bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 265: Impact of Changes in the Telephone Cardiopulmonary Resuscitation Instruction After Out-of-Hospital Cardiac Arrest
Authors: Nagao Ken , Hanada Hiroyuki , Tahara Yoshio , Nonogi Hiroshi , Yonemoto Naohiro , Gaieski David F , Ito Noritoshi , Hirose Hitoshi , Yagi Tsukasa , Chiba Nobutaka , Tachibana Eizo , Saku Keijiro , Simokawa Hiroaki
Published: July 2021

Background:
The international consensus on cardiopulmonary resuscitation (CPR) and emergency cardiovascular care science with treatment recommendations (CoSTR) 2010 changed the dispatcher-initiated telephone CPR instruction. Major changes of the telephone CPR instruction were simplified algorithm, elimination of “Look, listen, and feel for breathing” chest compressions first (C-A-B), chest compression only CPR if bystander was not trained in CPR, et al. However, few studies have investigated the efficacy of telephone CPR instruction based on the CoSTR 2010.

Methods:
From the All-Japan Utstein Registry for out-of-hospital cardiac arrest (OHCA) between 2006 and 2015, we enrolled adult (18 years or older) patients with bystander-witnessed OHCA and stratified by the two CoSTR eras (the CoSTR 2010 group from 2011 through 2015 versus the CoSTR 2005 group from 2006 through 2010). The primary endpoint was 30-day favorable neurological outcome after OHCA.

Results:
Of the 378,757 adult patients with bystander-witnessed OHCA, 199,117 (52.5%) received CPR based on the CoSTR 2010 and 179,640 (47.4%) received CPR based on the CoSTR 2005. In the whole cohort, the CoSTR 2010 group had higher proportion of cases receiving telephone CPR instruction than the CoSTR 2005 group (48.8% versus 40.9%, P<0.001). In the subgroups of patients receiving telephone CPR instruction, the CoSTR 2010 group had higher proportion of bystander chest compression-only CPR (60.5% versus 47.3%, p<0.001) and public access defibrillation (1.9% versus 0.9%, P<0.001) than the CoSTR 2005 group. Although those subgroups had similar proportion of initial shockable cardiac arrest rhythm (15.2 % in the CoSTR 2010 group versus 15.3 % in the CoSTR 2005 group, P=0.63), the CoSTR 2010 group had higher frequency of the favorable neurological outcome than the CoSTR 2005 group (4.5 % versus 3.7%%, P<0.001). In the subgroup of patients receiving telephone CPR instruction, an adjusted odds ratio for the favorable neurological outcome in the CoSTR 2010 group (reference, the CoSTR 2005 group) was 1.47 (95 % CI, 1.43-1.51, p<0.001).

Conclusions:
Telephone CPR instruction based on the CoSTR 2010 was the preferable approach to resuscitation for adult patients with bystander-witnessed OHCA.
Abstract 280: Cerebral Blood Flow and Oxygenation During CPR in Swine
Authors: Gould Jeffrey R , Lick Michael C , Kaufman Christopher L , Lampe Joshua W , Silver Annemarie E , Berger Paul S , Metzger Anja
Published: July 2021

Introduction:
Near-infrared spectroscopy (NIRS) has been used during cardiac arrest (CA) to non-invasively measure cerebral oxygenation. Studies have suggested that survival and neurological outcomes can be predicted using cerebral oxygenation, however, the physiology underlying cerebral oxygenation during CA is poorly understood. This exploratory study examined the behavior of cerebral blood flow and oxygenation in response to standard CPR (SCPR) and CPR with Active decompression and lift (ACD) and an impedance threshold device (ITD).

Methods:
Ventricular fibrillation was electrically induced in eight domestic swine. Following six minutes of untreated VF, SCPR (100 cpm at 20% anterior-posterior distance) was performed for six minutes. ACD+ITD was performed for an additional six minutes at the same rate and depth as SCPR, but with an additional 20% anterior-posterior distance of active lift. Cerebral blood flow was measured via microspheres and cerebral oxygenation was measured using NIRS. Animals were classified as responders if cerebral oxygenation increased within two minutes of initiating SCPR. Cerebral oxygenation did not change or declined during SCPR in non-responders.

Results:
Six out of eight animals were classified as responders. Cerebral blood flow and oxygenation increased with ACD+ITD compared to SCPR in responders but failed to increase for non-responders. Cerebral blood flow and oxygenation were lower during baseline (BL) in non-responders (Figure).

Conclusions:
ACD+ITD appears to improve cerebral blood flow and oxygenation. Changes in cerebral oxygenation during CA appear to be associated with measured changes in cerebral blood flow. NIRS may be clinically useful in estimating oxygenation and blood flow during low blood flow states and monitoring physiological responses to different interventions. Failure of improvement in NIRS during CPR may predict poor outcomes and/or the need for additional interventions guided by NIRS.
Abstract 308: Pupil Diameter Predicts the Outcome in Patients With Cardiopulmonary Arrest
Authors: Imamura Shunichi , Miyata Masaaki , Kamata Risa , Nomoto Yutaro , Yoshimoto Issei , Ohmure Kenta , Chaenn Hideto , Oketani Naoya , Ogawa Masakazu , Hamasaki Shuichi , Ohishi Mitsuru
Published: July 2021

Introduction:
Early prediction of the outcome in patients with cardiopulmonary arrest (CPA) is important to select the optimal management. The pupil diameter is a simple neurological examination and it predicts the prognosis in patient with stroke. However, the clinical significance of pupil diameter in CPA has not been elucidated.

Hypothesis:
We hypothesized that pupil diameter would predict the prognosis of CPA patients.

Methods:
We retrospectively analyzed consecutive 45 patients with CPA and return of spontaneous circulation (ROSC) after cardiopulmonary resuscitation in our hospital. We analyzed age, sex, cause of CPA, time during CPA, pupil diameter at admission and death in hospital.

Results:
The mean of age was 67±20 years and male were 34 (76%). The median of CPA time was 33 min [25%, 75%; 22, 46] and pupil diameter was 4.8 mm [3.0, 6.0]. The 26 (58%) patients died in hospital after ROSC. There was no significant difference in age and sex between survival (n=19) and dead (n=26). The CPA time was significantly shorter in survival than that in dead (21 min [10, 39] vs 30 min [30, 52], p=0.005). Furthermore, pupil diameter was significantly smaller in survival compared with dead (3.0mm [2.5, 4.3] vs 5.0mm [4.4, 6.0]) (Figure). The receiver-operating characteristic (ROC) curve for survival after ROSC demonstrated that the area under curve was 0.73 and provided an optimal cut-off value at 4.0mm in pupil diameter with 75% sensitivity and 75% specificity. When CPA time was 28 minutes, the area under curve was 0.76, and sensitivity and specificity were 78% and 71%, respectively.

Conclusion:
As same as CPA time, pupil diameter is suggested to predict the outcome after ROSC in CPA patients.
Abstract 311: Selection of Optimal Predictor and Critical Thresholds for Return of Spontaneous Circulation Using Non-Invasive Frequency-Domain Diffuse Optical Spectroscopy During Cardiopulmonary Resuscitation
Authors: Ko Tiffany S , Guo Wensheng , Mavroudis Constantine D , Morgan Ryan W , Baker Wesley M , Boorady Timothy , Marquez Alexandra M , Landis William P , Nadkarni Vinay M , Berg Robert A , Sutton Robert M , Yodh Arjun G , Licht Daniel J , Kilbaugh Todd J
Published: July 2021

Introduction:
We have shown that during CPR, novel non-invasive monitoring of cerebral tissue oxygenation (StO
2
, %) and total hemoglobin concentration (THC, μmol/L) by frequency-domain diffuse optical spectroscopy (FD-DOS) is associated with ROSC in a swine model of pediatric cardiac arrest. Our objective is to find the optimal non-invasive predictor for ROSC and assess feasibility of a stable critical threshold over time in early CPR.

Hypothesis:
Stable critical thresholds with high sensitivity or specificity for ROSC may be established in early CPR (<10 min) from non-invasive cerebral StO
2
and THC measurements initiated at CPR start.

Methods:
One-month-old swine (n=31) underwent 7 minutes of asphyxia, induction of ventricular fibrillation, and up to 20 minutes of CPR till ROSC or death (no ROSC). Absolute StO
2
and THC and absolute and relative change from 1 minute into CPR (time for chest molding and FD-DOS placement) were evaluated as ROSC predictors over time. For each variable, an ROC curve and two critical thresholds, maximizing specificity (=1) or sensitivity (=1), were determined at 1-min intervals from 2-10 minutes of CPR using univariate logistic regression. Optimal predictor was selected by highest mean AUC. A stable specificity or sensitivity threshold was feasible if the mean threshold had a specificity or sensitivity >0.9 over all intervals, respectively.

Results:
Absolute change in StO
2
(ΔStO
2
) had the highest mean (SD) AUC of 0.90 (0.07). Consistently >0.8, the AUC exceeded 0.9 after 7 minutes of CPR (
see
Fig.
). The mean specificity threshold (ΔStO
2
= +5.1%) and sensitivity threshold (ΔStO
2
= +1.4%) achieved an overall specificity of 0.93 and sensitivity of 0.98, respectively.

Conclusions:
Non-invasive monitoring of absolute change in StO
2
was most predictive of ROSC and stable critical thresholds with high specificity or sensitivity were established in early CPR. Future work will independently validate this promising tool for CPR optimization.
Abstract 351: Predictors of Neurological Outcome After Out-of-Hospital Cardiac Arrest With Ventricular Fibrillation Witnessed by Emergency Medical Service P.ersonnel., JCS-ReSS Study
Authors: Hashiba Katsutaka , Tahara Yoshio , Kimura Kazuo , Endo Tsutomu , Tamura Kouichi , Yonemoto Naohiro , Nonogi Hiroshi , Shimokawa Hiroaki , Nagao Ken
Published: July 2021

Background:
Effective advanced life support is one of the important link in the chain of survival. In Japan, the emergency medical service (EMS) personnel can perform defibrillation, advanced airway management, intravenous access and administration of epinephrine as an advanced life support intervention for the treatment of out-of-hospital cardiac arrest (OHCA). However, whether these interventions performed by EMS improves neurological outcomes remains unclear.

Objective:
To evaluate predictors of favorable neurological outcome in patients suffering OHCA with ventricular fibrillation (VF) witnessed by an EMS personnel.

Methods:
The Fire and Disaster Management Agency (FDMA) of Japan developed a nationwide database of a prospective population-based cohort using an Utstein-style template for OHCA patients since January 2005. To evaluate data after the publication of Guideline2010, data from January 2011 to December 2015 of this database was used for the current analysis. A multivariate logistic-regression analysis was performed to assess factors associated with favorable neurological outcome (defined as Cerebral Performance Category 1 or 2) 1 month after cardiac arrest.

Results:
Of the 629,471 patients documented for the study period, 2,301 adult patients with an OHCA of cardiac origin and VF for the initial rhythm witnessed by an EMS personnel were included in the present analysis. The overall mortality was 49.6%. Rate of return of spontaneous circulation and favorable neurological outcome were 53.4% and 44.8%, respectively. High age (OR0.387, 95%CI0.316-0.472, p<0.001), delayed defibrillation (OR0.598, 95%CI0.493-0.723, p<0.001), advanced airway management (OR0.305, 95%CI0.223-0.413, p<0.001), administration of epinephrine (OR0.356, 95%CI0.213-0.585, p<0.001) and multiple attempts of defibrillation (OR0.484, 95%CI0.402-0.582, p<0.001) were negatively associated with favorable neurological outcome.

Conclusion:
In patients with VF witnessed by EMS personnel, resuscitation efforts should simply focus on early defibrillation and CPR without advanced interventions.
Abstract 353: Performance of SOFA Score to Predict Mortality at Hospital Discharge After Cardiac Arrest
Authors: Grossestreuer Anne V , Yankama Tuyen , Moskowitz Ari , Mahoney-Pacheco Anthony , Konanki Varun , Leith Thomas , Patel Parth V , Berg Katherine M , Holmberg Mathias J , Donnino Michael W
Published: July 2021

Introduction:
Cardiac arrest (CA) outcomes, when dichotomized as survival/non-survival, limit statistical power of interventional studies and do not acknowledge hospital-level factors independent of post-CA sequelae. We explored the Sequential Organ Failure Assessment (SOFA) score at 72 hours post-CA as a surrogate outcome measure for mortality. We also assessed methods to account for death <72 hours post-CA in SOFA score computation.

Methods:
This was a single center retrospective study of post-CA patients from 1/08-12/17. SOFA score components were abstracted at baseline, 24, 48, and 72h post-CA. Thirteen ways of accounting for missing data were assessed. The outcome was mortality at hospital discharge. Model performance was assessed using area under the receiver-operator characteristic (AUC) curves and Hosmer-Lemeshow goodness of fit statistics.

Results:
Of 847 patients, 528 (62%) had complete baseline SOFA scores and 205 (24%) had complete scores at 72h. Death <72h occurred in 28%; 45% survived to hospital discharge. SOFA score at 72h without accounting for death had an AUC of 0.62. The best performing SOFA model at 72h with good calibration imputed a 20% increase over the last observed SOFA score in patients who expired <72h with an AUC of 0.79 (95% CI: 0.74-0.83). In terms of change in SOFA at 72h from baseline, the best performing model with good calibration imputed death <72h as the highest possible score (AUC: 0.88 [95% CI: 0.84-0.92]). These results were consistent when analyzing in- and out-of-hospital CA separately, although the change from baseline model was not well calibrated in in-hospital arrests.

Conclusions:
Without consideration of death, SOFA scores at 72 hours post-CA perform poorly. Imputing for early mortality improved the model. If this imputation structure is validated prospectively, SOFA could provide a scoring system to predict death at hospital discharge and serve as a surrogate outcome measure in interventional studies.
Abstract 354: A Prediction Model for Patients With Emergency Medical Technicians Witnessed Out-of-Hospital Cardiac Arrest
Authors: Hsieh Ming-Ju , Chiang Wen-Chu , Chang Wei-Tien , Yang Chih-Wei , Chien Yu-Chun , Wang Yao-Cheng , Ma Matthew Huei-Ming
Published: July 2021

Introduction:
In-hospital early warning system scores for prediction of clinical deterioration have been well-developed. However, such prediction tools in prehospital setting remain unavailable.

Hypothesis:
To develop a model for predicting patients with emergency medical technicians witnessed out-of-hospital cardiac arrest (EMT-witnessed OHCA) .

Methods:
We used the fire-based emergency medical service (EMS) data from Taipei city to develop the prediction model. Patients included in this study were those initially alive, non-traumatic, and aged ≧20 years. Data were extracted from records of ambulance run sheets and OHCA registry in Taipei. The primary outcome (i.e. EMT-witnessed OHCA) was defined as cardiac arrest occurring during EMT services before arrival at the receiving hospital. The prediction model was developed through the standard cross-validation method (i.e. divided dataset for training group and validation group). Area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow (HL) test were used to test discrimination and calibration. The point value system with Youden’s J Index was used to find the best cut-off value for practical application.

Results:
From 2011 to 2015, a total of 252,771 patients were included. Of them, 660 (0.26%) were EMT-witnessed OHCA. The prediction model, including gender, respiratory rate, heart rate, systolic blood pressure, level of consciousness and oxygen saturation, showed excellent discrimination (AUC 0.94) and calibration (
p
=0.42 for HL test). When applied to the validation dataset, it maintained good discriminatory ability (AUC 0.94) and calibration (
p
=0.11). The optimal cut-off value (≧13) of the point value system of the tool showed high sensitivity (87.84%) and specificity (86.20%).

Conclusions:
The newly developed prediction model will help identify high-risk patients with EMT-witnessed OHCA and indicate potential prevention by situation awareness in EMS.
Abstract P190: Do We Combine the Data for Analysis from VENUS and MARS? The Time Has Come for Consistent Sex-Based Analysis of Health Outcome Data
Authors: Norris Colleen M , Schopflocher Donald , Hardwicke-Brown Emeleigh , Galbraith P D , Knudtson Merril L , Ghali William A ,   APPROACH Investigators
Published: July 2021

Background
Previous investigations by our group have consistently identified important sex differences in HRQOL outcomes of patients with CAD with women reporting poorer HRQOL compared with men. The purpose of this study was to extend our previous work to determine whether sex differences and/or associations in bivariate analyses may provide insight in the modeling of health outcomes data.

Method
A descriptive analysis of the variables was performed. Sex differences on all variables were examined using
t
test and Chi-square analyses. The relationships between all clinical, demographic, socio-demographic and HRQOL outcome variables were examined stratified by sex.

Results
7062, 1- year HRQOL questionnaires were collected on patients catheterized between Jan 2006 and Dec 2009. 20.8% (1468 of 7062) were from women. Statistically significant sex differences were noted in 10/23 clinical and all 8 of the sociodemographic variables measured. A critical sex difference in the nature of the relationship between depression scores and age was identified. Whereas a quadratic relationship was seen in the men's group, the relationship in the women's group was cubic (figure 1). This implies that analyzing data by including sex, age, and depression scores in the same model will in essence sacrifice the unique nature of the relationship for at least one sex.

Conclusions
Our data suggests that
sex-based analyses
should be conducted particularly when modeling predictors of HRQOL outcome. Failing to do so may result in misleading conclusions that will miss opportunities to intervene early in clinically treatable circumstances and to improve the outcomes of men and women with CAD.
Abstract 328: The Importance of Using of Single Aortic Cross Clamp Technique to Reduce Brain Injury After Coronary Artery Bypass Grafting
Authors: Likosky Donald S , Dacey Lawrence J , Leavitt Bruce J , Sardella Gerald L , Helm Robert E , Russo Louis , Hernandez Felix , Kramer Robert S , Groom Robert C , Pieroni John , Baribeau Yvon R , Malenka David J , Ross Cathy S ,   The Northern New England Cardiovascular Disease Study Group
Published: July 2021

Introduction:
Brain injury is a common yet devastating complication of cardiac surgery. Several intra-operative practices have been identified that may reduce emboli and the systemic inflammatory response, two mediators of brain injury.

Hypothesis:
Practices which reduce emboli and the systemic inflammatory response will reduce brain injury

Methods:
We enrolled 3,994 patients undergoing coronary artery bypass grafting with or without valve surgery at eight medical centers in northern New England between 2008-2011. All procedures were performed with cardiopulmonary bypass. We studied the effect of intra-operative practices that may reduce mediators of brain injury, including: the use of: tip-to-tip coated circuits, echocardiography (transesophageal or epi-aortic), or the use of a single aortic cross-clamp. Brain injury was defined as the presence of stupor, coma, transient ischemic attack or stroke (defined as any focal neurologic deficit persisting post-operatively for more than 24 hours).

Results:
Brain injury was present in 7.4% (293/3994) of the patients. Adoption of practices varied, with 19.4% (765/3994) of patients receiving 1 practice, 26.0% (1024/3994) receiving 2 practices, and 34.4% (1356/3994) receiving 3 practices. Breakdown across individual practices were: 60.0% (2368/4014) coated circuits, 76.5% echocardiography (3015/4014), and 38.0% single clamp (1498/4104). Once adjusting for patient and disease characteristics and center, adoption of strategies was associated with a 15% reduced odds of brain injury (OR 0.85, ptrend 0.01). Use of a single clamp was associated with the greatest reduction in brain injury (Adj OR 0.63, p=0.02).

Conclusion:
While the use of any of three intra-operative practices were protective of brain injury, the use of a single clamp technique was associated with a nearly 40% reduced odds of brain injury after cardiac surgery. This analysis further confirms the benefit of a single aortic clamp approach for reducing neurologic injury.
Abstract 168: The Impact of Prehospital Care on STEMI Time to Treat
Authors: Langabeer James R , Henry Timothy D , DelliFraine Jami L , Segrest Wendy ,   Dallas Caruth AHA Advisory Board
Published: July 2021

In emergency cardiovascular care, delays often equate to poor patient outcomes. In patients experiencing ST-elevation myocardial infarction (STEMI), reducing systemic delays and receiving definitive treatment is a key goal of regionalized systems of care. Prehospital emergency care has been suggested to have an impact on improving STEMI patient outcomes, but little prior evidence exists in large suburban settings to establish relationships between EMS and hospital outcomes. In this study, we analyzed the entire population of non-transfer STEMI patients that underwent primary percutaneous coronary intervention (PCI) in Dallas County Texas from October 1, 2010 through December 31, 2011. Emergency medical services data from 24 agencies and 15 receiving hospitals collected and shared common, de-identified patient data. To control for confounding factors, we developed a robust generalized linear regression and relied on estimated marginal means analyses to assess the impact of EMS transport (versus self-transport) on hospital door to balloon (D2B) and total treatment time, defined as symptom onset to arterial reperfusion, or SOAR.

In our analyses, there were statistically 11.1 minute reductions in median D2B (and 64.5 minute median reductions in SOAR (both with p<.001) treatment times when EMS transported to the receiving facility compared to self-transport or walk-in. More importantly, when EMS field activated the cardiac catheterization laboratory based on agreed upon processes and protocols, D2B times were reduced by 38% (or 43 minutes) after controlling for confounding variables, and field activation was associated with a 21.9% reduction (73 minutes) in the mean SOAR time (both with p<.001). We found no significant relation with mortality or length of stay.

Based on these findings, we recommend regional quality improvement teams develop strategies for engaging EMS in STEMI treatment, to reduce both systemic delays and total coronary reperfusion times.
Abstract 101: A Learning Collaborative Model to Improve Door to Needle Time for Stroke Thrombolysis in Chicago
Authors: Prabhakaran Shyam , O’Neill Kathleen ,   Chicago Primary Stroke Cntrs
Published: July 2021

Background:
Door-to-needle (DTN) times have remained suboptimal despite overall increases in tissue plasminogen activator use (tPA) for stroke in Chicago. The American Heart Association’s (AHA) Quality Enhancement for Speedy Thrombolysis in Stroke (QUESTS) initiative aimed to identify barriers to reduce DTN times at Chicago’s 15 primary stroke centers (PSCs) and increase the proportion of patients treated with tPA within 60 minutes of hospital arrival.

Methods:
Starting in January 2013, we used face-to-face and on-site meetings with each PSC’s stroke team members to share AHA Target Stroke best practices and strategies to reduce DTN time. A survey of current practice was completed at each site to determine opportunities for improvement and repeated at 1 year to assess implementation of new strategies. We used the Get With The Guidelines (GWTG) Stroke registry to aggregate baseline data DTN times and track performance in each quarter of 2013.

Results:
At baseline, 5 strategies were notably under-utilized at Chicago’s 15 PSCs: 1) Direct to CT scanner (baseline: 0 sites; 1 year: 5 sites); 2) pre-mixing tPA (baseline: 1 site; 1 year: 14 sites); 3) tPA prior to laboratory results (baseline: 3 sites; 1 year: 7 sites); 4) stroke code activation at triage (baseline: 4 sites; 1 year: 13 sites); and 5) streamlined consent process (baseline: 0 sites; 1 year: 12 sites. The proportion of patients treated within 60 minutes increased in each quarter of 2013 from 25% in quarter 1 to 60% in quarter 4 (p<0.01). The median DTN time decreased from 89.5 minutes in quarter 1 to 55 minutes in quarter 4 (p<0.01).

Conclusions:
Using a learning collaborative model to implement strategies to reduce DTN times among 15 PSCs in Chicago, we observed major improvements within a few months. Regional collaboration and best practices sharing should be a model for rapid and sustainable system-wide quality improvement.
Maximizing Ventricular Function With Multimodal Cell-Based Gene Therapy
Authors: Yau Terrence M. , Kim Christopher , Li Guangming , Zhang Yaoguang , Weisel Richard D. , Li Ren-Ke
Published: July 2021

Background—

Angiogenesis is enhanced after transplantation of vascular endothelial growth factor (VEGF)-expressing cells into a myocardial scar. Insulin-like growth factor I (IGF-I) may induce hypertrophy and inhibit apoptosis. We evaluated the effect of cell-based IGF-I and VEGF multigene therapy on left ventricular (LV) function, cell survival, and apoptosis after bone marrow cell (BMC) transplantation.

Methods and Results—

Female Lewis rats underwent left anterior descending ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), IGF-I (BMC+IGF-I), VEGF and IGF-I (BMC+VEGF+IGF-I), or medium without cells (control) (n=4 per group×5 groups×4 time points). Three days and 1, 2, and 4 weeks after transplantation, VEGF and IGF-I expression was quantitated by real-time polymerase chain reaction, cell survival by polymerase chain reaction for sry2, apoptosis by TUNEL staining, LV function by echocardiography and myosin heavy chain, and light chain and troponin I by Western blot. One week after transplantation, IGF-I expression in the scar and border zone was greatest in BMC+IGF-I and BMC+VEGF+IGF-I rats (
P
<0.05). VEGF expression in the scar and border zone was greatest in BMC+VEGF and BMC+VEGF+IGF-I hearts (
P
<0.05). Transplanted cell survival was lowest in BMC, intermediate in BMC+VEGF and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (
P
<0.05). Apoptotic indices were significantly reduced in BMC+VEGF+IGF-I, BMC+VEGF, and BMC+IGF-I (
P
<0.05). Two and 4 weeks after transplantation, LV ejection fraction was lowest in control, intermediate in BMC, BMC+VEGF, and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I (
P
<0.05).

Conclusions—

Transplantation of VEGF- and IGF-I-expressing BMC reduced apoptosis, maximized transplanted cell survival, and enhanced LV function. Multimodal cell-based gene therapy may maximize the benefits of cell transplantation.
Ross Procedure and Left Ventricular Mass Regression
Authors: Duebener Lennart F. , Stierle Ulrich , Erasmi Armin , Bechtel Matthias F. , Zurakowski David , Böhm Jürgen O. , Botha Cornelius A. , Hemmer Wolfgang , Rein Joachim-Gerd , Sievers Hans-H.
Published: July 2021

Background—

Return of left ventricular mass to normal is considered to be a favorable result of aortic valve replacement. The Ross procedure provides near normal hemodynamics and thus allows studies of left ventricular (LV) reverse remodeling. LV mass regression may be influenced by surgical technique (subcoronary [SC] versus root replacement [RR]).

Methods and Results—

Data from the German Ross Registry were analyzed. A total of 646 patients (mean age: 43.6±12.7 years, range: 16 to 71 years; SC technique n=295, RR technique n=351) underwent a Ross procedure in 7 participating centers from 1990 to 2004. The patients underwent preoperative and postoperative echocardiographic evaluations. Mean follow-up time was 3.5±2.5 years (range 0.12 to 13.7 years). Follow-up completeness was 97%. The LV mass index (LVMI) decreased significantly during follow-up in both groups (SC: 209±53 preoperatively to 154±48 at 1-year follow-up, [
P
<0.01 versus preoperative values] to 149±51g/m
2
at 2-year follow-up, [
P
=NS 1-year versus 2-year follow-up] versus RR: from 195±56 preoperatively to 144±51 at 1-year follow-up [
P
<0.01 versus preoperative values] to 140±49g/m
2
[
P
=NS 1-year versus 2-year follow-up]). LVMI regression remained stagnant 1 year after the Ross procedure in most patients in both groups. On the basis of multivariate analysis, predictors for incomplete LVMI regression after the autograft procedure were high preoperative LVMI, smoking, and uncontrolled diastolic hypertension.

Conclusions—

At mid-term echocardiographic follow-up, patients of both groups had favorable autograft hemodynamics. Risk factors for incomplete postoperative LVMI regression in our study were smoking and persistent diastolic hypertension. This emphasizes the importance of cessation of smoking and treatment of arterial hypertension, even in younger patients, after corrected aortic valve disease.
Gene Transfer of a Broad Spectrum CC-Chemokine Inhibitor Reduces Vein Graft Atherosclerosis in Apolipoprotein E–Knockout Mice
Authors: Ali Ziad A. , Bursill Christina A. , Hu Yanhua , Choudhury Robin P. , Xu Qingbo , Greaves David R. , Channon Keith M.
Published: July 2021

Background—

Accelerated atherosclerosis is a major cause of vein graft failure after bypass surgery. Several CC-chemokines (CC-CKs) mediate monocyte/macrophage recruitment in native atherosclerotic plaques; we hypothesized that CC-CKs may be critical in the development of accelerated atherosclerosis in vein grafts.

Methods and Results—

Using in vivo gene transfer, we administered a soluble CC-CK binding protein (“35K”) to apolipoprotein E–knockout (ApoE−/−) mice that underwent interposition bypass grafting of the vena cava from isogenic donor mice to the common carotid artery. Two days before operation, a recombinant adenovirus encoding either 35K (Ad35K) or green fluorescent protein (AdGFP; control) was injected into recipient mice via the tail vein. 35K greatly reduced CC-CK activity in mouse plasma. After 14 days, vein graft atherosclerotic lesion area, smooth muscle α-actin–positive neointimal area, and total vessel wall thickness were strikingly reduced by Ad35K gene transfer compared with AdGFP controls. Furthermore, 35K gene transfer dramatically reduced macrophage content by ≈90% and cell proliferation by 95%. After 28 days, lesion area and vessel wall thickness remained significantly less in Ad35K mice.

Conclusion—

A single intravenous injection of the CC-CK inhibitor 35K significantly reduced atherosclerosis in carotid–caval vein grafts in ApoE−/− mice. This study highlights the importance of the CC-CK class in accelerated atherosclerosis, and its role as a potential target for improving vein graft patency.
Gene Profiling Changes in Cytoskeletal Proteins During Clinical Recovery After Left Ventricular–Assist Device Support
Authors: Birks Emma J. , Hall Jennifer L. , Barton Paul J.R. , Grindle Suzanne , Latif Najma , Hardy James P. , Rider James E. , Banner Nicholas R. , Khaghani Asghar , Miller Leslie W. , Yacoub Magdi H.
Published: July 2021

Background—

After left ventricular–assist device (LVAD) support, a proportion of patients recover sufficient ventricular function to enable explantation of the device. The exact molecular mechanisms involved in myocardial recovery remain unknown. Cytoskeletal proteins are essential for the structure and function of the cardiac myocyte and might play a major role.

Methods and Results—

A total of 15 patients with nonischemic cardiomyopathy who required LVAD implantation were studied; 6 recovered sufficiently to allow explantation of the device compared with 9 who did not recover and required transplantation. LV myocardial samples were collected at implantation and explantation/transplantation. Affymetrix microarray analysis was performed on the paired samples and analyzed with reference to sarcomeric and nonsarcomeric cytoskeletal proteins. In the recovery group, of the nonsarcomeric proteins, lamin A/C increased 1.5-fold (
P
<0.05) and spectrin 1.6-fold (
P
<0.05) between the times of implantation and explantation. Integrins β1, β6, and α7 decreased 1.7-fold (P<0.05), 2.4-fold (P<0.05), and 1.5-fold (P<0.05), respectively, but integrins α5 and β5 increased 2.3-fold (P<0.01) and 1.2-fold (
P
<0.01) at explantation. The following sarcomeric proteins changed in the recovered group only: β-actin increased 1.4-fold (
P
<0.05); α-tropomyosin, 1.3-fold (
P
<0.05); α1-actinin, 1.8-fold (
P
<0.01); and α-filamin A, 1.6-fold (
P
<0.05). Both troponin T3 and
α
2-actinin decreased by 1.6-fold at the time of explantation (
P
<0.05). Vinculin decreased 1.7-fold (
P
=0.001) in the recovered group but increased by 1.7-fold (
P
<0.05) in the nonrecovered group. Vinculin protein levels decreased 4.1-fold in the recovered group.

Conclusions—

Myocardial recovery was associated with a specific pattern of changes in sarcomeric, nonsarcomeric, and membrane-associated proteins, which could have important implications in understanding the mechanisms involved.
Importance of Geometry and Refractory Period in Sustaining Atrial Fibrillation
Authors: Byrd Gregory D. , Prasad Sandip M. , Ripplinger Crystal M. , Cassilly T. Ryan , Schuessler Richard B. , Boineau John P. , Damiano Ralph J.
Published: July 2021

Background—

The critical mass hypothesis for atrial fibrillation (AF) was proposed in 1914. There has never been a systematic investigation defining the relationship between tissue geometry and AF. The purpose of this study was to determine the association among the probability of maintaining AF and the width, area, weight, effective refractory period (ERP), and wavelength in atrial tissue.

Methods and Results—

Isolated canine atria (n=20) were perfused with Krebs-Henseleit solution. Baseline ERPs were obtained with and without acetylcholine (10E-3.5 mol/L) using single extra-stimulus pacing while unipolar electrograms were recorded from 250 sites. The tissue was then partitioned using bipolar radiofrequency ablation, and the ERPs were measured again with and without acetylcholine. Any section of tissue that maintained AF was divided until the arrhythmia was no longer inducible. ERPs and conduction velocities were measured in all of the sections after each ablation, and the wavelengths were calculated. The probability of AF was found to be correlated with increasing tissue areas, widths, and weights (
P
<0.001). The probability of AF was significantly associated with the length of the ERP and the wavelength (
P
<0.001). With shorter ERPs and shorter wavelengths, there was an increased probability of sustained AF.

Conclusions—

The probability of sustained AF was significantly associated with increasing tissue area, width, and weight and decreasing ERPs and wavelengths. These data may lead to a better understanding of the mechanism of AF and, thus, help to design more-effective interventional procedures in the future.
Nitric Oxide Modulation of Supraoptic Oxytocin and Vasopressin Neurons Involves Potentiation of Gabaergic Synaptic Inputs.
Authors: Stern Javier E , Ludwig Mike
Published: July 2021

P41

There is growing evidence that nitric oxide (NO) in the central nervous system functions as a local neuromodulator in water balance and osmotic regulation. However, the precise mechanisms by which these actions are mediated are still poorly understood. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in the supraoptic (SON) and paraventricular (PVN) nuclei. nNOS expression is up-regulated in conditions known to stimulate oxytocin (OT) and vasopressin (VP) hormone release, such as salt loading and water deprivation. Since several studies have shown that NO mainly decreases the excitability of OT and VP neurons, NO may function as a local inhibitory feedback on activated SON neurons. In the present study we combined in vivo and in vitro electrophysiological studies to investigate whether NO-induced inhibition of SON neurons is mediated by activation of GABAergic inputs in the SON. In vivo retrodialysis of the NO-donor SNP into the SON inhibited the firing activity of both OT and VP neurons. This inhibition was largely blocked by retrodialysis of the GABA
A
receptor antagonist bicuculline. In order to understand the cellular mechanisms linking NO and GABAergic systems in the SON, in vitro patch clamp recordings of GABA
A
synaptic currents were obtained from immunochemically identified neurons in hypothalamic slices. The frequency and amplitude of miniature GABA
A
synaptic currents in both OT and VP neurons were significantly increased by SNP. These results suggest that NO inhibition of neuronal excitability of OT and VP neurons is largely mediated by pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON. Thus, the proposed NO-GABAergic inhibitory feedback in the SON might constitute an important mechanism by which NO regulates osmotic and fluid balance homeostasis.
Abstract 403: Autonomic Blockade Improves “Endothelial Dysfunction” in Obesity-Associated Hypertensive Human Subjects
Authors: Gamboa Alfredo , Figueroa Rocio A , Okamoto Luis E , Diedrich Andre , Biaggioni Italo
Published: July 2021

Nitric oxide (NO) deficiency (“endothelial dysfunction”) is a hallmark of obesity and is thought to contribute to hypertension. In a previous study, however, we did not find differences in NO function between hypertensive and normotensive subjects if autonomic activity was removed with ganglionic blockade. We hypothesized, therefore, that sympathetic activation, known to occur in obesity hypertension, contributes to NO mediated endothelial dysfunction. To test this hypothesis we determined NO-mediated vasodilation (increase in forearm blood flow, FBF, to intrabrachial acetylcholine, ACh) and endothelial independent vasodilation (intrabrachial sodium nitroprusside, SNP) in obese hypertensive subjects (30<BMI<40 kg/m2) during intact and during autonomic blockade (trimethaphan 4 mg/min IV infusion). Seven obese subjects (49±3.6 years, 34±1 kg/m2, 165/94 ± 7/6 mm Hg) were studied on two separate occasions, one month apart, randomly assigned. As anticipated, autonomic blockade increased basal FBF (from 3.9±0.7 to 5.2±1.2 ml/100mL/min, p=0.078). As expected, NO-mediated vasodilation was blunted on the intact day: FBF increased from 3.6±0.6 to 10.1±1.1 with SNP, but only from 3.7±0.4 to 7.2±0.8 ml/100mL/min with ACh, p=0.047. In contrast, during autonomic blockade, FBF responses to SNP and ACh were similar (from 5.2±0.9 to 12.5±0.9 and from 6.2±1.1 to 11.4±1.6 ml/100mL/min, respectively, p= 0.578, figure). Our results support the concept that sympathetic activation contributes to the impairment in NO-mediated vasodilation seen in obesity hypertension, and provides further rationale to explore it as a therapeutic target.
Abstract 072: Newly Developed Personal Device can Detect Changes and Variations of Urinary Na/K Ratio with Standardized Low- and High-salt Meals in Healthy Volunteers
Authors: Yatabe Junichi , Yatabe Midori S , Takano Kozue , Watanabe Ami , Kurosawa Satsuki , Yonemoto Mizuho , Nochi Momoko , Ikeda Yuri , Iwahori Toshiyuki , Shiga Toshikazu , Watanabe Tsuyoshi , Kimura Junko
Published: July 2021

Background:
A low-sodium (Na), high-potassium (K) diet is recommended to suppress blood pressure elevation, but determining the absolute amounts of Na and K in a diet is difficult. A novel portable device was developed to allow easy measurement of urinary Na/K ratio on the spot. In this study, our aims were 1): to observe the changes of urinary Na/K ratio in subjects on low- and high-Na diet and 2): to determine if there are differences in urinary Na/K ratio between subjects with and without salt sensitivity.

Methods:
Healthy volunteers (14 subjects) ingested standardized low- (3 g NaCl /day) and high-Na (20 g NaCl/day) meals for 7 days each. Urinary Na/K ratio was measured at each voiding using a prototype device (Omron Healthcare). Collection of blood and 24-hour urine was conducted at the end of each diet period (unrestricted (NS), low-salt (LS), and high-salt (HS)). Those with mean blood pressure difference (LS vs. HS) ≥ 5% were determined as salt-sensitive (SS) and others salt-resistant (SR).

Results:
Urinary Na/K ratio reached a plateau approximately 3 days after each change in the Na level of the diet. Urinary Na/K ratio of spot urine correlated well with Na/K ratio of 24-hour urine. Average urinary Na/K ratio was 3.9 ± 1.9 on the last day of NS, 0.8 ± 0.3 on LS, and 6.9 ± 2.1 on HS. The variation of urinary Na/K ratio was small during the LS diet period. The change in urinary Na/K ratio of SS group tended to be slower than that of SR. This device may also be useful in diabetic and proteinuric patients as Na/K ratio was affected minimally by experimental glucose and protein addition.

Conclusion:
Using an easy-to-use device, measurements of urinary Na/K ratio keenly reflected the sodium level of the diet.
Abstract P633: Low Serum Vitamin D is Associated with Greater Impairment in Autonomic Function upon Head Up Tilt in Children with Orthostatic Intolerance
Authors: Shaltout Hossam A , Glock Michael S
Published: July 2021

In previous work we identified a group of children (n = 48) between the ages of 10-18 years whose diagnostic workup for chronic nausea unexplained by conventional diagnostic tests revealed that 60% had underlying cardiovascular instability (n = 30) presenting as orthostatic intolerance (OI). The OI could be sub-classified based on head up tilt (HUT) testing into three groups: Postural Orthostatic Tachycardia Syndrome (POTS), orthostatic hypotension (OH) and syncope. Children with OI in all three groups had a greater reduction in autonomic control upon HUT manifested as greater loss of baroreflex sensitivity (BRS) and heart rate variability (HRV) and higher norepinephrine levels compared to those in the non OI group. Vitamin D deficiency is associated with impaired vascular responses to vasoconstrictors and alterations in autonomic control mechanisms in adults. In this study we sought to determine if vitamin D level is lower in these pediatric OI subjects and if it correlates with the hemodynamic responses to tilt. Serum 25(OH)D tended to be lower in OI vs non OI (18.6 ± 0.7 ng/ml, n = 25, vs 22.2 ± 2.4 ng/ml, n = 15; p = 0.16). Most importantly 25(OH)D showed a high positive correlation with supine measures of BRS (seq ALL, R = 0.51, p = 0.05), HRV (rMSSD, R = 0.44, p = 0.02) only in the OI group and there was a trend for a negative correlation with sympathovagal balance ( LF/HF ratio: R =-0.35, p = 0.08). Low 25(OH)D correlated with greater loss of both BRS (R = 0.51, p = 0.01) and HRV (R = 0.44, p = 0.05) upon HUT. These findings support the concept that low vitamin D may contribute to impaired responses to tilt in OI subjects. Further work is needed to evaluate if vitamin D supplementation will improve the vascular and hemodynamic responses to tilt and help improve the OI symptoms. Our goal is to provide a safer therapeutic alternative for the treatment of OI in children.
Abstract 122: 20-HETE Antagonists Normalize Large Artery Stiffness and Systolic Blood Pressure in Metabolic Syndrome
Authors: Soler Amanda A , Hunter Ian , Joseph Gregory , Hutcheson Rebecca , Hutcheson Brenda , Yang Jenny , Zhang Frank F , Joshi Sachindra R , Bradford Chastity , Gotlinger Katherine H , Maniyar Rachana , Falck John R , Proctor Spencer , Schwartzman Michal L , Gupte Sachin A , Rocic Petra
Published: July 2021

Large artery stiffness is a causal factor in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome CYP450-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and in obesity in humans, but the role of 20-HETE in regulation of large artery remodeling in metabolic syndrome has not been investigated. Unlike normal (Sprague-Dawley (SD)) rats, large arteries (aorta, carotid and >100μM mesenteric arteries) of metabolic syndrome rats (JCR:LA-cp, JCR) express CYP4A and 4F, CYP450s which make 20-HETE in rats (2-fold increase vs. SD). Consequently, 20-HETE production is elevated in large arteries of JCR rats. We hypothesized that this elevated 20-HETE increases matrix metalloproteinase 12 (MMP12, an elastase) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. A 3-4 fold increase in 20-HETE production in large arteries of JCR vs. SD rats correlated with increased elastin degradation (3-6 fold) and increased arterial stiffness (~75%). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. Importantly, 20-HETE antagonists and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly decreased (~60% vs. untreated JCR) large artery stiffness in JCR rats. 20-HETE antagonists also decreased systolic (182±3 mmHg JCR, 145±3 mmHg JCR+20-HETE antagonists) but not diastolic (125±4 mmHg JCR, 124±4 mmHg JCR+20-HETE antagonists) blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II-dependent, and large artery stiffness in JCR rats was Ang II-independent. These results suggest that 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high CYP4A/4F expression and resultant high 20-HETE production in large conduit arterial stiffness, which is a primary determinant of systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.
Abstract P321: Clozapine-induced Hypertension: Role of the Dopamine Type 4 Receptor (D4R) in Human Renal Proximal Tubule Cells (RPTC)
Authors: Xu Peng , Kelly Dianna L , Kitchen Christopher , Gildea John J , Schiermeyer Katie A , Jose Pedro A , Norman Sarah M , McMahon Robert P , Wang Z , Felder Robin
Published: July 2021

Clozapine (CLZ), a potent D
4
R antagonist that is an effective antipsychotic drug for the treatment of schizophrenia, is associated with hypertension. The hypertensive side effect of CLZ may be through inhibition of the D
4
R because germline deletion of D
4
R in mice causes hypertension. The hypertension caused by germline deletion of D
4
R may, in part, be due to increased renal expression of the angiotensin type 1 receptor (AT
1
R) and renal expression of sodium exchangers, transporters, and pumps, e.g., NHE3, NKCC2, NCC, and Na
+
K
+
/ATPase, α subunit. CLZ administered subcutaneously (20mg/kg/day/x3 days, n=5) in mice induced hypertension, shifted the pressure-natriuresis plot to the right, and increased the renal expressions of NCC and Na
+
K
+
/ATPase, α subunit, relative to vehicle-treated mice (n=5). Activation of D
4
R decreased AT
1
R expression and Na
+
K
+
/ATPase activity in rat renal proximal tubule cells (RPTCs). Therefore, we studied two groups: subjects 18 to 75 years old with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder treated with CLZ for >2 months (CLZ, N=32) and untreated healthy controls (
HC
, N=20) without psychiatric illness. There were no significant differences in blood pressure (BP) between the two groups since more than half of the CLZ participants received antihypertensive medication. We studied RPTCs cultured from the participant’s urine (CLZ, N=18;
HC,
N=9) and treated those cells with 100 nM CLZ. CLZ decreased D
4
R expression in both
HC
and CLZ groups (
HC
, VEH 1.04±0.17 vs CLZ 0.73±0.09, n=9, paired t-test, P<0.05; CLZ, VEH 1.02±0.09 vs CLZ 0.75±0.06, n=16, paired t-test, P<0.01). CLZ also increased reactive oxygen species (Rosstar550 assay) in the
HC
but not CLZ-treated group (
HC
, VEH 0.92±0.07 vs CLZ 1.02±0.09, n=8,
paired
t-test
, P<0.05; CLZ VEH 1.09±0.18 vs CLZ 1.07±0.18, n=14). The density of plasma membrane AT
1
R tended to be higher in CLZ-treated hypertensive (CLX HP) than the CLZ-treated normotensive participants (CLZ NP): (
HC
, 0.28±0.08 n=8; CLZ NP, 0.10±0.02 n=4; CLZ HP, 0.81±0.31 n=7). Thus, CLZ may induce hypertension through a D
4
R/AT
1
R-mediated mechanism similar to that reported in D
4
R knockout mice. Additional studies will determine if CLZ increases sodium transport in human RPTCs.