bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 227: Patient and Provider Generated Appropriateness Ratings for Myocardial Perfusion Imaging: Agreement With Published Criteria
Authors: Winchester David E , Kline Kristopher , Plumb Jared , Huo Tianyao , Beyth Rebecca
Published: March 2022

Background:
Appropriate use criteria (AUC) for myocardial perfusion imaging (MPI) help doctors decide which patients may benefit from MPI. The AUC development process does not include patients. Ordering providers are included, but their opinions on AUC have not been more broadly studied. We conducted an anonymous survey of patients and providers on the appropriateness of MPI in various settings. We hypothesize that both groups will overestimate the appropriateness of MPI compared to AUC.

Methods:
We administered our survey to patients in primary care clinics, cardiology clinics, and nuclear medicine laboratories at our academic medical center and affiliated Veterans Affairs medical center. Participating providers were physicians, nurse practioners, and physician assistants within primary care, cardiology, and hospital medicine. The primary outcome was a comparison of patient and provider appropriateness ratings as compared to published AUC. Respondents used the same methodology as used to develop the AUC; five clinical scenarios were rated on a 1 (inappropriate) to 9 (appropriate) scale. Scenarios were based on common MPI indications and included appropriate, inappropriate, and uncertain examples (symptomatic with prior revascularization, symptomatic with low risk of heart disease, asymptomatic with low risk of heart disease, symptomatic with intermediate risk of heart disease, and asymptomatic with prior revascularization). We used subgroup analyses and logistic regression models for both groups to investigate associations between ratings and respondent characteristics.

Results:
The survey was completed by 449 respondents, 338 patients and 111 providers between June and August 2014. Patient sampling was distributed between cardiology clinic (32.2%), primary care clinic (36.0%), and nuclear medicine (31.9%) laboratory. Providers were cardiology (35.1%), primary care (37.7%), hospital medicine (22.8%), and other (4.4%); 86.8% physicians. Of the five scenarios, the patient and provider ratings differed from AUC for three. In two cases, the patient generated rating was higher than the provider or published rating (5 versus 3.5 and 3, p<0.0001; 5 versus 2 and 1, p<0.0001). In the third case, the provider generated rating was lower than both the patient and published rating (2 versus 6 and 6, p<0.0001). Subgroup comparisons and logistic regression did not reveal any significant correlations between ratings and respondent characteristics.

Conclusion:
In some clinical scenarios, patients and healthcare providers have differences of opinion about the appropriateness of nuclear MPI as compared to published AUC. Patients tended to overvalue MPI while healthcare providers undervalued one of the published AUC ratings. Evidence of differences in opinion raise the question as to what role patients should play in future iterations of AUC.
Abstract 234: Prehospital Electrocardiogram Transmission is Associated with Decreased First Medical Contact to Device Time in a Large Urban Emergency Medical Services System
Authors: Richards Chris , Pearlman Ken , Stein-Spencer Leslee , O’Neill Kathleen , Schroff Adhir , Purim-Shem-Tov Yanina , Markel Eddie , Weber Joseph , Miller Art , Schaer Gary
Published: March 2022

Introduction:
Early recognition and rapid revascularization is associated with improved outcomes in patients with STEMI. Increasingly, prehospital emergency medical services (EMS) providers acquire prehospital ECGs, transport patients to PCI-ready hospitals, and activate interventional cardiology teams in advance of hospital arrival (“door time”). Therefore, the time from first medical contact (FMC) with either EMS providers or the emergency department may be an important metric for overall system performance in the care of patients with STEMI.

Hypothesis:
A prehospital ECG transmission program will be associated with a decreased median FMC to revascularization device deployment (“device”) time.

Methods:
A retrospective cohort study of Action Registry-GWTG data in Chicago was performed. The Chicago Fire Department implemented a 12-lead ECG transmission program in 2012. Patients with confirmed STEMI from January through December 2013 were included. A baseline median FMC to device time was determined for the third quarter of 2012, at the start of the ECG transmission program. Descriptive statistics were used for analysis.

Results:
Over the study period, 352 patients experiencing STEMI were treated in 9 hospitals. Patients were predominantly male (66%), and 50% arrived by ambulance. The average median FMC to device time over the study period was 83 minutes, which was decreased from a baseline of 104 minutes. The median time from FMC to door and median time from catheterization laboratory arrival to device remained constant over the study period (24 minutes and 22 minutes respectively), but the median time from door to catheterization laboratory decreased from 42 minutes to 33 minutes.

Conclusions:
Implementation of a prehospital ECG transmission program was associated with a decreased median FMC to device time in a large urban city, with FMC to device times consistently less than 90 minutes. The median door to device time for all patients regardless of arrival mode decreased over implementation, suggesting improved care processes for all patients with STEMI.
Abstract 235: Prehospital STEMI Protocol Administering Aspirin, Ticagrelor, and Heparin Reduces Reperfusion Times
Authors: Mullvain Richard , Zotti Robert D , Derner Melissa
Published: March 2022

Background:
Emergency Medical Service (EMS) agencies serving large rural areas have not traditionally administered Ticagrelor or Heparin IV in the pre-hospital setting for STEMI patients who are ultimately transferred for Primary PCI. A recent international study demonstrated the safety of administering Ticagrelor by EMS. We hypothesized that allowing EMS to administer medications normally given in the hospital setting could be beneficial. A protocol was implemented with the goal being that if the ECG is Positive, give Aspirin, Ticagrelor, and Heparin, also known as (EPATH).

Methods:
Data was collected on 31 consecutive STEMI activations from a large rural area, from both the regional hospital and by the local EMS agency, prior to implementation of the EPATH Protocol, and 31 consecutive STEMI activations after implementing the EPATH Protocol. Data was stored on a Microsoft Excel spreadsheet, and analyzed using the calculation functions available within the database.

Findings:
Multiple STEMI performance Metrics improved, including the following: The median first EMS contact to Percutaneous Coronary Intervention (PCI) time was reduced by 28 minutes. The median 911 call to PCI time was reduced by 21 minutes. The rural referral hospital median door to PCI time was reduced by 22 minutes.

Conclusion:
After implementing the EPATH protocol in a large rural area, which allowed EMS to administer Prehospital Aspirin, Ticagrelor, and Heparin for STEMI, we observed an improvement in multiple STEMI performance metrics, including a 28 minute median reduction in first EMS contact to PCI time. Further research is warranted.
Abstract 246: Statin Medication Adherence Among Medicare Beneficiaries
Authors: Odom Erika , Ritchey Matthew , Chang Anping , Loustalot Fleetwood
Published: March 2022

Background:
High low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Statin therapy to lower LDL-C is recommended among specific high-risk populations; however, based on 2013 guidelines, less than 50% of those eligible are currently on statins. Older adults have a high burden of ASCVD; thus if prescribed, use and adherence to statins are a key part of preventing further morbidity and mortality. In this study, our primary objective was to describe adherence to generic and brand statins among Medicare Part D beneficiaries nationally and at the state level.

Methods:
Calendar year 2012 data were obtained for the Medicare Part D prescription drug file, which includes Medicare Advantage and Fee-for-service beneficiaries aged ≥65 years. Proportion of days covered (PDC) was calculated for enrollees with at least 2 statin fills on or after January 1, 2012 (first fill by October 1, 2012). PDC for statins was defined as total days’ supply divided by total eligible days (minus days as inpatient), multiplied by 100. Age-adjusted prevalence of being adherent (PDC ≥80%) was calculated overall and by state. State-based adjusted (i.e., for age, race/ethnicity, dual Medicare/Medicaid enrollee, and plan type) odds of adherence was determined using logistic regression, independently for generic and brand name statins.

Results:
Overall, 10.6 million beneficiaries using statins were included, with 80% on generic (adherence: 75.5%), 11% on brand (adherence: 66.2%), and 9% on a mix of generic and brand name (adherence: 71.7%) statins. Prevalence of adherence to generic was higher than brand statins across all sociodemographic variables. Age-adjusted prevalence of adherence to generic (68.6[DC]-83.7%[VT]) and brand name (60.1[MS]-81.9%[VT]) statins varied across states. Within state differences between prevalence of generic and brand statin adherence ranged from 1.28 (AK) to 15.11 (RI) percentage points (median: 8.44 for CT). State-based adjusted odds ratios of adherence to generic (range: aPR=.60, 95% CI [.60-.61] for NJ to aPR=1.33, 95%CI [1.29-1.37] for VT; CA median reference) and brand name (range: aPR=.64, 95%CI [.61-.67] for NV to aPR=1.82, 95%CI [1.76-1.88] for WV; KS median reference) statins varied.

Conclusion:
Almost three-fourths of beneficiaries were adherent to statins; however wide variation in adherence to generic versus brand statins within states and odds of adherence across states, reflects room for improvement. Greater costs of brand versus generic medications may be a contributing factor to lower adherence. The use of low-cost statins, coupled with clinician (e.g. counseling) and health care system (e.g. clinical decision supports) activities to promote medication adherence may be useful.
Abstract 248: Substance Abuse is Associated with Observation Status of Patients with Heart Failure at an Urban Academic Medical Center
Authors: Schuetz Rebecca , Dickens Carolyn , Groo Vicki , Vuckovic Karen
Published: March 2022

Background:
More than 80% of patients presenting to the emergency department (ED) with acute decompensated heart failure (ADHF) are admitted and categorized as either observation (OBS) or inpatient (IP)
post discharge
using Interqual criteria (severity of illness and intensity of service). Identifying patient characteristics upon
admission
to determine OBS or IP status may optimize hospital resource utilization.

Purpose:
To determine patient characteristics upon admission that are associated with the categorization (OBS vs IP) for patients with ADHF presenting to the ED of an urban academic medical center.

Methods:
Retrospective medical record review of 172 randomly selected adult patients from 2013 who presented to the ED with ADHF. Patients had been categorized as OBS vs IP after discharge based on Interqual Criteria. Based on the literature, we identified variables traditionally associated with an admitting diagnosis for heart failure (HF) including: symptoms (shortness of breath, paroxysmal nocturnal dyspnea, orthopnea, and lower extremity edema), physiologic measures (B-type natriuretic peptide and blood pressure), and patient characteristics (number of co-morbidities, type of HF- HF with reduced ejection fraction vs HF with preserved ejection fraction, 30 day readmission rate, gender, ethnicity, and history of substance abuse within the past 12 months). Chi square tests and student t-tests were used to compare variables between groups.

Results:
Of the 172 ADHF patients, 76% (n=131) were categorized as IP and 24% (n=41) were OBS. The majority of patients were African American (n = 130, 75.6%), female (n = 101, 58.7%) and had HF with a reduced ejection fraction (n = 99, 57.6%). There were no significant differences between the OBS and IP groups in terms of symptoms, B-type natriuretic peptide levels, blood pressure, number of co-morbidities, type of HF, 30 day readmission rate, gender, ethnicity, or socio-demographic characteristics. A history of substance abuse was more common among the OBS group versus the IP group (
p
= 0.013).

Conclusions:
In this single center retrospective medical record review comparing the categorization of patients presenting to the ED with ADHF as OBS vs IP, we found no difference in the traditional clinical variables between groups. However, a history of substance abuse was associated with the patient being categorized as OBS. Substance abuse may be an important non-traditional variable to consider in resource utilization.
Abstract 254: The Canadian GENESIS Gender Index may be the Key to Understanding Differences in Health Status Outcomes in Acute Coronary Syndrome.
Authors: Norris Colleen M , Johnson Nicole L , Hardwicke-Brown Emeleigh , Pelletier Roxanne , Pilote Louise
Published: March 2022

Background:
While it has been identified that gender (socially manufactured roles, behaviours, expressions and identities) plays a central role in men’s and women’s health, the distinction between gender and sex (biological attributes) has largely been ignored in health sciences research. One aspect of the GENESIS-PRAXY study was the development of a ‘gender index’ which measures gender and offers a pragmatic means to explore the relationship between sex, gender and health outcomes. The purpose of this study was to look at the unique contributions of sex, age and the GENESIS Gender Index (GGI) to baseline Seattle Angina Questionnaire (SAQ) dimensional scores in a cohort of patients undergoing cardiac catheterization for CAD.

Methods:
Questions that comprised the GGI were included in the follow-up questionnaire sent to patients in the APPROACH registry. For the purposes of these analyses, SAQ scores were dichotomized whereby respondents were given a score of 1 if they scored 100 (best possible score) on the SAQ scales, and 0 if less than 100. Logistic regression models were created including each of the SAQ dimensional scores as the dependent variables and sex, age and the GGI as the independent variables entered in unique blocks. The area under the curve (AUC) and resulting
c
statistics were calculated for each block.

Results:
GGI scores and baseline SAQ scores were calculated for 532 returned questionnaires sent between July 1st and August 31
st
2015 within one week of index catheterization. Men were more likely to report perfect SAQ dimensional scores compared to women and these relationships were significant in the Physical Limitation and Treatment Satisfaction scales (odds ratios 2.75 and 1.56 respectively). The inclusion of age into the models did not change the relationship between sex and the SAQ scales. However the inclusion of the GGI attenuated the relationship between sex and the SAQ scales whereby sex was no longer statistically independently predictive of SAQ scale scores. Furthermore
c statistics
indicated that including the GGI increased the discrimination of the models in all SAQ dimensional scales.

Conclusions:
This analyses adds to the literature that specifies that gender is a distinct constructs that can be measured by the GGI. More importantly, the increased predictive accuracy of the models that included the GGI suggests that the psychosocial variables included in the GGI provide more information in understanding the differences in outcomes between men and women undergoing catheterization for CAD.
Abstract 266: Trusted Third Party for Medication Adherence
Authors: Relish Michael , Young Peinie , Vogel Vicki , Spurlock Jeff , Lawnicki Victor , Clark Shannon , Pearce Heather
Published: March 2022

Background:
Humana currently sends messages to members as a reminder to remain adherent with their medication. Since some members may view insurance companies skeptically, we wanted to see if similar messaging reminders from trusted third parties would be more effective than messaging that came from their health insurance plans. The third parties included a celebrity (Florence Henderson), a pharmacist, and the member’s primary care physician (PCP).

Objective:
The primary purpose of this research was to test the relative impact of medication adherence messages emanating from different sources.

Methods:
In this prospective, randomized control study, 17,771 members were randomized to five treatment arms and two control arms. The study sample was comprised of MAPD members who had a baseline PDC between .60 and .85 in at least one of the following medication groups: hypertension, diabetes, and hyperlipidemia. Each study member received two communications from their trusted third party: a postcard and a pre-recorded phone call. Generally, the postcard and phone call would be from the same source; in one “combination” treatment arm, the postcard came from the pharmacist and the phone call came from the celebrity. The postcards were mailed in November 2014 and the pre-recorded calls were completed in December 2014. The main outcomes of interest were changes in PDC scores between November 2014 and May 2015.

Results:
Overall, the pharmacist-celebrity combination, pharmacist- only, and PCP treatments yielded the best results. The Pharmacist-celebrity treatment increased PDC scores by .037, the Pharmacist-only treatment increased PDC scores by .042, and the PCP treatment increased PDC scores by .033 over control (all significant at p=.05). All messages increased PDC scores for women, however only the pharmacist-celebrity treatment was statistically significant, with a PDC increase of .043 (p=.05). For men, the pharmacist-only, PCP, and pharmacist-celebrity treatments increased PDC scores by .079, .071, and .029, respectively, at p=.05. For the patients on hypertension medications, the pharmacist-only, PCP, and pharmacist-celebrity treatments increased PDC scores by .045, .043, and .041, respectively, at p=.05.

Conclusion:
There were statistically-significant improvements in adherence to hypertension medications for the pharmacist-only, PCP, and pharmacist-celebrity treatment arms. Men and women responded to third parties differently. Based on the results, we would like further test messages delivered from third parties to understand when and how sources induce different responses.
Abstract 4: Impact of Financial Penalties in Medicare’s Hospital Readmissions Reductions Program
Authors: Wasfy Jason H , Zigler Corwin M , Choirat Christine , Wang Yun , Dominici Francesca , Yeh Robert W
Published: March 2022

Background:
The Affordable Care Act (ACA) created financial penalties applied to reimbursements after October 1, 2012 for US hospitals for excess risk-standardized readmission rates (RSRRs) for specific conditions. In that context, we sought to determine the effects of health reform financial penalties on hospital readmission rates.

Methods:
We used a quasi-experimental interrupted time series design with a control group (no penalty hospitals) to analyze the Medicare FFS datafiles. We divided hospitals by initial penalty category. We fitted a piecewise linear model with a change point at passage of the ACA in March 2010 to hospital-specific RSSRs for every quarter from January 2000 to December 2013. We evaluated (1) if RSRRs were declining before and after the law, (2) if any decline accelerated post-law compared to pre-law, and (3) whether the penalized hospitals experienced a faster acceleration in improvement post-law than hospitals with no penalty (control group).

Results:
In the initial phase of penalties (October 2012-October 2013), 30.1% of hospitals received no penalty, 44.0% received a low penalty (less than half maximum), 16.8% received a high penalty (more than half maximum), and 9.0% received the maximum penalty. Compared to no penalty hospitals, hospitals with the maximum penalty were more likely to be major teaching hospitals (11.2% vs. 6.1%, p < 0.001) and were less likely to be in rural settings (22.9% vs. 29.9%, p < 0.001). Pre-law, combined-condition RSRRs were declining in the no penalty group (p < 0.0001) and increasing for the high penalty and maximum penalty groups (p < 0.0001). Post-law, combined-condition RSRRs declined for all penalty groups (p < 0.0001 for all). Rates of decline accelerated post-law for all penalty groups (p < 0.001 for all), with the greatest acceleration occurring in hospitals sustaining the highest penalties (p < 0.0001 for all comparisons of higher vs. lower penalty groups).

Conclusions and Relevance:
After health reform, hospital risk-standardized 30-day readmission rates for myocardial infarction, heart failure and pneumonia declined nationally faster than before health reform. Improvement in readmission rates was most marked for hospitals incurring the highest financial penalties.
Abstract 8: Hospice Use Following Implantable Cardioverter-Defibrillation Implantation in Older Patients: Results from the NCDR
Authors: Kramer Daniel , Reynolds Matthew , Normand Sharon-Lise , Parzynski Craig , Spertus John , Curtis Jeptha , Mor Vincent , Mitchell Susan
Published: March 2022

Background:
ICDs are frequently inserted in older patients, who are at high risk for short-term mortality. Though hospice is the main provider of end-of-life care in the United States, its use in patients following ICD implantation is not known. We aimed to describe the incidence, timing, regional variation, and predictors of hospice use in a nationally-representative sample of older patients following ICD placement.

Methods:
ICD registry data for Medicare fee-for-service patients aged >65 was linked to Medicare Hospice Claims from January 1, 2006 - December 31, 2010 using indirect identifiers. Use of hospice services among decedents in the Health Referral Region (HRR) where the ICD was placed was evaluated using the Dartmouth Health Atlas. Cumulative incidence of hospice admission was calculated and multivariable Cox regression was used to identify factors associated with time-to-hospice enrollment with both analyses accounting for the competing risk of death.

Results:
A total of 194,969 eligible older ICD recipients were identified, whose mean age was 75.5 + 6.4 years, 25.7% were female, and 89.6% were white; 80.0% had CHF, 46.6% had CRT devices, and 79.0% had primary prevention ICDs. During the follow-up period (median 1.92 years, 25%-75% IQR, 1.13 - 2.97,) a total of 52,990 (27.1%) patients died and 22,336 (11.4%) were enrolled in hospice care. Among the subset of patients who died, 36.8% received hospice services. The cumulative incidence of hospice use, accounting for the competing risk of death, was 4.7% (95% CI, 4.6% - 4.8%) within 1 year and 21.3% (95% CI, 20.7% - 21.8%) at 5 years. The median time from ICD implantation to hospice enrollment was 1.3 years (25% - 75% IQR, 209 days - 2.3 years); median length of stay in hospice was only 10 days (25% - 75% IQR, 4 - 36 days). In multivariable analysis, the following factors were most strongly associated with shorter time to hospice enrollment: older age, Class IV HF, LVEF < 20, lung disease, and HRR (Table).

Conclusions:
After accounting for the competing risk of death, the cumulative incidence rate of hospice admission in the 5 years following ICD placement was 21%. This finding indicates a need for a greater understanding of the clinical experience, symptom management, treatment preferences, and end-of-life outcomes for these patients.
Human Tissue Kallikrein Gene Transfer Accelerates Spontaneous Angiogenesis Response to Ischemia
Authors: Emanueli Costanza , Minasi Alessandra , Zacheo Antonella , Chao Julie , Chao Lee , Salis Bonaria Maria , Madeddu Paolo Roberto , Capogrossi M C
Published: March 2022

P205

Angiogenesis therapy is emerging as a new approach to rescue ischemic tissues not susceptible to benefit from revascularization. We investigated (1) if ischemia modulates the expression of kallikrein-kinin system (KKS) and (2) if potentiation of kinin generation by human tissue kallikrein (HK) gene transfer augments spontaneous angiogenesis and tissue perfusion in a mouse model of ischemia. Hindlimb ischemia, caused by surgical excision of femoral artery, increased capillary density (from 344±15 to 641±54 cap/mm
2
at 21 d after surgery, P<.001) and expression of kinin B
1
receptor gene in the adductor muscle. Chronic blockade of B
1
receptors blunted the spontaneous angiogenic response to ischemia (P<.01), while B
2
antagonism was ineffective. Seven days after surgery, 3.6x10
8
p.f.u. of adenovirus containing the HK gene under control of cytomegalovirus enhancer/promoter sequence (Ad.CMV-cHK) or the reporter gene (Ad.CMV-LacZ) was injected in the ischemic adductor. Transduction of injected muscle was demonstrated at mRNA and protein level. HK trasgene expression peaked between 3 and 7 days and was associated with increased concentration of kinins, cAMP, and cGMP. Immunoistochemical identification of endothelial cell antigen Factor VIII combined with blinded morphometric evaluation of capillary density demonstrated potentiation of angiogenesis in HK-transduced muscle (969±32 versus 541±18 cap/mm
2
in LacZ at 14 d, P<.001). HK-induced angiogenesis was limited to the site of injection and was associated with 40% increase in perfusion to ischemic limb (as measured by the use of laser Doppler flowmetry or radioactive microsphere) and preserved muscular energetic charge (88±2 vs 66±4% in LacZ, P<.001). Chronic blockade of kinin B
1
or B
2
receptors prevented HK-induced angiogenesis. We conclude that: (1) kinin receptors are differentialy modulated by ischemia, (2) B
1
receptor is implicated in spontaneous angiogenic response to ischemia, and (3) potentiation of kinin generation by HK accelerates post-ischemic recovery by stimulating angiogenesis. These results provide new insight into the role of the KKS in vascular medicine for therapeutic benefit.
Relative Contributions of Endothelin Receptor Subtypes in Chronic Angiotensin II Induced Hypertension.
Authors: Ballew Jennifer R , Fink Gregory D
Published: March 2022

1

We previously showed that a selective ETA receptor antagonist, ABT627, completely normalized mean arterial pressure (MAP) in rats with chronic Ang II induced hypertension (AIH), indicating that endogenous endothelin (ET-1) plays a critical role in AIH. The goal of these experiments was to determine the relative contributions of ETA and ETB receptor activation to AIH. Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high sodium intake, 6 mEq/day. Ang II was infused i.v. at 5 ng/min for 15 days; ET-1 antagonist was given during the middle 5 days. When injected acutely,
A192621
(12 mg/kg 2x /day), a selective ETB receptor antagonist, gradually increased MAP over 1 hour in AIH rats but produced a biphasic increase in control rats over the same time. With 5-day dosing,
A192621
significantly increased MAP in both AIH rats (130±9 to 158±8 mmHg) and uninfused control rats (110±3 to 129±7 mmHg).
A192621
produced a significant decrease in water balance in both groups within 24 hours after start of drug administration, but had no effect on sodium balance. When injected acutely,
A182086
(12 mg/kg 2x /day), an ETA/B receptor antagonist, produced a rapid drop in MAP in both groups to baseline levels over 1 hour. With 5-day dosing,
A182086
significantly reduced, but did not normalize, MAP in AIH rats (138±3 to 127±7 mmHg).
A182086
did not affect MAP in control rats (113±3 to 117±9 mmHg).
A182086
did not affect water or sodium balance in either group. In conclusion, blockade of ETB receptors in AIH potentiates hypertension development, most likely through augmentation of ET-1 vasoconstriction. For this reason, ETA/B receptor blockade is less effective than ETA receptor blockade at decreasing MAP in chronic AIH. We found no evidence that ET-1 receptor activation in the kidney plays a role in AIH.
PPARγ Activation Inhibits Il-6 and PDGF α-Receptor Expression Via a Nuclear Cofactor C/EBPδ in Vascular Smooth Muscle Cells.
Authors: Takata Yasunori , Kitami Yutaka , Yang Zhao-Hui
Published: March 2022

8

Objectives: A proinflammatory nuclear factor, CCAAT/enhancer-binding protein (C/EBP), regulates transcription of the genes including IL-6, platelet-derived growth factor α-receptor (PDGFαR), leptin, COX-2 and IGF-1 which are closely associated with hypertension, atherosclerosis and insulin resistance. The aim of this study is to investigate the effect of peroxisome proliferator-activated receptor (PPAR)γ activation on cytokine-induced IL-6 and PDGFαR expression, and to clarify underlying mechanisms of the action in vascular smooth muscle cells (VSMCs). Methods and Results: Rat cultured VSMCs were pretreated with troglitazone (TRO) (0-10 μM) or 15-deoxy-
12,14
Δ-prostaglandin J
2
(PGJ
2
) (0-5 μM) for 24 h, and then stimulated by IL-1β(10 ng/mL) for 6 h. While IL-1β alone markedly induced both protein and mRNA levels of IL-6 and PDGFαR, TRO or PGJ
2
significantly inhibited this induction in a dose-dependent manner. Cell proliferation activity was assessed by measurement of BrdU incorporation after treatment with PDGF. PDGF (20 ng/mL) significantly enhanced cell proliferation activity in IL-1β-stimulated cells whereas this enhanced effect was lost by pretreatment with TRO or PGJ
2
almost completely. Further, electromobility shift assay (EMSA) and supershift assay were performed for a C/EBP binding site that mainly regulates IL-6 and PDGFαR genes transcription. EMSA revealed that IL-1β markedly increased DNA-protein complex formation, and pretreatment with TRO or PGJ
2
reduced it almost completely. Supershift assay demonstrated that the retarded band seen in EMSA was supershifted by antibodies against C/EBPδ. On the other hand, TRO or PGJ
2
significantly suppressed IL-1β-induced C/EBPδ expression, and prostaglandin F
2
α, that acts as an inhibitor of PPARγ, diminished the suppressive effect of PPARγ activators on C/EBPδ expression. Conclusions: The effect of PPARγ activation on IL-6 and PDGFαR expression is mediated by suppression of C/EBPδ expression. These results suggest that cross-regulation of PPARγ and C/EBPδ is beneficial to events of vascular inflammation and resultant vascular remodeling.
Tonic Excitatory Amino Acid Input to Rostral Ventrolateral Medulla in Dahl Salt-Sensitive Rats
Authors: Ito Satoru , Komatsu Kazutoshi , Tsukamoto Kazuyoshi , Kanmatsuse Katsuo , Sved Alan F
Published: March 2022

16

We have previously reported that tonically active excitatory amino acid (EAA) inputs to the rostral ventrolateral medulla (RVLM) excite RVLM vasomotor neurons but also indirectly inhibit RVLM vasomotor neurons, and suggested that the balance of these influences is important in the maintenance of baseline arterial pressure (AP). In anesthetized normotensive Sprague-Dawley and Wistar rats injection of the EAA receptor antagonist kynurenic acid (KYN) into the RVLM did not alter AP. In contrast, in spontaneously hypertensive rats injection of KYN into the RVLM causes a decrease in AP, suggesting that this balance of excitatory and inhibitory influences is shifted toward excitation in this model of hypertension. Increases in dietary salt intake appear to increase the responsiveness of RVLM vasomotor neurons to excitatory inputs, but does not lead to increased AP. However, in Dahl salt-sensitive (DS) rats increased dietary salt intake causes hypertension. The goal of the present study was to examine the influence of tonically active EAA inputs to the RVLM in DS rats, to test the hypothesis that the balance of tonic excitation and inhibition of RVLM vasomotor neurons tonically driven by EAA-mediated inputs to RVLM is shifted toward excitation in DS rats. DS rats (male, 10 weeks of age) fed a diet containing either 0.3% NaCl 0r 8.0% NaCl for 3 weeks were anesthetized with chloralose and the dorsal surface of the brain stem was surgically exposed to allow injections to be made into the RVLM through glass micropipettes. MAP was elevated in DS rats fed the high salt diet compared to DS rats fed the low salt diet (173±3 vs. 123±4 mm Hg, n=8, p<0.05). Bilateral injection of KYN (2.7 nmol in 100 nl) into the RVLM decreased MAP by 16±2 mm Hg in DS rats fed the low salt diet. This effect was significantly larger in DS rats fed the high salt diet (40±2 mm Hg). These data suggest that an imbalance between the excitatory and inhibitory influences tonically active EAA-mediated inputs to RVLM vasomotor neurons may contribute to the sensitivity of DS rats to salt-induced hypertension.
Synthesis and Function of Cytochrome P450 4A1-Derived 20-Hydroxyeicosatetraenoic Acid in Rat Renal Arteries
Authors: Laniado-Schwartzman Michal , Wang Mong-Heng , Marji Jackleen , Zhang Fan , Kaide Jun-Ichi , Nasjletti Alberto
Published: March 2022

22

20-hydroxyeicosatetraenoic acid (20-HETE) is the principal arachidonic acid metabolite in tubular and vascular structures of the rat kidney. In the tubules it inhibits sodium reabsorption, while in the renal microcirculation it is a vasoconstrictor and a regulator of myogenic tone. 20-HETE synthesis is catalyzed by the cytochrome P450 (CYP) 4A isoforms (4A1, 4A2, 4A3 and 4A8). Our studies indicated that despite the high homology, these isoforms display distinct catalytic properties. CYP4A1 is the low Km isoform and thus, by far, the most efficient 20-HETE synthesizing enzyme. Whereas CYP4A1 is solely an ω-hydroxylase, CYP4A2 and CYP4A3 also catalyze arachidonate 11,12-epoxidation. Systemic administration of CYP4A1 antisense oligodeoxynucleotides reduced the level of CYP4A proteins and 20-HETE synthesis in renal vessels by 50%, and decreased blood pressure in SHR from 137±3 to 121±4 mmHg (p < 0.05). Immunoblot analysis and inhibitor studies indicated that within the renal vasculature CYP4A1 is primarily localized to the interlobar arteries. Transfection of CYP4A1 cDNA, cloned into the expression plasmid pcDNA3.1, to renal interlobar arteries increased CYP4A immunoreactivity by 3-fold and 20-HETE synthesis from 92±10 to 239±71 pg 20-HETE/mg/h. CYP4A1-transfected arteries demonstrated a marked increase in the constrictor responses to phenylephrine (EC
50
= 0.07±0.02 vs 0.37±0.04 μM). The increased constrictor responses to phenylephrine were greatly attenuated by DDMS, a selective inhibitor of 20-HETE synthesis (EC
50
from 0.07±0.01 to 0.74±0.11 μM) and by 20-HEDE, a specific 20-HETE antagonist (to 0.54±0.05 μM) without affecting the maximal response. The inhibitory effect of DDMS was reversed by addition of 20-HETE further substantiating the notion that increased endogenous levels of 20-HETE contributed to the increased vascular reactivity to phenylephrine in vessels expressing the CYP4A1 cDNA. Thus, 20-HETE of vascular origin serves as a stimulatory regulator of vascular responses to phenylephrine.
Increased Extracellular Signal-Regulated Kinase and Decreased Mitogen-Activated Protein Kinase Phosphatase-1 in Human Myocardium with Severe Congestive Heart Failure
Authors: Dong Yafeng , Conte Johns Hopkins Univ Baltimore John V , Wei Chiming
Published: March 2022

30

Mitogen-activated protein kinase (MAPK), also known as the extracellular signal regulated protein kinase (ERK), is a member of a family of serine/threonine kinases which are activated by various growth factors. To date, the expression of ERK and the nuclear dual-specificity tyrosine/threonine protein phosphatase MKP-1, a principal inactivating phosphatase of ERK1/ERK2 in many cell types, in myocardium with congestive heart failure (CHF) remain undefined. Therefore, the current study was designed to investigate ERK and MKP-1 activities in CHF patients. Cardiac tissue from normal subjects (n=5) and end-stage CHF patients (n=5) were obtained from cardiac transplantation. ERK and MKP-1 expression were determined by immunohistochemical staining (IHCS). The staining score (0-4) and positive staining area (0-100%) were determined. Both ERK and MKP-1 were expressed in nuclear and perinuclear regions of cardiomyocytes. In CHF patients, ERK phosphorylation IHCS score was significantly increased in right atrium (RA, 3.65±0.17), left atrium (LA, 3.66±0.14), right ventricle (RV, 3.72±0.11) and left ventricle (LV, 3.80±0.05) compared with normal subject RA (2.0±0.47, p<0.01), LA (1.26±0.48, p<0.01) and RV (1.02±0.37, p<0.01; normal LV tissue was not available). In contrast, MKP-1 IHCS score was significantly decreased in CHF patients (RA, 2.42±0.48; LA, 2.86±0.10; RV, 2.82±0.35; LV, 2.52±0.33) compared with normal subjects (RA, 3.92±0.04; LA, 3.75±0.10; RV, 3.77±0.06, p<0.01 vs. CHF patients). These studies first time demonstrated that ERK activity was significantly increased in human right and left atrial and ventricular myocardium with markedly decreased MKP-1 level in severe congestive heart failure. These data suggest that activation of MAPK and inhibition of MKP-1 may play a significant pathophysiological role in progression of cardiac hypertrophy and congestive heart failure.
Effect of Vasopeptidase Inhibition on Myocardial and Vascular Collagen in Stroke Prone Spontaneously Hypertensive Rats.
Authors: Pu Qian , Schiffrin Ernesto L
Published: March 2022

34

Left ventricular remodeling in hypertension is associated with cardiac interstitial and perivascular collagen deposition. The vasopeptidase inhibitor omapatrilat improves left ventricular remodeling in experimental heart failure. We hypothesized that omapatrilat would induce a regression of ventricular and vascular fibrosis in hypertension. We therefore investigated the effect of vasopeptidase inhibition on collagen deposition in heart and aorta of stroke prone spontaneously hypertensive rats (SHRSP). Ten-week old SHRSP were treated orally for 10 weeks with omapatrilat (40mg/kg/d). Collagen fibers in heart and descending thoracic aorta were stained with Sirius red. Collagen density was defined as the ratio of the area stained by Sirius red to the area of the studied field. After 10 weeks, systolic blood pressure was significantly (P<0.01) reduced in omapatrilat-treated vs untreated SHRSP. Collagen density was significantly decreased in the subendocardial myocardium of omapatrilat-treated vs untreated SHRSP (to 3.55 vs 7.53%, respectively, P<0.05) and in mid-myocardium (to 4.38 vs 7.92% respectively, P<0.01). Aortic collagen content decreased in omapatrilat-treated vs untreated SHRSP (to 22.7 vs 46.3×10
3
μm/mm section, respectively, P<0.05). In conclusion, in addition to being a potent anti-hypertensive agent, omapatrilat significantly improves ventricular and arterial structure in SHRSP with regression of collagen deposition.
Diminished Endothelial Function and Hypofibrinolysis in High Risk Patients with Hypertension and High Plasma Levels of Inflammatory Markers: Need for Anti-Inflammatory Strategy
Authors: Furumoto Tomoo , Fujii Satoshi , Saito Naotaka , Mikami Taisei , Kitabatake Akira
Published: March 2022

39

Hypertension and diminished fibrinolysis are major determinants of progression of atherosclerosis, which is now regarded as an inflammatory disease. Flow-mediated dilation (FMD) of brachial artery reflects endothelial function and is a sensitive index of early atherosclerosis. FMD is reduced in patients with hypertension. Whether antihypertensive therapy alters FMD, fibrinolytic function or inflammation in high risk patients is not elucidated. To characterize the relationships among markers of fibrinolysis, inflammation and FMD, plasma levels of tissue-type plasminogen activator (t-PA), a sensitive index of endothelial damage, and tumor necrosis factor (TNF)-α, an established marker of inflammation, were determined by high-sensitive enzyme linked immunosorbent assays in normotensive (N, n = 20) and hypertensive (H, n = 17; calcium blocker n = 13, ACE inhibitor n = 4) patients. Both groups were hospitalized for evaluation of coronary heart disease. FMD was determined by high-resolution ultrasound. Blood pressure of treated H (134 ± 7(SD) / 78 ± 5 mmHg) was not significantly different from that of N (123 ± 3 / 75 ± 3 mmHg). However, FMD was significantly reduced in H (8.9 ± 1.3% compared to N (16.8 ± 1.8%, p < 0.005). Nitroglycerine induced endothelium independent vasodilation was not altered in H (15.3 ± 1.5%) as compared to N (17.6 ± 1.5%, p = NS). Plasma t-PA levels were increased in H (10.5 ± 1.3 ng/ml) compared to N (8.4 ± 1.1 ng/ml), indicating continued endothelial damage despite blood pressure reduction. Plasma TNF-α levels were also increased in H (1.7 ± 0.2 pg/ml) compared to N (1.3 ± 0.1 pg/ml), indicating persistent inflammation. These results suggest that (1) antihypertensive therapy alone is not sufficient to improve endothelial dysfunction in hypertensive patients with high plasma levels of inflammatory markers, and (2) additional therapy to target inflammation is necessary to improve endothelial function and to prevent progression of coronary atherosclerosis in high risk hypertensive patients with subclinical inflammations.
Effect of Antioxidants on Salt-Induced Hypertension and Renal Dysfunction.
Authors: Trolliet Maria R , Forde Patrick , Rudd M. Audrey , Loscalzo Joseph
Published: March 2022

43

We have demonstrated that the development of salt-dependent hypertension and renal dysfunction in the Dahl salt-sensitive (DSS) rat is accompanied by the accumulation of reactive oxygen species (ROS). To determine whether oxidative stress contributes to the development of progressive renal dysfunction, we examined the effect of dietary vitamin E, a natural antioxidant, on a model of salt-dependent hypertension. Dahl salt-resistant (DSR) and DSS rats were kept on 8% NaCl (HS) or 8% NaCl + 1000 U./kg chow of vitamin E (HSE) for 2 weeks. During this time blood pressure was monitored using the tail plethismography method. After 14 days on the diets, DSS rats on HS diet were hypertensive, as compared to the DSR rats (171.3 ± 7.4 vs. 138.4 ± 2.4 mmHg; p<0.0001), whereas the animals on the HSE diet remained normotensive (125.1 ± 3.7 vs. 114.0 ± 5.4 mmHg). The animals were then instrumented for the evaluation of renal function, measured as clearance of para-aminohippuric acid (Cl
PAH
) and clearance of inulin (Cl
In
). As a measure of oxidative stress, kidney and blood samples were harvested for the determination of superoxide production and plasma 8-isoprostanes (8-IP), respectively. Results show that hypertensive DSS rats appear to have lower Cl
PAH
and Cl
In
, greater renal superoxide production, and greater plasma 8-IP concentration than the normotensive DSR rats (Cl
PAH
: 1.93 ± 0.15 vs. 4.11 ± 0.5 ml/min, p<0.005; Cl
In
: 1.21 ± 0.19 vs. 2.05 ± 0.60 ml/min., p<0.01; O
-
2
: 664 ± 33 vs. 374 ± 13 nmol/mg protein/min, p<0.05; and 8-IP: 1494.3 ± 93.4 vs. 386.6 ± 30.0 pM, p<0.001). However, when DSR and DSS rats were kept on the HSE diet, no differences were observed (Cl
PAH
: 3.31 ± 0.34 vs. 3.29 ± 0.45 ml/min; Cl
In
: 1.89 ± 0.16 vs. 2.03 ± 0.08 ml/min.; O
-
2
: 372 ± 10 vs. 344 ± 23 nmol/mg protein/min; and 8-IP: 276.1 ± 33.2 vs. 278.5 ± 28.3 pM). These results suggest that the incremental production of ROS during salt feeding in DSS rats plays a role in the development of hypertension and renal dysfunction in this model, and that the lipid-soluble antioxidant vitamin E can attenuate the production of ROS and prevent salt-induced hypertension and renal dysfunction.
The Role of Oxidative Stress in Dahl Salt-Sensitive Hypertension
Authors: Meng Shumei , Cason Garrick W , Racusen Lorraine C , Manning R. Davis
Published: March 2022

47

High sodium intake in the Dahl salt-sensitive (S) rat causes hypertension and renal damage. Our goal was to determine if long-term iv infusion of Tempol, a superoxide dismutase mimetic, would ameliorate the hypertension and reduce renal damage in Dahl S rats subjected to high sodium intake. Dahl S/Rapp rats with indwelling arterial and venous catheters were maintained by iv infusion for 3 weeks on either high Na(20.6 mEq/day)(HN), high Na + Tempol(125μmol/kg/h)(HNT)or low Na(0.9 mEq/day) + Tempol(LNT). Arterial pressure was measured 24 hours/day, and as seen in the figure, was significantly decreased in high Na S rats by Tempol.
†
-P<.05 compared to HNT,
*
-P<.05 compared to LNT. At the end of 3 weeks, rats were anesthetized with isoflurane, and kidneys were removed for histological examination. At this time, the percentage of glomeruli with either focal or global sclerosis in HN, HNT and LNT rats was 3.4±0.8
*
†,
1.4±0.4
†
and

0.6±0.08,

respectively, and glomerular cross-sectional area (mm
2
) was 14.3±0.4,12.9±0.5 and 12.2±0.6. Therefore, Tempol significantly reduced arterial pressure and indices of renal damage, glomerular sclerosis and glomerular cross-sectional area. These data suggest that oxidative stress significantly increases arterial pressure and exacerbates renal damage in salt-sensitive Dahl rats during increased sodium intake.
Transfer of a Single Genomic Region (RF-1) from the Fawn-Hooded Hypertensive Rat Onto the Genomic Background of the Aci Rat Results in Renal Impairment.
Authors: Provoost Abraham P , Shiozawa Masahide , Van Dokkum Richard P E
Published: March 2022

52

The fawn-hooded hypertensive (FHH) rat is an excellent experimental model to analyse the genetics of hypertension-associated renal damage. Male FHH rats spontaneously develop moderate hypertension and marked proteinuria early in life. Previous linkage analyses with crosses between FHH and ACI rats, revealed that at least five quantitative trait loci (QTLs), named
Rf-1
to
Rf-5
, were linked to proteinuria. The
Rf-1
locus on rat chromosome 1 had by far the highest LOD-score suggesting a major role in determining the severity of renal failure. The next step to identify the importance of the various QTLs is the generation of congenic strains for all five chromosomal regions. Here we report the first results obtained in
Rf-1
congenic rats. Using marker-assisted backcrossing, we transferred the
Rf-1
region, between the markers
D1Mit34
and
D1Mit156,
from the FHH genome onto the genomic background of the normotensive ACI rat. To determine the impact of
Rf-1 o
n the development of renal damage, we challenged the renal hemodynamic function of these congenic animals by unilateral nephrectomy (UNX) alone, or in combination with L-NAME-induced hypertension. The parental ACI strain was used as control. The various experimental groups consisted of 10-12 rats. During a 24 week follow-up period after UNX, the congenic strain, officially named ACI.FHH-
D1Mit34/Mit156
(
Rf-1B
for short), did develop significantly more proteinuria and albuminuria than the ACI rats. The differences between the
Rf-1B
congenic and ACI rats were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mm Hg,
i.e.
the level of hypertension normally present in the parental FHH strain. Histological analysis of the kidney showed that the incidence of glomerulosclerosis was also higher in the
Rf-1B
congenic rats. These findings provide the first direct evidence that the
Rf-1
region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increased blood pressure.