bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 8724: Short and Long-Term Mortality of Pediatric Stroke: A Fourteen Year Statewide Study
Authors: Gandhi Sampada K , McKinney James S , Sedjro Jeanine E , Cheng Jerry Q , Deng Yingzi , Cosgrove Nora M , Cabrera Javier , Kostis John B ,   For the Myocardial Infarction Data Acquisition System (MIDAS) Study Group
Published: April 2024

Objectives:
Since there are no recent data on the short and long-term mortality of pediatric stroke, we examined the 30-day, 1 year and 5 year mortality of children admitted to New Jersey (NJ) hospitals with a diagnosis of stroke using a statewide administrative database.

Methods:
We used the Myocardial Infarction Data Acquisition System (MIDAS) database, which includes demographic and clinical data on children (aged > 30 days to ≤ 19 years) admitted with a first time diagnosis of stroke to all non-federal hospitals in NJ between 1994 and 2007. Deaths were ascertained by matching the MIDAS records to death information from NJ Death Registration Files within 30 days, 1 year and 5 years from the index admission. Cox proportional hazards regression models were fitted to assess the effect of demographic characteristics and predisposing conditions of stroke on time to death.

Results:
Thirty-day, 1-year and 5-year mortality rates were 10.2%, 13.7% and 16.2% respectively (Figure 1a) among 1,034 children admitted during the study period. At all time periods, mortality rates from hemorrhagic stroke were 2-3 times higher compared to ischemic stroke and adjusted survival from hemorrhagic stroke was significantly lower compared to ischemic stroke (p< 0.0001) (Figure 1b, 1c, 1d). Twenty-four percent of the deaths were due to a cardiovascular cause, mostly comprising of cerebrovascular hemorrhage and congenital malformations of the circulatory system. The remaining 76% percent of the deaths were due to a non-cardiovascular cause such as cancer, diseases or malformations of nervous system. After adjusting for all covariates, important predictors of mortality were: type of stroke, prior history of cardiac dysrhythmia, CNS tumor, leukemia, human immunodeficiency virus (HIV) and meningitis.

Conclusion:
At 5 years, roughly 85% of the children with stroke were alive. However, children with hemorrhagic stroke were at a much higher risk of death compared to those with ischemic stroke.
Abstract 8772: Clinical Correlates of Pulmonary Artery Pulse Wave Velocity in Normal Subjects
Authors: Harada Kenji , Harada Yukiko , Toyono Manatomo
Published: April 2024

Background:
In contrast to systemic artery, much less is known about age-related change in pulmonary artery stiffness. Pulse wave velocity (PWV) is an index for vascular stiffness. The purpose of this study is to assess pulmonary artery PWV and investigate their relations to age, body mass index (BMI), pulmonary artery systolic pressure, left ventricular (LV) diastolic pressure, and systemic artery PWV in normal subjects.

Methods:
Echocardiography with tissue Doppler imaging was performed in 92 normal subjects from 6 to 80 years. To measure pulmonary artery PWV, pulsed Doppler flow wave transmission time (T) between main pulmonary artery proximal (pulmonary valve) and distal point (pulmonary artery bifurcation) were measured. The distance (D) from the pulsed Doppler sample volume in the pulmonary valve to the pulmonary artery bifurcation was measured. The pulmonary artery PWV was defined as T/D. Pulmonary artery systolic pressure was calculated by use of the modified Bernoulli equation, with right atrial pressure assumed to be 10 mmHg. The ratio of early transmitral flow velocity (E) to early mitral annular myocardial velocity (Em) was used as an echocardiography-derived estimate of LV diastolic pressure.

Results:
Average value of pulmonary artery PWV was 179±58 cm/sec (range: 78 to 450cm/sec), in good agreement with literature values measured using invasive means. Pulmonary artery PWV did not correlate with heart rate. There were significant relationships between pulmonary artery PWV and age (r = 0.69, p < 0.01), body mass index (r = 0.46, p < 0.01), and pulmonary artery systolic pressure (r = 0.54, p < 0.01). A weak but significant relationship between systemic arterial PWV and pulmonary artery PWV was observed (r = 0.38, p < 0.01). There was no significant relationship between pulmonary artery PWV and mitral E/Em.

Conclusions:
We provide the first evidence of age-related increase in pulmonary artery pulse wave velocity, its association with increasing pulmonary artery systolic pressure and systemic vascular stiffening, and its negative impact on body mass index. Pulmonary artery pulse wave velocity may serve as a novel cardiovascular risk factor.
Abstract 8779: Effect of Cathepsin a Inhibition on Cardiac Function and Remodeling in Rats with Heart Failure Induced by Ischemia and Long-Term Reperfusion
Authors: Linz Wolfgang , Hübschle Thomas , Horstick Georg , Wohlfahrt Paulus , Juretschke Hans-Paul , Linz Dominik , Neumann-Haefelin Claudia , Rütten Hartmut , Ruf Sven , Sadowski Thorsten
Published: April 2024

Introduction:
Cathepsin A (CathA) is a lysosomal carboxypeptidase involved in the cardiac metabolism of various peptide hormones. Its expression is significantly upregulated in the border zone after myocardial infarction (MI) in rats. Affymetrix profiling in MI patients revealed a similar regulation.

Method:
Male Wistar rats were randomized in: (1) Sham-OP, (2) I/R-Placebo (I/R=30min ischemia/reperfusion of the left coronary artery), (3) I/R-ramipril (RA 1 mg/kg/d p.o.), (4) I/R - CathA Inhibitor SAR1 (SAR1 30 mg/kg/d p.o.). After 9 weeks of treatment a magnetic resonance imaging (MRI)-investigation was done. Thereafter, left ventricles (LV) were fixed for histological evaluation and gene expression analysis by Taqman PCR. Brain natriuretic peptide (BNP) was measured in serum by ELISA.

Results:
Inhibition of CathA with SAR1 attenuated left ventricular (LV) remodeling observed after I/R without altering blood pressure. MRI analysis revealed preserved ventricular wall geometry in infarcted and non-infarcted regions. Global parameters such as ejection fraction, cardiac output, stroke volume, end-diastolic volume, end-systolic volume and left ventricle peak filling rate were significantly improved during dobutamin stress when compared to placebo treated I/R-rats. Especially the regional parameters such as wall motion and systolic wall thickness were improved in the infarcted area and even normalized in the non-infarcted area in SAR-treated I/R-rats. In contrast, RA treatment did not prevent the adverse remodeling. In all parameters SAR1 was clearly superior to RA. Histological investigations confirmed the beneficial effects of SAR1 treatment and serum levels of BNP were significantly reduced in SAR1 treated animals. LV gene expression of TGFβ, ANP, collagen type III and CD14 was decreased by ramipril and SAR1 treatment.

Conclusion:
We identified hitherto unknown functions of CathA in cardiac disease. Especially the dramatic improvement in LV wall geometry after inhibition of CathA with SAR1 makes this enzyme a highly promising target for the treatment of post-MI heart failure patients. SAR1 has the potential to introduce a new treatment option for patients with acute MI to further preserve myocardial function on top of standard treatment.
Abstract 8784: Mechanisms of Recurrent Spontaneous Ventricular Fibrillation in a Rabbit Model of Electrical Storm
Authors: Maruyama Mitsunori , Chua Su-Kiat , Ai Tomohiko , Park Hyung-Wook , Lee Young-Soo , Shen Mark J , Chang Po-Cheng , Lin Shien-Fong , Chen Peng-Sheng
Published: April 2024

Introduction:
Electrical storm (ES) is defined as recurrent spontaneous ventricular fibrillation (SVF) within a short period of time. The mechanism of ES remains unclear.

Objective:
To develop a model of ES in normal rabbit ventricles and to test the hypothesis that ATP-sensitive K
+
current (
I
KATP
) activation underlies the mechanisms of ES.

Methods and Results:
Intracellular Ca
2+
(Ca
i
) and membrane voltage were optically mapped in 32 Langendorff-perfused rabbit ventricles. At baseline, no SVF was observed after 5 attempts of the VF-defibrillation episodes. During the post-shock period, isoproterenol (0.3 μ mol/L) heterogeneously shortened 50% recovery of action potential duration (APD
50
) while lowering [K
+
]
o
during isoproterenol infusion prolonged Ca
i
transient duration (Ca
i
TD
50
). Increased difference between Ca
i
TD and APD (ΔCa
i
TD
50
-APD
50
) lead to late phase 3 early afterdepolarization, triggered activity and SVF. In 11 (69%) of 16 SVF episodes, the VF originated from a focal site with maximal or next to maximal ΔCa
i
TD
50
-APD
50
(Figure A). The focal wavefronts developed wavebreak at sites with large voltage gradient, leading to SVF. Suppression of
I
Ca,L
with nifedipine (10 μ mol/L) reliably prevented ES when given before, but not after, the development of SVF.
I
KATP
blockade with glibenclamide (5 μ mol/L) prolonged post-shock APD
50
and suppressed ES in all ventricles (Figure B). An
I
Kr
blocker E-4031 (1 μ mol/L) failed to terminate ES. The lactate concentration did not increase after 5 VF episodes.

Conclusions:
VF during beta-adrenergic stimulation causes non-ischemic activation of
I
KATP
and abbreviated APD
50
. Low [K
+
]
o
increases Ca
i
TD
50.
These two factors synergistically enlarge the postshock ΔCa
i
TD
50
-APD
50
and induce late phase 3 afterdepolarization, triggered activity, wavebreaks and recurrent SVF (electrical storm).
I
KATP
blockade effectively prolongs post-shock APD
50
and suppresses ES.
Abstract 8815: Role of Regulatory T Cells in Atheroprotective Effects of Granulocyte Colony-Stimulating Factor
Authors: Hasegawa Hiroshi , Takano Hiroyuki , Uchiyama Raita , Ueda Kazutaka , kameda Yoshihito , Kobayashi Yoshio , Komuro Issei
Published: April 2024

Background
We and others have previously reported that granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling and dysfunction after myocardial infarction in animal models and human. We have also reported that G-CSF inhibits the progression of atherosclerosis in animal models, but its precise mechanism is still elusive. Because G-CSF was recently reported to enhance the cell number and function of regulatory T cells (Tregs), we investigated whether Tregs are critical for the protective effects of G-CSF on atherosclerosis.

Methods
We examined the effects of G-CSF (200 rg/kg) or saline on the atherosclerosis using apolipoprotein E-deficient (ApoE
-/-
) mice. Twelve-week-old male ApoE
-/-
mice were subcutaneously administrated with 200 μg/kg of G-CSF or same volume of saline once a day for 5 consecutive days per a week for 4 weeks. After 28 days of G-CSF or saline treatment, mice were sacrificed and analyzed the atherosclerotic area of the aortic root. To deplete the function of Tregs, we injected intraperitoneally anti-mouse CD25 antibody (PC61). Furthermore, to determine the effect of Tregs, we examined the effects of G-CSF on atherosclerosis using ApoE
-/-
/CD28
-/-
double knockout mice that lack Tregs.

Results
Atherosclerotic lesion of aortic sinus was significantly reduced in the G-CSF-treated mice compared with the saline-treated mice (35% reduction, Pμ0.05). G-CSF reduced the expression level of interferon-γ by 31% and increased the expression level of interleukin-10 by 20% in atherosclerotic lesions of aortic sinus. G-CSF increased the number of CD4
+
CD25
+
Tregs in lymph nodes and spleen, and enhanced the suppressive function of Tregs in vitro. G-CSF markedly increased the number of Foxp3-positive Tregs in atherosclerotic lesions of aortic sinus. Blood lipid concentrations were not significantly different between the G-CSF-treated mice and the saline-treated mice. Administration of anti-CD25 antibody (PC61) that depletes Tregs abrogated these atheroprotective effects of G-CSF. Moreover, in ApoE
-/-
/CD28
-/-
mice, the protective effects of G-CSF on atherosclerosis were not recognized.

Conclusions
These findings suggest that Tregs play an important role in the atheroprotective effects of G-CSF.
Abstract 8826: Association of TIMI-3 Epicardial Blood Flow Before and After Percutaneous Coronary Intervention with Microvascular Obstruction in Patients with ST-Segment Elevation Myocardial Infarction
Authors: Yamamuro Atsushi , Kaji Shuichiro , Kinoshita Makoto , Ehara Natsuhiko , Kitai Takeshi , Kim Kitae , Kobori Atsushi , Tani Tomoko , Morioka Shigefumi , Kita Toru , Furukawa Yutaka
Published: April 2024

Background:
The beneficial effects of full restoration of the epicardial coronary flow (TIMI flow grade 3) and spontaneous reperfusion before percutaneous coronary intervention (PCI) are well known. However, previous studies evaluating the influence of pre-PCI and post-PCI TIMI flow grade on cardiac mortality reported conflicting results. The impact of epicardial flow before and after PCI on microvascular damage in patients with ST-segment elevation myocardial infarction (STEMI) has been insufficiently studied. The purpose of this study was to examine the interaction of TIMI-3 antegrade flow before and after PCI on degree of microvascular damage in patients with STEMI.

Methods:
Two hundred and eleven consecutive patients with first anterior STEMI who underwent successful PCI (post-TIMI 2,3 flow) were subjected to coronary flow measurement with a Doppler guidewire. The coronary flow velocity spectrum provided the following parameters: systolic peak velocity (SPV) and diastolic deceleration time (DDT). We defined the presence of microvascular obstruction as DDT of ≤ 600 ms and the presence of systolic flow reversal. We classified the patients into three categories according to the post-TIMI 2 flow (group 1), the pre-TIMI 0-2 and post-TIMI 3 flow (group 2), the pre- and post-TIMI 3 flow (group 3).

Results:
As for the relationship between the epicardial blood flow before and after PCI and the severity of microvascular damage, group 1 was at the highest risk of microvascular obstruction, while group 3 was at the lowest: 32/40 (80%) for group 1, 55/142 (39%) for group 2, and 0/29 (0%) for group 3 (p<0.05). The DDT were shortest in group 1 and longest in group 3 (358±226 vs. 596±227 vs. 784±133 ms; p<0.05) and the SPV were lowest in group 1 and highest in group 3 (-23±22 vs. -1±24 vs. 14±16 cm/s; p<0.05).

Conclusions:
In patients with STEMI, epicardial blood flow both before and after PCI may have significant impacts on ischemic microvascular damage. In particular, all patients who achieved reperfusion with TIMI-3 epicardial blood flow before and after PCI were successfully salvaged from microvascular obstruction. Of critical importance, the effect of pre-procedural TIMI-3 flow on microvascular integrity persisted even when corrected for post-procedural TIMI-3 flow.
Abstract 8840: P21-Activated Kinase Improves Myocardial Performance through Modulation of Troponin-T and Myosin Light Chain 2 during Global Myocardial Ischemia and Reperfusion Injury
Authors: Monasky Michelle M , Taglieri Domenico M , Patel Bindiya G , Chernoff Jonathan , Wolska Beata M , Ke Yunbo , Solaro R. J
Published: April 2024

Emerging evidence indicates a role for p21-activated kinase (Pak1) in ischemia/reperfusion (I/R), but it is not clear whether Pak1 activation during ischemia reduces or increases injury. We hypothesize that activation of the Pak1 signaling pathway activates NADPH oxidase and induces post-translational modifications in myofilament proteins, which promote cardioprotective mechanisms that prevent or reverse the detrimental effects of ischemic injury in mouse cardiac tissue. We subjected
ex vivo
hearts from WT (wild type, n=9) and Pak1-KO (knock-out, n=16) mice to 20 minutes of global ischemia followed by 30 minutes of reperfusion. Percent recovery of the left ventricular developed pressure (LVDP) after I/R injury (LVDP after I/R divided by the LVDP before ischemia) in Pak1-KO hearts was significantly reduced (37.6 ± 4.9%) compared to WT (49.9 ± 2.2%). End systolic pressure was significantly reduced after I/R injury in both WT (85.6 ± 1.7 before I/R to 69.8 ± 1.8 mmHg after I/R) and Pak1-KO hearts (90.8 ± 3.7 to 68.8 ± 3.2 mmHg after I/R), but was not significantly different between WT and Pak1-KO hearts. However, ANOVA revealed end diastolic pressure was significantly increased in Pak1-KO hearts during reperfusion, compared to WT controls. ProQ analysis showed TnT phosphorylation was increased at baseline in Pak1-KO hearts compared to WT, and increased in WT after I/R, but did not increase in Pak1-KO hearts after I/R. MLC2 phosphorylation was significantly decreased in Pak1-KO hearts compared to WT after I/R injury. The current study has advanced the field by demonstrating for the first time that Pak1 and p47
phox
establish a protein-protein interaction in left ventricular cardiac tissue as assessed by co-immunoprecipitation, and that Pak1 co-localizes with p47
phox
and p22
phox
in the adult mouse cardiac myocyte, as assessed by immunofluorescence. Additionally, Pak1 signaling acts upon myofilament proteins and is beneficial during I/R injury, in that Pak1 reduces end diastolic pressure and increases left ventricular developed pressure after I/R injury. Thus, the current study provides a novel pathway including the targets Pak1, p47
phox
, TnT, and MLC2 for development of pharmaceutical interventions for use in the clinic for patients with ischemic events.
Abstract 8851: Intracoronary Infusion of Cardiosphere-Derived Cells (icCDCs) Improves Cardiac Function by Stimulating Myocyte Proliferation in Non-Infarcted Hibernating Myocardium with No Effect in Normal Myocardium
Authors: Suzuki Gen , Leiker Merced M , Cimato Thomas R , Canty John M
Published: April 2024

Background:
icCDCs have been shown to improve function and reduce fibrotic area when regionally infused into infarcted myocardium. Their ability to improve flow and function in viable dysfunctional myocardium in the absence of scar is unclear.

Methods:
Swine (n=12) with collateral-dependent hibernating myocardium from a chronic LAD occlusion were studied 4-months after instrumentation in the closed-chest propofol sedated state. CDCs were isolated from myocardial biopsies at the time of initial instrumentation. We assessed regional flow, LAD wall thickening (%LADWT) and global EF before and 4 weeks after icCDCs (∼40x10
6
cells) into each of the 3 major coronary arteries. Autologous (n=3) as well as non-autologous CDCs with cyclosporine treatment (200mg/day; n=3) had similar effects and results were pooled and compared to untreated swine (n=6). Histological analysis was performed to assess the frequency of Ki-67 and phospho-Histone H3 (pHH3) positive myocytes along with myocyte nuclear density and myocyte diameter.

Results:
Infusion of icCDCs in normal animals (icCDCs; n=5 vs. untreated; n=6) did not affect regional (%LADWT 51±1% vs. 48±3%, p-ns) or global function (EF: 70±2% vs. 70±3%, p-ns). In contrast, in hibernating myocardium, %LADWT increased from 23±6 to 51±5 % (p<0.01) and EF increased from 57±1 to 71±4 % (p<0.01) after icCDCs. There was no change in LAD coronary flow reserve (adenosine vasodilated flow/ resting flow 1.88 ± 0.20 to 2.03 ± 0.31, p-ns). icCDCs increased the number of Ki-67 and pHH3 positive myocytes (Table). This was accompanied by a prominent increase in myocyte nuclear density with reduced myocyte size suggesting the formation of new myocytes.

Conclusion:
We conclude that icCDCs result in a robust improvement in function in hibernating myocardium. This is not secondary to increases in myocardial perfusion but is secondary to pronounced myocyte proliferation and regeneration with newly formed myocytes in diseased but not normal myocardium.
Abstract 8917: Dauricine Suppresses Early Afterdepolarizations and Torsade De Pointes In Rabbit Hearts with Long Qt2 Syndrome
Authors: Parikh Ashish A , Yang Xiao-Yan , Zeng Fan-Dian , Salama Guy
Published: April 2024

Background:
Dauricine (Dau) is a bisbenzylisoquinoline alkaloid derivative isolated from rhizome of Mensipermum dauricium DC, a Chinese herb. Dau has been shown to lower blood pressure, platelet aggregation, inflammatory response and arrhythmia. Dau has also been shown to inhibit the late Na
+
current,

I
NaL

,

I
Kr

and L-type Ca
2+
current,

I
CaL

by shifting the steady state inactivation and activation curves and prolonging the τ value of recovery.

Objectives:
The multiple targets of Dau make it challenging to explain the suppression of early afterdepolarizations (EADs) and Torsade de Pointes (TdP) in drug-induced Long QT 2 (LQT2) model in rabbit hearts by mapping Action Potential (AP) and Ca
2+
transients (Ca
i
T) and to mathematically model the effect of Dau and explain its possible mode of action.

Methods:
Experimental (Langendorff rabbit hearts labelled with Rhod-2/AM and PGH1 to simultaneously map Action Potential (AP) and Ca
2+
transients (Ca
i
T)) and simulations (
Shannon et al
. model) of rabbit AP and CaiT were used to investigate the effects of Dau (5µM) before and after LQT2 induced with Dofetilide (Dofe=0.5μ M) to block

I
Kr

.

Results:
In controls, Dau tended to prolong AP durations (APDs), CaiT durations (CTD) (p>0.5) but significantly reduced conduction velocity (CV) (p<0.05; n=5) in a rate independent manner. In LQT2, Dofe prolonged APDs (318±24 to 835±32 ms; p<0.01), CTDs (346±36 to 867±48ms; p<0.01) elicited EADs and TdP that were suppressed by Dau (p<0.01; n=5/5 hearts). Dau (5µM) reduced the Dofe-prolongation of APDs (835±32 to 542±93ms; p<0.01) and CTD (867±48 to 567±103ms; p<0.01) and reversed the Dofe-prolongation of Dispersion of Repolarization (DOR) (25±6 to 55± 15ms; p<0.01; reversed 55±15ms to 29±15ms; p<0.05). Simulations of the effects of Dofe, Dau and Dofe + Dau indicate that Dau's suppression of EADs is primarily mediated by reducing the Ca
i
overload by modifying the kinetics of

I
CaL

.

Conclusions:
Dau (5µM) markedly reduced CV and in LQT2 significantly shortening APDs, CTDs, reduced DOR and suppressed EADs and TdP. Simulations implicate the slowing down of activation and inactivation kinetics of

I
CaL

as the dominant anti-arrhythmic mechanism.
Abstract 8922: Association between Metabolic Syndrome and Concentric Left Ventricular Hypertrophy in Patients with Severe Calcific Aortic Stenosis Undergoing Aortic Valve Replacement
Authors: Clavel Marie-Annick , Capoulade Romain , Dumesnil Jean G , Mathieu Patrick , Després Jean-Pierre , Pibarot Philippe
Published: April 2024

Background:
We reported that in patients with mild to moderate aortic stenosis (AS), metabolic syndrome (MetS) is associated with more pronounced concentric LV hypertrophy. Severe LV concentric hypertrophy has been linked to reduced survival following aortic valve replacement (AVR). The aim of this study was to examine the relationship between MetS and prevalence of LV concentric hypertrophy in patients with severe AS referred to AVR.

Method and Results:
510 patients with severe AS underwent isolated AVR. Among 510 patients undergoing isolated AVR, 131 (26%) had the MetS and 109 (21%) had type 2 diabetes (T2D). Patients with T2D or MetS had larger waist circumference (T2D: 106±16; MetS: 104 ±12 vs.noMetS-noT2D: 96±13cm; p<0.0001), higher incidence of hypertension (86; 85 vs. 50%) and coronary artery disease (CAD: 22; 18 vs. 10%) compared to those with noMetS-no T2D. The severity of AS was similar in the 3 groups (Peak aortic jet velocity [Vmax]:417±81; 416 ±81 vs. 424±84mmHg; p=0.13). Patients were classified into four different LV patterns according to relative wall thickness ratio and LV mass indexed (LVMi) to a 2.7 power of height (Figure). Distribution of LV patterns was worse (p<0.0001) in T2D and MetS groups compared to noMetS-noT2D group (Figure). Diabetes and MetS were independently (p=0.02 and p=0.04) associated with higher LVMi after adjustment for age, gender, hypertension, Vmax, mitral regurgitation, CAD, history of myocardial infarction, and valvulo-arterial impedance. One year after AVR, decrease in LVMi was similar in the 3 groups (p=0.44) and thereby postoperative LVMi remained higher (p=0.003) in the T2D and MetS groups (49 ±14 and 53±12 g/m
2.7
) compared to noMetS-noT2D group (43±15 g/m
2.7
).

Conclusion:
MetS and T2D are independently associated with higher prevalence of LV concentric hypertrophy in patients with severe AS and with more residual hypertrophy following AVR, which may in turn increase short- and long- term postoperative mortality.
Abstract 8935: Differentiation of Left Atrial Volume by Time Measured by Speckle Tracking Echocardiography as a Novel Index of Left Atrial Global and Phasic Function
Authors: Matsuoka Reiko , Tanaka Ryuhei , Ono Koji , Watanabe Takatomo , Nagaya Maki , Onishi Noriyuki , Sato Noriaki , Fujii Tomoko , Kato Takashi , Abe Shintaro , Yoshizane Takashi , Goto Yoshiaki , Tokoro Fumitaka , Warita Syunichiro , Kojima Tai , Iwama Makoto , Hirose Takeshi , Tanihata Shintaro , Noda Toshiyuki , Iida Mami , Watanabe Sachiro , Kawasaki Masanori , Minatoguchi Shinya
Published: April 2024

Background:
Left atrial (LA) strain rate (SR) is proposed to assess LA relaxation, conduit function and contraction. Differentiation of strain by time (SR) is one dimensional parameter, but differentiation of LA volume by time (dV/dt) is three dimensional parameter. Thus, we hypothesized that LA dV/dt is more useful index of LA global and phasic function.

Methods:
We examined 138 subjects; normal (n=54, age 69±11 yrs, 30 men), hypertensive pts (HTN) with normal systolic function (n=84, age 71±9 yrs, 48 men). LA peak dV/dt and SR at systole, early diastole and atrial contraction were measured by speckle tracking which can automatically provide dV/dt from time-LA volume curve (Figure). LA peak dV/dt and SR in HTN were compared to normal. Time from onset of R wave on ECG to peak dV/dt at each phase was compared to that to peak SR.

Results:
Inter and intraobserver correlation coefficient for dV/dt at each phase was 0.97-0.99. There was a good relation between dV/dt and SR (r=0.94, p<0.01). Time to peak dV/dt was comparable to time to peak SR at each phase (208±62 vs. 189±56, 523±50 vs. 527±51, 921±161 vs. 920±162msec, respectively, p<0.01). Peak positive dV/dt and SR at systole in HTN were reduced compared to normal (178±35 vs. 204±47 ml/s, 1.1±0.3 vs. 1.3±0.4 s-
1
, respectively, p<0.05). Peak negative dV/dt and SR at early diastole in HTN were lower (-174±62 vs. -216±92ml/s, -0.9±0.3 vs. -1.4±0.6 s-
1
, respectively, p<0.05), associated with elevated E/e’ (9.0±1.9 vs. 7.2±1.9, p<0.01). Despite no difference in peak SR at atrial contraction between 2 groups, peak negative dV/dt in HTN was higher than normal (-222±67 vs. -147±74 ml/s, p<0.01).

Conclusions:
LA relaxation assessed by dV/dt and SR was reduced in HTN and conduit function was also reduced in HTN by impaired diastolic function. LA active contraction assessed by dV/dt was increased in HTN to compensate reduced conduit function. Measurement of LA dV/dt may be more promising method to assess LA function with highly acceptable variability.
Abstract 8951: Assessment of Pressure Reflection in the Pulmonary Circulation Using Echocardiography Identifies Patients with Normal as Well as Increased Pulmonary Vascular Resistance
Authors: Bech-Hanssen Odd , Rundqvist Bengt , Lindgren Fredrik , Selimovic Nedim
Published: April 2024

Background and aim.
Pulmonary hypertension (PH) is a frequent finding in patients with cardiopulmonary disorders. It is important to recognize PH due to increased pulmonary vascular resistance (PVR). In a recent study we describe a new echocardiography method to identify patients with increased PVR (>3 WU) based on detection of pressure reflection (PR) in the pulmonary artery (PA). The patient population was biased towards high PVR and therefore, in the present study we evaluate the method in a more representative population undergoing right heart catheterization.

Methods and results.
Echocardiography and catheterization were performed within one week in 108 patients. We selected 3 variables related to PR: the interval from valve opening to peak velocity in the PA (AcT, ms), the interval between PA peak velocity and peak tricuspid velocity (tPV-PP, ms), and the right ventricular pressure increase after peak velocity in the PA (augmented pressure, AP, mm Hg). Cut-of values indicating increased PVR for Act/tPV-PP/AP were 89 ms/>8 mmHg. Forty-six percent had left heart disease, 21% were heart transplant patients and 18% had pulmonary arterial hypertension. The proportion with increased PAMP (>25 mmHg) was 54%, increased pulmonary capillary wedge pressure (PCWP>12 mHg) 40%, increased PVR (>3 WU) 36% or both increased PVR and PCWP 15%. The table shows how the number of PR variables affected the diagnostic performance. The positive predictive value was 94% with equal to or > 2 PR variables and the negative predictive value was 92% with no PR variables present.

Conclusions.
Assessment of PR in the pulmonary circulation identifies patients with normal as well as increased PVR.
Abstract 8958: The Role of Right Ventricular Dysfunction/Venous Congestion in Cardiac-Renal Interactions
Authors: Testani Jeffrey M , Chen Melissa , McCauley Brian , Shannon Richard , Shen You-Tang
Published: April 2024

Introduction:
It has been thought that the primary driver of renal dysfunction (RD) in heart failure (HF) is diminished renal perfusion secondary to reduced cardiac output. However, this relationship has not been confirmed in recent clinical studies. Rather, strong associations between RD and right ventricular (RV) dysfunction/venous congestion have been identified.

Hypothesis:
If RV dysfunction/venous congestion are causative of HF induced RD, the addition of RV dysfunction to a standard left ventricular (LV) HF model should produce incremental RD, independent of changes in cardiac output.

Methods:
Eleven swine were chronically instrumented with intravascular catheters, intra-cardiac pressure transducers, and vascular flow probes on the ascending aorta and renal artery. After 2 weeks of recovery, biventricular failure was induced by serial microembolization of the pulmonary vascular bed (2-3 mg/kg of 65 micron glass spheres, times 6 infusions) followed by ventricular pacing at 170 BPM (RV+LV group, n=7). The remaining 4 pigs served as a pacing only control (LV group). Measurements of cardiac and renal parameters were made in the conscious state at baseline and after 2 weeks of pacing.

Results:
Baseline renal and cardiac parameters were similar between groups. After 2 weeks of pacing, LV end diastolic pressure was increased and LV dP/dT and cardiac output were decreased (p<0.05), however these parameters did not differ between groups (p≥ 0.19 for all). Notably, right atrial pressure was significantly higher (LV group=4.7 ± 1.3 vs. RV+LV group= 12.1 ± 1.1 mmHg, p=0.02) and renal blood flow was significantly lower in the RV+LV group (LV=144.0 ± 3.2 vs. RV+LV= 94.4 ± 16.0 ml/min, p=0.03) despite a similar mean cardiac output between groups (LV group=3.8 ± 0.3 vs. RV+LV group=4.0 ± 0.4 l/min, p=0.76).

Conclusion:
Despite a comparable degree of LV dysfunction and similar reductions in cardiac output, conscious swine with biventricular dysfunction had a disproportionate impairment in renal perfusion. These results provide mechanistic support for human observational studies linking RV dysfunction/venous congestion with RD.
Abstract 8976: Prognostic Value of Electrocardiographic Cornell product in Chronic Heart Failure Patients
Authors: Otaki Yoichiro , Takahashi Hiroki , Watanabe Tetsu , Kadowaki Shinpei , Narumi Taro , Honda Shintaro , Hasegawa Hiromasa , Funayama Akira , Netsu Shunsuke , Ishino Mitsunori , Nishiyama Satoshi , Arimoto Takanori , Shishido Tetsuro , Miyashita Takehiko , Miyamoto Takuya , Kubota Isao
Published: April 2024

Background
; Heart failure is the major and increasing health problem with a high mortality. Although electrocardiogram (ECG) is a valuable non-invasive procedures used routinely for the diagnosis of heart failure, few ECG parameters, which are related to cardiac prognosis in chronic heart failure (CHF), are known. Cornell product is one of the parameters for ECG left ventricular hypertrophy (LVH). However, clinical significance of Cornell product has not been studied in CHF patients. The purpose of present study is to examine whether Cornell product is related to cardiac function and can predict clinical outcomes in CHF patients.

Methods and Results
; We examined a standard 12-lead ECG in 356 consecutive CHF patients and calculated Cornell product {(S
v3
+ R
aVL
+ 0.6 in woman) × QRS duration}. Patients were prospectively followed during a median follow up period of 697 days, with the end points of cardiac death and cardiac events. There were 99 cardiac events, including 30 cardiac deaths and 69 re-admissions for worsening heart failure. In a simple linear regression analysis, Cornell product correlated with ejection fraction (EF) (r = 0.431, p < 0.0001). Cornell product was higher in patients with cardiac events than those without. In the univariate Cox proportional hazard analysis, age, NYHA functional class, brain natriuretic peptide, EF, and Cornell product were significant risk factor for cardiac events. A multivariate Cox proportional hazard analysis revealed that Cornell product was independent predictor of cardiac events in CHF patients. Kaplan-Meier analysis demonstrated that cardiac event rate was higher in patients with high Cornell product than patients with low Cornell product.

Conclusion
; Cornell product is a promising parameters to detect not only LVH but also cardiac systolic dysfunction in CHF patients. Cornell product can be a highly reliable non-invasive parameter for predicting cardiac prognosis in CHF patients.
Abstract 91: Influence of Early Return of Spontaneous Circulation and Early Induction of Cooling on Neurological Outcome in Patients Treated with Therapeutic Hypothermia After Out-of-Hospital Shockable Cardiac Arrest
Authors: Soga Taketomo , Nagao Ken , Yokoyama Hiroyuki , Yonemoto Naohiro , Nonogi Hiroshi ,   J-PULSE Hypo Group
Published: April 2024

BACKGROUND
Therapeutic hypothermia is a helpful therapeutic approach in patients who remain comatose after return of spontaneous circulation (ROSC). However, optimal time window for therapeutic hypothermia have not been known. We hypothesized that early achievement of ROSC and early induction of therapeutic hypothermia would be associated with favorable outcome.

METHODS
The J-PULSE-Hypo was conducted a multi-center registry to investigate the effects of therapeutic hypothermia. In this study, we investigated the relationship between neurological outcome at hospital discharge and time intervals from collapse to ROSC and from ROSC to induction of cooling. We constructed a receiver-operating-characteristics (ROC) curve to illustrate the various cutoff values of those time intervals.

RESULTS
Of the 452 unconscious patients who were treated with hypothermia after out-of-hospital cardiac arrest due to cardiac etiology, 301 who were cooled from 32°C to 34 °C after witnessed shockable cardiac arrest were included. The cutoff value for identification of favorable outcome was 28.5 minutes in the collapse-to-ROSC interval and 48.0 minutes in the ROSC-to-cooling interval. Significant difference was seen in favorable outcome among the 4 groups of patients who were classified according to those cutoff values (81% in group 1 of collapse-to-ROSC interval≤28 minutes and ROSC-to-cooling≤48 minutes, 78% in group 2 of collapse-to-ROSC interval≤28 minutes and ROSC-to-cooling>48 minutes, 46% in group 3 of collapse-to-ROSC interval>28 minutes and ROSC-to-cooling≤48 minutes, and 36% in group 4 of collapse-to-ROSC interval>28 minutes and ROSC-to-cooling>48 minutes, p<0.0001). In a logistic-regression model in which we adjusted for other independent predictors, those 4 groups remained associated with neurological outcome. The adjusted odds ratio for favorable outcome among those 4 groups was 10.8 (95%CI, 4.5-18.5) in groups 1, 8.5 (95%CI, 3.6-20.1) in group 2 and 2.0 (95%CI, 0.85-4.6) in group 3.

CONCLUSION
Early achievement of ROSC was associated with favorable outcome, but early induction of cooling did not influence on neurological outcome in unconscious patients treated with therapeutic hypothermia after out-of-hospital shockable cardiac arrest.
Abstract 9114: Circulating Biomarkers of Collagen Type I Metabolism Mark Right Ventricular Fibrosis and Indications for Pulmonary Valve Replacement in Adults with Repaired Tetralogy of Fallot
Authors: Chen Chun-An , Tseng Wen-Yih I , Wang Jou-Kou , Chen Ssu-Yuan , Chiu Hsin-Hui , Chang Chung-I , Chiu Ing-Sh , Chen Yih-Sharng , Lu Chun-Wei , Lin Ming-Tai , Wu Mei-Hwan
Published: April 2024

Background:
Right ventricular (RV) fibrosis is common in patients with repaired tetralogy of Fallot (rTOF). Previous works have shown that cardiac fibrosis could be monitored from circulating biomarkers of collagen metabolism. We assessed the hypothesis that the expression of circulating biomarkers of collagen type I metabolism is altered in rTOF, and could mark
in vivo
cardiac fibrosis and adverse outcomes.

Methods:
Serum biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I, PICP), degradation (carboxy-terminal telopeptide of collagen type I, CITP), and enzymes regulating collagen turnover (matrix metalloproteinases, MMPs, and type I tissue inhibitor, TIMP-1) were measured in 70 adults with rTOF and 91 age- and sex-matched controls. All patients underwent cardiac magnetic resonance (CMR) to evaluate biventricular function and late gadolinium enhancement (LGE). Patients were classified as with or without indications for pulmonary valve replacement (PVR) based on clinical symptoms, exercise capacity, and CMR-derived measurements.

Results:
In patients with rTOF, PICP (median 87.7 [25%-75% percentile 68.9-115.6] vs. 58.9 [48.4-71.9] ng/mL,
P
< 0.001) and PICP:CITP ratio (23.1 [17.5-30.7] vs. 16.5 [13.6-21.7],
P
< 0.001) were significantly higher than in controls. TIMP-1 was elevated (168.4 [145.7-180.3] vs. 107.3 [91.8-124.2] ng/mL,
P
< 0.001) without concomitant increase in MMP-1, -2, -3, and -9. Patients with PVR indications had higher PICP (
P
= 0.009) and PICP:CITP ratio (
P
= 0.078) than those without. In addition, a higher PICP correlated with a higher RV LGE score (
r
= 0.427,
P
< 0.001) and a lower exercise capacity (
r
= -0.465,
P
= 0.001). In multivariate analysis, PICP was associated with the probability of the presence of indications for PVR (odds ratio 1.80 per 10 ng/mL,
P
= 0.003).

Conclusions:
Collagen type I overproduction and uncoupled degradation were found in patients with rTOF. Circulating PICP not only correlated with RV LGE, but also linked to adverse markers of clinical outcome indicating the need for PVR. These findings may give us new insight into the pathophysiology of adverse RV remodeling in rTOF, and form the basis for the development of new therapeutic strategies in these patients.
Abstract 9167: Fetoscopic Placental Laser Photocoagulation Improves Right Ventricular Outflow Tract Obstruction in Twin-Twin Transfusion Syndrome
Authors: Wellen Shari L , Bebbington Michael , Tian Zhiyun , Rychik Jack
Published: April 2024

Background:
Twin-twin transfusion syndrome (TTTS) is a disease of monochorionic, diamniotic twin gestation associated with recipient twin cardiac manifestations, such as abnormal growth of the pulmonary artery (PA) and right ventricular outflow tract obstruction (RVOTO). Untreated, mortality is >80%, however fetoscopic placental laser photocoagulation (LP) improves survival.

Objectives:
To characterize the impact of LP on PA abnormalities and RVOTO in recipient TTTS twins.

Methods:
TTTS gestations with abnormal recipient PA growth and RVOTO that underwent LP between 1/1/2009 to 12/31/2010 were identified. We previously developed a comprehensive cardiovascular scoring system for TTTS (CHOP Score), which includes a domain grade for right-sided outflow abnormality (0 = no obstruction, 1 = PA equal in size to aorta, 2 = PA smaller than aorta, and 3 = frank RVOTO with pulmonary stenosis or atresia). Fetal echocardiograms were reviewed to determine the CHOP Score before, 1 day, 1 week, and 4 weeks after LP.

Results:
Of 76 twin pairs with TTTS who underwent LP at our center, 28 (36%) had right-sided outflow abnormality. Prior to LP, 15 had a PA equal in size to the aorta (group 1), 5 had a PA smaller than the aorta (group 2) and 8 had frank RVOTO (group 3). Median gestational age at LP was 20 wks (17 6/7-25 5/7 wks). The impact of LP is shown. All group 1 and group 2 fetuses had complete resolution by 4 wks after LP. In group 3, 1 patient with “functional” pulmonary atresia (no antegrade flow but with pulmonary insufficiency) had complete resolution 1 day after LP. Five patients (63%) with RVOTO at diagnosis did not respond to LP, of whom four required a catheter-based intervention after birth. All four remained biventricular repairs. There were 11 cases of fetal demise (6 donor, 5 recipient).

Conclusions:
Placental LP interrupts the pathophysiology of TTTS and leads to improvement in RVOTO. The disease model of TTTS provides an opportunity to study the unique plasticity of the human fetal heart.
Abstract 9169: Down-Regulation of miR-15 Family is Responsible for Overexpression of GATA-4 Mediated Cytoprotection
Authors: Yu Bin , Pasha Zeeshan , He Zhisong , Wang Yigang , Ashraf Muhammad , Xu Meifeng
Published: April 2024

We have previously reported that mesenchymal stem cells (MSC) preprogrammed to express GATA-4 (MSC
GATA-4
) significantly increased their survival in ischemic myocardium. However, it is unclear how upregulation of GATA-4 in MSC mediates cytoprotection. MicroRNAs (miR) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. In this study, we transduced GATA-4 into MSC. The expression of miR in MSC was assessed using miR microarray and quantitative real-time PCR. Bcl-2-like 2 (Bcl-w), one protein of miR-15 family targeted genes, was analyzed using qRT-PCR and western blot. Anoxia was used to mimic ischemic injury. FACS for annexin-V labeling cells was used to evaluate cell apoptosis and MTT intake was employed to study MSC survival. Our study indicated that overexpression of GATA-4 modulates the expression of several miR in MSC, including significantly decreased miR-15 family (e.g. miR-15b, miR-16, and miR-195) (
Fig. 1
). Bcl-2-like-2 (Bcl-w), which is one of target genes of miR-15 family and has an anti-apoptotic effect, was increased in MSC
GATA-4
. However, overexpression of miR-195 in MSC
GATA-4
(MSC
GATA-4-miR-195
) using a lentiviral vector transfection system significantly reduced Bcl-w compared to that in the negative control miR transfected MSC (MSC
GATA-4-miR-NC
) (
Fig. 2
). The apoptosis of MSC
GATA-4
following exposed to anoxia for 8 hours was lower than MSC
Null
, and it was abolished by transfecting miR-195 and siRNA-Bcl-w into MSC
GATA-4
(
Fig. 3
). These results indicate that overexpression of GATA-4 downregulates miR-15 family resulting in upregulation of Bcl-w, responsible for GATA-4 mediated cytoprotection.
Abstract 9177: Mitral Valve Adaptation in Chronic Aortic Regurgitation with Preserved Systolic Function: A Three-Dimensional Echocardiographic Study
Authors: Beaudoin Jonathan , Handschumacher Mark D , Hung Judy , Levine Robert A , Schwammenthal Ehud
Published: April 2024

Introduction:
Chronic aortic regurgitation (AR) causes left ventricular (LV) remodeling and ultimately heart failure. This creates the potential for functional mitral regurgitation (MR) caused by papillary muscle displacement and mitral valve tethering. However, MR is typically absent during the compensated stage of AR despite substantial LV dilatation. Increased mitral leaflet area has been identified in ischemic and non-ischemic heart failure. It is unknown whether increased mitral valve size could represent a compensatory mechanism capable of preventing MR in patients with LV dilatation due to chronic AR.

Hypothesis:
Chronic AR is associated with mitral valve enlargement and this can prevent functional MR in patients with LV dilatation. Our objective is to compare mitral valve leaflet area in patients with chronic AR and preserved systolic function to that of normal patients using 3D-echocardiography.

Methods:
From January to April 2011, we prospectively enrolled 44 patients (22 with at least moderate aortic regurgitation and 22 controls). 3D echocardiograms were performed to assess mitral valve geometry including total diastolic leaflet area measured by a previously validated method.

Results:
Both groups had normal ejection fraction (60 ± 7 % in AR vs 63 ± 7 % in normals, p=0.17). Only 1 AR patient had significant (more than mild) functional MR. LV volume by 3D echocardiography was significantly larger in the AR group (LV end-diastolic volume index: 80 ± 23 cm3/m2 vs 49 ± 12 cm3/m2, p<0.01). The mitral valve leaflet area indexed for body surface area was significantly increased in the AR group (8.9 ± 1.7 cm2/m2 vs 7.4 ± 1.2 cm2/m2, p<0.01). Patients with AR also had increased mitral leaflet thickness (2.3 ± 0.3 mm vs 2.0 ± 0.3 mm, p<0.01) regardless of AR jet impact on the valve. Mitral valve leaflet area significantly correlated with LV end-diastolic LV volume (p<0.01).

Conclusion:
Mitral valve leaflet area and thickness are significantly increased in patients with chronic AR and preserved ejection fraction. Area enlargement is proportional to LV volume, and can potentially explain why functional MR is uncommon in this population. Understanding the mechanisms underlying this adaptation could lead to new therapeutic interventions for functional MR.
Abstract 9198: Hypoxic Preconditioning Enhances the Angiogenic and Therapeutic Potential of Bone Marrow Cells with Age-Related Functional Impairment
Authors: Kubo Masayuki , Li Tao-Sheng , Kurazumi Hiroshi , Takemoto Yoshihiro , Ohshima Mako , Hamano Kimikazu
Published: April 2024

Background:
Previous studies have demonstrated that
ex vivo
hypoxic preconditioning (HP) of bone marrow cells (BMCs) can enhance their potency for inducing therapeutic angiogenesis, but experiments have all used cells from young healthy individuals. Considering that the response to hypoxia may differ depending on the quality of cells and that cell-based therapy were usually conducted in patients with advanced age, we investigated whether there was a difference in the response to HP between BMCs from old and young mice.

Methods and Results:
BMCs were collected from young (3 months) and old (20-22 months) C57BL/6 mice, and subjected to HP by incubating in 2% O
2
for 24 hour. Adhesion, survival and angiogenic potency were significantly worse (all P<0.05) in BMCs from old mice than in those from young mice, indicating an age-related functional impairment of the BMCs. Agreed well with previous studies using cells from young healthy mice, HP of BMCs from old mice resulted in a significant increase in adhesion (P<0.01) and survival (P<0.01). The hypoxia-preconditioned BMCs also had a significant increase in angiogenic potency, including the production of VEGF (P<0.05) and endothelial differentiation (P<0.05). All of these enhancements by HP were comparable between BMCs from old and young mice. On intramuscular implantation of BMCs into the ischemic hindlimbs of old mice, microvessel density and blood flow (Fig A) in the ischemic hindlimbs 14 days after treatment was significantly increased in the mice implanted with the hypoxia-preconditioned BMCs from old mice than in those implanted with the freshly isolated or the normoxia-cultured BMCs from old mice; a similar preconditioning effect was observed in BMCs from young mice (Fig B).

Conclusion:
HP-induced enhancement of angiogenic potential of BMCs from old mice follows the same trend as that of BMCs from young mice, suggesting that HP could be a useful method of enhancing the potential of BMCs for therapeutic angiogenesis.