bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 226: Patient and Clinician Reported Non-Routine Events During Periprocedural Cardiac Catheterization
Authors: Joshi Gagandeep , Leo Troy , Weinger Matthew , Fong Pete , Slagle Jason , Anders Shilo
Published: July 2021

Awareness in the realm of patient safety and quality improvement has become increasingly important in healthcare. Understanding the factors that influence these tenets can help improve the overall care for patients and potentially improve patient outcomes. One tool to assist in identifying those factors is the study of non-routine events (NREs). A non-routine event is defined as any event that deviates from optimal or expected care for a specific patient in a specific clinical situation. The goals of this study are to ascertain what aspects of their clinical encounters do patients and families view as “non-routine” and reflective of lower care safety or quality, delineate factors that influence the reporting of NREs and affect the nature of the reported NREs, and determine whether NREs obtained from patients/families significantly add to evidence about clinical system failure modes beyond that obtained from clinicians caring for the same patients. We concurrently captured and compared NRE’s reported by patients/families and their clinicians in patients having a cardiac catheterization. To date, the use of NREs to advance the quality of healthcare has primarily been identified in the surgical literature, making this project unique in regards to the use of NREs in the catheterization lab. At defined times in each care episode, trained researchers used a structured survey to identify and elucidate NREs from the patient, family members, and care providers. After we obtained informed consent, we obtained participant and system factors including individual (age, education, literacy, health status, satisfaction), contextual (self-reported stress, frustration, and performance level), and system (staffing and unit workload) factors. NREs will be characterized by incidence, source, type, and severity by two independent raters. Qualitative and multivariate statistical analyses will be performed. Of the 130 cases studied, we collected 189 patient reported NREs and 107 clinician-reported NRE’s. Ninety cases (69%) contained patient reported NREs while sixty cases (46%) contained clinician reported NREs, and forty-five (35%) cases contained both clinician and patient reported NREs. This site had 129 total patients and 130 total cases (one patient was interviewed on two separate encounters). Given ongoing data analysis, only preliminary findings can be concluded at this time: 1) patient and family members reported a substantial number of NREs with many related to the patients’ health, 2) virtually none of the patient reported NREs were reported or known by clinicians yet a substantial number were deemed relevant by patients to the quality and safety of their care, and 3) the reported NREs provided useful information about care delivery systems and how to address their shortcomings. Further studies are needed to elucidate the effect of studying patient NREs on outcomes such as morbidity and mortality.
Abstract 241: Registry vs. Real World: Revascularization Treatment and In-Hospital Mortality Among STEMI Patients
Authors: Pathak Elizabeth B
Published: July 2021

Objective:
Hospital-based cardiovascular disease registries provide important clinical data on treatments and outcomes. However, the voluntary paid-membership nature of these registries makes them vulnerable to selection bias. In this study, recent ST-elevation myocardial infarction (STEMI) patient treatment rates were compared between registry and non-registry hospitals.

Methods:
The published list of Florida hospitals in the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry during 2013-2014 was obtained from the ACTION website. All-payer hospital discharge data with 100% coverage were analyzed. STEMI patient characteristics, treatment, and outcomes were compared for registry vs. non-registry hospitals for one year, using detailed ICD-9-CM diagnosis and procedure codes. Treatments identified were primary percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), and infusion/injection of fibrinolytic drugs (LYTICS).

Results:
A minority of acute-care hospitals participated in the ACTION registry in Florida during 2013-2014, admitting 1/3 of STEMI patients. Statewide, there were 10,592 STEMI patients hospitalized. In the ACTION hospitals, treatment rates were: same-day PCI = 70.5%, CABG = 8.7%, PCI on a later day = 6.2%, PCI with timing unknown = 2.5%, LYTICS alone = 0.1%. Patients who received no treatment comprised 12.1% of patients in registry hospitals vs. 15.6% in non-registry hospitals. Registry no treatment rates were lower for all race-gender groups, with the greatest difference in Black women (15.7% vs. 21.8% no treatment). Treatment rates varied by age (see Figure). After Medicare eligibility age (65+), treatment differences narrowed. Unadjusted in-hospital mortality rates were greater in non-registry hospitals for patients who received same-day PCI (5.3% vs. 4.1%) and PCI later (5.5% vs. 2.5%), but were lower for CABG patients (5.3% vs. 8.0%).

Conclusions:
Patients treated at non-ACTION hospitals were somewhat less likely to receive any revascularization therapy, and had higher overall unadjusted rates of mortality. Registry participating institutions may be a selected “best practices” group of hospitals, from which national generalizations should be derived with caution.
Abstract 258: The Direct Healthcare Expenditures of Mitral Valve Disease: Evidence From US National Survey Data
Authors: Mallow Peter J , Chen Jie , Moore Matthew , Rizzo John A
Published: July 2021

Objectives:
This study quantified the incremental direct healthcare expenditures of mitral valve disease (MVD) to insurers and individuals, stratified by asymptomatic and symptomatic disease status.

Methods:
Using 1996-2011 data from the United States (US) Medical Expenditure Panel Survey (MEPS), a large nationally-representative database, this study performed multivariate analyses of the incremental annual healthcare expenditures for insurers and out-of-pocket expenditures for individuals with MVD compared to individuals with no valvular disease. The healthcare expenditures were reported at the individual and US aggregate levels. Individuals with MVD were identified by International Classification of Disease Codes, 9th revision and stratified as either symptomatic or asymptomatic based on the presence of comorbid conditions. Sensitivity analyses were performed to test the robustness of the results. All expenditure data were adjusted to 2011 using the Medical Care component of the Consumer Price Index (CPI).

Results:
The MEPS database included 1,051 individuals with MVD. Asymptomatic individuals comprised 70% (736) of the population. Asymptomatic MVD individuals incurred $1,755 more overall annual healthcare expenditures per individual compared to those without valvular disease. Symptomatic MVD individuals incurred $5,163 more overall annual healthcare expenditures per individual compared to those without valvular disease. For both asymptomatic and symptomatic patients, the majority of direct healthcare expenditures were borne by the insurer ($1,360 and $4,718, respectively) rather than the individual ($395 and $445, respectively). When aggregated to the US population, MVD accounted for an incremental annual expenditure of $2.6 billion. Asymptomatic MVD expenditures were $1.1 billion and symptomatic, $1.5 billion. Sensitivity analysis indicated that the incremental annual expenditures ranged from $2.1 billion to $3.1 billion.

Conclusions:
These findings indicated that the incremental burden of MVD was substantial in the overall US population. The majority of MVD patients are over 55 years of age and likely comprise a disproportionate share of the US aggregate burden. Further research is necessary to understand the individual economic burden in this age group.
Abstract 264: Timing of In-Hospital Cardiac Arrest and Association with Survival to Discharge and Subsequent Length of Stay
Authors: Qazi Abdul H , Kennedy Kevin , Chan Paul
Published: July 2021

Background:
In-hospital cardiac arrest (IHCA) is common and often fatal. To date, the time from admission to IHCA has not been described, and the association between timing of cardiac arrest and likelihood of survival to discharge and subsequent hospital length of stay (LOS) is unknown.

Methods:
Within the national Get with the Guidelines Resuscitation registry, we identified 175,904 patients admitted between 2000 and 2013 with an IHCA. For each patient, the time from admission to IHCA was determined and categorized as early (7 days). Multivariable hierarchical logistic regression models examined the association between timing of IHCA and both survival to discharge and, among survivors, subsequent LOS from date of IHCA.

Results:
Overall, the mean and median times from admission to IHCA were 5.3 ± 6.3 days and 3 days (IQR: 1-8), respectively. Nearly half (83,811 [47.6%]) of patients had their IHCA 7 days from admission, respectively. After adjustment for patient and and cardiac arrest factors, cardiac arrests occurring later during the hospitalization were associated with modestly lower survival (reference: 7 days: adjusted OR 0.89 [0.86-0.92]; P<.01). However, this association pertained only to patients with a shockable IHCA (P for interaction between shockable and non-shockable rhythms: <0.001). Lastly, among those surviving to discharge, later timing of IHCA was associated with much longer subsequent LOS (reference: 7 days: 6.8 additional days [6.3-7.3]; P<0.001).

Conclusion:
Most IHCA occur after the first 72 hours of admission. Patients with IHCA >3 days from admission had significantly lower hospital survival and longer hospitalizations from the time of cardiac arrest.
Abstract 270: Variation in Chronic Heart Failure and Ischemic Heart Disease Death Rates Among Veterans Affairs Medical Centers
Authors: Groeneveld Peter W , Richardson Diane , Medvedeva Elina , Hin Sakhena , Epstein Andrew J
Published: July 2021

Objectives:
Chronic heart failure (CHF) and ischemic heart disease (IHD) are common chronic cardiovascular conditions among patients in the Veterans Health Administration (VA), yet the extent of variation in death rates for these two chronic diseases across VA medical centers is unknown. We sought to measure this variation, as wide variation in cardiovascular death rates across VA medical centers could indicate underlying variation in health care quality.

Methods:
Administrative data were obtained from the VA Informatics and Computing Infrastructure (VINCI) system on all veterans receiving care in the VA from October 1, 2009 to March 31, 2014. Patients with an inpatient or outpatient administrative record that included an ICD-9 diagnosis code for CHF or IHD were selected into the CHF or IHD cohorts, respectively (patients could be members of both cohorts). Each patient was then assigned to the VA medical center (including its “satellite” clinics) at which he/she had received the plurality of VA medical care during this 4.5 year period. Patient mortality was assessed using the VA’s Vital Status File, which includes death information reported by VA health care facilities, the VA National Cemetery Administration, and the Social Security Administration. Each VA medical center’s CHF-specific and IHD-specific mortality rate was calculated and annualized (i.e., the death rate per year was calculated based on person-years at risk).

Results:
CHF patients (n=348,264) were followed for a mean of 3.6 years, and IHD patients (n=931,490) were followed for a mean of 4.0 years. For each chronic disease, there were only modest differences across VAMCs in the percentage of female patients, mean patient age, and the mean number of clinical comorbidities (as assessed by ICD-9 diagnosis codes). Across the VA’s 129 medical centers, the median annual death rate was 13.1% in the CHF cohort (minimum=10.0% [2032 deaths in 20,244 person-years], maximum=15.2% [597 deaths in 3934 person-years], p<0.001 for the min-max difference). The median annual death rate in the IHD cohort was 7.8% during the same time period (minimum=5.9% [259 deaths in 4368 person-years], maximum=9.0% [1255 deaths in 13,816 person-years], p<0.001 for the min-max difference).

Conclusions:
During 2010-2014 there were markedly different mortality rates among patients with CHF and IHD across VA medical centers nationwide. These mortality differences cannot be explained entirely by demographic or clinical differences among patient populations. Hence, it is possible that variation in cardiovascular care quality contributed to these mortality differences.
Prognostic Importance of Quantitative Exercise Doppler Echocardiography in Asymptomatic Valvular Aortic Stenosis
Authors: Lancellotti Patrizio , Lebois Florence , Simon Marc , Tombeux Christophe , Chauvel Christophe , Pierard Luc A.
Published: July 2021

Background—

In patients with asymptomatic valvular aortic stenosis, exercise testing may help to stratify the clinical risk. However, data are limited, and the role of quantitative exercise Doppler echocardiography has never been investigated.

Methods and Results—

Sixty-nine consecutive patients with severe asymptomatic aortic stenosis (aortic valve area <1 cm
2
) who prospectively underwent quantitative Doppler echocardiographic measurements at rest and during semisupine exercise test were followed up for 15±7 months. Of these, 26 had an abnormal response to exercise [occurrence of ≥1 of the following findings: angina, dyspnea, ≥2 mm ST segment depression, or fall or small (<20 mm Hg) rise in systolic blood pressure during the test] and 18 presented cardiac events during follow-up (symptoms in 2 patients, acute pulmonary edema in 2, aortic valve replacement in 12, and cardiac death in 2). In univariate analysis, patients who had cardiac events exhibited a higher increase in both peak (29±16 versus 22±14 mm Hg;
P
=0.019) and mean (23±8 versus 12±7 mm Hg;
P
=0.000003) transvalvular pressure gradients, whereas the left ventricular ejection fraction reached at peak stress was lower. These patients experienced more frequently symptoms during exercise (14 of 18 versus 12 of 51;
P
=0.0008). By multivariate Cox regression analysis, independent predictors of cardiac events were as follows: an increase in mean transaortic pressure gradient by ≥18 mm Hg during exercise (
P
=0.0015), an abnormal exercise test (
P
=0.0026), and an aortic valve area <0.75 cm
2
(
P
=0.0031). Exercise Doppler echocardiographic findings provided incremental prognostic value over resting echocardiographic and exercise electrocardiographic parameters.

Conclusions—

Quantitative Doppler exercise echocardiography could be useful to identify a high-risk subset of patients with asymptomatic valvular aortic stenosis and help for clinical decision making.
Survival Benefit of Exclusive Use of In Situ Arterial Conduits Over Combined Use of Arterial and Vein Grafts for Multiple Coronary Artery Bypass Grafting
Authors: Nishida Hiroshi , Tomizawa Yasuko , Endo Masahiro , Kurosawa Hiromi
Published: July 2021

Background—

The purpose of this study was to evaluate mortality after coronary artery bypass grafting (CABG) comparing the use of only in situ arterial grafts with the use of arterial and venous conduits.

Methods and Results—

From April 1985 to March 1999, 1159 patients with multivessel disease underwent elective, isolated, primary, multiple CABG with at least one in situ arterial conduit. Patients who were on chronic dialysis, had active malignant disease, or had free arterial conduits were excluded. The long-term results were compared between 532 patients who had CABG using only in situ arterial conduits (group A; mean follow-up, 7.8 years) and 627 patients who underwent CABG using in situ arterial conduits and saphenous vein grafts (group B; mean follow-up, 10.3 years). Actuarial survival and freedom from cardiac death were determined by the Kaplan-Meier method. Propensity score was included in the Cox multivariable regression model for adjustment of selection bias. Survival at 10 years after surgery was 81.4% in group A and 76.9% in group B (
P
=0.11). Freedom from cardiac death at 10 years was 93.4% in group A and 90.4% in group B. Hazard ratio for cardiac death was significantly lower in group A (0.61; 95% confidence interval, 0.38 to 1.00;
P
=0.05).

Conclusions—

Our data suggest that the exclusive use of in situ arterial grafts in CABG achieves significantly better long-term survival compared with combined use of arterial and vein grafts.
Resistance to Flow of Arterial Y-Grafts 6 Months After Coronary Artery Bypass Surgery
Authors: Glineur David , Noirhomme Philippe , Reisch Jim , El Khoury Gebrine , Astarci Parla , Hanet Claude
Published: July 2021

Background—

The use of both internal thoracic arteries (ITAs) as a Y-graft configuration has been proposed as a technique allowing complete arterial revascularization. Controversy remains, however, about the capacity of this Y-graft configuration to provide sufficient blood flow to the whole left coronary system and about possible steal phenomenon occurring during periods of maximal myocardial blood flow demand.

Methods and Results—

To evaluate graft conductance 6 months after Y-graft revascularization of the left coronary system with both ITAs, 11 consecutive patients were studied during cardiac catheterization. In all of the cases, the left ITA had been connected to the left anterior descending coronary artery (LAD) territory (mean, 1.3 anastomoses), and the free right ITA was anastomosed proximally to the left ITA and distally to the left circumflex (LCX) territory (mean, 1.9 anastomoses). Pressure and fractional flow reserve (FFR) were recorded using a 0.014-inch pressure wire advanced distally in the left ITA main stem close to the proximal anastomosis of the free right ITA (ITA-stem) and in the distal part of each ITA branch at the site of their implantation to the LAD (ITA-LAD) or LCX (ITA-LCX) system. At each of these sites, the pressure gradient between aorta and the graft was measured in basal condition and during maximal hyperemia induced by intragraft bolus injection of 40 μg of adenosine. In basal conditions, the pressure gradient was minimal between the aorta and the ITA-stem (2±2 mm Hg), the ITA-LAD (3±3 mm Hg), and the ITA-LCX (3±2 mm Hg;
P
value was not significant versus ITA-LAD). During maximal hyperemia, the pressure gradient increased to 7±2 mm Hg in the ITA-stem, to 9±5 mm Hg in the ITA-LAD, and to 9±3 in the ITA-LCX (
P
value not significant versus ITA-LAD). The fractional flow reserve was 0.93±0.03 in the ITA-stem, 0.91±0.04 in the ITA-LAD, and 0.91±0.03 in the ITA-LCX.

Conclusions—

A Y-graft configuration with a free right ITA attached to a pedicled left ITA allows an adequate revascularization of the whole left coronary system with an even distribution of perfusion pressure in both distal branches and minimal resistance to maximal blood flow.
Does the β
2
-Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading?
Authors: Tsuneyoshi Hiroshi , Oriyanhan Wnimunk , Kanemitsu Hideo , Shiina Reiko , Nishina Takeshi , Matsuoka Satoshi , Ikeda Tadashi , Komeda Masashi
Published: July 2021

Objective—

Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a β
2
-adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, β
2
-AR stimulation is reported to improve Ca
2+
handling and contribute to antiapoptosis. However, there is little information on the effects of clenbuterol during LV unloading.

Methods and Results—

We investigated LV atrophy and function after LV unloading produced by heterotopic heart transplantation in isogenic rats. After transplantation, rats were randomized to 1o f 2 groups (n=10 each). The clenbuterol group received 2 mg·kg
−1
·d
−1
of the drug for 2 weeks; the control group received normal saline. The weight of unloaded control hearts was 48% less than that of host hearts after 2 weeks of unloading. Clenbuterol significantly increased the weight of the host hearts but did not prevent unloading-induced LV atrophy. Papillary muscles were isolated and stimulated, and there was no difference in developed tension between the 2 groups. However, the inotropic response to the β-AR agonist isoproterenol significantly improved in the clenbuterol group. The mRNA expression of myocardial sarco(endo)plasmic reticulum Ca
2+
-ATPase 2a (SERCA2a) and fetal gene shift (myosin heavy chain [MHC] mRNA isozyme) was also significantly improved by clenbuterol treatment. There was no difference in β
1
-AR mRNA expression between the 2 groups. In contrast, β
2
-AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate β
2
-ARs. In the evaluation of apoptosis, mRNA expression of caspase-3, which is the central pathway for apoptosis, tended to be better in the clenbuterol group.

Conclusions—

During complete LV unloading, clenbuterol did not prevent myocardial atrophy but improved gene expression (SERCA2a, β-MHC) and β-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of β
2
-ARs.
Large Area of the False Lumen Favors Secondary Dilatation of the Aorta After Acute Type A Aortic Dissection
Authors: Immer Franz F. , Krähenbühl Eva , Hagen Urs , Stalder Mario , Berdat Pascal A. , Eckstein Friedrich S. , Schmidli Jürg , Carrel Thierry P.
Published: July 2021

Background—

Since 1994 patients with acute aortic dissection type A (AADA) are followed-up in our outpatient clinic. Early diagnosis of secondary dilatation of the diseased aorta is crucial to reduce late mortality in these patients. Aim of the present study is to asses the impact of a large volume in the false lumen of the diseased downstream aorta on secondary dilatation.

Methods and Results—

134 patients of 264 patients who underwent surgery for AADA (between January 1994 and June 2003) are followed-up at our outpatient clinic since 1994. 84 patients (62.7%) fulfilled the inclusion criteria. Areas of the true and the false lumens of the aorta were analyzed and a logistic regression was calculated at 5 levels of the aorta for each patient. Patients were divided in 3 groups: group 1 included 34 patients (40.5%) without progression, group 2 had 34 patients (40.5%) with slight progression, and group 3 had 16 patients (19.0%) with important progression, requiring surgery in all patients. In 87.5% of the patients the area of the original lumen was <0% in group 3, compared with 11.8% in group 2 and 8.8% in group 1 in relation to the total area of the aorta 6 months after surgery (
P
<0.001).

Conclusion—

A large false lumen, with an area of the true lumen <30% 6 months after surgery, is the strongest predictor for secondary dilatation of the diseased downstream aorta.
Embryonic Stem Cell Immunogenicity Increases Upon Differentiation After Transplantation Into Ischemic Myocardium
Authors: Swijnenburg Rutger-Jan , Tanaka Masashi , Vogel Hannes , Baker Jeanette , Kofidis Theo , Gunawan Feny , Lebl Darren R. , Caffarelli Anthony D. , de Bruin Jorg L. , Fedoseyeva Eugenia V. , Robbins Robert C.
Published: July 2021

Background—

We investigated whether differentiation of embryonic stem cells (ESCs) in ischemic myocardium enhances their immunogenicity, thereby increasing their chance for rejection.

Methods and Results—

In one series, 129/SvJ-derived mouse ESCs (ES-D3 line) were transplanted by direct myocardial injection (1×10
6
cells) into murine hearts of both allogeneic (BALB/c, n=20) and syngeneic (129/SvJ, n=12) recipients after left anterior artery ligation. Hearts were procured at 1, 2, 4, and 8 weeks after ESC transplantation and analyzed by immunohistochemistry to assess immune cell infiltration (CD3, CD4, CD8, B220, CD11c, Mac-1, and Gr-1) and ESC differentiation (hematoxylin and eosin). In a second series (allogeneic n=5, sham n=3), ESC transplantation was performed similarly; however after 2 weeks, left anterior descending artery-ligated and ESC-injected hearts were heterotopically transplanted into naive BALB/c recipients. After an additional 2 weeks, donor hearts were procured and analyzed by immunohistochemistry. In the first series, the size of all ESC grafts remained stable and there was no evidence of ESC differentiation 2 weeks after transplantation; however, after 4 weeks, both allogeneic and syngeneic ESC grafts showed the presence of teratoma. By 8 weeks, surviving ESCs could be detected in the syngeneic but not in the allogeneic group. Mild inflammatory cellular infiltrates were found in allogeneic recipients at 1 and 2 weeks after transplantation, progressing into vigorous infiltration at 4 and 8 weeks. The second series demonstrated similar vigorous infiltration of immune cells as early as 2 weeks after heterotopic transplantation.

Conclusion—

In vivo differentiated ESCs elicit an accelerated immune response as compared with undifferentiated ESCs. These data imply that clinical transplantation of allogeneic ESCs or ESC derivatives for treatment of cardiac failure might require immunosuppressive therapy.
Molecular Indices of Apoptosis After Intermittent Blood and Crystalloid Cardioplegia
Authors: Feng Jun , Bianchi Cesario , Sandmeyer Jennifer L. , Li Jianyi , Sellke Frank W.
Published: July 2021

Background—

We investigated whether intermittent blood and crystalloid cardioplegia differentially affect myocardial apoptosis and apoptosis gene-related proteins.

Methods and Results—

Rabbit hearts were perfused with Krebs-Henseleit buffer on a Langendorff apparatus. Control hearts (n=6) were perfused for 120 minutes without cardioplegic ischemia. Hearts were arrested for 60 minutes with warm (37°C) crystalloid cardioplegia (iW-CCP) (n=8) or with warm blood cardioplegia (iW-BCP) (n=8) administered intermittently. In cold (0 to 4°C) groups, hearts were arrested for 60 minutes with cold crystalloid cardioplegia (iC-CCP; n=8) or with cold blood cardioplegia (iC-BCP; n=6) administered intermittently. The hearts were reperfused for 30 minutes with Krebs-Henseleit buffer. iC-BCP significantly preserved the recovery of left ventricular and microvascular function compared with the other 3 experimental groups. There were no significant differences in total protein levels of caspase 3, Bcl-2, Bad, and Bax among the groups. iC-BCP significantly induced greater phosphorylation of Bad (5.6±0.8-fold) as compared with the other 3 groups (3.4±0.6-fold in iC-CCP,
P
<0.05; 2.5±0.3 in iW-BCP,
P
<0.05; and 1.4±0.2 in iW-CCP,
P
<0.01). iC-BCP induced less caspase 3 activation and apoptosis than the other 3 groups.

Conclusions—

iC-BCP is superior to the other cardioplegic solutions in increasing the phosphorylation of Bad, inhibiting the activation of caspase 3, and preventing apoptosis. These effects of iC-BCP were associated with preserved left ventricular function and endothelium-dependent relaxation of coronary microvessels.
Comparing Long-Term Survival of Patients With Multivessel Coronary Disease After CABG or PCI
Authors: Malenka David J. , Leavitt Bruce J. , Hearne Michael J. , Robb John F. , Baribeau Yvon R. , Ryan Thomas J. , Helm Robert E. , Kellett Mirle A. , Dauerman Harold L. , Dacey Lawrence J. , Silver M. Theodore , VerLee Peter N. , Weldner Paul W. , Hettleman Bruce D. , Olmstead Elaine M. , Piper Winthrop D. , O’Connor Gerald T.
Published: July 2021

Background—

Randomized trials comparing coronary artery bypass graft surgery (CABG) with percutaneous coronary interventions (PCIs) for patients with multivessel coronary disease (MVD) report similar long-term survival for CABG and PCI. These studies used a highly selected population of patients and providers, and their results may not be generalizable to actual care. Our goal in this study was to compare long-term survival of MVD patients treated with CABG vs PCI in contemporary practice.

Methods and Results—

From our northern New England registries of consecutive coronary revascularizations, we identified 10 198 CABG and 4295 PCI patients with MVD who may have been eligible for either procedure between 1994 and 2001. Vital status was obtained by linkage to the National Death Index. Proportional-hazards regression was used to calculate hazard ratios (HRs) for survival in CABG vs PCI patients after adjustment for comorbidities and disease characteristics. CABG patients were older; had more comorbidities, more 3-vessel disease, and lower ejection fractions; and were more completely revascularized. Adjusted long-term survival for patients with 3-vessel disease was better after CABG than PCI (HR, 0.60;
P
<0.01) but not for patients with 2-vessel disease (HR, 0.98;
P
=0.77). The survival advantage of CABG for 3-vessel disease patients was present in all patient populations, including women, diabetics, and the elderly and in the era of high stent utilization.

Conclusions—

In contemporary practice, survival for patients with 3-vessel coronary disease is better after CABG than PCI, an observation that patients and physicians should carefully consider when deciding on a revascularization strategy.
Gene Therapy for Hypertension: Recombinant Adeno-Associated Virus Vector Delivery of Angiotensin Type 1 Receptor Antisense in Hypertensive Double Transgenic Mice
Authors: Phillips M. Ian , Kimura Birgitta , Zhang Y. Clare , Gelband Craig H , Sigmund Curt D , Mohuczy Dagmara
Published: July 2021

P204

Introduction: The goal of gene therapy for hypertension is to produce prolonged reductions of high blood pressure with a single administration of a transgene. We have developed gene therapy using adeno-associated virus (AAV)antisense (AS) as a vector because it is safe, stable and effective. However, because large quantities of AAV are not yet available, our previous studies were in baby rats or by brain injections to achieve an effective concentration of AAV. Since mice are one-tenth the size of rats, systemic injection of AAV-AS achieves higher concentrations than in rats. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human AGT (hAGT) transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (∼156 mmHg), compared to controls (∼ 100 mmHg). Methods: dt mice with established baseline BP of >156 mmHg (n=5) were injected (100 μl) with a single dose of 4x10
10
infectious particles of rAAV-AT
1
R-AS. Blood pressure recordings by the tailcuff method were made once per week for 6 months. Results: One week after intracardiac injection of rAAV-AT
1
R-AS, blood pressure decreased by 35-50 mmHg (p<0.01,compared to baseline). The normalized blood pressure persisted for the full length of the study, 28 weeks. Individual mice were sacrificed at 14-28 weeks and tissues taken for detection of rAAV-AT
1
R- AS, At both time periods, the neo
r
transgene was present in lung, kidney, liver, heart, adrenal gland and fat. The rAAV was not detected in the brain. Renal arterioles (n=3) showed a reduced (50%)contractile response to doses of Ang II, compared to controls (n=3). Conclusion: The results demonstrated that a single systemic delivery of rAAV-AT
1
R-AS in adult, hypertensive mice produces a profound decrease in blood pressure for at least 6 months. The prolonged effect is due to the continuous expression of the AT
1
-R antisense transgene inhibiting AT
1
receptors.
Angiotensin II Promotes Anti-Apoptosis Via Akt-Kinase Phosphorylation, an Effect Ameliorated by High Dose Aspirin
Authors: Muller Dominik N , Shagdarsuren Erdenechimeg , Hampich Franziska , Dechend Ralf , Park Joon-Keun , Fiebeler Anette , Breu Volker , Mervaala Eero Ma , Haller Hermann , Luft Friedrich C
Published: July 2021

11

The balance between cell proliferation and apoptosis is essential for physiological function. We tested the hypothesis that angiotensin II (ANG II) has anti-apoptotic effects via the activation of AKT kinase in rats overexpressing the human renin and angiotensinogen genes (dTGR). dTGR are hypertensive (182±8 mm Hg) with severe renal damage (150-fold increased albuminuria), perivascular and interstitial fibrosis and vasculopathy, and die at 7 weeks. Renal NF-κB DNA binding activity is increased. We studied the time course of the pathogenesis from week 5 to week 7. Blood pressure, albuminuria, fibrosis, vasculopathy and monocyte infiltration increased over time. In contrast, KI-67 proliferating cells were more abundant in week 5 compared to week 7 as well as compared to non-transgenic rats. Phosphorylation of AKT kinase increased with the severity of the disease. Immunostaining of p-AKT and the activated NF-κB subunit p65 were observed in the glomeruli and endothelium. While Bcl-2 and phosphorylated Bad was predominantly expressed in the endothelium in week 7, the strongest bax immunostaining in the vessel wall media was observed in week 5. We then investigated the effect of chronic high dose aspirin (ASA; 600 mg/kg/d) on remodeling. While ASA did not change blood pressure, albuminuria and fibrosis were similar to non-transgenic controls. ASA completely normalized AKT protein synthesis as well as AKT phosphorylation and NF-κB DNA binding activity. Bax immunostaining at week 7 increased in the media, while Bcl-2 decreased. Western blot in dTGR kidney homogenates showed increased Bcl-2 levels compared ASA-treated and non-transgenic rats. We then confirmed the effect of ASA on p-AKT stimulating endothelial cells in vitro with ANG II (10-7 M; 10 min). Western blot showed reduced p-AKT in ASA pretreated cells. These results show that ANG II is anti-apoptotic by activating AKT kinase. ASA is able to restore the impaired balance of tissue remodeling. Finally, in addition to inhibiting I-κB kinase, ASA may exert a part of its ameliorating effects in this model by inhibiting AKT phosphorylation.
PPARγ Expression and Function in Mesangial Cells: Implication for Renal Disease
Authors: Nicholas Susanne Bernadette , Kawano Yasuko , Wakino Shu , Hsueh Willa A
Published: July 2021

7

Dominant negative mutations which inactivate the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear receptor in man are associated with severe insulin resistance, diabetes and hypertension (Barroso I et al. Nature, 1999;402:880-883). Using RNase protection assay, Western blot analysis and immunostaining of cultured primary rat mesangial cells, we identified the presence of PPARγ message and protein. Electrophoretic mobility of a labeled PPARγ response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARγ is functional in these cells. Addition of unlabelled PPRE efficiently competed away the PPARγ-PPRE protein complex, confirming specificity of binding of the PPARγ to the PPRE. PPARγ ligands, rosiglitazone (10 μM) and troglitazone (10 μM), both completely inhibited platelet derived growth factor (PDGF)-induced DNA synthesis measured as bromodeoxyuridine (BrdU) incorporation (p<0.05). When administered in anti-diabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 4 months (from 687.1 to 137.6 μg urinary albumin/mg creatinine, p<0.05), but did not affect hyperglycemia or hypertension in this model. These data suggest PPARγ activation may have direct effects to attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy. These results have therapeutic implications for diabetic glomerulosclerosis as well as proliferative mesangial diseases of the kidney.
Docosahexaenoic Acid, a Peroxisome Proliferator-Activated Receptor-α Activator, Induces Apoptosis in Vascular Smooth Muscle Cells by Activation of P38 Mitogen-Activated Protein Kinase
Authors: Diep Quy N , Touyz Rhian M , Schiffrin Ernesto L
Published: July 2021

9

Omega-3 fatty acids (n-3 FAs) exert a blood pressure-lowering effect in hypertension, possibly by influencing vascular structure. We previously demonstrated that n-3 FAs might induce vascular smooth muscle cell (VSMC) apoptosis, which could exert an effect on structure of blood vessels. This study investigated signaling pathways through which n-3 FAs mediate apoptosis in VSMCs. Cultured Mesenteric VSMCs from Sprague Dawley rats were stimulated with docosahexaenoic acid (DHA), a representative n-3 FA. Morphological changes of apoptosis and DNA fragmentation were examined by phase-contrast microscopy and fluorescence microscopy with Hoechst 33342 staining. To clarify possible pathways of apoptosis, expression of phosphorylated p38 mitogen-activated protein kinases (p38 MAPKs), bax, bcl-2, cytochrome C and peroxisome proliferator-activated receptors-α (PPARs-α) was evaluated by Western blot analysis. DHA treatment induced cell shrinkage, cell membrane blebbing and apoptotic bodies in VSMCs. DHA increased apoptosis (%) in a time-dependent manner to 1.5±0.1, 3.6±0.5, 7.1±0.4, 22.5±0.6, 50.8±1.8 and 61.4±0.9 after 0, 1, 3, 6, 17, and 24 h, respectively. DHA time-dependently activated p38 MAPKs, bax, PPARs-α and cytochrome C with maximal effects obtained after 5, 30 min, 1 h and 3 h, respectively to 551±42, 245±55, 310±12 and 407±14.7 % of controls, respectively. SB-203580 (10
-5
M) and SB-202190 (10
-5
M), selective p38 inhibitors, reduced DHA-elicited apoptosis and expression of PPARs-α, but had no effect on expression of bax or cytochrome C. The present results indicate that DHA induces apoptosis in VSMCs through at least two distinct mechanisms: (i) a p38-dependent pathway that regulates PPAR-α and (ii) a p38-independent pathway via dissipation of mitochondrial transmembrane potential. The death-signaling pathway mediated by DHA may involve an integration of these multiple pathways. By triggering VSMC apoptosis, DHA could play a pathophysiological role in vascular remodeling in cardiovascular disease.
Endothelin-B Receptors Play an Important Role in Modulating Chronic Pressure-Natriuresis and Blood Pressure Regulation in Response to Changes in Dietary Sodium Intake.
Authors: Granger Joey P , Cockrell Kathy L , Rinewalt Anna N , Alexander Barbara T
Published: July 2021

25

Activation of the ET
B
receptor by endothelin (ET-1) has been shown to inhibit renal tubule transport, dilate renal microcirculatory vessels, and inhibit renin release. The purpose of this study was to determine the role of ET and ET
B
receptors in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake. To test whether the renal production of ET is enhanced in response to elevation in Na intake, the effects of a low (0.4%), normal (1.0%), or high (8%) Na diet on 24hr urinary excretion of ET-1 and
mRNA
expression of preproendothelin (ribonuclease protection assay) were determined. Increasing Na intake from low to normal levels had no effect on urinary ET-1 excretion or renal expression of preproendothelin. In contrast, increasing Na intake from normal to high levels resulted in significant increases in urinary excretion of ET-1 (7223±968 vs 2127±167 pg/24hrs) and expression of preproendothelin (42.3±6.7 vs 25.4±1.8 densitometric units) in the renal medulla. To test whether ET
B
receptors play an important role in modulating arterial pressure in response to changes in Na intake, the relationship between arterial pressure and sodium excretion was determined in control rats and in ETB receptor antagonist-treated rats (A-192621, 30mg/kg/day for 7 days). Long-term ET
B
receptor blockade resulted in a significant rightward shift in the chronic pressure-natriuresis relationship. In control rats on a normal and high Na intake, AP was 122±3 and 132±3mmHg, respectively. In contrast, AP in ETB receptor antagonist-treated rats on a normal and high Na intake was 144±2 and 171±12mmHg, respectively. In summary, we report that the renal endothelin system is upregulated in response to increases in sodium intake. Blockade of the ET
B
receptors results in significant hypertension that is salt-sensitive. These results indicate that endothelin via ET
B
receptors plays an important role in modulating renal-pressure natriuresis and blood pressure regulation in response to changes in dietary Na intake.
Evidence That Reduced Renal Medullary NOS Activity of Dahl S Rats Enables Small Elevations of Avp to Produce Sustained Hypertension
Authors: Yuan Baozhi , Cowley Allen W
Published: July 2021

27

It remains unclear why sustained elevations of plasma arginine vasopressin (AVP), a potent vasoconstrictor and fluid retaining hormone, do not generally result in hypertension. Related to this, there have been 4 general observations: 1) AVP is elevated in many forms of human and experimental hypertension, including Dahl S rats; 2) AVP can stimulate nitric oxide synthases (NOS) and nitric oxide (NO) production in the renal medulla of normal rats; 3) AVP stimulated NO production can buffer AVP induced reductions of medullary blood flow; 4) partial reduction of medullary NOS activity (via medullary L-NAME infusion) unmasks chronic hypertensive effects of small elevations of plasma AVP (Hypertension. 2000; 35:740-745). In the present study, we hypothesize that Dahl salt-sensitive rats (DS) have reduced capacity to synthesize medullary NO which sensitizes them to the hypertensive effects of small elevations of circulating AVP. DS and Brown Norway (BN) rats with implanted arterial and venous catheters were fed a 0.4% salt diet and infused continuously for 14 days with a chronic “subpressor” dose of AVP (2 ng/kg/min). Conscious mean arterial pressure (MAP) was measured 2 hours daily with rats maintained in their home cages. MAP in DS rats increased during day1 of AVP infusion from a control level of 127 ± 0.9 mmHg to an average of 147 ± 1.6 mmHg after 14 days. MAP did not return to control values even within three days following the end of AVP infusion. BN rats showed no changes of MAP during 14 days of AVP infusion (90.4 ± 0.6 mmHg and 92.3 ± 0.4 mmHg). Northern blot analysis of renal tissue from vehicle (saline) infused rats demonstrated that NOS I and NOS III mRNA expression was significantly less in DS rats in the renal outer medulla compared to BN rats. We conclude that small, normally subpressor elevations of plasma AVP can produce chronic hypertension in DS rats, a phenomenon probably related to reduced renal medullary NO synthesis.
Fibroblast Growth Factor-2 Mediates Angiotensin Ii-Induced Cardiac Hypertrophy in Renovascular Hypertension
Authors: Pellieux Corinne , Foletti Alessandro , Sauthier Thercse , Jean-Francois Aubert , Friedrich Beermann , Hans-R. Brunner , Pedrazzini Thierry
Published: July 2021

29

In renovascular hypertension, angiotensin II leads to an elevation of blood pressure and to cardiac hypertrophy. The fibroblast growth factor-2 (FGF-2) has been implicated in cardiomyocyte growth. Therefore, we investigated whether FGF-2 could control the development of angiotensin II-induced cardiac hypertrophy. Mice deficient for the expression of FGF-2 were created, and the role of FGF-2 was investigated in the two kidney-one clip (2K1C) model of renin-dependent hypertension. The activation of the MAPK pathways were shown to be crucial in the intracellular signaling leading to cardiac hypertrophy. Therefore, we followed also the cardiac activation of JNK, ERK and the p38 kinase in these animals. Both wild-type and FGF-2 deficient (FGF-2 -/-) mice showed similar elevation of blood pressure in the 2K1C model. Interestingly, 2K1C FGF-2 -/- mice developed markedly reduced hypertrophy as compared to wild-types. Moreover, in 2K1C wild-types, cardiac hypertrophy developed in association with a concomitant stimulation of JNK, ERK and p38. In contrast, JNK activation was strongly decreased in hypertensive mice deficient for FGF-2, while p38 and ERK were less affected. These data suggest that FGF-2 is important in mediating angiotensin II-induced cardiac hypertrophy in renovascular hypertension via autocrine/paracrine mechanisms.
Oxidized-Ldl Enhances Coronary Vasoconstriction by Increasing the Activity of α and ε Protein Kinase C Isoforms
Authors: Jiardina Jena B , Tanner Dennis J , Khalil Raouf A
Published: July 2021

31

Oxidized low density lipoprotein (ox-LDL) plays a critical role in the development of atherosclerotic coronary vasospasm; however, the cellular mechanisms involved are not fully understood. We tested the hypothesis that ox-LDL enhances coronary vasoconstriction by increasing the activity of specific protein kinase C (PKC) isoforms in coronary smooth muscle. Active stress was measured in de-endothelialized porcine coronary artery strips, [Ca
2+
]
i
was monitored in single coronary smooth muscle cells loaded with fura-2, and the whole tissue, cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific anti-PKC antibodies using Western blot analysis. Ox-LDL (100 μg/ml) caused a slow but significant increase in active stress to 1.2±0.2 x10
3
N/m
2
, that was completely inhibited by the PKC inhibitors staurosporine and calphostin C, with no significant increase in [Ca
2+
]
i
. Ox-LDL enhanced coronary contraction to increasing concentrations of 5-hydroxytryptamine (5-HT) and extracellular KCl with no additional increases in [Ca
2+
]
i
. Direct activation of PKC by phorbol 12,13-dibutyrate (PDBu, 0.1 μM) caused a contraction similar in magnitude and time course to ox-LDL induced contraction. PDBu also enhanced 5-HT and KCl-induced contraction with no additional increases in [Ca
2+
]
i
. Both ox-LDL and PDBu caused an increase in PKC activity in the particulate fraction and a decrease in the cytosolic fraction and increased the particulate/cytosolic PKC activity ratio. Western blot analysis revealed α-, δ-, ε- and ζ-PKC isoforms. In unstimulated tissue, α- and ε-PKC were mainly cytosolic, δ-PKC was mainly in the particulate fraction, while ζ-PKC was equally distributed in the cytosolic and particulate fractions. Ox-LDL and PDBu caused translocation of α- and ε-PKC from the cytosolic to particulate fraction, with minimal effect on the distribution of δ-PKC and ζ-PKC. Native LDL did not significantly affect coronary contraction, [Ca
2+
]
i
or PKC activity. These results suggest that ox-LDL enhances coronary vasoconstriction via activation and translocation of α- and ε-PKC isoforms in coronary smooth muscle.
Linkage of Nedd4, a Regulator of the Epithelial Sodium Channel, to Primary Hypertension in Blacks
Authors: Pratt J. Howard , Rebhun John F , Flury Leah L , Foroud Tatiana
Published: July 2021

40

Salt-sensitive hypertension is common in blacks. A primary renal mechanism may account for the increase in sodium reabsorption since levels of mineralocorticoids, including aldosterone, are often reduced in blacks. Albeit milder, the hypertension in blacks resembles Liddle s syndrome, where mutations in the epithelial sodium channel result in increased numbers of functioning channels and sodium retention. In Liddle s syndrome, molecular mutations in the PY-motif at the COOH-terminus of either the α- or β-subunit prevents binding of Nedd4, an ubiquitin ligase that targets channels for removal from the cell surface. Thus, Nedd4 is a candidate mediator of risk for hypertension in blacks. To evaluate Nedd4 s role, we performed linkage analyses in 86-88 black hypertensive sib pairs. Subjects were genotyped for two highly polymorphic markers, D15S126 and D15S1016, with heterozygosity of 79% and 89%, respectively. Both are within a 5 cM interval of chromosome 15 that contains KIAA0093 or Nedd4. Among the affected sibling pairs, we observed increased allele sharing for D15S126 (π = 0.57; p=0.01) and D15S1016 (π =0.55; p=0.07). Using only hypertensive sibling pairs (n=42-45 pairs) with BMI <32 kg/M
2
resulted in greater allele sharing for both D15S126 (π =0.63; p=0.0001) and D15S1016 (π =0.57; p=0.06). In summary, we show evidence for linkage of hypertension to a region on chromosome 15 containing the gene for Nedd4. While these results need to be confirmed in other samples, they suggest that variability in Nedd4 or a nearby gene(s) confers a strong influence on differences in sodium homeostasis and blood pressure in blacks.