bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Aspirin Therapy Is Associated With Improved Postoperative Outcomes in Patients Undergoing Coronary Artery Bypass Grafting
Authors: Bybee Kevin A. , Powell Brian D. , Valeti Uma , Rosales A. Gabriela , Kopecky Stephen L. , Mullany Charles , Wright R. Scott
Published: July 2021

Background—

Aspirin is beneficial in the setting of atherosclerotic cardiovascular disease. There are limited data evaluating preoperative aspirin administration preceding coronary artery bypass grafting and associated postoperative outcomes.

Methods and Results—

Using prospectively collected data from 1636 consecutive patients undergoing first-time isolated coronary artery bypass surgery at our institution from January 2000 through December 2002, we evaluated the association between aspirin usage within the 5 days preceding coronary bypass surgery and risk of adverse in-hospital postoperative events. A logistic regression model, which included propensity scores, was used to adjust for remaining differences between groups. Overall, there were 36 deaths (2.2%) and 48 adverse cerebrovascular events (2.9%) in the postoperative hospitalization period. Patients receiving preoperative aspirin (n=1316) had significantly lower postoperative in-hospital mortality compared with those not receiving preoperative aspirin [1.7% versus 4.4%; adjusted odds ratio (OR), 0.34; 95% CI, 0.15 to 0.75;
P
=0.007]. Rates of postoperative cerebrovascular events were similar between groups (2.7% versus 3.8%; adjusted OR, 0.67; 95% CI, 0.32 to 1.50;
P
=0.31). Preoperative aspirin therapy was not associated with an increased risk of reoperation for bleeding (3.5% versus 3.4%;
P
=0.96) or requirement for postoperative blood product transfusion (adjusted OR, 1.17; 95% CI, 0.88 to 1.54;
P
=0.28).

Conclusions—

Aspirin usage within the 5 days preceding coronary artery bypass surgery is associated with a lower risk of postoperative in-hospital mortality and appears to be safe without an associated increased risk of reoperation for bleeding or need for blood product transfusion.
Early Outcome of a Randomized Comparison of Off-Pump and On-Pump Multiple Arterial Coronary Revascularization
Authors: Kobayashi Junjiro , Tashiro Tadashi , Ochi Masami , Yaku Hitoshi , Watanabe Go , Satoh Toshihiko , Tagusari Osamu , Nakajima Hiroyuki , Kitamura Soichiro
Published: July 2021

Background—

Previous randomized comparisons of off-pump and on-pump coronary artery bypass grafting (CABG) have yielded controversial results about the cardiac and neurological events and graft patency. In addition, these randomized studies were composed of CABG with a few arterial grafts. We performed a prospective randomized controlled study to compare off-pump and on-pump CABG with multiple arterial grafts.

Methods and Results—

Between July, 2002, and September, 2004, 167 consecutive unselected patients referred for elective primary CABG were randomly assigned to undergo multiple arterial off-pump CABG (n=81) or on-pump CABG (n=86). The clinical outcomes and S-100 protein, neuron-specific enolase, and maximum creatine kinase-MB levels were compared. Early graft patency was examined within 3 weeks after the operation by angiography. The number of grafts performed per patient (3.5±1.0 for off-pump CABG and 3.6±0.9 for on-pump CABG) and the number of arterial grafts performed per patient (3.3±1.0 for off-pump CABG and 3.4±0.9 for on-pump CABG) were similar. Completeness of revascularization (completed grafts/planned grafts) was 98% in both procedures. There were no hospital deaths in either group. The operation time was significantly (
P
<0.001) shorter in the off-pump group than in the on-pump group (267±60 minutes versus 307±59 minutes). The incidence of perioperative complications was similar. The frequency of no need for transfusion was higher in the off-pump group than in the on-pump group (80% versus 55%,
P
<0.001). The S-100 protein levels at the admission into the intensive care unit were significantly (
P
<0.001) lower in the off-pump group than in the on-pump group (0.20±0.11 ng/mL versus 0.34±0.22 ng/mL). The neuron-specific enolase levels at the intensive care unit admission were significantly (
P
<0.001) lower in the off-pump group than in the on-pump group (10.4±9.0 ng/mL versus 16.9±6.9 ng/mL). Maximum creatine kinase-MB levels were significantly (
P
=0.046) lower in the off-pump group than in the on-pump group (17.1±16.7 IU/L versus 21.5±10.6 IU/L). The overall early graft patency rate with or without stenosis was the same (98%) in both groups, but the rate without stenosis was slightly worse in the off-pump group (93%) than in the on-pump group (96%) (
P
=0.093). The stenosis-free patency rate in the right coronary area was significantly (
P
=0.028) worse in the off-pump CABG group (90%) than in the on-pump group (99%).

Conclusions—

Off-pump CABG with multiple arterial grafts was as safe as the conventional on-pump CABG, with similar completeness of revascularization and early graft patency.
In Vivo Visualization of Cardiac Allograft Rejection and Trafficking Passenger Leukocytes Using Bioluminescence Imaging
Authors: Tanaka Masashi , Swijnenburg Rutger-Jan , Gunawan Feny , Cao Yu-An , Yang Yang , Caffarelli Anthony D. , de Bruin Jorg L. , Contag Cristopher H. , Robbins Robert C.
Published: July 2021

Background—

We investigated the feasibility of bioluminescence imaging (BLI) for the in vivo assessment of cardiac allograft viability and visualization of passenger leukocytes during the course of acute rejection.

Methods and Results—

Hearts of FVB (H-2
q
) luciferase-green fluorescent protein transgenic mice (β-actin promoter) or FVB luciferase transgenic mice (CD5 promoter) were heterotopically transplanted into either BALB/c (H-2
d
) or FVB recipients. Light intensity emitting from the recipient animals was measured daily by in vivo BLI until 12 days after transplantation. Graft beating score (0 to 4) was assessed by daily abdominal palpation until 12 days after transplantation. Inflammatory cell infiltration (CD45 stain) and structural changes of green fluorescent protein-positive cardiomyocytes were followed by immunohistochemistry. All cardiac allografts were acutely rejected by 12 days after transplantation. The intensity of light emitting from cardiac allografts declined 4 days after transplantation and correlated with graft beating scores (
R
2
=0.91,
P
=0.02). Immunohistochemistry confirmed these results by showing an increase of CD45
+
inflammatory cell infiltration and destruction of green fluorescent protein-positive cardiomyocytes in the cardiac allografts during acute rejection. In vivo BLI visualized migration and proliferation of CD5
+
passenger leukocytes in both syngeneic and allogeneic recipients. In the allograft recipients, light signal from CD5
+
passenger leukocytes peaked at 6 hours and diminished by 12 hours, whereas in the syngeneic recipients, the signal remained high until 10 days after transplantation.

Conclusions—

BLI is a useful modality for the quantitative assessment of in vivo cardiac graft viability and tracking of passenger leukocytes in vivo during the course of acute rejection.
Ross Procedure in Infants and Toddlers Followed Into Childhood
Authors: Williams Ismee A. , Quaegebeur Jan M. , Hsu Daphne T. , Gersony Welton M. , Bourlon Francois , Mosca Ralph S. , Gersony Deborah R. , Solowiejczyk David E.
Published: July 2021

Background—

The Ross procedure is commonly used to treat aortic valve disease in pediatric and adult patients. For infants, data are limited regarding survival, reintervention, autograft growth, and function.

Methods and Results—

The Ross procedure was performed in 27 infants <18 months of age (median age 5.7 months). All patients had congenital aortic stenosis (AS); associated lesions included subAS (n=9), supravalvular AS (n=2), coarctation (n=5), and interrupted aortic arch (n=2). Median follow-up was 6.1 years (range 0.2 to 12.9). There were 3 early deaths and no late deaths. Freedom from reintervention for homograft dysfunction was 87% at 8 years; freedom from autograft reintervention was 100%. Follow-up echocardiograms were available in 17 patients. Estimated peak autograft gradient was 55 mm Hg in one patient and <10 mm Hg in 16. Mild autograft insufficiency was seen in 4 patients; 13 had none. Autograft diameter was measured early postoperatively and at latest follow-up. The mean
z
score increased from 0.63 to 3.2 (
P
<0.01) at the annulus and from 0.26 to 2.2 (
P
<0.01) at the sinus. In a subgroup, the mean autograft
z
score increased significantly from the postoperative period to 1 year for both the annulus (0.72 to 3.2,
P
<0.01) and the sinus (0.26 to 2.2,
P
<0.01), but remained unchanged thereafter.

Conclusions—

The Ross procedure effectively relieves AS in infants. Homograft reintervention occurred in 13% within 8 years. No patient developed significant autograft insufficiency or required autograft reintervention during the follow-up period. Dilatation of the autograft occurred during the first year after surgery and stabilized thereafter.
Female Gender Is an Independent Predictor of Operative Mortality After Coronary Artery Bypass Graft Surgery
Authors: Blankstein Ron , Ward R. Parker , Arnsdorf Morton , Jones Barbara , Lou You-Bei , Pine Michael
Published: July 2021

Background—

Women have a higher operative mortality (OM) after coronary artery bypass graft (CABG) surgery than men. Suggested contributing factors have included women’s increased age, advanced disease, comorbidities, and smaller body surface area (BSA). It is unclear whether women’s increased risk factors fully account for this difference or whether female gender within itself is associated with increased OM. We attempted to determine whether, all other factors being equal, there is a significant difference in OM between men and women undergoing CABG.

Methods and Results—

We retrospectively reviewed a clinical database of 15,440 patients who underwent CABG at 31 Midwestern hospitals in 1999–2000. Each patient record consisted of >400 data elements. Risk-adjusted mortality rates were computed using a predictive equation derived by stepwise logistic regression. Overall, women were older, had a higher incidence of diabetes and valvular disease, and were more likely to be presenting in shock. The OM for the entire population was 2.88% (women 4.24% versus men 2.23%,
P
<0.0001). Lower BSA was found to be an independent predictor of increased mortality, and a direct inverse relationship between BSA and OM was noted. After adjusting for all comorbidities including BSA, female gender remained an independent predictor of increased mortality (risk-adjusted OM was 3.81% for women and 2.43% for men). Thus, whereas risk adjustment reduced women’s OM from 90% higher than men’s to 22% higher, a significant difference remained.

Conclusions—

In this contemporary data set from 31 Midwestern hospitals, female gender was an independent predictor of perioperative mortality, even after accounting for all comorbidities, including low BSA.
Mitral Valve Repair for Functional Mitral Regurgitation in End-Stage Dilated Cardiomyopathy
Authors: De Bonis Michele , Lapenna Elisabetta , La Canna Giovanni , Ficarra Eleonora , Pagliaro Marco , Torracca Lucia , Maisano Francesco , Alfieri Ottavio
Published: July 2021

Background—

The aim of this study was to assess the results of mitral valve (MV) repair in functional mitral regurgitation because of end-stage dilated cardiomyopathy (DCM).

Methods and Results—

Seventy-seven patients with end-stage idiopathic (26 patients) or ischemic (51 patients) DCM underwent MV repair for functional mitral regurgitation (3 to 4+/4+). Fifty-eight patients (75.3%) were in New York Heart Association class III, and 19 (24.6%) were in IV. In 23 patients (29.8%) with a coaptation depth <1 cm, an isolated undersized annuloplasty was used. In the remaining 54 (70.1%), with a coaptation depth ≥1 cm, the “edge-to-edge” technique was associated with the annuloplasty. In most of the cases (88.3%), a complete rigid/semirigid ring was used. Concomitant coronary artery bypass graft was performed in 39 patients (50.6%). Hospital mortality was 3.8% (3 of 77). Actuarial survival was 90.7±3.64%, and freedom from cardiac events was 81.8±7.96% at 2.7 years. At a mean follow-up of 18.4±9.8 months (range, 1 month to 5 years) New York Heart Association class improved from 3.4±0.4 to 1.4±0.6 (
P
<0.0001). Mitral repair failure (recurrence of MR ≥3+/4+) was documented in 7 patients (9%): 2 in the edge-to-edge (2 of 54, 3.7%) and 5 in the isolated annuloplasty group (5 of 23, 21.7%) (
P
=0.03). Freedom from repair failure at 1.5 years was 95.0±3.4% and 77±12.1%, respectively (
P
=0.04). The absence of the edge-to-edge was the only predictor of repair failure (
P
=0.03). When residual MR was absent or mild, a reverse left ventricular remodeling was clearly documented.

Conclusions—

In patients with end-stage DCM, MV repair is feasible with low hospital mortality and important symptomatic improvement. The association of the edge-to-edge technique to the undersized annuloplasty can significantly improve the durability of the repair.
Annular Geometry in Patients With Chronic Ischemic Mitral Regurgitation
Authors: Kaji Shuichiro , Nasu Michihiro , Yamamuro Atsushi , Tanabe Kazuaki , Nagai Kunihiko , Tani Tomoko , Tamita Koichi , Shiratori Kenichi , Kinoshita Makoto , Senda Michio , Okada Yukikatsu , Morioka Shigefumi
Published: July 2021

Background—

Although animal studies showed that annular remodeling may be related to the pathogenesis of chronic ischemic mitral regurgitation (CIMR), little was known in humans. A better understanding of the precise 3D geometry of the mitral valvular-ventricular complex in CIMR is needed to devise a better surgical technique. The purpose of the study was to elucidate mitral annular geometry in patients with CIMR using cardiac MRI.

Methods and Results—

Thirty-eight patients with previous inferior or posterior myocardial infarction were studied. With the 3D reconstruction of the mitral annulus and subvalvular apparatus from a series of longitudinal cine MRIs, end-systolic mitral annulus dimensions and 3D geometry were calculated. Patients were grouped by mitral regurgitation grade using echocardiography (≥2+, n=15 versus ≤1+, n=23). Both septal-lateral and commissure-commissure mitral annular diameters were significantly greater in CIMR(+) patients (35±5 versus 30±4 mm,
P
=0.005; 46±6 versus 39±4 mm,
P
<0.001, respectively). The length of the fibrous annulus was significantly larger in CIMR(+) patients (28±3 versus 24±3 mm;
P
<0.001). The height of the annular “saddle horn” above a best-fit plane was lower in CIMR(+) patients (4.2±1.2 versus 6.0±1.8 mm;
P
=0.002), and the annular height to commissural width ratio was significantly lower in CIMR(+) patients (12±3 versus 21±5%;
P
<0.001).

Conclusions—

Patients with CIMR had greater septal-lateral and commissure-commissure mitral annular dimension, larger intertrigonal distance, and flattened saddle shape of mitral annulus. These associated geometric alterations may be important in the pathogenesis of CIMR.
Gene Expression Changes in Leukocytes During Cardiopulmonary Bypass Are Dependent on Circuit Coating
Authors: Seeburger Joerg , Hoffmann Jan , Wendel Hans Peter , Ziemer Gerhard , Aebert Hermann
Published: July 2021

Background—

Cardiopulmonary bypass (CPB) results in a systemic inflammatory response. Leukocytes play a crucial role in inflammatory reactions. Their gene expression profile in the context of CPB is unknown.

Methods and Results—

In a prospective, randomized, and double-blind clinical trial, 12 male patients underwent elective coronary artery bypass grafting with either heparin-coated (group H) or protein-coated (group P) CPB circuits. Oligonucleotide microarray analyses of 22 283 genes were performed on circulating leukocytes, collected immediately before surgery and 6 hours after CPB. Microarray results were validated with real-time polymerase chain reaction. All patients had uneventful surgery, and no significant differences between groups were observed during the clinical course. Multiple statistical analyses with different methods were performed. Compared with preoperative expression at a threshold value of
P
<0.01, postoperative expression revealed 814 upregulated and 1187 downregulated genes in group H compared with 99 upregulated and 231 downregulated in group P (
P
<0.001). Fifty genes exhibited a >4-fold increase and 27 exhibited a >4-fold decrease in group H, whereas only 7 genes exhibited upregulation and 7 revealed downregulation in group P. Microarray-pathway-profile-finder analyses determined 1405 upregulated and 1454 downregulated pathways in group H compared with 552 upregulated and 818 downregulated pathways in group P (
P
<0.01). Pathways related to inflammatory response exhibited highest z scores in group H, reflecting cellular inflammatory activation.

Conclusions—

Heparin coating resulted in a more profound alteration in leukocyte gene expression when compared with protein coating. Microarray analyses present an innovative approach for the evaluation and understanding of inflammatory reactions associated with CPB.
Physiologic Compensation Is Supranormal in Compensated Aortic Stenosis: Does it Return to Normal After Aortic Valve Replacement or Is it Blunted by Coexistent Coronary Artery Disease?
Authors: Biederman Robert W.W. , Doyle Mark , Yamrozik June , Williams Ronald B. , Rathi Vikas K. , Vido Diane , Caruppannan Ketheswaram , Osman Nael , Bress Valerie , Rayarao Geetha , Biederman Caroline M. , Mankad Sunil , Magovern James A. , Reichek Nathaniel
Published: July 2021

Background—

In compensated aortic stenosis (AS), cardiac performance measured at the ventricular chamber is typically supranormal, whereas measurements at the myocardium are often impaired. We investigated intramyocardial mechanics after aortic valve replacement (AVR) and the effects relative to the presence or absence of coronary artery disease (CAD+ or CAD−), respectively.

Methods and Results—

Twenty-nine patients (46 to 91years, 10 female) with late but not decompensated AS underwent cardiovascular MRI before AVR (PRE), with follow-up at 6±1 (EARLY) and 13±2 months (LATE) to determine radiofrequency tissue-tagged left ventricle (LV) transmural circumferential strain, torsion, structure, and function. At the myocardial level, concentric LV hypertrophy regressed 18% LATE (93±22 versus 77±17g/m
2
;
P
<0.0001), whereas at the LV chamber level, ejection fraction was supranormal PRE, 67±6% (ranging as high as 83%) decreasing to 59±6% LATE (
P
<0.05), representing not dysfunction but a return to more normal LV physiology. Between the CAD+ and CAD− groups, intramyocardial strain was similar PRE (19±10 versus 20±10) but different LATE, with dichotomization specifically related to the CAD state. In the CAD− patients, strain increased to 23±10% (+20%), whereas in CAD+ patients it fell to 16±11% (−26%), representing a nearly 50% decline after AVR (
P
<0.05). This was particularly evident at the apex, where CAD− strain LATE improved 17%, whereas for CAD+ it decreased 2.5-fold. Transmural strain and myocardial torsion followed a similar pattern, critically dependent on CAD. AVR impacted LV geometry and mitral apparatus, resulting in decreased mitral regurgitation, negating the double valve consideration.

Conclusions—

In AS patients after AVR, reverse remodeling of the supranormal systolic function parallels improvement in cardiovascular MRI-derived regression of LV hypertrophy and LV intramyocardial strain. However, discordant effects are evident after AVR, driven by CAD status, suggesting that the typical AVR benefits are experienced disproportionately by those without CAD and not by those obliged to undergo concomitant coronary artery bypass grafting/AVR.
Aprotinin Preserves Cellular Junctions and Reduces Myocardial Edema After Regional Ischemia and Cardioplegic Arrest
Authors: Khan Tanveer A. , Bianchi Cesario , Araujo Eugenio , Voisine Pierre , Xu Shu-Hua , Feng Jun , Li Jian , Sellke Frank W.
Published: July 2021

Background—

Cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest has been associated with myocardial edema attributable to vascular permeability, which is regulated in part by thrombin-induced alterations in cellular junctions. Aprotinin has been demonstrated to prevent activation of the thrombin protease-activated receptor, and we hypothesized that aprotinin preserves myocardial cellular junctions and prevents myocardial edema in a porcine model of regional ischemia and cardioplegic arrest.

Methods and Results—

Fourteen pigs were subjected to 30 minutes of regional ischemia, followed by 60 minutes of CPB, with 45 minutes of crystalloid cardioplegia, then 90 minutes of post-CPB reperfusion. The treatment group (n=7) was administered aprotinin (40 000 kallikrein inhibitor units [KIU]/kg loading dose, 40 000 KIU/kg pump prime, and 10 000 KIU/kg per hour continuous infusion). Control animals (n=7) received normal saline. Myocardial vascular endothelial (VE)-cadherin, β-catenin and γ-catenin, and associated mitogen-activated protein kinase (MAPK) pathways were assessed by immunoblot and immunoprecipitation. Histologic analysis of the cellular junctions was done by immunofluorescence. Myocardial tissue water content was measured. VE-cadherin, β-catenin, and γ-catenin levels were significantly greater in the aprotinin group (all
P
<0.05). Immunfluorescence confirmed that aprotinin prevented loss of coronary endothelial adherens junction continuity. Aprotinin reduced tyrosine phosphorylation in myocardial tissue sections. Phospho-p38 activity was ≈30% lower in the aprotinin group (
P
=0.007). The aprotinin group demonstrated decreased myocardial tissue water content (81.2±0.5% versus 83.5±0.3%;
P
=0.01) and reduced intravenous fluid requirements (2.9±0.2 L versus 4.0±0.4 L;
P
=0.03).

Conclusions—

Aprotinin preserves adherens junctions after regional ischemia and cardioplegic arrest through a mechanism potentially involving the p38 MAPK pathway, resulting in preservation of the VE barrier and reduced myocardial tissue edema.
The Role of Endothelin and Oxidative Stress in the Slow Pressor Responses to Angiotensin II (ANG II).
Authors: Ortiz-Ruiz Clara M , Sanabria Elizabeth , Manriquez Melissa C , Bolterman Rodney J , Juncos Luis A , Romero Juan C
Published: July 2021

44

Chronic infusion of subpressor doses of Ang II causes blood pressure to increase progressively over several days. The mechanisms underlying this response are unknown but may involve Ang II-induced generation of additional vasoconstrictor processes. In this study, we tested whether endothelin and/or oxidative stress are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1; n=6) or Ang II (group 2; n=5) intravenously at 5 ng/kg/min
via
osmotic pumps for 15 days into Sprague Dawley rats. In addition to the Ang II infusion, groups 3 and 4 (n=6 each) received 30 mg/kg/day of either losartan (an angiotensin AT
1
receptor blocker) or bosentan (a blocker of both endothelin receptors, ET
A
and ET
B
) in their drinking water. We measured systolic blood pressure (SBP) during the infusion, and the levels of circulating Ang II and isoprostanes (a marker of oxidative stress) at the conclusion of the experiments. Rats infused with vehicle had no change in SBP (from 138±13 to 138±2 mmHg) and normal levels of Ang II (34.5±9 pg/ml) and isoprostanes (111±10 pg/ml). Ang II infusion increased SBP from 133±10 to 158±8 mmHg, as well as circulating levels of Ang II (144±65 pg/ml) and isoprostanes (156±19 pg/ml). Losartan treatment abolished Ang II induced increases in SBP (SBP went from 137±5 to 120±4 mmHg), and isoprostanes (115±15 pg/ml), without altering Ang II levels (101±30 pg/ml). Bosentan also blocked Ang II-induced increases in SBP (from 135±4 to 139±3) but did not alter the increased isoprostane levels (146±14 pg/ml). Surprisingly, bosentan blunted the increase in Ang II levels (51±10 pg/ml). In conclusion, low dose Ang II-induced increases in SBP and oxidant stress depend on the AT
1
receptor. Endothelin receptor blockade also reduces SBP, but it does so independently of reducing oxidative stress (as measured by isoprostanes).
Tnfα-Induced Hypertension in Pregnant Rats Is Associated with Increased [Ca
2+
]
I
Signaling in Renal Arterial Smooth Muscle
Authors: Sirous Zohreh N , Cockrell Kathy L , Alexander Barbara T , Grnager Joey P , Khalil Raouf A
Published: July 2021

61

Placental ischemia during late pregnancy triggers the release of tumor necrosis factor α (TNFα), which may contribute to the increased vascular resistance associated with pregnancy-induced hypertension (PIH). We have reported that elevation of plasma TNFα 2-fold increases blood pressure and renal vascular resistance in pregnant rats; however, the cellular mechanisms involved are unclear. In this study, we investigated whether TNFα infusion in pregnant rats (10 ng/kg/day for 7 days) is associated with increases in [Ca
2+
]
i
and contractility of renal arterial smooth muscle. Pregnant (MAP = 96±3mmHg), TNFα-infused pregnant (123±3mmHg), virgin (108±5mmHg) and TNFα-infused virgin (110±3mmHg) Sprague-Dawley rats were used. Single smooth muscle cells were freshly isolated from the renal interlobular arteries and loaded with fura-2. In cells of pregnant rats incubated in Hank’s solution (1 mM Ca
2+
), the resting length was 74±6 μm and [Ca
2+
]
i
was 82±4 nM. In TNFα-infused pregnant rats, the resting cell length was shorter (54±3 μm) and [Ca
2+
]
i
was higher (119±4 nM) than pregnant rats. In pregnant rats, angiotensin II (AII, 10
-7
M) caused a transient increase in [Ca
2+
]
i
to 372±9 nM, a maintained increase to 149±8 nM and 21±2% cell contraction. The Ca
2+
channel agonist BAY K8644 (10
-6
M) caused an increase in [Ca
2+
]
i
to 249±11 nM and 18±2% cell contraction. In TNFα-infused pregnant rats, the maintained AII- and BAY K8644-induced [Ca
2+
]
i
(186±4 and 307±6 nM) and cell contraction (29±3% and 27±3%) were significantly > pregnant rats. AII and BAY K8644-induced contraction and [Ca
2+
]
i
were not significantly different between untreated and TNFα-infused virgin rats. In Ca
2+
-free Hank’s, AII and caffeine (10 mM)-induced [Ca
2+
]
i
transient and cell contraction were not significantly different in different groups of rats. Thus, TNFα-induced hypertension in pregnant rats is associated with increased [Ca
2+
]
i
in renal arterial smooth muscle cells due to enhanced Ca
2+
entry from extracellular space. TNFα, via increasing smooth muscle contractility and [Ca
2+
]
i
, may represent a possible mediator of the increased vascular resistance associated with PIH.
Role of Free Radicals and Angiotensin II in Blood Pressure Regulation in a Renal Model of Hypertension in Rat
Authors: Dobrian Anca D , Prewitt Russell L
Published: July 2021

P17

One kidney one clip (1K1C) or uninephrectomized controls were treated with either the SOD mimetic tempol (T) (0.5 mmol/kg/day), AT1 receptor inhibitor losartan (L) (50mM/kg/day), or both(L+T) (n=6/group), for 2 weeks. At the end of the study,systolic BP decreased on average by 21% in T- and 29% in L-treated compared to untreated 1K1C (217±4.4 mmHg) and was normalized in the L+T group (123.5±3.3 mmHg). Mean BP also decreased from 130±3.7 mmHg in 1K1C to 83±2.8mmHg in the L+T treated group. The differences were significant (p<0.003) as tested with Bonferroni multiple comparisons test. Also, aortic wall area was reduced by 18% in the L or T treated 1K1C and by 30% in the L+T rats, compared to 1K1C (0.548±0.03 mm2). Plasma renin activity was increased from 4.8±0.3 in 1K1C to 15.9±0.9 ng/ml/h in L - but not T- 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin (25μM) chemiluminescence was significantly decreased by ∼40% in all L, T and L+T groups compared to 1K1C controls (1065±200 RLU/mg DNAx10
5
). The nitrotyrosine ELISA assay in the kidney displayed a significant reduction from 59±13 ng/mg protein in
1K1C
to 12.5±5 ng/mg protein in the L+T
1K1C
rats. Western blotting for nNOS in the kidney cortex and medulla showed a protein increase in both fractions of
1K1C
vs controls and was normalized by the L+T treatment. Collectively, data show a synergistic effect of L and T on the blood pressure reduction in 1K1C rats. The mechanism may involve the reduced superoxide production and decreased kidney nNOS expression in the treated animals. Also, the reduced nitrosylation of the proteins in the kidney might have an important effect on blood pressure regulation.
GABA-A Function and Receptor Binding in the Paraventricular Nucleus in Chronic Renal Wrap Hypertension
Authors: Haywood Joseph R , Craig Teresa , Hensler Julie , Hinojosa-Laborde Carmen
Published: July 2021

P48

The onset of renal wrap hypertension is associated with a reduced tonic GABA inhibition in the paraventricular nucleus (PVN) on the sympathetic nervous system. This reduced functional inhibition occurs without a change in GABA-A receptor binding in the PVN. The goal of the present study was to determine if GABAergic transmission and GABA binding is altered in chronic renal wrap hypertensive rats. Sprague-Dawley rats were made hypertensive or sham-operated. Four weeks later, animals were prepared with femoral artery catheters for the measurement of arterial pressure. Subgroups were also prepared with bilateral cannulae directed at the PVN. The renal wrap rats had higher mean arterial pressure (MAP): 139±4 mmHg vs.113±2 mmHg, but heart rate (HR) was not different (354±12 bpm vs. 369±6 bpm) as compared to control animals. Administration of the GABA-A antagonist, bicuculline, into the PVN caused a greater increase in MAP and HR in wrap animals (25±2 mmHg and 150±30 bpm) compared to sham operated rats (16±2 mmHg and 89±12 bpm). GABA-A binding sites in the PVN were estimated using in vivo autoradiography. [3H]-Flunitrazepam was used as the receptor ligand. Magnocellular neurons of the PVN showed a higher density of receptors than other areas of the nucleus. However, the number of binding sites was not different between normotensive and hypertensive rats in either the high density (1825±56 vs. 1756±41 fmol/mg protein) or low density (1454±26 vs. 1433±57 fmol/mg protein) regions of PVN. These data indicate that the inhibition by GABA in the PVN is augmented in the chronic stage of hypertension, and appears to be unrelated to a change in the number of GABA binding sites. The increased GABAergic inhibition is in contrast to the reduced inhibition that has been observed during the onset of hypertension.
Complex Abnormalities in Baroreflex Function in Patients with Monogenic Hypertension and Neurovascular Contact
Authors: Jordan Jens , Toka Hakan , Heusser Karsten , Toka Okan , Shannon John R , Tank Jens , Schobel Hans P , Diedrich Andre , Haller Herrmann , Luft Friedrich C
Published: July 2021

P53

We have shown that autosomal-dominant hypertension with brachydactyly regularly features brainstem neurovascular compression (NVC). To seek mechanisms by which NVC could influence blood pressure, we conducted extensive autonomic tests in 5 affected persons (18-34 yrs.). Cold pressor testing, hand-grip testing, and upright posture all increased BP excessively. Baseline muscle sympathetic nerve activity was 15±4.6 bursts/min in patients, 12±6 bursts/min in normotensive controls, and 14±9 bursts/min in borderline hypertensive controls (ns). The increase in nerve traffic during cold pressor testing was not excessive. Urinary norepinephrine excretion was 19±4.0 μg/24 hours (normal range 23-105 μg/ 24 hours). Blood pressure during ganglionic blockade was134±4.9/ 82±4.1 mmHg in patients and 90±6/49±2.4 mmHg in controls (p<0.05). In patients, plasma vasopressin concentration changed from 0.47±0.03 pg/ml at baseline to 0.84±0.23 pg/ml during ganglionic blockade. In contrast, in control subjects, plasma vasopressin concentration increased profoundly from 1.6±0.17 pg/ml at baseline to 39±13 pg/ml during ganglionic blockade. The phenylephrine dose that increased SBP 12.5 mmHg was 8.0±2.0 μg in patients and 135±35 μg in control subjects before ganglionic blockade (p<0.01). During ganglionic blockade, the dose of phenylephrine that increased SBP 12.5 mmHg was 5.4±0.4 μg in patients and 13±4.8 μg in control subjects. The baroreflex slope was 9.4±1.6 msec/mmHg. We conclude that in these patients, basal BP was increased even during interruption of sympathetic and parasympathetic nerve traffic. However, sympathetic stimuli caused an excessive increase in BP. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that the ability of the baroreflex to buffer changes in blood pressure is severely impaired despite retained heart rate control.
Mitogen-Activated Protein Kinases Are Differently Activated in Early Hypertrophic Response to Acute Pressure Overload in Rat Myocardium
Authors: Junior Wilson Nadruz , Saad Mario A
Published: July 2021

P55

Mitogen-activated protein kinases (MAPKs) have been reported as important signaling molecules mediating cardiomyocyte hypertrophic response to various stimuli. Four subfamilies of MAPKs have been described in mammalian cells: c-jun NH2 terminal kinases (JNKs), p38-MAPKs (p38), extracellular response kinases (ERKs) and big MAP-kinase (BMK). Our objective was to study the activation of these kinases in the early phases of hypertrophic response, which is currently obscure. Transverse aorta constriction (TAC) was performed in male Wistar rats (160-200g) and left ventricles were studied up to 3 h following the surgery. To study the activation of ERKs, JNKs and p38, heart homogenates were separated into cytosolic (C) and nuclear (N) fractions and their kinase activities were determined by Western Blot using anti p-ERK, p-JNK and p-p38 antibodies. The membranes were then stripped and blotted with anti-ERK, anti-JNK and anti-p38 to determine the protein contents. The amount of BMK was studied in total homogenates using anti-BMK antibody and its activity was studied by measuring its
in vitro
autophosphorylation. ERK1/2 were transiently activated in both subcellular fractions, reaching a maximum 30 min after TAC (ERK1 - 236% in C and 196% in N; ERK2 - 280% in C and 248% in N) and returning toward basal levels after 1 h. p38 showed a sustained increase in its activity only in C (to 259%) but not in N after 1 h of TAC. JNKs showed a biphasic response with an early and major increase in their activities after 10 min (to 313% for JNK1 and to 288% for JNK2 in C) and a second and minor one following 3 h of TAC. In parallel, TAC induced a significant nuclear translocation of JNK1. The total amount of BMK remained stable during the studied period. We observed a progressive increase in its kinase activity which was directly related to TAC time course (45% in 10 min; 159% in 1 h and 173 % in 2h). These results indicate that pressure overload induces an early activation of the four subfamilies of MAPKs. Differences in their time course activation suggest that they might play different roles in the early hypertrophic response in adult rat myocardium.
Myocardial Infarct Evolution and Cardiac Remodeling in Mice
Authors: Yang Fang , Liu Yun-He , Yang Xiao-Ping , Xu Jiang , Carretero Oscar A
Published: July 2021

P62

A mouse model of myocardial infarction (MI) has been widely used since genetically engineered mice became available, which allows us to study gene regulation of cardiac phenotype, function, and pathophysiology of heart failure. However, some basic information, such as the healing process, infarct expansion and LV remodeling after MI in mice, is lacking. To clarify this process, 42 male C57B1/6J mice underwent coronary artery ligation and were killed at 1, 2, 4, or 7 days, or 2, 3, or 4 weeks after MI. Left ventricular (LV) morphology and function were evaluated by histopathology and echocardiography. We found that at the margin of the necrotic myocardium, infiltration by neutrophils was noticeable at 1 and 2 days. Marked infiltration by mononuclear cells occurred at day 4. Lymphocyte infiltration was apparent at 7 and 14 days. Massive proliferation of fibroblasts and fibrocytes and accumulation of collagen began at day 14 and scar formation was completed by day 21. The infarct expansion index increased gradually from 0.62 ± 0.12 at day 1 to 1.66 ± 0.35 at day 14, which reached a maximum, then decreased slightly to 1.51 ± 0.26 at day 28. In non-infarcted areas of the heart, myocyte cross-sectional area and collagen content increased from 161 ± 17 μm
2
and 5.7 ± 0.3% at day 1 to 252 ± 8 μm
2
and 10.8 ± 0.8% at day 21, respectively, and remained similar at day 28. Infarct size was 47%, 52% and 47% at day 1, 14 and 28 respectively. Increased LV diastolic chamber dimension and mass and decreased shortening fraction (SF) appeared as early as 2 weeks after MI and continued for 4 weeks (table). Thus this study provides important qualitative and quantitative information on the natural history of MI and validation of the mouse model.
The Effect of Race on Circadian Patterns of Blood Pressure: Results from the Dietary Approaches to Stop Hypertension (DASH) Feeding Study
Authors: Appel Lawrence J , Charleston Jeanne , Conlin Paul R , Erlinger Thomas P , Harsha David W , Miller Edgar R , Moore Thomas J , Svetkey Laura P
Published: July 2021

P122

In most studies, American blacks have a blunted nocturnal decline in BP compared to non-blacks. A major limitation of such analyses has been the inability to control for factors that influence BP (diet, weight, physical activity and socioeconomic status). We used data from the run-in period of the DASH feeding study to determine whether racial differences in circadian BP persist after adjusting for traditional determinants of BP. At end of run-in, a 3 week period when all participants had been fed a common diet (3 gm/d of Na, 1.7 gm/d of K), we obtained ambulatory BP. Participants (198 blacks and 156 non-blacks) had a baseline random-zero SBP <160 and DBP of 80-95 mmHg (mean 131/85 mmHg in both groups). Main results are displayed below. In summary, blacks who had the same baseline BP and who ate the same diet as non-blacks had a blunted nocturnal decline in BP, even after adjustment for other factors that influence BP. Sustained nocturnal BP may partially explain the excess burden of BP-related cardiovascular disease in blacks.
Cgmp-Dependent Calcium Desensitization Contributes to Vasodilator Response to Nitric Oxide in Rat Middle Cerebral Arteries
Authors: Sun Cheng-wen , Harder David R , Roman Richard J
Published: July 2021

P142

We have recently reported that a cGMP-dependent mechanism as well as a cGMP-independent activation of K
Ca
channels secondary to a fall in 20-HETE contributes to the vasodilator response to NO in the cerebral circulation. The present study examines the mechanism for the cGMP-dependent component of the vasodilator response to NO in rat middle cerebral arteries (MCA). Administration of a NO donor, dose-dependently, increased the diameter of serotonin preconstricted MCA to 69.3±5.8% of control (n=6). 8-Br-cGMP (10
-8
to 10
-4
M) mimicked the effect of NO and increased the diameter of MCA to 58.7±3.6% of control (n=6). Blockade of K
Ca
channels with IBTX (10
-7
M, n=6) or depolarization with a 80 mM K
+
media (n=6)reduced the vasodilator response of MCA to NO by 70±6%, but they had little effect on the vasodilator response to 8-Br-cGMP. This suggests that activation of K
+
channels contribute to the vasodilator response to NO in MCA, but not the response to 8-Br-cGMP. We therefore examined the effects of NO and cGMP on Ca
2+
-induced contraction of rat MCAs permeablized with α-toxin (10 μg/ml) and ionomycin (10 μM). Elevations in bath Ca
2+
, from 10
-8
to 10
-5
M, decreased the diameter of these vessels by 60.9±3.7%. A NO donor, DEA-NONOate (10
-6
M, n=6)and 8-Br-cGMP (10
-4
M, n=6) both attenuated the vasoconstrictor response to elevations in bath Ca
2+
by 60%. Inhibition of guanylyl cyclase with ODQ (10
-5
M) prevented the effects of the NO donor, but not 8-Br-cGMP. These results indicate that the cGMP, PKG-dependent component of the vasodilator response of NO in rat MCA is mediated by desensitization of the contractile mechanism to calcium rather than activation of K
+
channels.
Src-Dependent Erk1/2-Mediated Signaling Pathways and Associated Ang Ii-Stimulated Growth Responses Are Altered in Vascular Smooth Muscle Cells from Arteries of Hypertensive Patients.
Authors: Touyz Rhian M , He Gang , Wu Xiao-Hua , Park Jeong Bae , Mabrouk Mohammed El , Schiffrin Ernesto L
Published: July 2021

P154

Molecular mechanisms underlying vascular remodeling in human hypertension are unclear. We investigated c-Src and ERK1/2 activity, proto-oncogene expression, activating protein 1 (AP-1) DNA-binding activity, and DNA and protein synthesis in Ang II-stimulated vascular smooth muscle cells (VSMC) derived from small peripheral arteries from normotensive subjects (NT) (n=5) and age-matched untreated hypertensive patients (HT) (n=10). The media and media:lumen ratio were greater (p<0.05) in arteries from HT than NT, indicating vascular remodeling. Ang II-dose-dependently increased synthesis of DNA and protein, with enhanced effects (p<0.01) in VSMCs from HT. PD98059, a selective inhibitor of the ERK1/2 pathway, attenuated (p<0.01) Ang II-stimulated growth. PD98059 effects were greater in HT than NT. In NT, Ang II transiently increased ERK1/2 phosphorylation. In HT, Ang II-stimulated ERK1/2 activation was significantly augmented (p<0.05 vs NT) and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 activity and normalized responses in HT. Ang II-induced c-Src phosphorylation was 2-3 fold greater in HT than NT. In HT, kinase activation was followed by overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. PD98059 attenuated these responses. In HT cells transfected with c-fos antisense oligodeoxynucleotide (ODN), Ang II-stimulated DNA synthesis was reduced compared with sense ODN. These novel findings suggest that vascular remodeling is associated with augmented Ang II-stimulated VSMC growth, which is mediated via hyperactivation of c-Src-regulated, ERK1/2-dependent pathways leading to overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. Our data define a signal transduction pathway in VSMCs that could contribute to structural changes and vascular remodeling in essential hypertension.
Mineralocorticoid Receptor Activation by Aldosterone or Corticosterone Induces Hypertension, Myocardial Infarction and Proteinuria
Authors: Tao Qing-Feng , vasquez Diego Martinez , Rocha Ricardo , Williams Gordon H , Adler Gail K
Published: July 2021

P165

Aldosterone through its interaction with the mineralocorticoid receptor (MR) plays a critical role in the development of hypertension and cardiovascular injury (CVI). Normally, MR is protected by 11β-hydroxysteroid dehydrogenase (11β-HSD) which inactivates glucocorticoids preventing their binding to MR. We hypothesis that if activation of MR by either aldosterone or glucocorticoids induces hypertension and CVI, then the inhibition of 11β-HSD with glycyrrhizin (GA), a natural inhibitor of 11β-HSD, should induce damage similar to that observed with aldosterone. Sprague-Dawley rats were uninephrectomized, and treated for 4 weeks with 1% NaCl (in drinking water) for the control group, 1% NaCl + aldosterone infusion (0.75 μg/h), or 1% NaCl + GA (3.5 g/l in drinking water). After 4 weeks, aldosterone and GA caused significant increases in blood pressure compared to control rats ([mean ± SEM] 211± 9, 205 ± 12, 120 ± 9 mmHg, respectively, p<0.001). Both aldosterone- and GA-treated rats had a significant increase in proteinuria (152.2 ± 8.7 and 107.7 ± 19.5 mg/d, respectively) versus controls (51.2 ± 9.5 mg/d). There was a significant increase (p<0.001) in heart to body weight ratio in the rats treated with aldosterone or GA compared with control (3.92 ± 0.10, 3.98 ± 0.88, and 3.24 ± 0.92 mg/g, respectively). Hearts of GA and aldosterone treated rats showed similar histological changes consisting of biventricular myocardial necrosis and fibrinoid necrosis of small coronary arteries and arterioles. These data suggests that in rodents activation of MR by either aldosterone or corticosterone leads to severe hypertension, vascular injury, proteinuria and myocardial infarction. Thus, 11β-HSD plays an important role in protecting the organism from injury.
Spironolactone Ameliorates Angiotensin Ii-Induced Renal Damage Via the Inhibition of Ap-1 and Nf-κB
Authors: Park Joon-Keun , Stille Kolja , Muller Dominik N , Shagdarsuren Erdenechimeg , Dechend Ralf , Fiebeler Anette , Schmidt Folke , Bieringer Markus , Breu Volker , Ganten Detlev , Luft Friedrich C , Haller Hermann
Published: July 2021

P168

Recently, clinical trials have demonstrated the efficacy of spironolactone (SPIRO) in men. Nevertheless the molecular mechanism of action not completely understood. Locally generated angiotensin II (ANG II) stimulates aldosterone. Therefore, we have tested the hypothesis that SPIRO ameliorates ANG II-induced renal damage. Furthermore, we investigated the effect of SPIRO on the transcription factors AP-1 and NF-κB. We treated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) from week 5 to 7 with SPIRO (20 mg/kg/d). Plasma aldosterone was significantly increased in dTGR vs. SPIRO treated and non-transgenic (SD) rats (p<0.05). Untreated dTGR showed high systolic blood pressure (182±8 mm Hg), severe renal damage with 150-fold increased albuminuria, vasculopathy and perivascular and interstitial fibrosis. Chronic SPIRO treatment reduced mortality and vasculopathy completely, despite blood pressure levels of 161±11. 24-hour albuminuria was reduced from 59±15 in dTGR to 3.5±2 mg/d; p<0.01). Electrophoretic mobility gel shift analysis demonstrated a reduction of renal AP-1 and NF-κB DNA binding activity after SPIRO treatment. Immunohistological analysis showed that SPIRO also prevented the expression of AP-1 and/or NF-kB regulated matrix molecules fibronectin and laminin. The reno-protective effect of SPIRO was accompanied with a reduction of monocyte/macrophage infiltration. These findings show that blockade of aldosterone signaling ameliorates ANG II-induced renal damage. SPIRO action was at least partially mediated via AP-1 and NF-κB.