bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13443: Function Follows Form: Shape and Substrate Stiffness Drive Maturity in Human Cardiomyocytes Differentiated From Pluripotent Stem Cells
Authors: Ribeiro Alexandre , Ang Yen-Sin , Fu Jidong , Rivas Renee , Srivastava Deepak , Pruitt Beth L
Published: July 2021

Introduction:
Heart function relies on the contractility of its muscle cells (cardiomyocytes). Human pluripotent stem cells (hPSC) can be differentiated into cardiomyocytes (hPSC-CMs). However, while their myogenic maturity increases with time, they do not resemble adult cardiomyocytes in their morphology, structural organization, mechanical output and electrophysiology. The low maturity of hPSC-CMs limits their potential to model, study and treat heart diseases.

Hypothesis:
Since the organization of sarcomeres regulates the mechanical output of cardiomyocytes, we hypothesized that enhanced sarcomere maturity correlates with the mechanical output of these cells and the physiology of matured cardiomyocytes.

Methods:
We cultured single hPSC-CMs on 2000 μm2 rectangular protein patterns on polyacrylamide substrates with a modulus of 10 kPa to resemble the morphology of ventricular cardiomyocytes and match healthy adult ventricular stiffness. We infected seeded cells with rAV CAG-LifeAct-Tag RFP to label actin and image sarcomeres in contracting live cells. We estimated forces generated during single-cell contractile events with traction force microscopy and calculated power (force x cell shortening velocity). We varied cell elongation by changing the cell aspect ratio (1:1 to 7:1) and maintaining constant area. We used substrates having stiffness of 6 kPa (embryonic myocardium), 10 kPa (adult) and 35 kPa (infarcted myocardium).

Results:
Optimized power output was observed in cells with a 7:1 aspect ratio. The size, organization and dynamics of sarcomeres in these elongated hPSC-CMs are more mature. Optimized power output was observed in cells with a 7:1 aspect ratio. The power generated by hPSC-CMs on 35 kPa substrates was significantly reduced, while reduced variations in the power output across different aspect ratios was observed in 6 kPa. Forces generated by patterned hPSC-CMs were related to the organization, dynamics and size of sarcomeres. Electrophysiological parameters closer to that of mature cardiomyocytes were also observed with patch-clamp measurements in these hPSC-CMs with mature sarcomere organization.

Conclusions:
Stiffness and shape contribute to the structural and electrophysiological maturation of hPSC-CMs.
Abstract 13486: Risk Stratification of Ventricular Fibrillation in Brugada Syndrome Using Non-invasive Scoring Methods
Authors: Kawazoe Hiroshi , Nakano Yukiko , Tokuyama Takehito , Uchimura Yuko , Watanabe Yoshikazu , Sairaku Akinori , Matsumura Hiroya , Kishimoto Shinji , Tomomori Shunsuke , Kihara Yasuki
Published: July 2021

Aim:
Risk stratification of ventricular fibrillation (VF) in Brugada syndrome remains controversial and it is difficult to describe using one parameter. We investigated whether we are able to assess VF risk using our non-invasive scoring method of each Brugada syndrome patients.

Methods:
We enrolled 46 patients with Brugada syndrome (45 men, average age 42 ± 3 years). Thirteen of the subjects had VF history or subsequent VF events (VF+) after implantable cardioverter defibrillator implantation. The frequency of Type1 Brugada ECG and positive TWA were significantly higher in VF+ patients than those without (Type 1 ECG 50% vs 4.8%, P=0.0003 and positive TWA 73.3% vs 6.7%, P<0.0001). We allocated each one point to type 1 Brugada type ECG, family history of sudden cardiac death, history of syncope, positive late potential, and positive time domain T wave alternance as Brugada risk score and count up the score the points in an each subject. The area under the receiver-operator characteristic (ROC) curve for ≥3 points was 0.907 indicating that this Brugada risk score ≥3 points had a high degree of discrimination VF+ Brugada syndrome patients. The positive Brugada risk score was associated with VF history or events with a sensitivity of 85%, specificity of 88%, positive predictive value 73% and negative predictive value 93%.

Conclusions:
The new scoring method using previous reported non-invasive risk factors of VF in Brugada syndrome is useful for assessing risk stratification in daily medical practice.
Abstract 13508: Obesity Phenotype and the Risk of Hypertension and Type 2 Diabetes: Does Cardiorespiratory Fitness Matter?
Authors: Jae Sae Young , Carnethon Mercedes , Park Won Hah , Fernhall Bo
Published: July 2021

There is conflicting evidence regarding the association between metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUNW) with incident hypertension and type 2 diabetes. The role of cardiorespiratory fitness on these associations has not been fully explored. We tested the hypothesis that obesity phenotypes predict incident hypertension and type 2 diabetes, but cardiorespiratory fitness modifies these associations in a prospective study of apparently healthy men. 3800 men (mean age 48±6 yrs, range 20-76 yrs) participated in two health examinations during 1998-2009. All subjects were free of hypertension and type 2 diabetes at baseline examination. MHO was defined as obesity (body mass index ≥ 25 kg/m2) with no more than one metabolic abnormality, and MUNW was defined as body mass index < 23 kg/m2) with two or more abnormalities. Cardiorespiratory fitness was directly measured by peak oxygen uptake during a treadmill test. Incident hypertension and type 2 diabetes were defined as blood pressure ≥140/90mmHg and as ≥6.5% of HbA1c or ≥126mg/dl of fasting glucose at second examination, respectively. During an average follow-up of 5 years (1-12 yrs), there were 371 (9.8%) men incident hypertension and 170 (4.5%) men incident type 2 diabetes. MHO and MUNW were present in 844 (22%) and 249 (6.6%) men. Compared with metabolically healthy normal weight men, MHO and MUNW men were at increased risk for hypertension (relative risk (RR) =1.82, 95% Confidence Interval (CI): 1.29-2.56 and 1.75, 1.11-2.74) and type 2 diabetes (RR=3.68, 1.92-7.07 and 5.35, 2.61-10.94), respectively. These risks in MHO and MUNW men were still persisted with adjustment for confounder variables and cardiorespiratory fitness (hypertension=1.57, 1.05-2.34 and 1.59, 1.01-2.51; type 2 diabetes=3.35, 1.63-6.89 and 4.76, 2.32-9.77). Metabolically healthy obese or metabolically unhealthy normal weight men were at increased risk of hypertension and type 2 diabetes compared with metabolically healthy normal weight men. However, these associations were not attenuated by cardiorespiratory fitness or other confounder factors.
Abstract 13531: Weight Gain after Smoking Cessation Doesn’t Matter
Authors: Tsuji Hisako , Shiojima Ichiro
Published: July 2021

Background:
Although smoking cessation reduces mortality, weight gain is concerned because it may weaken the benefit of quitting. All-cause mortality of quitters according to weight change after smoking cessation was compared to that of smokers.

Methods:
Among subjects who received annual health checkups from 1997 through 2013 in Moriguchi City, Osaka, Japan, 5,204 subjects were extracted who were smokers at the first time they received the checkup and had 3 consecutive annual checkups. Of those, smokers were defined who reported smoking at all 3 consecutive checkups. Quitters were defined who reported smoking at the first checkup but not smoking at the second and the third checkups of a 3 consecutive checkups. Smokers who reported not smoking and quitters who reported smoking at any checkups after the 3 consecutive checkups used for the definition were excluded. The oldest 3 consecutive checkups were used as clinical and follow-up data of smokers. The 3 consecutive checkups in which a subject met the criteria of quitters were used as clinical and follow-up data of quitters. Weight change was assessed between the first and the second checkups of the 3 consecutive checkups. According to weight change, quitters were divided into 3 groups; no weight gain (n=362), weight gain no more than 2 kg (n=458) and weight gain more than 2 kg (n=485). All-cause mortality of 3 groups was compared to smokers using multivariate proportional hazards regression analysis adjusted for age, sex, hypertension, diabetes and hyperlipidemia.

Results:
There were 2803 smokers and 1,305 quitters. Mean age was 54±15 years with 65% of men. There were 449 deaths during 9.7±4.7 years (median 9.8 years) follow-up. Mean weight was 59.9±11.0 kg and mean number of checkups the subjects received was 8.0±4.3 times. Compared to smokers, quitters of no weight gain group (relative risk (RR)=0.66, 95% confidence interval (CI)=0.47-0.93, p=0.0164), weight gain no more than 2 kg group (RR=0.51, 95%CI=0.36-0.71, p<0.0001), and weight gain more than 2 kg group (RR=0.74, 95%CI=0.55-0.99, p=0.0426) had significantly lower mortality.

Conclusions:
Quitters had significantly lower mortality than smokers regardless of weight change after smoking cessation.
Abstract 13597: The Association Between Tissue Morphology Assessed With Optical Coherence Tomography and Mid-term Results After Paclitaxel-coated Balloon Dilatation
Authors: Tada Takeshi , Kadota Kazushige , Habara Seiji , Tanaka Hiroyuki , Fuku Yasushi , Goto Tsuyoshi , Mitsudo Kazuaki
Published: July 2021

Introduction:
It was reported that mid-term results after paclitaxel-coated balloon (PCB) dilatation for in-stent restenosis (ISR) lesions might differ depending on the tissue morphology of ISR lesions assessed with optical coherence tomography (OCT). It was also reported that ISR lesions after drug-eluting stent (DES) implantation was associated with poorer mid-term outcomes compared with those after bare-metal stent (BMS) implantation after PCB dilatation. The aim of this study was to define the impact of OCT findings on recurrence of ISR after PCB dilatation.

Methods:
Between October 2008 and December 2013, we performed percutaneous coronary intervention for 210 ISR lesions in 180 patients using PCB (143 men, mean age 68.8±9.4 years). The restenotic tissue structure at the minimum lumen area site (homogeneous, heterogeneous, or layered type) was assessed with OCT. We examined the association between tissue structure and acute/mid-term (6-8 months) results including acute gain, late loss, ISR and target lesion revascularization rates. Furthermore, we also examined the distribution of tissue structure types in each previous procedure type including BMS/DES implantation and PCB dilatation.

Results:
The mean follow-up period was 194±36 days. The association of tissue structure with mid-term results is shown in the figure. The late loss was significantly larger in lesions with heterogeneous structure than in those with homogeneous and layered structures. The prevalence of heterogeneous structure in each previous procedure type is also shown in the figure. The prevalence of heterogeneous structure was significantly lower in lesions after BMS implantation than in those after PCB dilatation.

Conclusions:
The tissue morphology of ISR lesion assessed with OCT may have an impact on the mid-term efficacy of PCB. The difference in distribution of tissue structure types may also be related to the difference between efficacies of PCB with each previous procedure type.
Abstract 13613: Feasibility of Single Beat Three-dimensional Echocardiography for Analysis of Right Ventricular Systolic Function in Neonatal Heart
Authors: Hashimoto Ikuo , Watanabe Kazuhiro , Ibuki Keijirou , Ichida Fukiko
Published: July 2021

Background:
The function of the right ventricle (RV) is difficult to evaluate by 2-dimensional echocardiography because it has more complex geometry and function than the left ventricle. The aim of our study was to evaluate right ventricular (RV) systolic function in the neonate using newly developed single beat 3-dimensional echocardiography (sb3DE).

Method and Results:
We enrolled 15 healthy or premature neonates (0 to 53 days after birth). We scanned one beat full volume using Siemens ACUSON SC2000 (Siemens AG) echocardiography with 4Z1c Full Volume transducer without ECG-gating. RV end-diastolic (RVEDV) and systolic volume (RVESV) were computed with special software dedicated to analysis for RV volume. RV ejection fraction (RVEF) and RV stroke volume (3D-RVSV) were also calculated. While RV stroke volume was also determined from the recordings of ejection blood flow velocity and diameter at the level of the pulmonary orifice in the RV outflow tract (Doppler-RVSV). Tricuspid annular plane systolic excursion (TAPSE) was also measured by 2D echocardiography.

Results:
It took 15 minutes for total acquisition of echo data including one beat full volume and 4 - 5 minutes to compute for RVEDV and RVESV. Full volume data were obtained successfully in all cases with average volume rate of 60 volumes / sec. RVEDV ranged from 5.1 to 10.7 ml (average 7.5 ml), RVESV ranged from 2.3 to 5.8 ml (average 3.9 ml). There was a good correlation between 3D-RVSV and Doppler-RVSV (r = 0.77). Bland-Altman plots revealed that 3D-RVSV was underestimated by an average of 1.78 ml compared to Doppler-RVSV. TAPSE positively correlated with 3D-RVEF (r = 0.58, P = 0.038).

Conclusions:
Newly developed sb3DE enables us to perform 3-dimensional acquisition of RV volume without ECG-gating even in neonate. However, 3D-RVSV currently tends to be underestimated in the neonatal measurement.
Abstract 13650: Microrna Signatures in the Transition From Left Ventricular Hypertrophy to Cardiac Dysfunction
Authors: Swinnen Melissa , Hermans Hadewich , Quattrocelli Mattia , Pokreisz Peter , Gillijns Hilde , Caluwé Ellen , Block Kenneth , Janssens Stefan
Published: July 2021

Purpose:
Left ventricular hypertrophy (LVH) is not just a compensatory response to increased biomechanical stress but is often associated with unfavorable outcome in patients. Mechanisms that govern transition from subclinical LVH to LV dysfunction are incompletely understood. Lately, single microRNAs (miRs), a class of small non-coding RNAs, have been implicated in LVH, but the expression dynamics and their role in transition to LV dysfunction remain unknown.

Methods:
We subjected mice to transverse aortic constriction (TAC) for 2, 4 and 10 weeks(wks) or to Ang-2 infusion for 4wks. Cardiac function was examined using serial echocardiography (TTE) and compared to sham mice (SH). MiR profiles in LV tissue were studied using the Nanostring platform, with significant differences between TAC or Ang2 vs SH set at a >2 up-or down-regulation with p<0.01. Western blotting and luciferase assay were performed for target confirmation.

The impact of up-regulated miRs was validated in vivo by administration of specific AntagomiR vs Scrambled miRs (SCR) after TAC. Results-TTE showed a modest increase in LV end-systolic dimensions and a decline in fractional shortening (FS) after 4wks TAC and Ang2 . However, after 10wks TAC, LV dilation was present together with a reduction in FS (table1). Cardiac miR signatures indicated that 3 miRs were selectively up-regulated when transition to LV dysfunction was present at 10wks TAC. A common target gene for 2 of these up-regulated miRs (miR764-3p and miR-130b-3p) was confirmed. Moreover, in vivo antagomiR treatment for both miRs protected against cardiac dysfunction and fibrosis(table 1).

Conclusion:
miR analyses show important time- and stressor-dependent dynamic expression patterns during pressure overload. The miR signatures associated with transition from LVH to LV dysfunction and subsequent targeted antagomiR administration may hold promise for future therapy.
Abstract 13703: Patients With Familial Hypercholesterolemia Are Protected Against Type II Diabetes - a Cross-sectional Study in 63,000 Individuals Tested for the Presence of LDL Receptor Mutations
Authors: Besseling Joost , Defesche Joep , Kastelein John J , Hutten Barbara A , Hovingh Gerard K
Published: July 2021

Introduction:
Familial Hypercholesterolemia (FH) is a prevalent single gene disorder characterized by decreased transmembrane cholesterol transport (TCT). In clinical practice, it was noticed that FH patients are less prone to develop type 2 diabetes mellitus (T2DM). In contrast, statin use increases TCT and, intriguingly, increases risk for T2DM.

Hypothesis:
Hence, we hypothesized that perturbations in TCT contribute to the development of T2DM, and we investigated whether T2DM prevalence is indeed lower in FH.

Methods:
All Dutch individuals who underwent DNA testing for FH between 1994 and 2014 were enrolled. We compared T2DM prevalence between FH patients and unaffected relatives. Additionally, we tested whether more severe FH mutations were associated with an even lower risk for T2DM; i.e. LDLR vs. APOB, and receptor-negative vs. receptor-deficient LDLR mutations, with unaffected relatives as reference, after adjustment for potential confounders.

Results:
Unadjusted, the prevalence of T2DM proved to be 1.8% in 25,137 FH patients (n=440) (adjusted: 1.4%) versus 2.9% in 38,183 unaffected relatives (n=1,119) (p<0.001). The adjusted odds ratios for T2DM in LDLR vs. APOB, and in receptor-negative vs. receptor-deficient LDLR mutation carriers were 0.44 (95% CI: 0.37 - 0.52) vs. 0.63 (95% CI: 0.47 - 0.85), and 0.37 (95% CI: 0.28 - 0.47) vs. 0.48 (95% CI: 0.39 - 0.58), respectively, compared to unaffected relatives (p-for-trend<0.001 in both associations).

Conclusions:
The prevalence of T2DM in FH patients is 50% lower than in unaffected relatives. Moreover, the more severe the FH mutation, the lower the prevalence of T2DM. Together with the observed association between statin use and T2DM, our findings suggest a role for cholesterol metabolism in the pathogenesis of T2DM and point to novel targets for disease modification.
Abstract 13743: Prognostic Values of Ratio of Serum Eicosapentaenoic Acid to Arachidonic Acid on Clinical Outcome after Endovascular Therapy in Patients with Peripheral Artery Disease due to Femoropopliteal Artery Lesions
Authors: Hishikari Keiichi , Kimura Shigeki , Yamakami Yosuke , Kojima Keisuke , Shigeta Takatoshi , Sagawa Yuichiro , Otani Hirohumi , Sugiyama Tomoyo , Kuwahara Taishi , Hikita Hiroyuki , Takahashi Atsushi , Isobe Mitsuaki
Published: July 2021

Background:
Peripheral artery disease (PAD) patients have a substantially increased risk of mortality and cardiovascular morbidity than those without PAD. However, risk prediction tools have not been established among patients with PAD to identify who is likely destined for adverse clinical outcome. Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio has emerged as predictor of mortality endpoints in vascular diseases, especially, coronary artery disease and cerebrovascular disease. In contrast, the prognostic value of EPA/AA ratios in patients with PAD is unclear. We sought to examine whether assessment of serum ratio of EPA/AA in patients with PAD due to femoropopliteal artery lesions can predict clinical outcome after endovascular therapy (EVT).

Methods:
We obtained serum EPA/AA ratio in 132 consecutive patients with PAD due to femoropopliteal artery lesions before EVT. We analyzed the incidence of major adverse event (MAE) including major adverse limb event (MALE) and any-cause death. The clinical characteristics and laboratory variables were compared and analyzed between MAE group and non-MAE group. Cox regression analyses were used for survival tests. Receiver operating characteristics (ROC) curve analysis was used to determine an optimal cutoff value for EPA/AA ratio to predict MAE after EVT.

Results:
At a median follow-up of 17 months, MALE occurred in 39 patients (29.5%) and 10 patients (7.6%) died. Significantly lower level of preprocedural serum EPA/AA ratio was observed in the MAE group than non-MAE group. Multivariable Cox analysis showed critical limb ischemia (hazard ratio, 2.93; 95% confidence interval [CI], 1.59-5.40; P = 0.001) and preprocedural serum EPA/AA ratio (hazard ratio, 0.08; 95% CI, 0.02-0.43; P = 0.003) were independent predictors of MAE after EVT. The cutoff value of EPA/AA ratio via ROC curve analysis was 0.29 (66.3% sensitivity, 73.5% specificity).

Conclusions:
Our findings suggest that lower serum EPA/AA ratio is associated with a greater risk of MALE and any-cause death after EVT in patients with PAD due to femoropopliteal artery lesions.
Abstract 13746: Relationships between Neointimal Tissue Characteristics and Occurrence of Periprocedural Myocardial Infarction in Lesions with In-Stent Restenosis
Authors: Kimura Shigeki , Yamakami Yosuke , Kojima Keisuke , Sagawa Yuichiro , Ohtani Hirofumi , Hishikari Keiichi , Sugiyama Tomoyo , Hikita Hiroyuki , Takahashi Atsushi , Isobe Mitsuaki
Published: July 2021

Background:
Recent studies have reported several types of neointimal tissues including neoatherosclerotic progression in stent restenosis. However, the influence of neointimal tissue characteristics on outcomes after percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) remains unclear. Periprocedural myocardial infarction (PMI) is related to poor outcomes after PCI. We assessed relationships neointimal tissue characteristics and occurrence of PMI after PCI in ISR lesions.

Methods:
We investigated 45 ISR lesions in 45 stable angina pectoris (SAP) patients who underwent pre- and post-PCI coronary angioscopy (CAS) and optical coherence tomography (OCT) examination. We excluded patients with hemodialysis. All lesions were divided into lesions with PMI, defined as high-sensitivity cardiac troponin-T (hs-cTnT) values after PCI ≥5 times of the upper reference limit in patients with normal baseline values or ≥5 times of baseline values if hs-cTnT values were elevated before PCI, and those without. Clinical and lesion characteristics including intrastent neointimal tissues were compared between two groups.

Results:
PMI was observed in 15 (33.3%) lesions. Clinical characteristics including stent types and terms after stenting were similar between lesions with and without PMI. CAS analysis showed higher frequency of white neointimal proliferation with irregular surface or yellow neointima at the culprit site before PCI (86.7% vs. 43.3%, p=0.009) and atheromatous appearance (CAS-AP), defined as yellow plaque including complex thrombi underneath disrupted neointimal coverage after ballooning (66.7% vs. 16.7%, p=0.003) in lesions with PMI than those without. OCT analysis demonstrated higher frequency of heterogeneous neointima or neointimal thin-cap fibroatheroma in lesions with PMI (73.3% vs. 33.3%, p=0.02). Multivariate analysis including clinical and lesion characteristics and procedural results showed CAS-AP as an independent predictor for occurrence of PMI (odds ratio:6.90, 95% CI:1.68-28.41, p=0.008).

Conclusions:
In ISR lesions with SAP patients, the assessment of neointimal tissue characteristics by using CAS and OCT images may be useful for the prediction of occurrence of PMI.
Abstract 13750: A Promising Highly Sensitive and Quantitative Assays of Tumorigenicity Essential for Facilitating Safety Studies of Human Induced Pluripotent Stem Cells -derived Cardiomyocytes for Future Therapeutic Application
Authors: Ito Emiko , Miyagawa Shigeru , Saito Atsuhiro , Fukushima Satsuki , Masuda Shigeo , Kawamura Takuji , Imanishi Yukiko , Sougawa Nagako , Shiozaki Motoko , Iseoka Hiroko , Harada Akima , Takeda Maki , Sato Yoji , Sawa Yoshiki
Published: July 2021

Background:
Although transplantation of cardiomyocytes derived from induced pluripotent stem cells (iPSCs) into the heart is a promising approach for heart disease, the presence of residual undifferentiated iPSCs may limit safety of this treatment. Transplantation of human iPSCs (hiPSCs) into immune-deficient mice leads to the formation of differentiated tumors comprising all three germ layers, resembling spontaneous human teratomas. Teratoma assays are considered to be a standard for demonstrating the differentiation potential of hiPSCs and hold promise as a standard for assessing the safety of hiPSC-derived cardiomyocytes intended for therapeutic applications.

Methods and Results:
We examined three in vitro tumorigenicity assays (soft agar colony formation assay, flow cytometry assay and quantitative real-time polymerase chain reaction [qRT-PCR] assay) and in vivo assay to detect residual undifferentiated cells. Soft agar colony formation assay was unable to detect hiPSCs. Next, we tied to detect residual undifferentiated cells by flow cytometry using six antibodies which recognize stem cell marker antigens, (Oct3/4, Nanog, SSEA-3, SSEA-4, TRA1-60, and TRA1-81). The anti-TRA1-60 antibody clearly distinguished hiPSCs from cardiomyocytes; it deteced 0.1% residual undifferentiated hiPSCs that were spiked in primary cardiomyocytes. Furthermore, to identify highly selective markers for undifferentiated hiPSCs, we compared mRNA levels of Oct3/4, Nanog, Sox2, Lin28 and Rex1 in hiPSCs and primary cardiomyocytes by qRT-PCR. Lin28 mRNA was not detected in primary cardiomyocytes, whereas the qRT-PCR assay detected 0.01% residual undifferentiated hiPSCs that were spiked in primary cardiomyocytes. In vivo study, the potency of teratoma formation was tested in immune-deficient mice. Among iPSC-derived cardiomyocytes, cells that contain more than 2% Lin28 positive fraction formed tumors. However, cell population that contained a Lin28 fraction less than 2% did not form tumors.

Conclusion:
We established core parameters for detecting residual tumor-forming cells. Our results provide highly sensitive and quantitative assays essential for facilitating safety studies of hiPSC-derived cardiomyocytes for future therapeutic application.
Abstract 13789: A New, Comprehensive, Hospital-Level Time-to-Treatment Metric for Primary Percutaneous Coronary Intervention: A Report From the AHA Mission: Lifeline Program
Authors: Roe Matthew , French William , Hellkamp Anne , Thomas Laine , Bates Eric , Manoukian Steven , Kontos Michael , Suter Robert , Henry Timothy , Dauerman Harold ,   for the AHA Mission: Lifeline® Investigators
Published: July 2021

Background:
Regional ST-elevation myocardial infarction (STEMI) networks have been established to improve timely access to primary percutaneous coronary intervention (PCI) in the United States, but the assessment of hospital-level performance in this setting is challenging due to the stratification of reperfusion timing metrics by initial mode of patient presentation.

Methods:
We developed a new hospital-level time-to-treatment metric for primary PCI at 588 PCI-capable hospitals (>40 patients/yr) participating in the AHA Mission: Lifeline® program from 2007[[Unable to Display Character: –]]2013. Patients were categorized as Group 1: Self or ambulance transport with no pre-hospital electrocardiogram (ECG), Group 2: Ambulance transport with ST-elevation on a pre-hospital ECG, and Group 3: Inter-hospital transfer with ST-elevation on an ECG at the referring hospital. Timing metrics for these populations were 1: Door-to-device time, 2: First medical contact-to-device time, 3: First door-to-device time, respectively. Patient times were converted to minutes ahead or behind of their group-specific mean, and overall hospital performance was measured by taking the mean time for all STEMI patients at a given site (using the new “centered time-to-device” metric with negative values behind the mean representing longer time intervals).

Results:
A total of 120,208 STEMI patients were evaluated across 588 hospitals with a median number of 85 (25
th
, 75
th
percentiles: 61, 128) patients/hospital/year. The median hospital-level proportion of patients in Groups 1, 2, and 3 were 46%, 33%, and 20%, respectively. Significant differences in time-to-treatment and “centered time-to-device” were seen from lowest to highest hospital tertiles (Table).

Conclusions:
A new, comprehensive hospital-level assessment of time-to-treatment for primary PCI that accounts for all STEMI patients treated at a given hospital, regardless of mode of presentation, reliably distinguished top-performing hospitals.
Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling
Authors: Hammad Sally K , Zi Min , Prehar Sukhpal , Little Robert , Neyses Ludwig , Cartwright Elizabeth J
Published: July 2021

Introduction:
Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in
ATP2B1
, the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk.

Hypothesis:
PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy.

Aims:
We aim to examine whether there is a
functional
link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function.

Methods and Results:
To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1
Ht
). PMCA1
Ht
mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain.

To study the mice under hypertensive stress conditions, 3 month old PMCA1
Ht
and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1
Ht
mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12.

Moreover, PMCA1
Ht
mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm
2
), compared to WT mice (340.4±9.8 μm
2
), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01.

Echocardiography showed no significant changes between PMCA1
Ht
and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1
Ht
mice showed no sign of lung congestion as indicated by lung weight to body weight ratio.

Conclusion:
ATP2B1
deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.
Abstract 13855: The Impact of Plasma Levels of Receptor for Advanced Glycation End-products and High Mobility Group Box 1 in Patients With Pulmonary Hypertension
Authors: Suzuki Satoshi , Nakazato Kazuhiko , Sugimoto Koichi , Yoshihisa Akiomi , Yamaki Takayoshi , Kunii Hiroyuki , Suzuki Hitoshi , Saitoh Shu-ichi , Takeishi Yasuchika
Published: July 2021

Background:
In pulmonary hypertension (PH), the increase of pulmonary artery pressure by vasoconstriction, remodeling of small pulmonary arteries, and chronic pulmonary thromboembolism result in right ventricular failure and ultimately death. Nuclear protein, high mobility group box 1 (HMGB1), stabilizes nucleosome, and on release into extracellular environment, HMGB1 acts as a pro-inflammatory cytokine by activating pattern recognition receptors including receptor for advanced glycation end-products (RAGE). HMGB1 is one of endogenous ligands of RAGE, and HMGB1 and RAGE are ubiquitously expressed in various organs. Several reports have recently revealed that RAGE is expressed in pulmonary artery in patients with PH, and HMGB1 contributes to migration of vascular smooth muscle cells in PH patient. The purpose of this study was to examine the clinical significance of circulating levels of HMGB1 and RAGE in patients with PH.

Methods and Results:
Plasma levels of HMGB1 and soluble RAGE were measured in 33 patients with PH (9 in idiopathic PH, 7 in PH related to collagen disease, 9 in chronic thromboembolic PH (CTEPH), 8 in others) and 30 normal subjects as control. Plasma levels of HMGB1 were not difference between PH patients and control subjects, however, plasma levels of soluble RAGE were significantly higher in patients with PH than in control (1464.2 vs. 831.7 pg/ml, P=0.008). Plasma soluble RAGE levels were higher in idiopathic PH (P<0.001), PH related to collagen disease (P=0.050), and CTEPH (P=0.002) than control. In addition, there was statistically significant positive correlation between pressure gradient of tricuspid valve and plasma level of soluble RAGE (R=0.403, P=0.019).

Conclusions:
Plasma levels of soluble RAGE, but not HMGB1, might be a novel marker which reflects the pathological conditions in patients with PH.
Abstract 13861: Trends in Utilization of Mechanical Circulatory Assist Devices in Patients Presenting with ST Elevation Myocardial Infarction
Authors: Agarwal Shikhar , Menon Venu
Published: July 2021

Despite significant controversy about the efficacy, mechanical circulatory support (MCS) is often utilized in patients with cardiogenic shock after ST elevation myocardial infarction (STEMI). We aimed to characterize the trends and outcomes following the use of MCS devices in patients presenting with STEMI.

Methods:
We used the 2003-2011 US Nationwide Inpatient Sample for this study. All admissions with a principal diagnosis of STEMI were identified using standard ICD codes. MCS devices included intra aortic balloon pump or Impella and were identified using ICD procedure codes.

Results:
Of a total of 372984 admissions with STEMI, we identified 35685 (9.3%) cases that required MCS. Over the study duration, there was a significant increase in the utilization of MCS from 7.6% in 2003 to 10.5% in 2011 (Panel A). This increase in the use of MCS was accompanied by a significant increase in the incidence of cardiogenic shock in the study population (Panel A). Despite an increase in the overall cardiogenic shock incidence, there was a significant increase in the relative utilization of MCS in cardiogenic shock (Panel B) during the study duration. Of all the cardiogenic shock cases, utilization of MCS increased from 48.6% in 2003 to 57.4% in 2009, followed by a small decline to 54.7% in 2011.

Among patients with cardiogenic shock, in-hospital mortality rate was 31.5% in patients with MCS as compared to 42.4% in those treated without MCS (p<0.001). Using multivariable hierarchical regression modeling, we found a significant reduction in adjusted in-hospital mortality with MCS, among patients with cardiogenic shock [OR (95% CI): 0.82 (0.77-0.88), p<0.001].

Conclusions:
Over the last decade, there has been a significant increase in the utilization of MCS in patients with STEMI. In contrast to the results of the IABP trial, the use of MCS was associated with a significant reduction in in-hospital mortality in this real world nationwide experience.
Abstract 13916: A Novel Biomarker of Oxidative Stress is Predictive of Incident Death and Myocardial Infarction in Patients with Coronary Artery Disease
Authors: Patel Riyaz S , Ghasemzadeh Nima , Eapen Danny J , Sher Salman , Arshad Shawn , Veledar Emir , Samady Habib , Zafari A. Maziar , Sperling Laurence , Vaccarino Viola , Jones Dean P , Quyyumi Arshed A
Published: July 2021

Introduction:
Oxidative stress (OS) is implicated in cellular damage and atherosclerosis, yet clinical experience of free radical scavengers has been uniformly disappointing, promoting the concept that clinically important OS may be mediated by alternative non-free radical processes.

Hypothesis:
We hypothesized that novel aminothiol markers of non-free radical mediated OS would predict incident adverse outcomes in patients at high risk for CAD

Methods:
1411 consecutive patients undergoing coronary angiography (mean age 63 years, male 66%), were recruited from the Emory Cardiovascular Biobank study. Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were measured by high performance liquid chromatography at baseline and patients followed prospectively for a primary composite endpoint of death or non-fatal MI.

Results:
During a mean follow up of 3.9± 2.2 years, 19% died or suffered a non-fatal MI. The adjusted hazard ratios for all cause death/MI based on high vs low cut-points for the oxidized disulphide cystine was 1.65 (95% CI, 1.27-2.15); for reduced glutathione was 0.69 (0.52-0.92), and for the ratio of cystine/glutathione was 1.79 (1.39-2.30). Compared to a model containing clinical risk factors and CRP, addition of the cystine/glutathione ratio improved the C-Statistic (p=0.03) and also correctly reclassified 17% of events and 23% of non-events. When combined with high/low CRP into a 3 level multi-marker score, those with 2 high markers had an annualized event rate of 12.8% compared to 4.5% and 1.4% for those with 1 raised marker or none, respectively. Similar associations were found for all-cause and cardiovascular death endpoints and also in stratified analysis for those with and without significant CAD.

Conclusions:
A high extracellular oxidant burden and reduced intracellular antioxidant capacity quantified by the plasma aminothiols, cystine, glutathione and their respective ratio, is associated with adverse events in patients with CAD, a finding that is independent of and additive to any inflammatory burden. Further studies are needed to validate these findings, which support an alternative model of oxidative stress independent of free radical biology.
Abstract 13939: Incidence Rate of Hyperkalemia-related Hospitalization After Initiation of a Mineralocorticoid Receptor Antagonist in Patients with Heart Failure
Authors: Chauhan Vishal R , Dev Sandesh , Pham Michael , Lin Shoutz , Heidenreich Paul
Published: July 2021

Background:
Several clinical trials have demonstrated that mineralocorticoid receptor antagonists (MRA) markedly reduce morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction. Despite their benefits, MRAs are associated with hyperkalemia potentially leading to hospitalization. The ACC/AHA guidelines recommend monitoring of serum potassium at 3, 7, 30, 60 and 90 days after initiation of MRA.

Methods:
We identified patients in the Veterans Health Care System from 2003 to 2013, with a diagnosis of HF who were started on an MRA. The incidence of hospitalization for hyperkalemia was measured at 3 days, 7 days, 14 days, 30 days, 60 days, 90 days and 1 year after the initiation of an MRA.

Results:
There were 179,541 patients identified with a diagnosis of HF and started on an MRA. Baseline characteristics for the patients included a mean age of 69.5 ±11.4, 98% male, 17% black, 48% with diabetes and 83% with hypertension. HF-related medications included a beta-blocker in 47%, an ACE inhibitor in 54%, ARB in 13%, and a loop diuretic in 58%. The baseline mean creatinine was 1.35±0.9 mg/dl. The incidence rate of hospitalization for hyperkalemia per 10,000 persons per month was 1.7 at 3 days, 3.3 at 7 days, 6.5 at 14 days, 8.3 at 30 days, 7.9 at 60 days, 6.6 at 90 days and 3.7 at 1 year. For those taking an ACEi or ARB (high risk group, n=113,678, 63.3%), the incidence rate was 0.9 at 3 days, 3.4 at 7 days, 7.4 at 14 days, 10.1 at 30 days, 10.1 at 60 days, 8.3 at 90 days and 4.7 days at 1 year. The prevalence of moderate hyperkalemia (k ≥ 5.5) among 65,641 monitored within 14 days after MRA initiation was 7.1% and that of severe hyperkalemia (k ≥ 6.0) among 85,220 monitored within 30 days after MRA initiation was 3.2%.

Conclusions:
The incidence rate of hospitalization for hyperkalemia in this study peaked at 30 days after MRA initiation but was very low overall. Future studies to optimize the frequency of monitoring, while maintaining low rates of serious hyperkalemia may be warranted.
Abstract 13955: Establishing a Prehospital Protocol for Local Emergency Services Improves Symptom Onset-to-Balloon Time in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Brester Dawn A , Schmidt Matthew , Witmer William T , Weslow Scott T , Mathias David , Sahajpal Katie
Published: July 2021

Background:
Delay in symptom recognition and calling 911 for patients with ST-segment elevation myocardial infarction (STEMI) continues to challenge many hospitals’ STEMI systems. Research has historically focused on door-to-balloon time and inpatient treatment, with little known on the impact of engaging emergency services (EMS) to provide a team approach to patient care, from community education to prehospital activation.

Purpose:
Evaluate the impact of a collaboration with local EMS agencies in our institution’s STEMI system designed to develop a prehospital protocol and joint community education efforts.

Methods:
Data collected from NCDR ACTION Registry-Mission Lifeline reports from 2011 to 2013 was analyzed to identify recent trends in prehospital STEMI quality metrics. After evaluation of 2011 data, a regional plan was developed and implemented in 2012 to address prehospital system barriers, including public education and revision of a prehospital protocol.

Results:
In 2011, a majority of patients used private transport when having a STEMI. Following protocol implementation, STEMI patients were able to identify symptoms earlier and appropriately call 911 earlier. As a result, a first medical contact (FMC)-to-balloon time of < 90 minutes increased to 72% of patients, time from symptom onset to balloon decreased, and postprocedure complication rate improved (Table).

Conclusions:
Establishing a collaborative prehospital protocol between hospitals and EMS can have a positive impact on outcomes in STEMI patients. With more awareness and earlier notification of incoming STEMI patients, hospitals can significantly decrease symptom onset-to-balloon time. Evaluation of time from symptom onset to device activation may be a better way to measure quality than door-to-balloon time, as evidenced by a decrease in postprocedure complications associated with decreased overall times.
Abstract 14004: Pharmacodynamic Profiles of Ticagrelor in Patients With ST-Elevation Myocardial Infarction: A Prospective Randomized Comparison of Escalating Loading Dose Regimens
Authors: Franchi Francesco , Rollini Fabiana , Cho Jung Rae , Bhatti Mona , DeGroat Christopher , Ferrante Elisabetta , Dunn Elizabeth C , Nanavati Amit , Carraway Edward , Suryadevara Siva , Zenni Martin M , Guzman Luis A , Bass Theodore A , Angiolillo Dominick J
Published: July 2021

Background:
Pharmacodynamic (PD) studies have shown that in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI), ticagrelor is associated with suboptimal platelet inhibition and elevated rates of high on-treatment platelet reactivity (HPR) in the early hours after loading dose (LD) administration. Impaired absorption affecting drug pharmacokinetics (PK) has been hypothesized as a contributing factor suggesting increasing LD regimens to improve PK/PD profiles. To date there are no randomized studies which have investigated the PK/PD effects of escalating ticagrelor LD regimens in patients undergoing PPCI.

Methods:
In this prospective, randomized study, STEMI patients undergoing PPCI (n=52) were randomized 1:1:1 to receive 180mg, 270mg or 360mg LD of ticagrelor. PK and PD analysis were performed before and at 6 time points after LD. PD assessments included P2Y
12
reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by VASP. PK assessments included plasma concentrations of ticagrelor and its metabolite AR-C124910XX.

Results:
At baseline there were no differences in platelet reactivity between groups. At 2 hrs (primary endpoint), there were no differences in PRU between groups (p=0.54). There were no differences in PRU between groups during the overall study time course (p=0.17; Figure). Accordingly, HPR (PRU>208) at 2 hrs was observed in 30% of patients and was not reduced by escalating ticagrelor LD regimens. Consistent PD findings were observed with VASP-PRI. PK data tracked PD results, with a non-dose related delay in peak plasma concentrations of both ticagrelor and AR-C124910XX, particularly in HPR patients.

Conclusions:
In STEMI patients undergoing PPCI, increasing the LD regimen of ticagrelor did not translate into more prompt or potent P2Y
12
inhibition, which is attributed to impaired absorption in the early hours after drug administration.
Abstract 14017: Contemporary Management Strategies Provide Low Mortality Rates for Young Patients with Hypertrophic Cardiomyopathy
Authors: Rowin Ethan J , Maron Martin S , Casey Susan A , Lesser John R , Garberich Ross F , Link Mark S , Maron Barry J
Published: July 2021

Background:
Historically, youthful age has been considered the time period of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely a consequence of increased risk of sudden cardiac death. However, the last two decades have witnessed emergence of an expanded risk stratification algorithm resulting in more reliable identification of at-risk patients and enhanced utilization of implantable cardioverter-defibrillators (ICD) for sudden death prevention. However, whether these advances have significantly altered mortality rates for young HCM patients is currently unresolved.

Objective:
Define the clinical course and adverse event rate in children and young adults with HCM.

Methods:
We studied the long-term outcomes of 321 consecutive HCM patients presenting at 2 institutions between 10 and 29 years of age, and followed over 7.2 ± 4.8 years.

Results:
Over follow-up, 302 patients (94%) survived to 27 ± 5 years, with the majority (96%) experiencing no or mild symptoms at last evaluation. HCM-related death occurred in 16 patients (5%; 0.7%/year): arrhythmic sudden death (n=12), complications following heart transplant (n=3), and progressive heart failure (n=1). In contrast, aborted HCM-related mortality occurred in 41 other high-risk HCM patients (implantable cardioverter-defibrillator (ICD) interventions for ventricular tachyarrhythmia [n =24], resuscitated out of hospital cardiac arrest [n=7], and heart transplant for advanced unrelenting heart failure [n=10]), 2.0%/year, and at a rate almost 3-fold higher than actual HCM mortality. Survival at 5- and 10-years (considering only HCM deaths) was excellent at 97% and 92%, and not significantly different from survival rates recently reported in HCM patients identified during mid-life (ages 30 to 59 years old; 98% and 94%, p=0.23).

Conclusions:
In a cohort of young HCM patients contemporary treatment strategies have resulted in low mortality (<1%/year), due largely to identification of high-risk patients who benefit from sudden death prevention with the ICD, creating the opportunity for extended longevity.