bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Optimal Conditions for Lung Graft Storage With Euro-Collins Solution by Use of a Rat Orthotopic Lung Transplant Model
Authors: Kayano Koichi , Toda Koichi , Naka Yoshifumi , Pinsky David J.
Published: July 2021

Background
—Lung preservation disrupts normal vascular homeostasis, resulting in increased permeability, vasoconstriction, and endothelial cell adhesion for neutrophils. We hypothesized that a storage strategy that best preserves post–lung transplantation (LTX) vascular homeostasis might be organ and species specific. Because of the potential utility of a rat LTX model for developing improved lung preservation strategies, we have attempted to identify the optimal physical conditions for rat lung graft storage.

Methods and Results
—Conditions that were tested included harvest inflation pressure (0, 10, or 20 mm Hg), inflation gas composition (100% N
2
, room air, or 100% O
2
), and storage temperature (4°, 10°, or 15°C). Modified Euro-Collins solution served as the base preservation solution for all experiments, with a preservation duration of 4 to 6 hours. Arterial oxygenation (Pa
o
2
, mm Hg), pulmonary vascular resistance (mm Hg/mL per minute), recipient survival (%), and graft neutrophil infiltration (ΔAbs
460 nm
/min) were measured 30 minutes after transplantation of the left lung and exclusion of the right lung from the circulation. All tested conditions significantly affect post-LTX vascular homeostasis. Inflation at 10 mm Hg pressure preserved lungs significantly better than did other pressures. There was a tendency for room air to improve all measured variables compared with 100% N
2
or 100% O
2
and a significant improvement in recipient survival with room air storage. Of the 3 storage temperatures investigated, 10°C storage provided the best preservation in terms of Pa
o
2
, graft neutrophil infiltration, and survival.

Conclusions
—We conclude that storage at 10°C, 10 mm Hg inflation pressure, with room air establishes optimal lung storage conditions with Euro-Collins solution in this rat LTX model. These data suggest that these conditions should be used to evaluate new and potentially improved preservation strategies.
Formation of Cell Junctions Between Grafted and Host Cardiomyocytes at the Border Zone of Rat Myocardial Infarction
Authors: Matsushita Tsutomu , Oyamada Masahito , Kurata Hiroyuki , Masuda Shinsuke , Takahashi Akiyuki , Emmoto Takeshi , Shiraishi Isao , Wada Yukio , Oka Takahiro , Takamatsu Tetsuro
Published: July 2021

Background
—Cardiomyocyte transplantation is an innovative strategy for the treatment of heart failure after myocardial infarction. Cell junctions show diverse temporal polarization toward intercalated disks during postnatal development and exhibit altered distribution in diseased hearts. To elucidate the formation of cell junctions between grafted and host cardiomyocytes at the border zone of myocardial infarction, the 3D distribution of cell junctions was examined using immunohistochemistry and confocal microscopy.

Methods and Results
—Neonatal cardiomyocytes obtained from 3-day-old rats by collagenase digestion and Percoll density centrifugation were injected into the border zones of infarction sites 10 days after coronary ligation in adult rats. At 4 to 14 days after transplantation, hearts were harvested and processed by immunohistochemistry. Antibodies against connexin43, desmoplakin, and cadherin were used to analyze the distribution of gap junctions, desmosomes, and adherens junctions, respectively. Grafted cardiomyocytes were identified by immunohistochemistry for α-smooth muscle actin. Grafted cardiomyocytes tended to align parallel to the host cardiomyocytes. Connexin43, desmoplakin, and cadherin were localized between grafted cardiomyocytes themselves and between grafted and host cardiomyocytes. Semiquantitative analysis revealed that all junctions showed increasing polarization to longitudinal cell termini, especially at the border of grafted and host cardiomyocytes, as time advanced from 4 to 7 days after transplantation.

Conclusions
—These findings indicate that grafted cardiomyocytes foster electrical pathways with host counterparts through the gap junction and suggest that the environment in infarcted hearts could influence the localization of gap junctions, desmosomes, and adherens junctions.
Perioperative Prognostic Value of Dipyridamole Echocardiography in Vascular Surgery
Authors: Sicari Rosa , Ripoli Andrea , Picano Eugenio , Djordjevic-Dikic Ana , Di Giovanbattista Raniero , Minardi Giovanni , Matskeplishvili Simon , Ambatiello Sergei , Pulignano Giovanni , Accarino Mario , Lusa Anna Maria , Franco Del Rosso Gian , Pedrinelli Roberto , Buziashvili Yuri
Published: July 2021

Background
—Patients undergoing major vascular surgery are at a relatively high risk of cardiac events, and pharmacological stress echocardiography is increasingly used for perioperative risk stratification. The aim of the current study was to evaluate the value of dipyridamole echocardiography test (up to 0.84 mg/kg over 10 minutes) in predicting cardiac events in a large-scale, multicenter, prospective, observational study design.

Methods and Results
—Five hundred nine patients (mean age 66±10 years) were studied before vascular surgery by dipyridamole stress echocardiography in 11 different centers. All patients underwent preoperative clinical risk assessment according to the American Heart Association guidelines. No major complications occurred during dipyridamole stress echocardiography. Technically adequate images were obtained in all patients; however, in 4 patients only the low dipyridamole dose (0.56 mg/kg over 4 minutes) was given for limiting side effects. Eighty-eight (17.3%) had a positive test. Perioperative events occurred in 31 (6.1%) patients: 6 deaths, 11 myocardial infarctions, and 14 episodes of unstable angina. Sensitivity and specificity of dipyridamole stress echocardiography for predicting spontaneous cardiac events were 81% and 87%, respectively, with a positive predictive value of 28% and negative predictive value of 99%. By multivariate analysis, the difference between wall motion score index at rest and peak stress (Δwall motion score index), test positivity, and ST-segment depression during dipyridamole infusion were independent predictors of any perioperative cardiac event.

Conclusions
—Dipyridamole stress echocardiography is safe and well tolerated in patients undergoing major vascular surgery and provides an effective preoperative screening test for the risk stratification of these patients, mainly because of the extremely high negative predictive value, which is a potent predictor of complication-free procedure.
Platelet-Activating Factor Acetylhydrolase Prevents Myocardial Ischemia-Reperfusion Injury
Authors: Morgan Elizabeth N. , Boyle Edward M. , Yun Wang , Kovacich John C. , Canty Timothy G. , Chi Emil , Pohlman Timothy H. , Verrier Edward D.
Published: July 2021

Background
—Platelet-activating factor (PAF) is one of the most potent biological mediators of tissue injury. PAF acetylhydrolase (PAF-AH) is a recently isolated naturally occurring enzyme that hydrolyzes PAF and renders it inactive. We hypothesize that inhibition of PAF with PAF-AH will reduce myocardial ischemia-reperfusion (I/R) injury in vivo.

Methods and Results
—The coronary ligation model was used in New Zealand white rabbits. The large branch of the marginal coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. Fifteen minutes before reperfusion, animals were given either 2 mg/kg of vehicle or of PAF-AH. At the completion of 120 minutes of reperfusion, percentage of necrosis, degree of neutrophil infiltration, and measurements of regional contractility were assessed. Data are expressed as the mean±SEM and compared by Student’s
t
test or Mann-Whitney ANOVA. Both groups of animals showed an equivalent area at risk; however, 46.7±11% was necrotic in the animal treated with vehicle. In contrast, 20.9±7.0% was necrotic in the animals treated with PAF-AH (
P
<0.05). Systolic shortening and wall thickness were significantly greater in those animals treated with PAF-AH at 15, 30, 60, and 120 minutes of reperfusion (
P
<0.05). Quantification of neutrophil infiltration showed a 62% reduction in the PAF-AH treated animals compared with those treated with vehicle alone.

Conclusions
—PAF-AH is a potent cardioprotective agent in an in vivo model of I/R injury.
The Role of Gene Therapy for Intimal Hyperplasia of Bypass Grafts
Authors: Cable David G. , Caccitolo James A. , Caplice Noel , O’Brien Timothy , Simari Robert D. , Daly Richard C. , Dearani Joseph A. , Mullany Charles J. , Orszulak Thomas A. , Schaff Hartzell V.
Published: July 2021

Background
—Proliferation of the intima is an early lesion of saphenous vein graft disease. Early patency rates of radial artery grafts are acceptable, but little is known about their risk of intimal hyperplasia.

Methods and Results
—To develop a model of intimal hyperplasia, we incubated human saphenous veins, internal mammary arteries, and radial arteries (n=6, 8, and 10, respectively) in an organ culture with Rosewell Park Memorial Institute 1640 (30% serum) for 0, 4, 7, 10, and 14 days. Quantitative histological studies were performed, and the average intimal-to-medial (I/M) ratio was calculated for each incubation interval. After 10 and 14 days of culture, the I/M ratio increased in the saphenous veins (
P
=0.03,
P
=0.04 versus 0 day, respectively). No significant increase occurred in the I/M ratio in either the internal mammary or radial arteries. Next, the ability of adenoviral gene transfers to inhibit intimal hyperplasia in the saphenous veins was evaluated. Adenoviral-mediated gene transfer of nitric oxide synthase significantly reduced the I/M ratio at 14 days compared with vehicle (
P
=0.001) and virus (
P
=0.004) controls.

Conclusions
—The human saphenous vein has a greater propensity for intimal hyperplasia than arterial grafts; the human radial artery behaves similarly to the internal mammary artery. In the future, gene therapy may augment nitric oxide synthase, limiting vein graft disease.
Deformational Dynamics of the Aortic Root
Authors: Dagum Paul , Green G. Randall , Nistal Francisco J. , Daughters George T. , Timek Tomasz A. , Foppiano Linda E. , Bolger Ann F. , Ingels Neil B. , Miller D. Craig
Published: July 2021

Background
—Current surgical methods for treating aortic valve and aortic root pathology vary widely, and the basis for selecting one repair or replacement alternative over another continues to evolve. More precise knowledge of the interaction between normal aortic root dynamics and aortic valve mechanics may clarify the implications of various surgical procedures on long-term valve function and durability.

Methods and Results
—To investigate the role of aortic root dynamics on valve function, we studied the deformation modes of the left, right, and noncoronary aortic root regions during isovolumic contraction, ejection, isovolumic relaxation, and diastole. Radiopaque markers were implanted at the top of the 3 commissures (sinotubular ridge) and at the annular base of the 3 sinuses in 6 adult sheep. After a 1-week recovery, ECG and left ventricular and aortic pressures were recorded in conscious, sedated animals, and the 3D marker coordinates were computed from biplane videofluorograms (60 Hz). Left ventricular preload, contractility, and afterload were independently manipulated to assess the effects of changing hemodynamics on aortic root 3D dynamic deformation. The ovine aortic root undergoes complex, asymmetric deformations during the various phases of the cardiac cycle, including aortoventricular and sinotubular junction strain and aortic root elongation, compression, shear, and torsional deformation. These deformations were not homogeneous among the left, right, and noncoronary regions. Furthermore, changes in left ventricular volume, pressure, and contractility affected the degree of deformation in a nonuniform manner in the 3 regions studied, and these effects varied during isovolumic contraction, ejection, isovolumic relaxation, and diastole.

Conclusions
—These complex 3D aortic root deformations probably minimize aortic cusp stresses by creating optimal cusp loading conditions and minimizing transvalvular turbulence. Aortic valve repair techniques or methods of replacement using unstented autograft, allograft, or xenograft tissue valves that best preserve this normal pattern of aortic root dynamics should translate into a lower risk of long-term cusp deterioration.
Functional Evaluation of the Medtronic Stentless Porcine Xenograft Mitral Valve in Sheep
Authors: Dagum Paul , Green G. Randall , Timek Tomasz A. , Daughters George T. , Foppiano Linda E. , Tye Terrance L. , Bolger Ann F. , Ingels Neil B. , Miller D. Craig
Published: July 2021

Background
—Recently, renewed interest in allograft and stentless “freehand” bileaflet xenograft mitral valve replacement has arisen. The variability of human papillary tip anatomy and scarcity of donors limit allograft availability, making xenograft mitral valves an attractive alternative; however, these valves require new surgical implantation techniques, and assessment of their hemodynamics and functional geometry is lacking.

Methods
—Seven sheep underwent implantation of a new stentless, glutaraldehyde-preserved porcine mitral valve (Physiological Mitral Valve [PMV], Medtronic) and were studied acutely under open-chest conditions. A new method of retrograde cardioplegia was developed. Hemodynamic valve function was assessed by epicardial Doppler echocardiography. 3D motion of miniature radiopaque markers sutured to the valve leaflets, annulus, and papillary tips was measured. Six other sheep with implanted markers served as controls.

Results
—Both papillary muscle tips avulsed in the first animal, leaving 6 other animals. Mitral regurgitation was not observed in any xenograft valve. The peak and mean transvalvular gradients were 4.6±1.8 mm Hg and 2.6±1.5 mm Hg, respectively. The average mitral valve area was 5.7±1.6 cm
2
. Valve closure in the xenograft group occurred later (30±11 ms,
P
<0.015) and at higher left-ventricular pressure (61±9 mm Hg,
P
<0.001) than in the control group; furthermore, leaflet coaptation was displaced more apically (5.6±2.2 mm,
P
<0.001) and septally (5.8±1.5 mm,
P
<0.001), and the anterolateral papillary tip underwent greater septal-lateral displacement (2.7±1.5 mm,
P
<0.001). Annular contraction during the cardiac cycle was similar in the 2 groups (xenograft 9.2±4.5% versus control 10.6±4.5% [mean±SD; 2-factor ANOVA model]).

Conclusions
—Successful freehand stentless porcine mitral valve implantation is feasible in sheep and was associated with excellent early postoperative hemodynamics. Physiological mitral valve annular contraction and functional leaflet closure mechanics were preserved. Long-term valve durability, calcification, and hemodynamic performance remain to be determined in models.
Mitral Annular Dilatation and Papillary Muscle Dislocation Without Mitral Regurgitation in Sheep
Authors: Green G. Randall , Dagum Paul , Glasson Julie R. , Daughters George T. , Bolger Ann F. , Foppiano Linda E. , Berry Gerald J. , Ingels Neil B. , Miller D. Craig
Published: July 2021

Background
—Asymmetrical mitral annular (MA) dilatation and papillary muscle dislocation are implicated in the pathogenesis of functional mitral regurgitation (MR).

Methods and Results
—To determine the mechanism by which annular and papillary muscle geometric alterations result in MR, we implanted radiopaque markers in the left ventricle, mitral annulus, anterior and posterior mitral leaflets, and papillary muscle tips and bases in 2 groups of sheep. One group served as controls (CTL, n=7); an experimental group (EXP, n=9) underwent topical phenol application to obliterate anterior annular and leaflet muscle (confirmed histologically ex vivo). After 1 week of recovery, markers were imaged with biplane videofluoroscopy, and hemodynamic data were recorded. MA area (computed from 3-dimensional marker coordinates) was 11% to 13% larger in the EXP group than in the CTL group (
P
<0.05 by ANOVA). This area increase resulted exclusively from intercommissural axis increase except in 1 heart with large (>1 cm) increases in both the intercommissural and septolateral annular axes. The anterior papillary muscle tip in EXP was displaced from CTL by 2.9±0.23 mm toward the anterolateral left ventricle and 2.5±0.12 mm toward the mitral annulus at end systole; the posterior papillary muscle geometry was unchanged. Transthoracic echocardiography revealed MR only in the heart exhibiting biaxial annular enlargement.

Conclusions
—MA dilatation in the intercommissural dimension with anterior papillary muscle tip displacement toward the annulus is insufficient to produce MR in sheep. Functional MR may require MA dilatation in the septolateral axis, as observed with proximal circumflex coronary occlusion.
Midterm Echocardiographic Follow-Up After Ross Operation
Authors: Briand Martin , Pibarot Philippe , Dumesnil Jean G. , Cartier Paul
Published: July 2021

Background
—The pulmonary autograft (Ross) operation is an attractive treatment for aortic valve disease, but hemodynamic follow-up is not well defined.

Methods and Results
—One hundred thirty-two consecutive patients (62% male, mean age 40±11 years) were followed up to 5 years after the Ross operation. Echocardiography was performed early (within 30 days), 3 to 6 months, and yearly after surgery. The valve effective orifice area (EOA) and mean transvalvular gradient of both aortic and pulmonary valves were measured, and transvalvular regurgitation was assessed by using color Doppler echocardiography. EOA was indexed for body surface area. The hemodynamic performance was excellent for both the aortic and pulmonary valves early after surgery (gradient, 3±4 and 3±4 mm Hg, respectively). It remained stable thereafter for the aortic valve, whereas there was a significant deterioration of the EOA (−0.74±0.82 cm
2
) and gradient (+6±8 mm Hg) for the pulmonary valve, which occurred mostly during the first 6 months after surgery. This hemodynamic deterioration resulted in suboptimal (defined as an EOA index <0.85 cm
2
/m
2
) hemodynamics in 19.3% of the patients, to the extent that 3 (2%) of the 132 patients eventually had to be subjected to further surgery for severe pulmonary valve stenosis.

Conclusions
—The pulmonary autograft provides continued excellent hemodynamics in the aortic position, whereas moderately high gradients can be found across the pulmonary homograft in some patients. Further studies are necessary to identify the factors responsible for the deterioration of the hemodynamic performance of the homograft in the pulmonary position and to determine its impact on right ventricular function and clinical status.
Early In Vivo Experience With Tissue-Engineered Trileaflet Heart Valves
Authors: Sodian Ralf , Hoerstrup Simon P. , Sperling Jason S. , Daebritz Sabine , Martin David P. , Moran Adrian M. , Kim Byung S. , Schoen Frederick J. , Vacanti Joseph P. , Mayer John E.
Published: July 2021

Background
—Tissue engineering is a new approach in which techniques are being developed to transplant autologous cells onto biodegradable scaffolds to ultimately form new functional autologous tissue. Workers at our laboratory have focused on tissue engineering of heart valves. The present study was designed to evaluate the implantation of a whole trileaflet tissue-engineered heart valve in the pulmonary position in a lamb model.

Methods and Results
—We constructed a biodegradable and biocompatible trileaflet heart valve scaffold that was fabricated from a porous polyhydroxyalkanoate (pore size 180 to 240 μm; Tepha Inc). Vascular cells were harvested from ovine carotid arteries, expanded in vitro, and seeded onto our heart valve scaffold. With the use of cardiopulmonary bypass, the native pulmonary leaflets were resected, and 2-cm segments of pulmonary artery were replaced by autologous cell–seeded heart valve constructs (n=4). One animal received an acellular valved conduit. No animal received any anticoagulation therapy. Animals were killed at 1, 5, 13, and 17 weeks. Explanted valves were examined histologically with scanning electron microscopy, biochemically, and biomechanically. All animals survived the procedure. The valves showed minimal regurgitation, and valve gradients were <20 mm Hg on echocardiography. The maximum gradient was 10 mm Hg with direct pressures. Macroscopically, the tissue-engineered constructs were covered with tissue, and there was no thrombus formation on any of the specimens. Scanning electron microscopy showed smooth flow surfaces during the follow-up period. Histological examination demonstrated laminated fibrous tissue with predominant glycosaminoglycans as extracellular matrix. 4-Hydroxyproline assays demonstrated an increase in collagen content as a percentage of native pulmonary artery (1 week 45.8%, 17 weeks 116%). DNA assays showed a comparable number of cells in all explanted samples. There was no tissue formation in the acellular control.

Conclusions
—Tissue-engineered heart valve scaffolds fabricated from polyhydroxyalkanoates can be used for implantation in the pulmonary position with an appropriate function for 120 days in lambs.
Systemic Inflammatory Response in Cardiac Allograft Vasculopathy
Authors: Pethig Klaus , Heublein Bernd , Kutschka Ingo , Haverich Axel
Published: July 2021

Background
—Response to immunologic and nonimmunologic injury has been reported to initiate the development of cardiac allograft vasculopathy (CAVD). Although histopathologic examinations reveal signs of focal inflammation, little is known about the systemic inflammatory response in this accelerated coronary syndrome.

Methods and Results
—Therefore, we investigated high-sensitive C-reactive protein (CRP) in a large cohort of heart transplant (HTX) recipients (n=102, 90 male, mean age 45.2±11.5 years, 6.1±3.3 years after HTX) in correlation with a progression of luminal obstruction as assessed by serial coronary angiography (defined as an increase of focal stenosis ≥30% or detection of a new lesion) after a mean interval of 1.8±1.0 years. Patients with signs of an acute rejection or infection were excluded. In the entire group, CRP levels ranged from 0.2 to 12.7 mg/L (mean 2.6±2.7 mg/L). Patients with progressive CAVD (n=35) presented with significantly higher levels of CRP (4.1±3.3 mg/L) than did those with a nonprogressive course (n=67) (1.8±1.9 mg/L,
P
=0.001). These observations were independent of the initial indication for HTX (atherosclerotic disorder versus cardiomyopathy,
P
=0.18) and the severity of CAVD at baseline examination (
P
=0.12).

Conclusions
—Progressive cardiac allograft vasculopathy is accompanied by a systemic inflammatory reaction, which gives further insight into the pathogenesis of this coronary syndrome and may well serve as an indicator for patients at risk.
Ischemic but Not Pharmacological Preconditioning Requires Protein Synthesis
Authors: Matsuyama Nanritsu , Leavens John E. , McKinnon David , Gaudette Glenn R. , Aksehirli Tunc O. , Krukenkamp Irvin B.
Published: July 2021

Background
—Ischemic preconditioning (IPC) and pharmacological preconditioning (PPC) have both been shown to confer cardioprotective effects. However, the role of protein synthesis in preconditioning is unclear.

Methods and Results
—Isolated rabbit hearts were treated with cycloheximide (CHx, 10 μmol/L), a protein synthesis inhibitor at the translational level, before 2 cycles of IPC (5 minutes of global ischemia/5 minutes of reperfusion, n=6) or PPC by pinacidil (PIN, 10 μmol/L; n=6), an ATP-sensitive potassium channel opener. Six rabbit hearts received actinomycin D (Act D, 20 μmol/L; n=6), a protein synthesis inhibitor at the transcriptional level, before IPC. The left anterior descending coronary artery was then occluded for 60 minutes and reperfused for 120 minutes. Control hearts received no treatment before prolonged ischemia (n=6). Left ventricular pressure, action potential duration, and coronary flow were measured. Infarct size is expressed as a percentage of the area at risk. IPC (n=6) and PIN (n=8) hearts experienced reduced infarct size compared with control hearts (22±3% and 27±2% versus 46±3%, IPC and PIN versus control;
P
<0.01). Translational blockade (CHx) reversed the IPC infarct size reduction effect (22±3% versus 48±4%, IPC versus CHx+IPC;
P
<0.01) but not the effects of pinacidil (27±2% versus 29±3%, PIN versus CHx+PIN;
P
=NS). Transcriptional blockade (Act D) did not abolish the IPC effect (23±5% versus 22±3%, Act D+IPC versus IPC;
P
=NS). There were no significant differences in electromechanical function consequent to CHx and Act D treatment.

Conclusions
—These findings suggest an important role for protein synthesis in the mechanism for IPC-mediated protection at the translational level, which may be different from PPC.
Anti-Stunning and Anti-Infarct Effects of Adenosine-Enhanced Ischemic Preconditioning
Authors: Toyoda Yoshiya , Di Gregorio Vincenzo , Parker Robert A. , Levitsky Sidney , McCully James D.
Published: July 2021

Background
—Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing post-ischemic functional recovery. In this study, the anti-infarct effects and the anti-stunning effects of APC in contributing to enhanced post-ischemic functional recovery were determined and compared with IPC.

Methods and Results
—Sheep (n=96) were subjected to 15, 30, 45, or 60 minutes of regional ischemia and 120 minutes of reperfusion. IPC hearts received 5 minutes of regional ischemia and 5 minutes of reperfusion before ischemia/reperfusion. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine hearts (ADO) received a bolus injection of adenosine before ischemia/reperfusion. Regional ischemia (RI) hearts received no pretreatment. Infarct size/area at risk was determined by tetrazolium staining. Regional myocardial function was determined by sonomicrometry. Segment shortening after 15 minutes of ischemia in which no infarct was incurred was 32.1±10.6% in RI, 70.6±8.5% in IPC, and 77.4±6.0% in APC hearts. Segment shortening after 30 minutes of ischemia was 60.7±6.3% in APC hearts (
P
<0.05 versus RI, ADO, IPC) but was <37% in all other groups. Infarct size/area at risk after 30 and 60 minutes of ischemia was, respectively, 25.8±5.7% and 49.8±6.0% in RI, 12.9±3.0% and 29.2±5.0% in ADO, 11.6±2.4% and 24.6±2.7% in IPC, and 5.1±1.6% and 12.4±2.0% in APC hearts (
P
<0.05 versus RI, ADO, IPC).

Conclusions
—APC and IPC exhibit anti-infarct and anti-stunning effects in the ovine heart, but these effects are rapidly diminished with IPC. APC significantly extends these effects, providing for significantly enhanced infarct size reduction and post-ischemic functional recovery (
P
<0.05 versus IPC).
Late Results of the Warm Heart Trial
Authors: Fremes Stephen E. , Tamariz Miguel G. , Abramov Dan , Christakis George T. , Sever Jeri Y. , Sykora Kathy , Goldman Bernard S. , Feindel Christopher M. S. , Lichtenstein Samuel V.
Published: July 2021

Background
—The Warm Heart Trial randomized 1732 CABG patients to receive warm or cold blood cardioplegia. In the warm cardioplegia patients, nonfatal perioperative cardiac events were significantly decreased and the mortality rate was nonsignificantly decreased (1.4% versus 2.5%,
P
=0.12). The purpose of the present study was to evaluate the late results of these trial patients.

Methods and Results
—Randomization was stratified according to surgeon and urgency of the operation. Seven hundred sixty-two patients recruited from 1 of the centers were followed through the hospital clinic for late events. Late survival (including perioperative deaths) at 72 months was nonsignificantly greater in the warm cardioplegia patients (94.5±1.7%, mean±SEM) than in the cold cardioplegia patients (90.9±2.6%). Independent predictors of mortality by Cox proportional hazards model were redo CABG, diabetes mellitus, renal insufficiency, and increasing age. The influence of nonfatal perioperative events (perioperative myocardial infarction according to computerized ECG readings or low output syndrome as determined by an outcome committee) on late survival was also analyzed. Late survival at 84 months was significantly reduced in the group who experienced nonfatal perioperative outcomes (94.5±1.7% versus 84.9±4.5%,
P
<0.001) and remained a significant predictor after adjustment for other important variables (risk ratio 6.4, 95% CI 1.87 to 8.73,
P
<0.0001).

Conclusions
—Effective myocardial protection through either cold or warm blood cardioplegia is essential, because late survival is significantly reduced in patients with nonfatal perioperative cardiac outcomes.
Myocardial Protection by Preconditioning of Heart With Losartan, an Angiotensin II Type 1–Receptor Blocker
Authors: Sato Motoaki , Engelman Richard M. , Otani Hajime , Maulik Nilanjana , Rousou John A. , Flack Joseph E. , Deaton David W. , Das Dipak K.
Published: July 2021

Background
—Ischemic preconditioning (PC) represents a state-of-the-art technique for myocardial preservation. Although certain intracellular mediators have been shown to play a role in PC, the exact nature of the trigger for PC is not known. Our previous study demonstrated that intracellular bradykinin released from the heart during ischemia/reperfusion plays a role in myocardial preservation. This study was undertaken to further examine the mechanism of bradykinin-mediated PC.

Methods and Results
—Since the bradykinin B
2
receptor is likely to provide cardioprotection by blocking angiotensin II formation, we determined the effects of an angiotensin II type 1 (AT
1
) receptor blocker, losartan, and a bradykinin B
2
receptor blocker, HOE 140, on myocardial protection. Isolated rat hearts were perfused initially by the Langendorff mode with Krebs-Henseleit buffer (KHB) for 15 minutes in the absence (control) or presence of losartan (4.5 μmol/L) and/or HOE 140 (10 μmol/L). After conversion to the working mode for 10 minutes (baseline), randomly assigned control and experimental hearts were subjected to 30 minutes of normothermic global ischemia followed by 2 hours of reperfusion. Myocardial function, infarct size, cardiomyocyte apoptosis, and amount of bradykinin/angiotensin released from the hearts were measured at baseline and during reperfusion while in the working mode. Significant postischemic ventricular recovery was demonstrated by improved developed pressure and aortic flow and reduced myocardial infarct size and apoptotic cell death with losartan, whereas the reverse was true for HOE 140. The functional recovery and infarct size–lowering ability of losartan were partially blocked and the antiapoptotic function of losartan was completely blocked by HOE 140.

Conclusions
—The results document that losartan reduced whereas HOE 140 increased myocardial ischemia/reperfusion injury by blocking AT
1
and bradykinin B
2
receptors, respectively, suggesting a role of the bradykinin B
2
receptor in PC. Losartan provided cardioprotection through both bradykinin-dependent and bradykinin-independent mechanisms.
Vesnarinone Restores Contractility and Calcium Handling in Early Endotoxemia
Authors: Takeuchi Koh , del Nido Pedro J. , Poutias Dimitrios N. , Cowan Douglas B. , Munakata Mamoru , McGowan Francis X.
Published: July 2021

Background
—Endotoxin (lipopolysaccharide, LPS) is a trigger of the systemic inflammatory response. We have previously found that vesnarinone and amrinone, when given before LPS, prevented cytokine production and LPS-related cardiac dysfunction. We tested the hypothesis that vesnarinone would improve intracellular Ca
2+
handling and calcium-activated contractile force after the onset of endotoxemia.

Methods and Results
—Adult rabbits received a bolus injection of LPS or vehicle. Vesnarinone (3 mg/kg) was given intravenously 90 minutes later. Two hours after LPS administration, hearts were perfused in the isolated Langendorff mode. Peak left ventricular developed pressure, ±dp/dt, oxygen consumption (MV̇
o
2
), and rate×pressure product were evaluated in conjunction with fluorescent spectroscopic determinations of intracellular calcium concentrations (Ca
i
) and the rate of Ca
i
transient decline during diastole (τCa). Peak left ventricular developed pressure and ±dp/dt were significantly lower in the LPS group. These were completely restored by vesnarinone. There was significantly slower diastolic calcium removal (increased τCa) in LPS hearts that was also corrected by vesnarinone; however, the cytosolic calcium overload characteristic of LPS hearts was only partially improved. Reduced mechanical inefficiency (the ratio of rate-pressure product to MV̇
o
2
) and myofilament sensitivity to Ca
i
were also significantly improved by vesnarinone.

Conclusions
—Acute endotoxemia caused contractile protein calcium insensitivity, oxygen wastage, and abnormal calcium cycling. Vesnarinone, given in the rescue mode, normalized LPS-induced myocardial dysfunction and partially restored abnormal calcium cycling. Although the mechanisms responsible for these effects require further clarification, it appears that agents such as vesnarinone may be useful to treat inflammatory-induced myocardial dysfunction.
Tissue Engineering of Pulmonary Heart Valves on Allogenic Acellular Matrix Conduits
Authors: Steinhoff Gustav , Stock Ulrich , Karim Najibulla , Mertsching Heike , Timke Adine , Meliss Rolf R. , Pethig Klaus , Haverich Axel , Bader Augustinus
Published: July 2021

Background
—Tissue engineering using in vitro–cultivated autologous vascular wall cells is a new approach to biological heart valve replacement. In the present study, we analyzed a new concept to process allogenic acellular matrix scaffolds of pulmonary heart valves after in vitro seeding with the use of autologous cells in a sheep model.

Methods and Results
—Allogenic heart valve conduits were acellularized by a 48-hour trypsin/EDTA incubation to extract endothelial cells and myofibroblasts. The acellularization procedure resulted in an almost complete removal of cells. After that procedure, a static reseeding of the upper surface of the valve was performed sequentially with autologous myofibroblasts for 6 days and endothelial cells for 2 days, resulting in a patchy cellular restitution on the valve surface. The in vivo function was tested in a sheep model of orthotopic pulmonary valve conduit transplantation. Three of 4 unseeded control valves and 5 of 6 tissue-engineered valves showed normal function up to 3 months. Unseeded allogenic acellular control valves showed partial degeneration (2 of 4 valves) and no interstitial valve tissue reconstitution. Tissue-engineered valves showed complete histological restitution of valve tissue and confluent endothelial surface coverage in all cases. Immunohistological analysis revealed cellular reconstitution of endothelial cells (von Willebrand factor), myofibroblasts (α-actin), and matrix synthesis (procollagen I). There were histological signs of inflammatory reactions to subvalvar muscle leading to calcifications, but these were not found in valve and pulmonary artery tissue.

Conclusions
—The in vitro tissue-engineering approach using acellular matrix conduits leads to the in vivo reconstitution of viable heart valve tissue.
Subcostal ecocardiography for the evaluation of left ventricular hypertrophy in older populations.
Authors: Bari Mauro Di , Cavallini Maria C , Alfieri Walter De , Salti Francesca , Baldereschi Giorgio J , Pini Riccardo , Masotti Giulio , Marchionni Niccolo’
Published: July 2021

P27

Background: Left ventricle (LV) hypertrophy is a major risk factor for mortality and morbidity. Unfortunately, the echocardiographic evaluation of LV mass from the parasternal (PS) approach is frequently limited in older, obese or emphysematous individuals. This poses a selection bias to the epidemiological assessment of LV hypertrophy. Methods: In order to assess whether the subcostal (SC) view may reliably substitute the PS view to evaluate LV mass in older adults, 614 unselected persons aged ≥65 years participating in a population-based survey on heart failure in the elderly, and 54 randomly selected healthy individuals 35-64 years old, underwent a complete echocardiographic examination including M-mode PS and SC scanning. Results: Overall, both PS and SC views were available for LV mass estimate (Devereux’s formula) in 314 subjects(age: 69.9±0.5 years, mean±SEM) with normal LV kinetics and sinus rhythm. The SC view underestimated (p<0.001) LV diastolic dimension (LVDD) and overestimated (p<0.012) free wall thickness (FWT), whereas septum thickness was similar in the two views. As a consequence, LV mass was underestimated from the SC view (76.2±1.2 g/m

2

) as compared to the PS view (87.9±1.4 g/m

2

; p<0.001). The SC view was 99% specific but only 25% sensitive for the diagnosis of LV hypertrophy (LV mass >116 and >104 g/m

2

in men and women, respectively), based on the PS view. When age, body weight and gender were entered in multivariate regression models with the SC measures, the first two variables significantly contributed to the prediction of both LVDD and FWT, and gender only to the prediction of LVDD. LV mass was recalculated using measures from the SC view, corrected on the basis of the regression equations. The corrected value did not differ from that obtained from the PS view and the sensitivity of the SC view for the diagnosis of LV hypertrophy increased to 51% with unmodified specificity (98%). Conclusions: The SC view significantly underestimates LV mass. However, correction for simple demographic and anthropometric variables greatly improves its reliability for estimating LV mass and hypertrophy in unselected older adults.
Evidence of an Increase in Baseline Brachial Artery Lumen Diameter Independent of Body Mass Index (BMI) among Women with Polycystic Ovary Syndrome (PCOS)Compared to Age-Matched Control Women
Authors: Talbott Evelyn O. , Zborowski Jeanne V. , Sutton-Tyrrell Kim , Guzick David S. , Kuller Lewis H.
Published: July 2021

P29

PCOS is a reproductive endocrine disorder, characterized by chronic anovulation, androgen excess, and insulin resistance, affecting approximately 5% of the female population. PCOS is associated with an increase in CHD risk factors, including LDL cholesterol,triglycerides, obesity,and hypertension. Endothelial dysfunction has been implicated in the development and progression of atherosclerosis and has been shown to be adversely affected in males with high free testosterone levels and in men and women with increased insulin resistance. We recruited 83 women with PCOS (42.3 ± 5.8 years) from our Pittsburgh cohort and 91 controls of similar age (43.4 ± 5.4 years) to evaluate endothelium-dependent vascular function using brachial artery ultrasonography. Women on hormone replacement or oral contraceptives were excluded from the analysis. The mean BMI ± SD was 31.7 ± 8.7 and 27.1 ± 6.4 kg/m

2

in cases and controls, respectively. The groups were also similar with respect to smoking status. No difference was observed in BMI-adjusted flow mediated vasodilation (FMD) between PCOS cases and controls (p=.630). However, baseline brachial lumen diameter (LD) was significantly higher among women with PCOS compared to controls (Mean ± SE = 3.30 ± .06 vs. 3.12 ± .05) after adjustment(p=.023). Further adjustment for LDLc, HDLc, triglycerides, systolic blood pressure (SBP), or insulin did not alter the PCOS-brachial lumen diameter association. Independently of case status and BMI, HDLc was significantly associated with baseline LD(p=.001); DBP was of borderline significance(p=.099). These findings suggested that PCOS may be associated with a compensatory enlargement of the arteries in response to accelerated arterial wall thickening and/or arterial stiffening. Further analyses within PCOS cases suggested that testosterone and insulin may mediate endothelial function (FMD). Future studies are needed to futher explore vascular changes and the implication for cardio- and cerebrovascular events in this high risk population.
Disparities in Cholesterol Screening in the United States. Falling Short of a National Health Objective
Authors: Brown David W , Giles Wayne H , Greenlund Kurt J , Croft Janet B
Published: July 2021

P40

Objectives: To determine whether the Year 2000 national health objective for cholesterol screening was attained and to identify disparities in cholesterol screening across racial or ethnic and socioeconomic groups. Methods: Using data from the 1999 Behavioral Risk Factor Surveillance System, we estimated the proportion of adults aged ≥20 years who were screened for high blood cholesterol within the preceding 5 years. Results: Overall, an estimated 70.8% of the US population was screened for cholesterol, falling short of the Year 2000 objective of 75%. Screening prevalence was lowest at ages 20-44 years (58.2%) in contrast to ages 45-64 years (81.9%) and ages ≥65 years (87.1%). Screening prevalence was also lowest among Hispanics, especially Hispanic men. The likelihood of screening decreased with decreasing income level (p<0.05) and persons with health insurance were 1.6 times more likely to have been screened during the past 5 years than adults with no insurance (p<0.05). Conclusions: Significant disparities in cholesterol screening exist across age, sex, racial or ethnic, and socioeconomic groups in the United States. As we look to attain the objectives of Healthy People 2010, state and local health officials and policy makers should be aware of these disparities in order to design and target effective cholesterol screening programs and cardiovascular disease prevention programs to those most in need.
Beta-blocker use in acute myocardial infarction patients with congestive heart failure
Authors: Lui Stephanie W , Harper Carolyn , Redberg Rita
Published: July 2021

P49

Background: Beta-blockers have been shown to improve outcomes for patients with acute myocardial infarction (AMI), but have been used reluctantly in AMI patients with congestive heart failure (CHF). However, recent studies have shown that the benefits of beta-blockers outweigh the risks in AMI patients with CHF, and that beta-blockers are a safe and effective treatment for these patients. The purpose of this study is to evaluate the use of beta-blockers in AMI patients with CHF. Methods: A random sample of 4,478 patients aged 65 and older was selected from all fee-for-service Medicare beneficiaries discharged from California hospitals between January to June, 1998 with a principal diagnosis of AMI. After unconfirmed AMI cases and those with unknown discharge status were excluded, there were 2,680 cases for analysis. Results: In this study, 48.2% (1,291) of all AMI patients, and 66.2% (290/438) of those with no contraindications received a beta-blocker. Overall, 40.1% (1,074) had CHF plus other contraindications, and 11.6% (312) had CHF but had no other contraindications. Controlling for age, race, and gender, and compared to those with no contraindications, beta-blocker prescription rates were significantly lower among patients who had CHF as the only documented reason for not prescribing a beta-blocker (OR=0.3, 95% CI=0.3-0.5). Conclusions: Beta-blockers are underutilized in this sample of AMI patients. CHF is an independent predictor for non-prescription of a beta-blocker. Despite evidence from recent studies suggesting its benefit, beta-blocker use is still suboptimal in AMI patients, particularly those with CHF.
Relationships of Changes in Height, Weight and Body Mass Index to Changes in Blood Lipids From Age 8 to 18 Years: Project Heartbeat!
Authors: Zong Jihong , Labarthe Darwin R , Harrist Ronald , Dai Shifan , Mueller William H
Published: July 2021

P64

Background: To study the relationships of changes in anthropometric variables - height, weight, and body mass index (BMI) - to changes in blood lipids (TC, LDL-C, HDL-C and TG) in children and adolescents aged from 8 to 18 years. Methods and Results: Cohorts of three different age levels 8, 11 and 14 years at baseline were enrolled in the study. Each member of these three cohorts was examined three times per year for up to four years. The composition of the study population and the descriptive statistics for the continuous variables at baseline were summarized. Ethnicity was categorized as Black (21.1%) and non-Black (79.9%). Non-Black includes White (74.6%), Hispanic (3.7%), Asian (1.0%) and American Indian (0.6%). The relationships of changes in anthropometric variables and in blood lipids were evaluated by adding height, weight, or BMI and associated interaction terms separately to the basic age-sex models, derived in previous analyses. A multilevel modeling technique was used. Likelihood ratio tests were conducted by calculating the deviation of -2log(likelihood) within the basic model and alternative models. Height or height gain had significant negative associations with changes in TC, LDL-C and HDL-C with estimated coefficients of -0.763, -0.448 and -0.301, respectively. The estimated coefficients between weight gain and changes in TC, LDL-C and TG were 0.337, 0.370 and 0.1473, respectively, and -0.305 for HDL-C. The estimates of relationships between changes in BMI and in TC, LDL-C, HDL-C and TG were 2.122, 1.884, -0.885 and 4.673, respectively. An interaction between weight (or BMI) and ethnicity was significant in the models for triglycerides only. Sex-Age interactions were significant in most models. Effective effects of race were significant in the models for LDL-C, HDL-C and TG. Conclusions: The results of this longitudinal analysis indicated a very strong association between increasing BMI and changes in blood lipids within the period of childhood and adolescence. These findings have implications for assessing changes in blood lipids, especially among those experiencing the greatest increases in BMI.
Insulin Resistance Syndrome and Echocardiographic Left Ventricular Mass in African-Americans
Authors: Burchfiel Cecil M , Skelton Thomas N , Andrew Michael E , Garrison Robert J , Arnett Donna K , Jones Daniel W , Taylor Herman A
Published: July 2021

P70

The insulin resistance syndrome (IRS) has been associated with cardiovascular disease (CVD), but few studies have examined its relationship with subclinical measures such as echocardiographic left ventricular (LV) mass. This relationship is likely to be of particular importance in African-Americans where both IRS and elevated LV mass are common. Complete information was available for 1633 African-American women and men aged 49-73 who were enrolled in the Atherosclerosis Risk in Communities (ARIC) Study when M-mode echocardiography was performed at one of the four ARIC sites in Jackson, Mississippi (1993-1996). LV mass was calculated according to American Society of Echocardiography methods using the cube formula and was indexed by height. Participants were categorized by the number (0, 1, 2, or 3) of IRS characteristics (hypertension, dyslipidemia (low HDL cholesterol or high triglyceride), and glucose intolerance (diabetes or fasting glucose values ≥110 mg/dl)). Age-adjusted mean LV mass/height (g/m) increased progressively with increasing number of IRS disorders in both women and men (128.9, 148.6, 161.0, 171.6 and 135.9, 157.4, 170.6, 171.6 respectively, p<0.001, tests for trend). Associations were slightly stronger in women than in men and were similar when participants were stratified by age, BMI and waist circumference. These associations were not altered by adjustment for smoking and alcohol intake, and were only slightly attenuated with adjustment for BMI and waist circumference. Analyses focusing on the components of LV mass revealed that posterior wall and interventricular septal thickness, but not LV chamber size, were significantly associated with the number of IRS disorders. In this large population-based study of middle-aged African-American women and men the degree of IRS clustering was strongly and independently related to LV mass and these associations are consistent with a possible influence of insulin resistance on myocardial thickening rather than chamber size.