USAT) and multiple simultaneous modalities.

Results:
In 54 eligible studies with 1,333 patients, 1,357 CBT procedures were performed. Patients undergoing USAT had the lowest in-hospital mortality rate whereas patients undergoing RT had the highest in-hospital mortality rate (p = 0.011, Table). Intrapulmonary thrombolysis had the highest pooled rate of safety outcome whereas MF had the lowest rate among various techniques (p = 0.034, Table).

Conclusion:
There is significant heterogeneity in mortality and safety outcomes between various CBT modalities. Our analysis is limited by variance in study quality and baseline characteristics. More investigation is required to determine the optimal type of CBT for high-risk PE.
Abstract 16916: Mmp14 in Vascular Smooth Muscles Protects Mice From Atherogenesis
Authors: Barnes II Richard H , Ohman Miina K , Weiss Stephen J , Eitzman Daniel T , Chun Tae-Hwa
Published: July 2021

Rationale:
The matrix metalloproteinase (MMP) family plays diverse but critical role in the remodeling of collagen-rich extracellular matrix (ECM) environment in cardiovascular diseases. A membrane-type MMP, MMP14 (MT1-MMP) plays a key role in pericellular collagen remodeling. Despite the known role played by macrophage MMP14 in collagen remodeling of atheroma, the cell type-specific role of MMP14 in atherogenesis has not been fully defined.

Objective:
We aimed to define the consequence of whole-body MMP14 haploinsufficiency on atherogenesis and then determine the cell type that is responsible for MMP14-dependent modification of atherogenesis.

Methods and Results:
MMP14(+/-)ApoE(-/-) mice displayed a significant increase in atherogenesis in the whole arterial tree compared to MMP14(+/+)ApoE(-/-) mice (18.1±0.8 vs. 14.9±0.9% in males and 23.6±1.6 vs. 15.1±1.3% in females, P < 0.01). No difference in cholesterol level was found. When adipocyte MMP14 was deleted in aP2-Cre-ERT2/MMP14(f/f)/ApoE(-/-) mice (adipo-KO), profibrotic and proinflammatory changes in the visceral adipose tissue were observed; however, no significant effects on atherogenesis were noted (male Cre(-)/MMP14(f/f)/ApoE(-/-) control 8.5±1.5 vs. adipo-KO 4.6±1.5%, n = 4). On the other hand, the deletion of MMP14 from vascular smooth muscle cells (VSMCs) in SM22-Cre/MMP14(f/f)/ApoE(-/-) (VSMC-KO), markedly increased atherosclerotic area (male VSMC-KO 34.6±2.6%, P < 0.0001 compared to Cre(-) control, n = 11). The histology at aortic root after 8 weeks of Western diet demonstrates the significantly increased number of VSMCs with positive Ki67 staining coupled with the infiltration of F4/80-positive macrophages in VSMC-KO mice. Primary VSMCs isolated from VSMC-KO aortas displayed augmented stress fiber formation and increased proliferation capacity in vitro.

Conclusions:
MMP14 expressed in VSMCs plays a protective role against atherogenesis in ApoE-null mice. The loss of MMP14 causes the proliferative response of VSMCs in atherogenic conditions.
Abstract 16939: Reversible Myocardial Ischemia Sufficient to Produce Transient Stunning Leads to Delayed Cardiac Troponin I Release That Reflects Focal Myocyte Apoptosis in the Absence of Pathological Infarction
Authors: Weil Brian R , Young Rebeccah F , Shen Xiaomeng , Suzuki Gen , Qu Jun , Canty John M
Published: July 2021

Introduction:
The release of cardiac troponin I (cTnI) after reversible ischemia is controversial. It has been hypothesized that elevations in serum cTnI in this scenario reflect selective release from an exchangeable pool rather than cellular necrosis since irreversible injury with sarcolemmal membrane disruption does not begin until ischemia exceeds 15 minutes following a total coronary occlusion.

Objective:
To determine whether cTnI release occurs after a brief coronary occlusion when the duration of ischemia is insufficient to induce myocyte necrosis.

Methods:
Closed-chest propofol-anesthetized swine (n=10) were subjected to a 10 minute LAD occlusion. Blood sampling was performed to measure serum cTnI concentrations before, during and after ischemia. Myocardial tissue was collected either 1 hour (n=5) or 24 hours (n=5) after reperfusion for pathological assessment of infarction (TTC) and apoptosis (TUNEL).

Results:
Regional LAD wall thickening was 60 ± 4% at baseline and became dyskinetic during coronary occlusion (-4 ± 2%, p<0.05). One hour after reperfusion, wall thickening improved but remained depressed relative to baseline, indicative of myocardial stunning (37 ± 4%, p<0.05). It returned to normal after 24 hours (59 ± 2%). Serum cTnI was 0.01 ± 0.01 ng/mL at baseline and remained unchanged at the end of ischemia. A slight increase in cTnI was observed 1 hour after reperfusion (0.06 ± 0.02 ng/mL, p<0.05 vs. baseline), followed by a marked elevation at 24 hours (1.02 ± 0.57 ng/mL, p<0.05 vs. baseline). TTC staining demonstrated no evidence of infarction. Heart tissue collected 1 hour after reperfusion demonstrated a regional increase in apoptotic myocytes (LAD: 17.7 ± 3.7 myocytes/cm
2
vs. Remote: 3.1 ± 2.0 myocytes/cm
2
, p<0.05). Myocyte apoptosis normalized 24 hours after reperfusion (LAD: 5.2 ± 2.3 myocytes/cm
2
vs. Remote: 3.6 ± 1.5 myocytes/cm
2
) when serum cTnI remained elevated.

Conclusion:
A duration of reversible ischemia compatible with angina can lead to cTnI release that is similar in magnitude to that occurring with myocardial infarction. Rather than infarction or release from an exchangeable cTnI pool, the rise in serum cTnI is delayed and appears to reflect focal programmed myocyte death from apoptosis rather than myocardial necrosis.
Abstract 16943: Obesity Moderates the Relationship Between Depressive Symptoms and Diet Quality in Overweight and Obese Adults in Rural Kentucky
Authors: Abshire Demetrius A , Lennie Terry A , Chung Misook L , Biddle Martha J , Moser Debra K
Published: July 2021

Background:
Although depressive symptoms have been linked to poor diet quality, little is known about this relationship among overweight and obese adults in rural Kentucky where rates of cardiovascular disease (CVD) are high. Identifying the impact of depressive symptoms on diet quality by obesity status may aid in identifying those at highest risk for CVD due to poor dietary habits.

Purpose:
To determine if obesity moderates the association between depressive symptoms and diet quality in overweight and obese rural adults at high risk for CVD.

Methods:
Rural adults in Kentucky (n=948; age=53±15; 73% female; 96% Caucasian; body mass index [BMI]=34±7; 67% obese) completed an assessment of depressive symptoms using the 9-item Patient Health Questionnaire and diet quality using a food frequency questionnaire that generated the 2005 Healthy Eating Index score. They were grouped into overweight (BMI 25-29.99kg/m
2
) and obese (BMI ≥30kg/m
2
) groups. Multiple linear regression was used to determine the moderation effect by entering the interaction term of depressive symptoms and obesity level.

Results:
Depressive symptom scores were higher in obese adults than overweight adults (5.9 ± 4.8 vs. 4.6 ± 4.1, p<0.001). Depressive symptoms predicted poor diet quality (B= -0.618, p<0.001, R
2
=0.019). The interaction between depressive symptoms and obesity status was significant (Figure 1) in predicting diet quality and indicated the relationship between depressive symptoms and poor diet quality was stronger in the overweight group than obese group.

Conclusion:
Although obese rural Kentuckians have more depressive symptoms, the negative impact of depressive symptoms on diet quality is stronger among those who are overweight. Treating depressive symptoms may facilitate healthy eating in this population, particularly those who are overweight.
Abstract 16966: Effect of Adding Ezetimibe to Statins versus Statin Monotherapy in Cardiovascular Risk Reduction in Patients With Coronary Artery Disease - A Meta-analysis
Authors: Banerji Dahlia , Akram Yasir , Somalaraju Sandeep , Bajaj Rishi , Pacifico Luigi
Published: July 2021

Introduction:
Statin therapy has been proven to reduce LDL levels and the risk of cardiovascular events. We sought to evaluate the incremental role of Ezetimibe in addition to on-going Statin therapy to assess changes in lipid profile and cardiovascular events.

Methods:
A comprehensive search in Medline Indexed and Non-indexed was performed to search for randomized controlled trials that examined the role of Ezetimibe plus Statins compared to Statin monotherapy on lipid profile and cardiovascular event rate in patients with coronary artery disease (CAD). We used the mean change for continuous variables and event rates for dichotomous variables for calculating p- values.

Results:
We included a total of 17 Randomized Control Trials (RCTs) with 22,603 patients, in our meta-analysis. Among these, 15 studies assessed biochemical improvement, whereas 2 RCTs with 18,186 patients evaluated the clinical outcomes. Summary effects were estimated using random effects model. The cumulative estimate showed that addition of Ezetimibe to Statins resulted in an overall mean reduction of total cholesterol (mean change -14.69 mg/dL, 95% CI -18.03, -10.34, p <0.00001), LDL (mean change -12.92 mg/dL, 95% CI -15.5, -12.34, p <0.00001), and triglycerides (mean change -9.94 mg/dL, 95% CI -13.33, -6.55, p <0.00001). However, there was no significant improvement in HDL level. There was also an 11% reduction in mortality with Ezetimibe addition (Odds Ratio 0.89, 95% CI 0.82, 0.96, p =0.002).

ConclusioN:
In conclusion, addition of Ezetimibe to a Statin in patients with CAD results in a significant reduction in total cholesterol, LDL and triglycerides and also demonstrates a significant mortality benefit.
Abstract 17017: Risk Prediction of Death and Failure in Patients With Atrio-pulmonary Connections: 40 Years Experience in Australia and New Zealand
Authors: Poh Chin L , Zannino Diana , Weintraub Robert G , Winlaw David S , Radford Dorothy J , Grigg Leeanne E , Wheaton Gavin R , Bullock Andrew , Justo Robert N , Gentles Thomas L , Celermajer David S , d'Udekem Yves
Published: July 2021

Objective:
To identify parameters predictive of death and failure in patients with an atrio-pulmonary connection Fontan.

Methods:
Retrospective analysis of long-term follow-up data using the Australia and New Zealand Fontan Registry

Results:
There were 245 patients surviving hospital discharge after an atriopulmonary Fontan from 1975 to 1994. At latest follow-up, 54 pts died, 29 underwent heart transplantation and 93 had Fontan failure (death, transplantation, Fontan conversion, protein losing enteropathy, severe left ventricular dysfunction on echocardiography or NYHA3). Twenty-eight years survival, freedom from death and transplantation and freedom from Fontan failure were respectively 62% (95%CI 55-71%), 58% (95% CI 50-67%) and 40% (95% CI 33-50%). Predictors of death and transplantation were dextrocardia (HR 1.8;p= 0.05), longer Fontan bypass time (HR= 1.01, p=0.05) and moderate or more late atrioventricular valve regurgitation (HR 3.97; p=0.02). One hundred and seven patients developed atrial arrhythmias, with first documented event at 15.7 years (IQR 10.5-19.3) post Fontan completion. Development of arrhythmia increased the likelihood of death or transplantation (HR 3.05, p<0.001) and Fontan failure (HR 4.7, p<0.001). Thromboembolic events occurred in 42 patients, 30 (71%) of whom were on warfarin but less than half (12/30) within therapeutic range. Thirty-nine patients underwent Fontan conversion. Threshold for conversion was lower in one center in which patients were operated earlier with better functional status, shorter history of arrhythmias and less antiarrhythmic medications. Conversion resulted in a reduced risk of Fontan failure (HR 0.48) in patients cared for by the center with lower conversion threshold but an increased risk in the remaining centres (HR 5.65) (p=0.023).

Conclusions:
Arrhythmias is an early sign predicting failure of the Fontan circulation of those with an atrio-pulmonary Fontan. Fontan conversion is only associated with improved outcomes when timely performed.
Abstract 17051: Relationship Between Neurohormonal Blockade Dose and Clinical Outcome in Patients With Heart Failure With Recovered Ejection Fraction
Authors: Kim Min-Seok , Choi Hyo-In , Park Jin-Oh , Kim Ju Hyeon , Jeong Yeong jin , Kim Jae-Joong
Published: July 2021

Introduction:
Heart failure (HF) patients who recover left ventricular function (HF-Recovered) have reported to have a different prognosis compared to HF with reduced or preserved ejection fraction (EF). However, no study has analyzed the dosage of neurohormonal blockade in these patients.

Hypothesis:
Higher dose of neurohormonal blockade might be important for better outcomes in HF-Recovered patients.

Methods:
HF-Recovered patients were defined with left ventricular EF ≥40% at time of study entry and retrospectively checked EF <40%. 256 patients were enrolled between Mars 2009 and September 2014.

Results:
Of the study population, 48.8% received <50% of the target dose of angiotensin-converting enzymes inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs), whereas 51.2% received ≥50% of the target dose at time of EF ≥40%. 55.5% received <50% of the target dose of β-blockers (BBs), whereas 44.5% received ≥50% of the target dose. 31.3% increased the dose of ACEIs/ARBs or BBs at time of EF ≥40% (uptitration group), and 68.8% maintained the doses (maintenance group). During an average of 29.8 months of follow-up, 35 patients (13.7%) were died. In multivariable Cox proportional hazard analysis, ≥50% of the target dose of BBs was associated with lower all-cause mortality (HR=0.38, 95% CI 0.16-0.88, p=0.024). This dose-survival relationship was not the case for ACEIs/ARBs. Figure shows survival curves according to the uptitration or dose of BBs at time of EF ≥40%. Dose of BBs at time of EF ≥40% was lower among uptitration group than maintenance group. However, last follow-up doses of BBs between two groups were the same. Moreover, higher dose of BBs at time of EF recovery was associated with higher last follow-up dose.

Conclusions:
The dose of BBs was associated with mortality in HF-Recovered patients. High dose of neurohormonal blockade, especially BBs may prevent future adverse events, even if EF was recovered to ≥40% suggesting the importance of dose-uptitrating effort.
Abstract 17056: Nanoparticles-mediated Targeting of Pioglitazone Reduces Myocardial Ischemia-reperfusion Injury and Cardiac Remodeling by Antagonizing Monocyte-mediated Inflammation in Preclinical Animal Models
Authors: Tokutome Masaki , Matoba Tetsuya , Nakano Yasuhiro , Nakano Kaku , Egashira Kensuke
Published: July 2021

Background:
Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury and cardiac remodeling. However, no anti-inflammatory therapy has been developed for clinical myocardial IR injury. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocyte/macrophage. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes ameliorates IR injury and cardiac remodeling in preclinical animal models.

Methods and Results:
We formulated poly (lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NPs). In mouse IR model, nanoparticles were delivered predominantly to circulating monocytes and to cardiomyocytes and macrophages in the IR heart. Intravenous treatment with Pio-NPs containing ≥0.1 mg/kg of pioglitazone at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662 (Fig. A). In contrast, pioglitazone solution at doses up to 3.0 mg/kg showed no therapeutic effects (Fig. A). Pio-NPs reduced inflammatory gene expression and inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart (Fig. B). Pio-NPs showed no therapeutic effects in mice lacking CCR2. In a mouse model of myocardial infarction, intravenous treatment with Pio-NPs for 3 days after LAD ligation attenuated cardiac remodeling, improved cardiac function, and reduced recruitment of macrophage and polarization of macrophages toward M2 phenotype (Fig. C, D).

Finally, in a mini-pig model of myocardial IR injury, Pio-NPs induced cardioprotection from IR injury, indicating the pre-clinical proof of concept.

Conclusion:
Nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and monocytes can be developed as a novel modality that offers organ protection by antagonizing monocyte-mediated inflammation in acute MI.
Abstract 17062: Can Automated Rate-only CPR Feedback be Detrimental to Chest Compression Depth? A CPR Simulation Study of 141 Untrained Operators
Authors: Torney Hannah , O'Hare Peter , Davis Laura , Delafont Bruno , McCartney Ben , McReynolds Hannah , Di Maio Rebecca , Bond Raymond , McEneaney David
Published: July 2021

Introduction:
A number of public access defibrillators incorporate computerised audio-visual feedback mechanisms to help responders deliver cardiopulmonary resuscitation (CPR) according to current guidelines. A 2013 American Heart Association statement suggested that chest compression fraction (CCF) and compression rate should be prioritised over compression depth, chest recoil and ventilations. This usability study assessed the effect of real-time rate-only feedback on chest compression depth.

Methods:
Randomly selected users were recruited in a shopping mall (n=141; 15-65+ years) to deliver CPR using a public access defibrillator in a simulated scenario. Participants were randomly assigned one of two devices - (1) with CPR rate feedback in the form of a machine-interface comprising of audio-voice prompts and light emitting diodes; (2) without CPR feedback. Participants were instructed to turn on the device and follow the prompts, with no information on how to perform CPR provided. CPR rate and depth were captured by measuring displacement of a potentiometer contained in a specially designed manikin. The device was connected to the manikin via the electrode leads. The effect of rate-only feedback on compression depth and CPR fraction were assessed.

Results:
ANCOVA analysis between the two devices provided a mean difference (Standard Error; SE) of 4.52mm (1.38mm) indicating a statistically significant difference (p-value=0.001) between measured CPR depth favouring the device with CPR rate feedback. There was no significant difference in CCF between the devices. ANCOVA analysis provided a mean difference (SE) of 2.9% (1.9%) for the device with CPR rate feedback compared to the device without CPR rate feedback.

Conclusion:
The incorporation of clear, intuitive, audio-visual machine-interface that delivers CPR feedback can assist trained and untrained users in the optimisation of chest compression rate and maintain a high CCF. In conclusion, CPR rate-only feedback was not detrimental to chest compression depth and suggests rate-only feedback may improve compression depth.
Abstract 17128: Primary Prevention With Implantable Cardioverter Defibrillator in High-risk Long-QT Syndrome Patients
Authors: Biton Yitschak , Rosero Spencer , Moss Arthur J , Goldenberg Ilan , Mcnitt Scott , Polonsky Bronislava , Zareba Wojciech
Published: July 2021

Background:
Implantable cardioverter defibrillator (ICD) is currently indicated for the treatment of long QT syndrome (LQTS) patients who survived aborted cardiac arrest. However, data regarding the role of ICD in primary prevention in patients with LQTS is scarce.

Methods:
The study population comprised 212 LQTS patients (65% genotype positive) from the Rochester LQTS Registry who had ICD implantation for primary prevention. Cox regression model was used to identify clinical variables that were associated with appropriate shock and inappropriate shock. The efficacy of β-blockers was determined using a time-dependent analysis.

Results:
During a median follow up time of 9.2±4.9 years the cumulative event rates of appropriate shocks and inappropriate shocks were 23% and 34% respectively. In the entire cohort appropriate shock was associated with QTc ≥ 550 msec (HR=3.94; CI 2.08-7.46; p<0.001) and prior syncope on β-blockers (HR=1.92;(CI 1.01-3.65, p=0.047), β-blockers trended to be protective (HR=0.52; CI 0.26-1.07; p=0.075). Importantly, prior syncope was only important if it happened while on β-blockers. Inappropriate shock was significantly associated with age below 15 at implantation (HR=1.94; CI 1.11-3.38; p=0.019). In patients with positive genotype, appropriate shock was associated with QTc ≥ 550 msec (HR=5.37; CI 2.38-12.10; p<0.001), implantation age ≤ 15 years (HR=2.77; CI 1.08-7.11; p=0.034), LQT2 vs. LQT1 (HR=2.47; CI 0.93-6.52; p=0.069), and multiple mutations vs. LQT1 (HR=2.87; CI 0.88-9.42; p=0.081); β-blockers were significantly protective (HR=0.23, CI 0.09-0.59, p=0.002).

Conclusions:
Among LQTS patients in whom ICD is implanted for primary prevention, QTc duration and history of syncope while on β-blockers therapy are associated increased risk for appropriate shock. β-blocker treatment remains important in this high-risk group. Those with an ICD implanted before age 15 were at a higher risk of receiving an inappropriate shock.
Abstract 17144: Architecture of Atrial Fibrosis is Associated With Increased Risk of Recurrence Post Af Treatment
Authors: Gal Pim , Pacchia Christina F , White Robert , Morris Alan , Cates Joshua , Kaur Gagandeep , elvan arif , Marrouche Nassir
Published: July 2021

Background:
Previous studies reported the association between left atrial (LA) fibrosis as assessed by delayed enhancement (DE)-MRI and arrhythmia recurrence post AF ablation. In this study we report the significance of atrial fibrotic infiltrations architecture in predicting treatment failure.

Methods:
271 patients (mean age was 59 years, 64% had paroxysmal AF) from the multicenter prospective DECAAF study were included in this sub-analysis. We assessed the location and size of patchy fibrotic atrial tissue infiltrations (figure 1) in all patients who underwent ablation of AF. Due to the strong correlation between LA fibrosis and the largest patch(r=0.875, P<0.001), a Z-transformation of LA fibrosis and the sum of LA fibrosis and largest patch was performed. This allowed direct comparison of hazard ratios (HR) in a Cox proportional hazard model.

Results:
Mean LA fibrosis score was 18%, the mean largest patch was 21.5 cm2. AF recurrences were associated with the largest patch size per quartile: Q1: 15%, Q2: 28%, Q3: 34%, Q4: 45%, P<0.001. The HR for the standardized LA fibrosis was 1.317, P=0.009.compared to 1.437 for the standardized sum of LA fibrosis and largest patch size, demonstrating that the addition of largest patch to the LA fibrosis score improved the predictive properties of the model. In a multivariate model with age, AF type and LA volume, the standardized sum of LA fibrosis and largest patch size was significantly associated with AF recurrences post-ablation (HR 1.404, P=0.001).

Conclusion:
From our preliminary data not only the quantity but also the architectural presentation of atrial tissue fibrotic infiltrations was significantly associated with AF treatment failure. This finding would help better understand the severity of AF in addition to improving patient selection undergoing various treatments of AF.