bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 205: Minimizing Post Procedural Bleeding Complications - A Quality Improvement Initiative
Authors: Ramamoorthy Sivaranjani , Shurpin Kathleen
Published: March 2022

Objectives:
The primary purpose of this study is to implement the National Cardiovascular Data Registry (NCDR) CathPCI bleeding risk score pre-procedurally, in order to identify the patients who are at high risk for bleeding complications and secondly, to examine accurate documentation to decrease hemorrhagic complications among adult patients undergoing percutaneous coronary intervention (PCI).

Background:
Bleeding is one of the most common complications of PCI. The NCDR CathPCI bleeding risk score can predict patient risk for bleeding complications pre-procedurally. This tool is recognized as an assessment tool that can modify bleeding risk among adult patients undergoing PCI. This validated, individualized bleeding risk score (BRS) is useful in clinical decision making to promote quality of care, patient safety, and patient satisfaction and PCI outcomes. Specific outcomes evaluated in this project include number of blood transfusion and length of stay (LOS). Currently, this BRS tool is under utilized in the clinical setting.

Methods:
A cross sectional study design was implemented for this quality improvement project in a major medical center in the Northeast. Retrospective clinical data review was conducted for adult patients who underwent PCI prior to initiation of the NCDR CathPCI assessment tool. A data collection form was implemented to obtain this retrospective data related to bleeding complications. The NCDR CathPCI bleeding score tool was then implemented for adult patients who underwent PCI. Prospective data collection after implementing NCDR cathPCI bleeding risk tool is in progress.

Results:
The preliminary findings of the retrospective data review prior to implementation of the NCDR CathPCI bleeding score suggests that, 34.4% of the patients who received blood transfusions had documented bleeding complications (hematoma 15.6% (10 of 64); retro-peritoneal bleeding 9.4% (6 of 64); gastrointestinal bleeding 9.4% (6 of 64). Only 14.1% (9 of 64) of these patients had a drop in hemoglobin of 3grams from the baseline prior to transfusion. There was also a lack of documentation of hematoma size. Chronically anemic patients who received blood transfusion without bleeding complications accounted for 65.6% (42 of 64) of the patients reviewed in the retrospective data review. Average LOS of patients who required blood transfusion was an average of 1.34 days when compared with patients who did not develop bleeding complications. Final results of the prospective data analysis post implementation of the NCDR CathPCI assessment tool are pending.

Conclusion:
Pending.
Abstract 214: Is Goal-Striving Stress Associated With Cardiovascular Disease Among Jackson Heart Study Participants?
Authors: Dawkins Milton R , Sims Mario , Diez-Roux Ana , Jackson James , Reese-Smith Jacqueline , Addison Clifton , Payton Marinelle , Jenkins Brenda
Published: March 2022

Introduction:
It is known that psychosocial stress is associated with cardiovascular disease (CVD). Recent research has reported that goal-striving stress (GSS) is associated with poor health outcomes for African Americans. GSS is the “¼discrepancy between aspiration and achievement, and the level of disappointment experienced if goals are not reached.” As far as we know, no research has examined the relationship between GSS and CVD prevalence among African Americans. Thus, the purpose of the current study was to investigate the association between GSS and CVD prevalence among a large sample of African Americans.

Methods:
The Jackson Heart Study (JHS) includes 5,181 men (37%) and women who completed a baseline survey to capture data on psychosocial variables, CVD history, demographic variables, and CVD risk factors. It was hypothesized that higher levels of GSS would be associated with CVD prevalence. The average GSS level was 4.49. GSS was categorized into tertiles with CVD prevalence and associations assessed cross-sectionally by multivariable logistic regression analysis that adjusted for demographic, behavioral and clinical risk factors.

Results:
It was found that GSS was significantly associated with CVD for tertiles 1, 2, and 3 at 41.26%, 36.25%, and 22.49% respectively. Additionally, GSS was significantly associated with CVD prevalence per unit increase after adjusting for age and sex (OR 1.03, 95% CI 1.02-1.05), SES (OR 1.03, 95% CI 1.02-1.05), and smoking, diet, physical activity, and sleep (OR 1.03, 95% CI 1.01-1.05). However, there was slight attenuation after adjustment for CVD risk factors (OR 1.01, 95% CI 0.99-1.04).

Conclusions:
The present study represents an important contribution to the literature in that it appears to be the first to empirically investigate the link between GSS and CVD prevalence among African American men and women.
Abstract 219: Marriage May Hold the Key to Lower Readmission Rates
Authors: Larin Katherine , Sylvester Rachel , Costin Nathaniel , Bradford Morgan , Kline-Rogers Eva , Eagle Kim A , Rubenfire Melvyn , Bumpus Sherry
Published: March 2022

Background:
Prior studies have shown that marital status can affect readmission rates. This study sought to determine whether marital status impacts patient outcomes in a population of BRIDGE (a post-discharge transitional cardiac care clinic) patients.

Methods:
Analysis was conducted for all BRIDGE patients referred from 2008-2013 with valid marital status information (n=1534). The population was divided into two cohorts, married (n=887) and not married (n=647). The unmarried group included those who marked “single” (n=406), “widowed” (n=218), or “other” (n=23). Outcome variables included 30, 60, 90, and 180 day readmission, ED visit, and death rates, and BRIDGE attendance and depression rates.

Results:
Married patients were significantly less likely to have an ED visit within 90 (20.0% v 23.8%, p=0.011) and 180 (30.1% v 33.5%, p=0.017) days of discharge. Married patients were also significantly less likely to have depression (20.1% v 29.6%, p<0.001) and were more likely to attend BRIDGE (74.0% v 69.6%, p=0.060), though not significantly.

Conclusions:
Marriage is associated with fewer long-term ED visits and lower rates of depression. These findings raise the question of whether providers should approach care and discharge instructions differently for patients who lack a spouse or other social support.
Abstract 221: Multiple Heart Failure Hospitalizations: Winning the War
Authors: Agunanne Enoch , Abbas Aamer , Mukherjee Debabrata
Published: March 2022

Background:
The lifetime risk of developing Heart Failure (HF) is 20% for Americans ≥40 years of age. In the United States, greater than 650,000 new HF cases are diagnosed annually. HF prevalence is highest in the >65 years group. Importantly, 1 in 5 Americans will be >65 years of age by 2050. Additionally, HF has high absolute mortality rates of approximately 50% within 5 years of diagnosis. The total cost of HF care in the United States exceeds $30 billion annually. Prior studies acknowledged that more research is needed to identify processes that are clearly associated with reduced readmissions.

Objective:
The objective was to examine the practice of proactive monitoring and communication of body weights among HF patient and their Health providers; and investigate its relationship with rate of rehospitalization for HF.

Methods:
In the retrospective phase of this study, analysis of the admission and 30, 60 to 90-day rehospitalization rates in HF patients at University Medical Center (UMC) between Oct 2010 and Oct 2013 was done. Inclusion criteria were: admission/re hospitalizations with HF. This included all stages of HF and both HF with reduced and preserved ejection fraction groups. Exclusion criteria were: patients lost to follow-up, death in hospital, transfer to another acute care facility, and discharge against medical advice. Demographics were also obtained. This phase was done as a baseline with primary purpose of studying the patterns of HF admissions in the index institution. In the prospective phase, data were collected from HF patients’ hospitalizations between September 2014 and February 2015. Inclusion/exclusion criteria were same as in retrospective phase. In this phase, the patients were randomly assigned to 2 groups: control and intervention. The control group received standard management for heart failure. The study (intervention) group received additional education that included keeping daily log of body weights and communications to Health Provider when post discharge weight exceeded 5 pounds. For both arms, HF rehospitalizations within 30 and 60-90 day periods were studied.

Results:
The HF 30-day rehospitalizations had an average rate of 18% over a 2 year period in the retrospective study. This was statistically not different from the HF 30-day rehospitalizations in the control arm of the prospective study. Following intervention, the HF 30-day rehospitalizations were fewer in the intervention group than in the control (6% [3 of 50] vs 18% [9 of 50]respectively; P < 0.05). Additionally, the HF 60 to 90-day rehospitalizations were fewer in the intervention group than in the control (10%[5 of 50] vs 30%[15 of 50] respectively; P < 0.05).

Conclusion:
Proactive monitoring of body weights in HF patients will lead to reduced HF rehospitalization in the short term. Subsequent studies will focus on longer term monitoring of HF rehospitalizations.
Abstract 231: Portrayal of Inappropriate Use of Myocardial Perfusion Imaging on Social Media and the Worldwide Web
Authors: Winchester David E , Baxter Diana , Beyth Rebecca J
Published: March 2022

Background:
Approximately 14.8% of nuclear myocardial perfusion imaging (MPI) tests in the United States are unnecessary. Patients and doctors are increasingly using social media and the web as part of their health care decisions. Little is known about the accuracy of information about MPI available to patients on social media which may affect patient education and joint decision making. The goal of this investigation was to determine whether information for patients on social media portrays an accurate representation of the risks and appropriate usage of MPI.

Methods:
We searched on Google Video, Google Web, and Twitter using search terms “nuclear stress test” (NST), “myocardial perfusion imaging”, and “choosing wisely stress test” (CW). Search results that did not specifically discuss MPI, were duplicative, or not English were discarded. Each search was continued until results were no longer relevant to the search term and topic. We evaluated all results for mention of radiation risks, alternative testing, possibility of false positive/negatives, and discouragement of unnecessary use such as annual/low risk/asymptomatic screening. For the primary outcome, we compared how frequently the results from each search term discussed unnecessary MPI.

Results:
None of our search results yielded material that encouraged unnecessary MPI. Radiation risks, alternative test options, and false positives/negatives were inconsistently discussed across search terms and sources. (Table) Depending on the search term, discouragement of unnecessary testing varied, 1.79% for NST, 10% for MPI, 64.4% for CW. In pairwise comparisons, search results for NST were less likely to discourage unnecessary testing than MPI (odds ratio [OR] 0.179, 95% confidence interval [CI] 0.044-.68, p = 0.005) and MPI was less likely to discourage unnecessary screening than CW (OR 0.155, 95% CI 0.059-0.393, (<0.0001).

Conclusion:
Publicly available information on the internet and social media does not encourage unnecessary testing. Depending on the search term used, unnecessary testing may be commonly or rarely discouraged. Important topics related to nuclear MPI, such as radiation and alternative testing options are not widely discussed.
Abstract 236: Prevalence of ECG Recording Errors in a University Hospital ECG Database
Authors: Moses Andrew , Malozzi Christopher , Omar Bassam
Published: March 2022

Background:
Electrocardiographic recording can suffer from several potential errors which may impact their proper interpretation and patient care.

Objective:
To assess the prevalence of reported ECG errors in a university hospital database with a mix of inpatient and outpatient electrocardiograms (ECG).

Methods:
The first 1000 ECGs performed during one month were downloaded and individually analyzed for reported errors and artifacts. There were 237 (23.7%) outpatient ECGs and 763 (76.3%) inpatient or emergency department ECGs. The types of errors are reported as absolute numbers and as percentages of the total errors.

Results:
Among 1000 ECGs analyzed, 65 ECGs (6.5%) contained error or artifact statements. Among those, 15 ECGs (23.1%) were perceived precordial lead misplacements simulating anterior myocardial infarctions. There were 5 ECGs (7.7%) with lead reversals; 3 of which were precordial lead reversals (4.6%) and 2 were limb lead reversals (3.1%). A total of 45 ECGs (69.2%) contained baseline artifacts; 27 ECGs (41.5%) had AC noise artifacts, and 18 ECGs (27.7%) had baseline wander artifacts. Out of the total ECGs with reported errors, 60 ECGs (92.3%) were performed in the inpatient or emergency department setting, while 5 ECGs (7.7%) were performed in the outpatient setting.

Discussion:
Electrocardiography remains the cornerstone of early diagnosis and treatment of cardiac disease in the inpatient and outpatient setting. ECG recording artifacts have been reported with variable frequency, with inpatient recordings likely suffering greater errors, depending on the acuity of the situation. We observed that in the outpatient setting, there was 2.1% (5/237) prevalence of recording error, while in the inpatient and emergency department setting there was 7.9% (60/763) prevalence of ECG recording errors. Despite the overall small percentages, this is an alarming problem, especially with regards to inpatient ECGs when the results often prompt critical treatment decisions. The reason for the discrepancy between inpatient and outpatient ECG errors is not clear. Potential causes may include the intensity of the situation with compromise of proper lead placement, such as use of Mason-Likar configuration or placing leads above the left breast in female patients or unavailability of proper recording surfaces as in trauma or burn patients, but may also be caused by the lack of availability of adequately trained staff especially in the after-hour situations. Adequate training of staff to perform proper ECGs, and creation of robust electrocardiographic interpretation algorithms to recognize more recording errors on-screen before printing is called for.
Abstract 261: The Impact of Exercise Training on Depression, Anxiety and Physical Capacity in Women After Myocardial Infarction
Authors: Korzeniowska-Kubacka Iwona , Piotrowska Dorota , Bilinska Maria , Piotrowicz Ryszard
Published: March 2022

Introduction:
Anxiety and depression are commonly observed risk factors in CAD patients, especially in women, and are also strong predictors of mortality in patients after myocardial infarction (MI).

Objectives:
The aim of the study was to assess the effectiveness of exercise training on depression, anxiety and physical capacity in women after MI.

Methods:
The study comprised 30 women aged 59.2±8.1 after MI. All subjects underwent an 8-week training program (TP) consisted of 24 interval trainings. At the beginning of and after completing the TP, all pts underwent (1) a symptom limited exercise stress test (EST) during which the following parameters were analyzed: maximal workload (W), duration (min), double product- DP (mmHg/min) at rest and at peak effort; (2) depression intensity assessed with the Beck Depression Inventory (BDI); (3) anxiety assessed with State-Trait Anxiety Inventory (STAI).

Results:
The depression intensity decreased significantly after TP (14.8±8.7 vs 10.5±8.8; p< 0.01). The initial anxiety manifestation for state anxiety was found to be 45.7±9.8 and decreased to 40.8±7.8 (p< 0.01) after TP.

Physical capacity improved significantly after TP: max workload 92.2±22.2 vs 108.6±26.1 (p< 0.001), EST duration 4.4±1.2 vs 5.4±1.4 (p<0.001), DP at rest 8584.8±1416 vs 8031.0±1562 (p<0.001), DP at peak effort 19511.9±3092 vs 20848.9±3970 (p<0.001).

Conclusions:

1. Participating in a training program beneficially contributed to a decrease in depression and anxiety manifestation in post-MI women.

2. Physical capacity improved significantly after training program.
Abstract 263: The Use of a Blood-Based Age/Sex/Gene Expression Test Helped Define Symptomatic Patients Unlikely to Benefit From Additional Anatomic or Functional Cardiac Testing: A Case Series Analysis in the Outpatient Cardiology Setting
Authors: Burkle Jaime , Hoffman David , Cheng Jin , Monane Mark
Published: March 2022

Background:
More effective tactics are needed to evaluate patients with suspected symptomatic obstructive coronary artery disease (CAD). Results from recent studies such as PROMISE demonstrated that < 10% of these patients had a cardiac cause for their symptoms. A previously validated blood-based test, incorporating age, sex, and gene expression levels, demonstrated a 96% negative predictive value among symptomatic, non-diabetic patients in the evaluation of obstructive CAD at a threshold score of 15 or less, where a low score is indicative of low likelihood of obstructive CAD.

Objective:
The objective of this retrospective, case-control study (NCT02223286) was to evaluate the use of an age/sex/gene expression score (ASGES) and conventional anatomic and functional testing in the diagnostic work-up of patients referred for assessment of stable symptoms suggestive of obstructive CAD in the cardiologist’s office.

Methods:
In this post-hoc case series analysis, patients with stable symptoms suggestive of obstructive CAD referred to two cardiologists underwent both ASGES (range 1-40) testing and additional cardiac testing, which included ETT, stress echo, MPI, or CCTA. Demographics and clinical factors as well as ASGES results (predefined as low score/low likelihood of obstructive CAD [ASGES ≤15] or elevated score/elevated likelihood of obstructive CAD [ASGES >15]) and other cardiac test results were collected.

Results:
Among 67 patients in this analysis, the mean age was 52 years, 60% of the patients were female, 30% were smokers, 54% had hypertension, and 60% had dyslipidemia. The mean ASGES score was 13, and 63% (42/67) of the patients had an ASGES ≤15 (low score). Upon additional cardiac testing, 0% (0/42) of patients with a low score as compared to 20% (5/25) of patients with an elevated score had at least one abnormal anatomical or functional cardiac test result (p<0.01).

Conclusion:
In this case series analysis, utilization of additional cardiac testing in low ASGES patients did not add new information for further clinical-decision making. Based on these findings, a strategy of using the ASGES test early in the diagnostic process may lead to a reduction of further cardiac testing among low ASGES patients who have a low likelihood of obstructive CAD.
Abstract 267: Use of Real-time Feedback to Improve Outcomes for In-Hospital Cardiac Arrest: One Center’s Experience
Authors: Harzand Arash , Shah Amit , Gunter Penny , Mladineo Christine , Zafari A. Maziar
Published: March 2022

Background:
In a 2013 consensus statement, the American Heart Association encouraged the use of real-time feedback during cardiopulmonary resuscitation (CPR) as a recommended best practice for in-hospital cardiac arrest (IHCA). Recent evidence suggests that the use of real-time feedback may lead to improvements in CPR quality in this setting; however there is a paucity of data on its widespread use and effect on outcomes.

Methods:
In a single-center retrospective cohort study, we reviewed IHCA event and outcome data from an institutional registry between June 2011 and October 2015. Charts were reviewed to retrieve missing data. Data on CPR-sensing defibrillator (Philips MRx) usage was obtained by direct download from defibrillators. Chi square and fisher exact tests were used for analysis.

Results:
We captured 220 reported episodes of IHCA for analysis. CPR-sensing defibrillators were used in only 17 cases (or 7.7% of total events). Return of spontaneous circulation (ROSC) was achieved in 60% of cases. Pulseless electrical activity (PEA) and asystole were the most commonly reported initial rhythm (78.2%), followed by ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) (14.1%) and undocumented cases (7.7%). There was no difference in rates of ROSC or sustained ROSC >20 minutes (p=0.38) based on initial rhythm. Survival to discharge and at 1 year was significantly higher in the VF/pulseless VT group than in the PEA/asystole group (46% vs. 14%, p<0.0001, and 30.4% vs. 5.8%, p=0.0007, respectively). Use of real-time feedback during CPR was not associated with any improvement in the rates of ROSC (p=0.67), survival to discharge (p=0.58) or survival at 1 year (p=0.19).

Conclusions:
CPR-sensing defibrillators for real-time feedback were used only in a small minority of cases and were not associated with any improvement in outcomes. Sustained efforts are needed; larger and adequately powered studies may provide clinically relevant information regarding the utility of CPR-sensing defibrillators.
Abstract 271: Variation in Practice Characteristics and Geographic Uptake of Novel Centers for Medicare and Medicaid Services Payment Model for CV Risk Reduction
Authors: Brown Nina C , Burd Carlye , Sanghavi Darshak
Published: March 2022

Background:
The Million Hearts® Cardiovascular Disease risk reduction model was developed to reduce CVD risk through patient level risk assessment and shared-decision making. Budgeted for $63 million (CMMI + Trust fund dollars should be included), it is the first CMS model to pay for prevention by tying payments to panel-wide 10-year risk eduction. The Model’s simple design does not require large operational or organizational changes and might appeal to a wider range of practices that have not previously enrolled in CMMI models.

Model Design & Payment:
The 5-year Model incentivizes providers to use the American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease (ASCVD) risk calculator to manage their highest risk patients. To test the efficacy of the model, half of all practices will be randomly assigned to the intervention group with the remaining practices assigned to the control group. For intervention practices, a monthly performance payment of up to $10 per beneficiary is provided based upon the total risk reduction. Practice enrollment was encouraged via partnership with major professional societies, social media, peer-reviewed publications, and direct outreach.

Discussion on Model and Participating Physician Group Practices:
The model attracted a broad range of 462 physician practices from all 50 states, including a high percentage of rural (35.3% 163 of 462), primary care/specialty clinics (48.9% 226 of 462) and community health centers (13.0% 60 of 462). The applicant pool represents 3,451 service delivery sites, employing 21,696 providers, delivering care to 4,864,390 Medicare beneficiaries. Over one half practices are small (39.8% 176 of 462, 5 or fewer providers) and medium (14.3% 66 of 462, 6-10 providers) in size. It is likely the model’s administrative simplicity drove large numbers of smaller practices that operate outside large health systems to apply. In addition, for the majority of practices that applied (42.2% 195 of 462), this is the first CMS model they participate in - another indication that the Model has attracted new practice types and sizes than other CMS Innovation models.
Intermittent Hypoxia Leads to Endothelin-Dependent Hypertension in a Rat Model of Sleep Apnea.
Authors: Kanagy Nancy L , Walker Benjimen R , Malvin Gary M , Nelin Leif D
Published: March 2022

2

Clinical studies of sleep apnea demonstrate that the associated hypoxia/hypercapnia (IH) causes systemic hypertension. Additional studies have found that patients with sleep apnea have elevated plasma levels of endothelin. We hypothesized that IH causes sustained hypertension by increasing endothelin production. Three days after surgery to implant arterial and venous catheters, rats were placed in chambers flushed with room air for 90 secs (21% O
2
/0% CO
2
) followed by 90 secs hypoxic/hypercapnic air (5% O
2
/5% CO
2
). This cycle was repeated throughout an 8 hr daily exposure period. Mean arterial pressure (MAP) was measured daily before the start of IH exposure. After 12 days of IH when MAP was significantly elevated (day 1=105±4 mmHg, day 12=140±7 mmHg), cumulative doses of a non-selective ET-receptor antagonist (
PD145065
) was administered iv to rats in room air.
PD145065
caused a concentration-dependent decrease in MAP in IH rats but did not alter blood pressure in non-IH control rats. We conclude that increased endothelin synthesis during IH causes hypertension.
Endothelin Antagonism Inhibits Collagen I Gene Activation and Leads to the Regression of Renal Vascular Fibrosis During Hypertension
Authors: Boffa Jean-Jacques , Lu Ying , Dussaule Jean-Claude , Chatziantoniou Christos
Published: March 2022

5

In previous studies (J.Clin.Invest. 101: 2781, 1998) we have observed that endothelin participates in the development of nephroangio- and glomerulo-sclerosis during hypertension. The present study has investigated whether endothelin antagonism leads to the regression of renal sclerotic lesions observed in late phases of hypertension. Experiments were performed in transgenic mice harboring the luciferase reporter gene under the control of the collagen I-α2 chain promoter. Hypertension was induced by inhibiting endogenous NO synthesis (L-NAME) for a 30-wk period. Systolic pressure gradually increased folIowing L-NAME administration, reaching a plateau of 165 mmHg after 10 wk of treatment. At the same time, collagen I gene expression was increased four-and ten-fold compared to control in afferent arterioles and glomeruli, respectively (p<0.01). This increase was accompanied by abnormal accumulation of collagens within the renal vasculature, as evidenced by Sirius red staining. When renal vascular lesions were established (20 wk of L-NAME treatment), bosentan, a mixed endothelin antagonist, was administered in a subgroup of animals for an additional period of 10 wk. Bosentan co-administration did not alter the increased systolic pressure at 30 wk (167±4 vs. 165±5 mmHg for the L-NAME and L-NAME+bosentan groups, respectively); in contrast, collagen I gene activity returned to control levels in renal vessels and glomeruli during endothelin receptor antagonism. This effect of bosentan was accompanied by a net improvement of renal vascular morphology as collagen and extracellular matrix deposition were substentially reduced in this group of animals (p<0.01 vs. L-NAME 20 and/or 30 wk). These data indicate that endothelin participates in the mechanisms maintaining renal vascular fibrosis by activating collagen I gene. Antagonism of endothelin normalizes collagen synthesis and regresses renal vascular fibrosis without altering systemic hemodynamics, suggesting thus, that endothelin receptor antagonists can provide a complementary approach to treat renal fibrotic complications associated to hypertension.
Hypoxia Upregulates AT1 Receptor Expression and Ang II Response to Osteopontin and Proliferation of Cultured Vascular Smooth Muscle (VSM) Cells
Authors: Sodhi Chhinder , Batlle Daniel , Sahai Atul
Published: March 2022

13

Hypertension is often associated with arterial vasoconstriction which, if severe, may cause local hypoxia. Hypoxia, in turn, stimulates osteopontin (OPN, an adhesion molecule) synthesis and proliferation of VSM cells, which are the key events in the development of atherosclerosis. In the present study, we examined the effect of hypoxia on the expression of Ang II receptor AT1 in cultured VSM cells, and determined whether Ang II-induced regulation of AT1, OPN, and proliferation of VSM cells are altered under hypoxic conditions. Rat aortic VSM cells in culture were rendered quiescent and exposed in a serum-free medium either to hypoxia (3% O
2
) or normoxia (18% O
2
) for 2-24 hours in the absence or presence of 1 uM Ang II. Northern blot analysis shows 40-90% increases in AT1 mRNA levels by hypoxia. Consistent with the upregulation of AT1 mRNA levels, hypoxia induced a 125% increase in [
125
I]Ang II binding, suggesting an increase in AT1 receptor density. Parallel to the increases in AT1 expression, cells exposed to hypoxia produced 40-50% stimulation of OPN mRNA and protein levels as assessed by northern and western blot analysis. Treatment with Ang II for 24 hours under normoxic conditions resulted in a 235% and 45% increases in OPN and [
3
H]-thymidine incorporation, respectively. However, under hypoxic conditions Ang II-induced increases in OPN and [
3
H]-thymidine incorporation were enhanced to 387% and 173%, respectively. Incubation with Ang II for 24 hours under normoxic conditions resulted in a 62% inhibition of AT1 mRNA levels. By contrast, the downregulation of AT1 expression by Ang II was blunted under conditions of hypoxia. In conclusion, hypoxia upregulates the expression of AT1 receptors in cultured VSM cells and blocks the downregulation of AT1 expression expected with excess of Ang II. This hypoxia-induced increase in AT1 receptors may, in part, explain the enhancement of OPN synthesis and proliferation of VSM cells observed with Ang II in an environment of hypoxia associated with local vasoconstriction.
Baroreflexes Prevent Neurally Induced Sodium Retention in Angiotensin Hypertension
Authors: Lohmeier Thomas E , Lohmeier Justin R , Haque Atif , Hildebrandt Drew A
Published: March 2022

14

Recent studies indicate that renal sympathetic nerve activity is chronically supressed during angiotensin (ANG II) hypertension. To determine whether cardiopulmonary reflexes and/or arterial baroreflexes mediate this chronic renal sympathoinhibition, experiments were conducted in 5 conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (DEN) and innervated (INN) kidneys. Dogs were studied before and after deafferentation of cardiopulmonary receptors and arterial baroreceptors (CPD + SAD). After control measurements, ANG II was infused for 5 days at a rate of 5 ng/kg/min; this was followed by a 5-day recovery period. In the intact state, 24-h control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from DEN and INN kidneys (DEN/INN) were 98±4 mm Hg and 1.04±0.04 respectively. As expected, sodium retention occurred for several days during ANG II infusion before sodium balance was achieved at an increase in MAP of 30-35 mm Hg. Throughout ANG II infusion, there was a substantially greater rate of sodium excretion from INN versus DEN kidneys (day 5 DEN/INN-sodium = 0.51±0.05), indicating chronic suppression of renal sympathetic nerve activity. CPD + SAD did not influence baseline values for either MAP or the DEN/INN-sodium, nor did it alter the severity of ANG II hypertension. However, after CPD + SAD there was an appreciably lower, rather than a greater, rate of sodium excretion from INN versus DEN kidneys during ANG II hypertension (day 5 DEN/INN-sodium = 2.02±0.14). These data indicate that cardiac and/or arterial baroreflexes chronically inhibit renal sympathetic nerve activity during ANG II hypertension and that in the absence of these reflexes, ANG II has sustained renal sympathoexcitatory effects that promote sodium retention.
Deficiency of Endogenous Angiotensin-(1-7) in the Nucleus Tractus Solitarii of (mREN2)27 Transgenic Rats May Account for Diminished Baroreceptor Reflex Function.
Authors: Diz Debra I , Westwood Brian M
Published: March 2022

17

Endogenous Ang-(1-7) facilitates and Ang II attenuates gain sensitivity of the baroreceptor reflex control of heart rate (HR) on the basis of injections of the Ang-(1-7) antagonist [D-Ala
7
]-Ang-(1-7) or Ang II AT
1
antagonists into the solitary tract nucleus (nTS). In (mREN2)27 renin transgenic rats (TGR+), there is a 2 fold elevation of Ang II in the medulla oblongata while Ang-(1-7) levels are 50% that observed in normotensive SD rats. To determine the potential role of Ang-(1-7) in altered reflex function as a result of an imbalance of Ang peptides in the nTS, the baroreceptor reflex control of HR and cardiac chemoreceptor reflex were tested before and after bilateral injection of the [D-Ala
7
]-Ang-(1-7) antagonist (144 pmol/120 nl) directly into the nTS of either SD or TGR+. HR and blood pressure (BP) responses to graded doses of phenylephrine were used to determine the slope of the relationship between changes in BP and changes in pulse interval for each animal (baroreceptor reflex sensitivity). TGR+ exhibited an impaired baroreflex compared with SD (0.9 ± 0.2 msec/mm Hg in SD, n = 8, versus 0.4 ±0.1 msec/mm Hg in TGR+, n = 6; p < 0.05). [D-Ala
7
]-Ang-(1-7) attenuated the reflex (0.9 ± 0.2 msec/mm Hg before versus 0.4 ± 0.1 msec/mm Hg 10 minutes after antagonist, p < 0.05) in SD rats. There was no effect of [D-Ala
7
]-Ang-(1-7) on the baroreflex in TGR+ (0.4 ± 0.1 msec/mm Hg before versus 0.4 ± 0.1 msec/mm Hg after) or on cardiac chemoreceptor activation by phenylbiguanide (10 μg/kg, iv bolus) in either strain [SD: -40 ± 7 mm Hg and -120 ± 36 beats/min before versus -36 ± 6 mm Hg and -108 ± 38 beats/min after; TGR+: -24 ± 5 mm Hg and -76 ± 31 beats/min before versus -25 ± 4 mm Hg and -106 ± 44 beats/min after]. The present findings indicate that endogenous Ang-(1-7) provides tonic input at novel, non-AT
1
, non-AT
2
receptors in nTS to facilitate reflex control of HR in normotensive but not hypertensive rats. Our studies further reveal that tonic effects of Ang-(1-7) in the nTS influence baro- but not cardiac chemoreceptor activation. (HL-38535, HL-51952, HL-07790)
AT
1
Receptor Antagonist Combats Oxidative Stress in the JGA of the SHR
Authors: Welch William J , Wilcox Christopher S
Published: March 2022

24

The tubuloglomerular feedback (TGF) responses of the SHR are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT
1
-R). Since AT
1
-R enhance oxygen radical (O
2
-
) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula densa (MD)-derived nitric oxide (NO) because of excessive AT
1
-R-dependent generation of O
2
-
. Groups (n=6-9) of SHR and control WKY rats received vehicle (Veh), the AT
1
-R antagonist candesartan (Cand; 3 mg·kg
-1
·d
-1
) or non-specific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared to WKY, the elevated mean arterial pressure of SHR (WKY: 125±2 vs. SHR: 163±9 mmHg; p<0.001) was reduced (p<0.001) similarly in SHR by Cand and HHR (121±5 and 116±5 mmHg, ns). The SHR had an increased maximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR; 11.2±0.5 vs. WKY; 8.3±0.4 mmHg; p<0.01) and a reduced TGF response to blockade of neuronal (n) NOS in the MD with luminal 7-nitroindazole (7-NI: ΔTGF in WKY: +2.8±0.4 vs. SHR +1.1±0.6 mmHg; p<0.05). Although the elevated TGF responses of SHR were normalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (ΔTGF with 7-NI: +1.8±0.4 vs. Cand +3.4±0.5 mmHg; p<0.05). To abrogate the local effects of O
2
-
, tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (ΔTGF with 7-NI during tempol: Veh, +6.3±1.0 and HHR, +4.5±0.8 mmHg; p<0.01 vs. no tempol for both) implying that the effects of NO had been prevented because of excessive O
2
-
. In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (ΔTGF with 7-NI during tempol: +2.9±0.9; ns compared to no tempol). In conclusion, TGF responses of SHR are exaggerated due to effects of hypertension and AT
1
-R. AT
1
-R blockade specifically diminishes oxidative stress and restores NO signaling in the JGA of the SHR.
The Role of Egr-1 in the Cardiac Remodeling During Chronic Pressure Overload
Authors: Fratta Luigi , Calogero Antonella , d’Amati Giulia , Poulet Roberta , Arcella Antonella , Notte Antonella , Trimarco Bruno , Lembo Giuseppe
Published: March 2022

28

Early growth response-1 (Egr-1) is a transcription factor which is activated in the left ventricle during the onset of myocardial hypertrophy in response to pressure overload, but its role in cardiac remodeling is still unclear. The recent generation by homologous recombination of mice which have ablated Egr-1 allows to explore this issue. In particular, we exposed Egr-1 null mice (-/-, n=18) and their wild-type littermates (+/+, n=20) to chronic pressure overload induced by transverse aortic constriction (TAC) between left carotid artery and truncus anonimus. In sham operated mice (+/+ n=6; -/- n=7) basal fractional shortening, as an index of left ventricular function evaluated by transthoracic echocardiography, (47.4±.6 vs 48.4±.7 %, n.s.) and left ventricular weight/body weight ratio (LVW/BW, mg/g), an index of left ventricular mass, (3.2±.1 vs 3.1±.1 mg/g, n.s.) were comparable in +/+ and -/- mice. After 7 days of chronic pressure overload, despite systolic pressure gradient across the stenosis was comparable between the two mice strains (62±5 vs 67±6 mmHg, n.s.), -/- mice showed a lower LVW/BW as compared to +/+ mice (4.4±.2 vs 5.7±.3 mg/g, p<0.01). Moreover, the histological analysis disclosed a markedly reduced left ventricle perivascular and interstitial fibrosis in -/- TAC mice as compared to that observed in +/+ TAC mice. Interestingly, left ventricular gene expression of fibronectin and collagen I and III was significantly reduced in -/- TAC mice when compared with +/+ TAC mice. These data demonstrate that Egr-1 activation affects the stromal reaction involved in the cardiac remodeling due to pressure overload, suggesting that Egr-1 may be a molecular target of novel therapeutic strategies focused to modulate specific features of the cardiac hypertrophic remodeling.
Antihypertensive Pharmacogenetics: The C825T Polymorphism of G-Protein β
3
Subunit (
GNB3
) Is Associated with Greater Blood Pressure (BP) Response to Diuretic Therapy in Essential Hypertension (EHT)
Authors: Turner Stephen T , Schwartz Gary L , Chapman Arlene B , Boerwinkle Eric
Published: March 2022

37

Knowledge of genetic factors that influence pharmacodynamics of responses to antihypertensive drugs may provide insights into molecular mechanisms contributing to elevation of BP and response to treatment. The T-allele of the C825T polymorphism of the gene coding for the G-protein β
3
subunit (
GNB3
) has been associated with increased Na
+
-H
+
exchange and low plasma renin in individuals with EHT. Moreover, diminished counterregulatory activity of the renin-angiotensin system has been associated with greater BP declines in response to negative sodium balance induced by diuretic therapy. To assess the possible influence of
GNB3
genotype on BP response to diuretic therapy, we measured the C825T polymorphism in community-based samples of 204 blacks (139 women, 65 men) and 192 whites (77 women, 115 men) with EHT (mean age=48±7 years) who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. In univariate analyses, the TT genotype was significantly associated with lower plasma renin activity (
p
<0.001) and higher plasma aldosterone concentration (
p
<0.019). In addition, mean declines in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 6±2 mmHg (
p
<0.001) and 5±1 mmHg (
p
<0.001) greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between homozygote groups. Other univariate predictors of greater declines in both SBP and DBP were higher pretreatment BP (
p
<0.001), black race (
p
<0.001), female gender (
p
<0.005), older age (
p
≤0.064), lower waist/hip ratio (p≤0.087), and lower plasma renin activity (
p
<0.001). Even after considering effects of these other predictors, the TT genotype remained associated with greater declines in SBP (
p
<0.058) and DBP (
p
<0.001). Thus, the C825T polymorphism of GNB3 may help identify individuals with EHT who are more responsive to diuretic therapy and may have Na
+
-dependent BP elevation.
24 H Ambulatory Blood Pressure Variability and Carotid Artery Damage: Baseline Data from the Elsa Study.
Authors: Mancia Giuseppe , Parati Gianfranco , Hennig Michael , Flatau Birgit , Omboni Stefano , Luca Ospedale S. , Bond Gene , Zanchetti Alberto
Published: March 2022

38

Aim of our study was to evaluate the relationship of carotid intima-media thickness (IMT) with clinic (C) and 24 h ambulatory blood pressure (ABP) and with 24 h BP variability (V), from baseline data of the European Lacidipine Study on Atherosclerosis (ELSA). Design and Methods: In 1663 hypertensive patients in washout from treatment (56.2± 7.6 years; 54.4% males) several measures of maximum IMT were obtained from up to 12 different carotid sites by intensively trained and repeatedly certified sonographers. CBP was the average of 3 sitting measurements. From ABP recordings (Spacelabs 90207 or Takeda TM2021) we obtained: 1) 24 h, day and night average SBP and DBP, 2) day-night SBP and DBP differences of means ( -Δ), 3) 24h, day and night SBP and DBP standard deviations (SD, measure of BPV).Similar calculations were done for PP and HR. The influence of ABP and C variables on IMT was investigated by univariate and multiple regression analyses. Results: In the univariate analysis IMT was not related to C or 24h DBP, but was significantly related to C SBP (r from 0.16 to 0.21; p<0.001 for all), to C PP (r from 0.18 to 0.23; p<0.001) and even more to 24h SBP (r from 0.17 to 0.23; p<0.001) and to 24h PP (r from 0.24 to 0.32; p<0.001). In the multiple regression analysis, after accounting for age and average 24 h SBP or PP (p<0.001), IMT was positively associated with SBP and PP 24h SD (p<0.001) and negatively with SBP and PP day-night Δ and with 24h HR SD (p<0.05). Conclusions: This is the first demonstration from one of the largest available databases that the vascular adverse consequences of hypertension 1)are related more closely to 24h PP and SBP means than to C values, and 2)are related not only to mean BP levels but also to the degree of PP and SBP fluctuations over 24h.
Antihypertensive Pharmacogenetics: Effects of Angiotensin-Converting-Enzyme (ACE) Genotype-By-Gender Interaction on Blood Pressure (BP) Responses to a Thiazide Diuretic in Essential Hypertension (EHT)
Authors: Schwartz Gary L , Turner Stephen T , Chapman Arlene B , Boerwinkle Eric
Published: March 2022

41

Previous studies suggest that genetic factors influence the BP response to changes in Na
+
balance by altering activity of the renin-angiotensin system. The insertion/deletion (I/D) polymorphism of the ACE gene is known to be associated with variation in plasma ACE activity and may influence BP in a gender-specific manner. To assess effects of the ACE genotype and gender on BP responses to diuretic therapy, we measured the I/D polymorphism in community-based samples of 197 Blacks (133 women, 64 men) and 187 Whites (77 women, 110 men) with EHT (mean age= 48±7 years), who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. Consistent with other studies, the D-allele was associated with significant codominant increases in plasma ACE activity in all race-gender groups. Univariate predictors of greater declines in both systolic BP (SBP) and diastolic BP (DBP) were higher pretreatment BP (
P
<0.001), Black race (
P
≤0.005), female gender (
P
<0.001), older age (
P
≤0.064), and lower waist/hip ratio (
P
≤0.087). In linear models that considered the effects of all predictors, there was significant interaction between the effects of ACE genotype and gender on the responses of both SBP (
P
≤0.004) and DBP (
P
<0.001) to HCTZ. Among women of both races, mean declines in SBP (
P
≤0.012) and DBP (
P
≤0.025) were greater in II than in DD homozygotes. In contrast, among men of both races mean declines in SBP (
P
≤0.164) and DBP (
P
≤0.007) were greater in DD than in II homozygotes. In both genders, BP declines were intermediate in heterozygotes. Thus, although the effects of ACE genotype on plasma ACE activity are independent of gender, the effects of ACE genotype on BP responses to thiazide diuretic therapy appear to be gender-specific.
Hypertension in Transgenic Mice Expressing the Rac-1 Protein in Vascular Smooth Muscle
Authors: Morris Mariana , Marialuisa Marcelo , Goldschmidt-Clermont Pascal , Hassanain Hamdy
Published: March 2022

46

A novel transgenic mice has been generated which overexpresses the constitutively activated mutant form of human Rac 1 (Rac-CA), a small GTP-binding protein of the Rho family, in smooth muscle cells. Experiments were conducted to determine whether chronic activation of Rac-1 affects blood pressure (BP) and heart rate (HR). Male Rac-CA and control mice were prepared for chronic cardiovascular monitoring using carotid arterial catheters infused with heparinized saline. BP and HR were measured continuously for more than 4 days. Results show an increased BP in Rac-CA with no change in HR or water intake. BP was consistently higher in Rac-CA mice (Figure), averaging 122±4 vs 109±4 mm Hg during the dark phase (Rac-CA vs Control). HR showed a night/day rhythm with no differences between the Rac-CA and Controls, respectively, 640±15 vs 610±11 bpm (dark) and 572 ±39 vs 578 ±18 (light). These results illustrate that alteration in intracellular signaling (reactive oxygen species) in vascular smooth muscle produces changes in blood pressure. The mild to moderate hypertension observed in this animal model is similar to the human condition.
Genetic Modifiers of Mortality and Kidney Structure in Type 1a (AT1A) Angiotensin II Receptor Deficiency
Authors: Le Thu H , Fogo Agnes , Oliverio Michael I , Peterson Andrew S , Smithies Oliver , Coffman Thomas M
Published: March 2022

50

We have previously reported significant background gene effects on the phenotype of mice with targeted deletion of the AT
1A
receptor gene (
Agtr1a
). On 129 or C57BL/6 backgrounds, most
Agtr1a-/-
mice die before weaning and those that survive develop marked abnormalities of kidney structure, including atrophy of the renal papilla and medial thickening of small renal arteries. In contrast, peri-natal survival and kidney structure are normal in F
1
(C57BL/6 x 129)
Agtr1a-/-
animals, suggesting that there are distinct recessive genetic modifiers on both the C57BL/6 and 129 backgrounds that modulate the phenotype of AT
1A
receptor-deficiency. To further explore the characteristics of these modifying loci, we performed inter-crosses between F
1
(C57BL/6 x 129)
Agtr1a-
/- mice and evaluated the phenotypes of the resulting F2
Agtr1a-/-
progeny. A simple model of two recessive modifier loci, one from each strain with complete penetrance, predicts that 44% of these F2 animals should manifest the trait of interest (either mortality or vascular pathology). Among 70 consecutive F2 progeny, only 4 pups were lost between birth and 21 days of age (94% survival). On pathological examination of the surviving mice, 33 or 50% had typical renal vascular pathology, while the remaining 33 had normal renal vessels. The frequency of post-natal mortality was significantly less than that predicted by this 2 locus model (p<0.0003 by chi-square), suggesting that there are multiple modifying loci for this trait. On the other hand, for renal vascular pathology, the observed number of affected F2 animals (50%) was not significantly different from the number predicted by our hypothetical model (p=0.31 by chi-square). These findings support a model of two distinct recessive modifier loci, one from each strain, that confer susceptibility to vascular pathology. Efforts are underway to indentify these genetic modifiers by genomic micro-satellite analysis.