bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival After Reconstructive Surgery for Hypoplastic Left Heart Syndrome
Authors: Mahle William T. , Spray Thomas L. , Wernovsky Gil , Gaynor J. William , Clark Bernard J.
Published: July 2021

Background
—There are limited data regarding the long-term survival of patients who have undergone reconstructive surgery for hypoplastic left heart syndrome (HLHS). We reviewed the 15-year experience at our institution to examine survival in the context of continued improvements in early operative results.

Methods and Results
—Between 1984 and 1999, 840 patients underwent stage I surgery for HLHS. From review of medical records and direct patient contact, survival status was determined. The 1-, 2-, 5-, 10-, and 15-year survival for the entire cohort was 51%, 43%, 40%, 39%, and 39%, respectively. Late death occurred in 14 of the 291 patients discharged to home after the Fontan procedure, although only 1 patient has died beyond 5 years of age. Heart transplantation after stage I reconstruction was performed in 5 patients. Later era of stage I surgery was associated with significantly improved survival (
P
<0.001). Three-year survival for patients undergoing stage I reconstruction from 1995 to 1998 was 66% versus 28% for those patients undergoing surgery from 1984 to 1988. Age >14 days at stage I and weight <2.5 kg at stage I were also associated with higher mortality (
P
=0.004 and
P
=0.01, respectively). Other variables, including anatomic subtype, heterotaxia, and age at subsequent staging procedures, were not associated with survival.

Conclusions
—Over the 15-year course of this study, early- and intermediate-term survival for patients with HLHS undergoing staged palliation increased significantly. Late death and the need for cardiac transplantation were uncommon.
Effects of Respiration and Gravity on Infradiaphragmatic Venous Flow in Normal and Fontan Patients
Authors: Hsia Tain-Yen , Khambadkone Sachin , Redington Andrew N. , Migliavacca Francesco , Deanfield John E. , de Leval Marc R.
Published: July 2021

Background
—In the Fontan circulation, pulmonary and systemic vascular resistances are in series. The implications of this unique arrangement on infradiaphragmatic venous physiology are poorly understood.

Methods and Results
—We studied the effects of respiration and gravity on infradiaphragmatic venous flows in 20 normal healthy volunteers (control) and 48 Fontan patients (atriopulmonary connection [APC] n=15, total cavopulmonary connection [TCPC] n=30). Hepatic venous (HV), subhepatic inferior vena caval (IVC), and portal venous (PV) flow rates were measured with Doppler ultrasonography during inspiration and expiration in both the supine and upright positions. The inspiratory-to-expiratory flow rate ratio was calculated to reflect the effect of respiration, and the supine-to-upright flow rate ratio was calculated to assess the effect of gravity. HV flow depended heavily on inspiration in TCPC compared with both control and APC subjects (inspiratory-to-expiratory flow rate ratio 3.4, 1.7, and 1.6, respectively;
P
<0.0001). Normal PV flow was higher in expiration, but this effect was lost in TCPC and APC patients (inspiratory-to-expiratory flow rate ratio 0.8, 1.0, and 1.1, respectively;
P
=0.01). The respiratory influence on IVC flow was the same in all groups. Gravity decreased HV flow more in APC than in TCPC patients (supine-to-upright flow rate ratio 3.2 versus 2.1, respectively;
P
<0.04) but reduced PV flow equally in all groups.

Conclusions
—Gravity and respiration have important influences on infradiaphragmatic venous return in Fontan patients. Although gravity exerts a significant detrimental effect on lower body venous return, which is more marked in APC than in TCPC patients, the beneficial effects of respiration in TCPC patients are mediated primarily by an increase in HV flow. These effects may have important short- and long-term implications for the hemodynamics of the Fontan circulation.
Surgical Management of Mitral Regurgitation After Repair of Endocardial Cushion Defects
Authors: Moran Adrian M. , Daebritz Sabine , Keane John F. , Mayer John E.
Published: July 2021

Background
—Mitral regurgitation (MR) represents the principal indication for reoperation in patients after repair of atrioventricular septal defects (AVSD). Reports of mitral valvuloplasty (MVP) in such patients are few; the alternative, mitral valve replacement (MVR), necessitates commitment to future valve replacement and long-term anticoagulation. We sought to determine the outcome of those patients who underwent either MVP or MVR between January 1, 1988, and December 31, 1998, for significant MR after repair of AVSD. Furthermore, we sought to identify (a) morphological predictors necessitating MVR, and (b) predictors of future reoperation within the MVP group.

Methods and Results
—Retrospective review of clinical, operative, and echocardiographic data were performed. There were 46 patients identified (37 MVP and 9 MVR). The median age at initial AVSD repair was 0.6 years, and the age at subsequent mitral valve operation was 2.8 years. The early postoperative mortality rate was 2.2%, and survival at 1 and 10 years was 89.9% and 86.6%, respectively. A high rate of complete heart block was noted within the MVR group (37.5%). Freedom from later mitral valve reoperation for both groups was similar. No significant morphological predictors necessitating MVR were found. Predictors of reoperation within the MVP group included the presence of moderate or worse MR in the early postoperative period. In both groups New York Heart Association class, degree of MR, growth, and ventricular volumes improved.

Conclusions
—Mitral valve surgery significantly improves clinical status, with a sustained improvement in ventricular chamber size. MR can be successfully managed in patients after repair of AVSD independent of morphological type. Overall survival is acceptable, and further reoperation within the MVP group is influenced by early outcome of repair.
Infections During Left Ventricular Assist Device Support Do Not Affect Posttransplant Outcomes
Authors: Sinha Prashant , Chen Jonathan M. , Flannery Margaret , Scully Brian E. , Oz Mehmet C. , Edwards Niloo M.
Published: July 2021

Background
—Although infections acquired during ventricular assist device support may increase the risk of infection and have an impact on transplant survival, their true posttransplant consequences remain to be determined. This study evaluates the impact of an outpatient program, newer devices, and an updated infection management protocol on infection-related patient outcomes after transplant.

Methods and Results
—Eighty-six patients received a left ventricular assist device (LVAD) between June 1996 and June 1999. Fifty patients transplanted during the same period, without prior device support, were used as controls; they were matched to transplanted LVAD recipients by age, sex, diagnosis, and transplant date. The nature of and actuarial freedom from peritransplant and posttransplant infections were compared at 6 months after transplant; actuarial patient survival was compared at 3 years. Infection was defined as leukocytosis or leukopenia, with a positive culture requiring either medical or surgical intervention. Forty-four patients (51%) were successfully discharged home on LVAD support, and 61 (71%) were transplanted. A high incidence of infection during device support did not have an impact on pretransplant or posttransplant mortality, posttransplant infectious rate, or overall patient survival. Active infections at transplant also did not significantly influence 6-month mortality. In comparison, LVAD recipients had a lower freedom from infection than did controls (
P
<0.05); however, 3-year survival did not differ: 79% and 87% for the LVAD and control groups, respectively.

Conclusions
—Although LVADs increase the risk of infection in the early posttransplant period, this appears not to have an impact on transplantability or patient survival and likely reflects effective infection control in both inpatient and outpatient settings.
Cardiac Exercise Hemodynamics Late After Partial Left Ventriculectomy
Authors: James Karen B. , Haas Garrie , Lutton Suzanne R. , Prior David , Wolski Kathy , Buda Tiffany , McCarthy Patrick M.
Published: July 2021

Background
—Although some patients report favorable activity levels late after partial left ventriculectomy (PLV), their exercise physiology has not been well described.

Methods and Results
—We performed upright bicycle hemodynamics in 10 patients (9 men) aged 56±12 years at 1.7 years after PLV. Ejection fraction was 25±4%. Patients biked 10±7 minutes. With exercise, the mean pulmonary arterial pressure rose from 36±12 to 52±10 mm Hg (
P
=0.0003). The mean pulmonary capillary wedge pressure rose from 25±14 to 36±9 mm Hg (
P
=0.0566), and the cardiac index rose from 2.2±0.5 to 3.8±1.6 L · min
−1
· m
−2
(
P
=0.0077). The mixed venous oxygenation with exercise declined from 44±9% to 24±17% (
P
=0.0220), and the pulmonary vascular resistance increased from 2.0±0.9 to 2.3±1.1 Wood units (
P
=0.5566).

Conclusions
—In late follow-up after PLV with exercise, the cardiac index is significantly augmented. However, there are further rises in pulmonary artery and pulmonary capillary wedge pressures, suggesting abnormal compliance, with marked decline in mixed venous oxygenation. Elucidating late physiology after PLV may help pave the way for future innovative heart failure surgeries.
Heat Shock Treatment Enhances Graft Cell Survival in Skeletal Myoblast Transplantation to the Heart
Authors: Suzuki Ken , Smolenski Ryszard T. , Jayakumar Jay , Murtuza Bari , Brand Nigel J. , Yacoub Magdi H.
Published: July 2021

Background
—Graft survival after skeletal myoblast transplantation is affected by various pathological processes caused by environmental stress. Heat shock is known to afford protection of several aspects of cell metabolism and function. We hypothesized that prior heat shock treatment of graft cells would improve their survival after cell transplantation.

Methods and Results
—L6 rat skeletal myoblasts expressing β-galactosidase (β-gal) were subjected to heat shock (42°C, 1 hour). Increased expression of heat shock protein 72 was detected 24 hours later in the heat-shocked cells. After hypoxia-reoxygenation in vitro, lactate dehydrogenase leakage was significantly attenuated in the heat-shocked cells; in addition, the percentage of early apoptosis was lower in this group measured by flow cytometry with annexin V staining. For the in vivo study, 1×10
6
heat-shocked (hsCTx) or normal-cultured (CTx) myoblasts were infused into the explanted rat hearts through the coronary artery followed by heterotopic heart transplantation. β-gal activity was significantly higher in the hsCTx group after cell transplantation, with an estimated 8×10
6
surviving cells per heart in the hsCTx group and 5×10
6
cells in the CTx group on day 28. Discrete loci of grafted cells were globally observed in the myocardium of the hsCTx and CTx groups, with a higher frequency in the hsCTx group. Surviving myoblasts occasionally differentiated into myotubes and had integrated with the native cardiomyocytes.

Conclusions
—Heat-shocked skeletal myoblasts demonstrated improved tolerance to hypoxia-reoxygenation insult in vitro and enhanced survival when grafted into the heart. Heat shock treatment could be useful in improving graft cell survival in cell transplantation.
Ex Vivo Antisense Oligonucleotides to Proliferating Cell Nuclear Antigen and Cdc2 Kinase Inhibit Graft Coronary Artery Disease
Authors: Miniati Douglas N. , Hoyt E. Grant , Feeley Brian T. , Poston Robert S. , Robbins Robert C.
Published: July 2021

Background
—The long-term success of cardiac transplantation is limited by graft coronary artery disease (GCAD). Antisense oligonucleotides (ASs) to proliferating cell nuclear antigen (PCNA) and Cdc2 kinase (Cdc2 k) can arrest cell cycle progression and inhibit neointimal hyperplasia. Transforming growth factor-β
1
(TGF-β
1
) has been implicated in vascular smooth muscle cell (VSMC) activation. The role of TGF-β
1
in GCAD remains unclear. We hypothesized that ASs to PCNA and Cdc2 k would inhibit VSMC proliferation and GCAD.

Methods and Results
—In vitro VSMC proliferation was determined after pretreatment with AS solution or medium alone followed by angiotensin II stimulation. PVG-to-ACI rat heterotopic cardiac transplantation procedures were performed after ex vivo pressure-mediated transfection of ASs to PCNA and Cdc2k or saline alone. At postoperative days 30, 60, and 90, allografts were assessed for GCAD, percent neointimal macrophages and VSMCs, and TGF-β
1
activity. AS pretreatment significantly attenuated VSMC proliferation. At postoperative day 90, percent affected arteries, percent occlusion, and intima-media ratio demonstrated severe GCAD in saline-treated allografts, whereas these parameters were significantly lower in AS-treated allografts. Percent neointimal macrophages and VSMCs was reduced in AS-treated allografts. TGF-β
1
activity was increased in saline compared with AS-treated allografts and nontransplanted heart controls.

Conclusions
—ASs to PCNA and Cdc2 k inhibit VSMC proliferation in vitro and reduce GCAD, percent neointimal VSMCs and macrophages, and TGF-β
1
activity in vivo. TGF-β
1
may play a “response to injury” role in the development of GCAD. The prevention of GCAD via AS inhibition of cell cycle regulatory genes before reperfusion may offer a useful clinical alternative to current therapeutic strategies.
Novel Method to Enhance Sternal Healing After Harvesting Bilateral Internal Thoracic Arteries With Use of Basic Fibroblast Growth Factor
Authors: Iwakura Atsushi , Tabata Yasuhiko , Miyao Manabu , Ozeki Makoto , Tamura Nobushige , Ikai Akio , Nishimura Kazunobu , Nakamura Tatsuo , Shimizu Yasuhiko , Fujita Masatoshi , Komeda Masashi
Published: July 2021

Background
—Poor healing of the sternum often limits the use of bilateral internal thoracic arteries (BITAs) in coronary bypass surgery, especially for diabetic patients. We have reported that basic fibroblast growth factor (bFGF) enhanced regeneration of the skull. This study was designed to evaluate the effects of topical use of bFGF on sternal healing after removing the BITAs.

Methods and Results
—Forty-five Wistar rats were subjected to median sternotomy and were divided into 3 groups: 15 had the BITAs removed and had a bFGF sheet applied on the posterior table of the sternum (group A), 15 had just the BITAs removed (group B), and 15 had intact BITAs (group C). Five and 10 rats were euthanized 2 and 4 weeks after surgery, respectively, in all 3 groups. Peristernal blood flow, measured with use of a noncontact laser flowmeter, decreased after removal of the BITAs (
P
<0.001). Four weeks after the surgery, PBF markedly increased only in group A (9.7±1.2, 6.5±0.6, and 8.2±0.5 mL · min
−1
· 100 g
−1
for groups A, B, and C, respectively;
P
<0.01 by ANOVA). Four weeks after surgery, the following findings were obtained only in group A: (1) nearly completely healed sternum filled with regenerated bone tissue, (2) marked angiogenesis around the sternum, and (3) osteoblasts in an active form around the edge of the sternum.

Conclusions
—The results suggest that use of the bFGF sheet offset the sternal ischemia and accelerated sternal healing. This method may help to decrease sternal necrosis in high-risk patients or allow extended use of BITAs in coronary bypass surgery.
Cardioplegic Strategies for Calcium Control
Authors: Fukuhiro Yoshiaki , Wowk Michelle , Ou Ruchong , Rosenfeldt Franklin , Pepe Salvatore
Published: July 2021

Background—Ca2+overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca2+overload has been to reduce Ca2+in the cardioplegic solution (CP). Recent reports suggest that Na+/H+exchange inhibitors can also prevent Ca2+overload. We compared 4 crystalloid CPs that might minimize Ca2+overload in comparison with standard Mg2+-containing CP: (1) low Ca2+CP (0.25 mmol/L), (2) citrate CP/normal Mg2+(1 mmol/L Mg2+), (3) citrate CP/high Mg2+(9 mmol/L Mg2+), and (4) the addition of the Na+/H+exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca2+and Mg2+in CPs.

Methods and Results—Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37°C arrest and reperfusion with CPs with different Ca2+concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg2+and Ca2+. Because only Ca2+was required to be low, the further addition of Mg2+increased free Mg2+, but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3±2.5% without citrate versus 41.6±3% for citrate with normal Mg2+,P<0.05, versus 22.4±6.2% for citrate with high Mg2+,P<0.05). Low-Ca2+CP (0.25 mmol/L Ca2+) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca2+) (AF 47.6±1.7% versus 58.3±2.5%,P<0.05). The addition of HOE-642 (1 μmol/L) to CP significantly improved postischemia function (47.6±1.7% without HOE-642 versus 62.4±1.7% with HOE-642,P<0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca2+manipulation.

Conclusions—(1) A lowered Ca2+concentration in CP is beneficial in Mg2+-containing cardioplegia. (2) The use of citrate to chelate Ca2+is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg2+. (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca2+and Mg2+. (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca2+.
Elevated Tumor Necrosis Factor-α and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts
Authors: Birks Emma J. , Burton Paul B. J. , Owen Virginia , Mullen Antony J. , Hunt Diane , Banner Nicholas R. , Barton Paul J. R. , Yacoub Magdi H.
Published: July 2021

Background
—Myocardial dysfunction is a common and important problem in donor hearts. The mechanisms responsible remain unclear. We have studied the cytokines tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) in the myocardium and serum from donors with myocardial dysfunction (unused donors) and compared them with donors with good ventricular function (used donors) and patients with advanced heart failure (HF).

Methods and Results
—Clinical details and ventricular function were assessed in 46 donors (31 used, 15 unused). Real-time reverse transcription–polymerase chain reaction, Western blotting, and immunocytochemistry were performed on myocardium and immunoassays on serum. TNF-α mRNA was 1.6-fold higher in unused than in used donors (
P
<0.005) and 1.74-fold higher than in 36 patients with HF. IL-6 mRNA was 2.4-fold higher in unused than in used donors (
P
<0.0001) and 4.67-fold higher than in HF (
P
<0.0001). Western blotting showed higher TNF-α in unused (218.3±6.4, n=4 versus 187.3±5.4, n=3 OD units) than used donors (
P
<0.05). TNF-α expression was localized to cardiac myocytes. Serum TNF-α was higher in unused (8.72±1.3 pg/mL, n=13) than in used (6.12±0.8 pg/mL, n=25,
P
<0.05) donors and HF (4.0±0.4 pg/mL, n=17,
P
<0.005). Serum TNF-α receptors did not differ between unused (4.3±0.8 and 8.6±1.6 ng/mL, n=10) and used (3.5±0.4 and 6.5±1.1 ng/mL, n=24) donors. There was a trend for higher serum IL-6 in unused (16.5±2.9 pg/mL, n=9) compared with used (13.9±1.6 pg/mL, n=26,
P
=NS) donors.

Conclusions
—This study documented an increase in the expression of TNF-α and IL-6 in the myocardium of all donor hearts that was more marked in the dysfunctional (unused) donor hearts. This was accompanied by similar changes in the serum. This might have important therapeutic implications.
Hypercholesterolemia Inhibits Angiogenesis in Response to Hindlimb Ischemia
Authors: Duan Junli , Murohara Toyoaki , Ikeda Hisao , Katoh Atsushi , Shintani Satoshi , Sasaki Ken-ichiro , Kawata Hidemichi , Yamamoto Naoki , Imaizumi Tsutomu
Published: July 2021

Background
—Endothelium-derived nitric oxide (EDNO) plays an important role in the regulation of angiogenesis, whereas hypercholesterolemia (HC) impairs EDNO release. We examined the hypothesis that HC may inhibit ischemia-induced angiogenesis by inhibition of EDNO in a rat model of unilateral hindlimb ischemia and that oral
l
-arginine supplementation, a substrate for NO synthase, may prevent HC-related impairment of angiogenesis.

Methods and Results
—Male Sprague-Dawley rats were fed (A) standard diet (control), (B) 2% high-cholesterol diet (HC group), or (C) high-cholesterol diet with oral
l
-arginine (2.25% in drinking water) (HC+L-arg group). At 2 weeks of the dietary intervention, unilateral limb ischemia was surgically induced in all animals. Dietary HC groups (B and C) revealed elevated total and LDL cholesterol levels compared with control animals. Laser Doppler blood flow analyses showed significant decreases in the ischemic/normal limb blood flow ratio in the HC group compared with controls (
P
<0.05) when followed up until 4 weeks after surgery. Selective angiography and immunohistochemical analyses in the ischemic limb at postoperative day 14 revealed significantly lower angiographic scores (
P
<0.01) and capillary densities (
P
<0.01) in the HC group than controls, which were associated with decreased tissue contents of NO
x
and cGMP. Oral
l
-arginine supplementation (HC+L-arg) significantly improved all parameters of the laser Doppler blood perfusion ratio, angiographic scores, and capillary densities (
P
<0.01 versus HC group), which were accompanied by significant elevations in serum
l
-arginine levels and tissue NO
x
and cGMP contents.

Conclusions
—Collateral vessel formation and angiogenesis in response to hindlimb ischemia were significantly attenuated in rats with dietary HC. The mechanism may be related to the reduced NO bioactivity in the ischemic tissues. Augmentation of the tissue NO activity by oral
l
-arginine supplementation restored the impaired angiogenesis in HC.
Aortic Valve Repair for Adult Congenital Heart Disease
Authors: Rao Vivek , Van Arsdell Glen S. , David Tirone E. , Azakie Anthony , Williams William G.
Published: July 2021

Background
—Aortic valve–preserving procedures have resulted in excellent outcomes in selected patients, particularly those with normal aortic valve leaflets and dilated aortic roots. However, several congenital heart lesions are associated with abnormal aortic valve leaflets. The long-term results of aortic valve repair for these lesions are not well defined.

Methods and Results
—We reviewed the clinical records of 54 adult (age >18 years) patients who underwent repair of congenital abnormalities of the aortic valve between 1976 and September 1999. Follow-up data were available on 52 (96%) patients (mean 50±67 months, range 1 to 266). Patients underwent repair at a mean age of 34±14 years with associated diagnoses of subaortic stenosis (n=10), ventricular septal defect with prolapsing aortic valve (n=17), bicuspid aortic valve (n=23), sinus of Valsalva aneurysm (n=10), and bacterial endocarditis (n=2). There was 1 operative death (1.9%) and 3 late deaths. Survival at 5 and 10 years was 98±2% and 74±12%, respectively. Freedom from reoperation was 74±9% and 51±15% at 5 and 10 years, respectively. The presence of a ventricular septal defect predicted failure of valve repair (59% versus 22%,
P
=0.01). A bicuspid aortic valve, subaortic stenosis, or the requirement for mitral valve surgery did not affect outcomes.

Conclusions
—Aortic valve repair in adult patients with congenital heart disease can be performed with minimal morbidity and mortality rates. The medium-term results of repair are acceptable, regardless of valvular or associated pathology. However, only 31 patients (57%) demonstrated long-term competence of the aortic valve, suggesting that most adult patients with congenital aortic valve disease will eventually require aortic valve replacement.
Bioengineered Cardiac Grafts
Authors: Leor Jonathan , Aboulafia-Etzion Sharon , Dar Ayelet , Shapiro Lilia , Barbash Israel M. , Battler Alexander , Granot Yosef , Cohen Smadar
Published: July 2021

Background
—The myocardium is unable to regenerate because cardiomyocytes cannot replicate after injury. The heart is therefore an attractive target for tissue engineering to replace infarcted myocardium and enhance cardiac function. We tested the feasibility of bioengineering cardiac tissue within novel 3-dimensional (3D) scaffolds.

Methods and Results
—We isolated and grew fetal cardiac cells within 3D porous alginate scaffolds. The cell constructs were cultured for 4 days to evaluate viability and morphology before implantation. Light microscopy revealed that within 2 to 3 days in culture, the dissociated cardiac cells form distinctive, multicellular contracting aggregates within the scaffold pores. Seven days after myocardial infarction, rats were randomized to biograft implantation (n=6) or sham-operation (n=6) into the myocardial scar. Echocardiography study was performed before and 65±5 days after implantation to assess left ventricular (LV) remodeling and function. Hearts were harvested 9 weeks after implantation. Visual examination of the biograft revealed intensive neovascularization from the neighboring coronary network. Histological examination revealed the presence of myofibers embedded in collagen fibers and a large number of blood vessels. The specimens showed almost complete disappearance of the scaffold and good integration into the host. Although control animals developed significant LV dilatation accompanied by progressive deterioration in LV contractility, in the biograft-treated rats, attenuation of LV dilatation and no change in LV contractility were observed.

Conclusions
—Alginate scaffolds provide a conducive environment to facilitate the 3D culturing of cardiac cells. After implantation into the infarcted myocardium, the biografts stimulated intense neovascularization and attenuated LV dilatation and failure in experimental rats compared with controls. This strategy can be used for regeneration and healing of the infarcted myocardium.
Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid Fortified Cereal Grain Flour
Authors: Bostom Andrew G , Liaugaudas Gintaras , Jacques Paul F , Rosenberg Irwin H , Selhub Jacob
Published: July 2021

P86

Background: The prevalence of both deficient plasma folate status, and elevated total (t) plasma levels of the putatively atherothrombotic amino acid homocysteine (Hcy), have been dramatically reduced since the recent advent of fortification of all enriched cereal grain flour products with physiological amounts (i.e., 140 μg/ 100 g flour) of folic acid. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid based B-vitamin supplementation among stable coronary artery disease (CAD) patients. Methods and Results: Using a 2x2 factorial design, we randomly assigned 131 stable CAD patients (mean age 60.1 years; 29.8 % women) to folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d [ FA group] or FA placebo [PL] , ± B6 [ B6 group] 50 mg/d or B6 placebo[PL], for 12 weeks of treatment. All pre-treatment and final on-treatment analyte values were based on the average of two blood collections performed within 1-week. Geometric mean pre-treatment, on-treatment, and pre-treatment minus on-treatment change in (Δ) tHcy levels (μmol/L), were- FA, B6 (n=31): 8.7 (pre-), 7.4 (on-), Δ= -1.3; B6, PL (n=32): 8.7 (pre-), 9.1 (on-), Δ= + 0.4; FA, PL (n=34): 9.0 (pre-), 8.0 (on-), Δ= - 1.0; PL, PL (n=34): 8.4 (pre-), 8.5 (on-), Δ= + 0.1. ANCOVA adjusted for baseline tHcy levels revealed that the very modest (i.e., ∼ 1.0 μmol/L) reductions in fasting values afforded by the FA containing treatments were statistically significant (p <0.05). Conclusions: In the era of cereal grain flour products fortified with physiological amounts of folic acid, stable CAD patients supplemented with high dose, folic acid containing B-vitamin regimens experience only very modest reductions in their mean plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.
Effect of Aerobic Exercise on Blood Pressure: A Meta-Analysis of Randomized Controlled Trials
Authors: Whelton Seamus P , Chin Ashley , He Jiang
Published: July 2021

P97

Physical activity has been associated with reduced blood pressure in observational epidemiological studies and individual clinical trials. We conducted a meta-analysis of randomized controlled trials to determine the effect of aerobic exercise on blood pressure. We searched English-language articles published before June 2000. Thirty-nine randomized controlled trials (1,418 subjects) in which aerobic exercise was the only difference between the intervention and control groups were selected for the analysis. Employing a standardized protocol and data extraction form, two of the investigators independently abstracted data on study design, sample size, participant characteristics, type of intervention, follow-up duration, and treatment outcomes. Using a random-effects model, data from each trial was pooled and weighted by the inverse of its variance. Aerobic exercise was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressure of -4.84 mm Hg (-3.30 to -6.37) and -3.12 mm Hg (-2.10 to -4.14), respectively. The reduction in blood pressure was similar in hypertensive and normotensive participants. This meta-analysis indicates that aerobic exercise reduces blood pressure in hypertensive and normotensive populations. An increase in aerobic physical activity should be considered as an important component of lifestyle modification for the prevention and treatment of high blood pressure.
Diabetes and Long-Term Survival After Acute Myocardial Infarction:
Authors: Mukamal Kenneth J , Nesto Richard W , Cohen Mylan C , Muller James E
Published: July 2021

0027

Some, but not all, recent studies have found that diabetes is independently associated with long-term mortality following hospitalization for acute myocardial infarction. These studies have also failed to control for certain possible confounding factors, such as alcohol use, physical exertion, and socioeconomic status. In the Determinants of Myocardial Infarction Onset Study, trained interviewers performed chart reviews and face-to-face interviews with 1935 patients hospitalized with acute myocardial infarction between 1989 and 1993. We used Cox proportional hazards regression to determine the effect of diabetes on long-term survival after adjustment for sociodemographic characteristics, medical history, and acute infarct-related complications. Of the 1935 patients, 320 (17%) died during a median follow-up of 3.8 years. Diabetes was associated with higher total mortality in adjusted analyses (hazard ratio 1.6; 95% confidence interval, 1.3-2.1). The magnitude of the effect of diabetes was identical to that of a previous myocardial infarction. The effect of diabetes was not significantly modified by age, smoking, household income, use of thrombolytic therapy, type of hypoglycemic treatment, or duration of diagnosed diabetes, but the mortality risk associated with diabetes was higher among women than among men (adjusted hazard ratios 2.8 versus 1.3; p=0.02). In summary, diabetes is independently associated with increased mortality following acute myocardial infarction, particularly among women. The increase in risk is of the same magnitude as a previous myocardial infarction and provides further support for aggressive treatment of coronary risk factors among diabetic patients.
Transmyocardial Laser Revascularization Remodels the Intrinsic Cardiac Nervous System in a Chronic Setting
Authors: Arora R.C. , Hirsch G.M. , Hirsch K. , Armour J.A.
Published: July 2021

Background

Prospective trials have demonstrated that transmyocardial laser revascularization (TMLR) imparts symptomatic relief to patients with refractory angina. Because peak clinical effectiveness of TMLR is usually delayed by several months, it has been proposed that ventricular denervation is one mechanism whereby TMLR imparts symptomatic relief. We have demonstrated that TMLR does not denervate the heart in the acute setting, nor does it modify the intrinsic cardiac nervous system (ICNS) in the acute setting. However, the long-term effects of TMLR on the ICNS remain unknown.

Methods and Results

A holmium:yttrium-aluminum-garnet laser created 20 channels through the anterolateral left ventricular free wall of 10 dogs. Four weeks later, the function of cardiac sensory inputs to the ICNS was studied by applying veratridine (7.5 μmol/L) to ventricular sensory fields. Chronotropic and inotropic responses elicited by cardiac sympathetic or parasympathetic efferent neurons stimulated electrically (10 Hz, 4 V, 4 ms) or chemically (nicotine 5 to 20 μg/kg IV) were also assessed. Chemical activation of epicardial sensory neurites with veratridine elicited expected ICNS excitatory responses. Electrical stimulation of sympathetic and parasympathetic efferent neurons induced expected altered cardiac responses. In contrast, the responsiveness of the ICNS to systemically administered nicotine was obtunded.

Conclusions

Although chronic TMLR does not affect cardiac afferent or extracardiac efferent neuronal function, it does “remodel” the ICNS so that its responsiveness to a known potent chemical agonist (ie, nicotine) becomes obtunded. Remodeling of the ICNS may account in part for the delayed symptomatic relief that TMLR imparts to patients with refractory angina.
Long-Term Survival After Mitral Valve Replacement in Children Aged <5 Years
Authors: Caldarone Christopher A. , Raghuveer Geetha , Hills Christine B. , Atkins Dianne L. , Burns Trudy L. , Behrendt Douglas M. , Moller James H.
Published: July 2021

Background

Short- and long-term outcomes after prosthetic mitral valve replacement (MVR) in children aged <5 years are ill-defined and generally perceived as poor. The experience of the Pediatric Cardiac Care Consortium (45 centers, 1982 to 1999) was reviewed.

Methods and Results

MVR was performed 176 times on 139 patients. Median follow-up was 6.2 years (range 0 to 20 years, 96% complete). Age at initial MVR was 1.9±1.4 years. Complications after initial MVR included heart block requiring pacemaker (16%), endocarditis (6%), thrombosis (3%), and stroke (2%). Patient survival was as follows: 1 year, 79%; 5 years, 75%; and 10 years, 74%. The majority of deaths occurred early after initial MVR, with little late attrition despite repeat MVR and chronic anticoagulation. Among survivors, the 5-year freedom from reoperation was 81%. Age-adjusted multivariable predictors of death include the presence of complete atrioventricular canal (hazard ratio 4.76, 95% CI 1.59 to 14.30), Shone’s syndrome (hazard ratio 3.68, 95% CI 1.14 to 11.89), and increased ratio of prosthetic valve size to patient weight (relative risk 1.77 per mm/kg increment, 95% CI 1.06 to 2.97). Age- and diagnosis-adjusted prosthetic size/weight ratios predicted a 1-year survival of 91% for size/weight ratio 2, 79% for size/weight ratio 3, 61% for size/weight ratio 4, and 37% for size/weight ratio 5.

Conclusions

Early mortality after MVR can be predicted on the basis of diagnosis and the size/weight ratio. Late mortality is low. These data can assist in choosing between MVR and alternative palliative strategies.
Are Outcomes of Surgical Versus Transcatheter Balloon Valvotomy Equivalent in Neonatal Critical Aortic Stenosis?
Authors: McCrindle Brian W. , Blackstone Eugene H. , Williams William G. , Sittiwangkul Rekwan , Spray Thomas L. , Azakie Anthony , Jonas Richard A. ,   the members of the Congenital Heart Surgeons Society
Published: July 2021

Background

For neonates with critical aortic valve stenosis who are selected for biventricular repair, valvotomy can be achieved surgically (SAV) or by transcatheter balloon dilation (BAV).

Methods and Results

Data regarding 110 neonates with critical aortic valve stenosis were evaluated in a study by the Congenital Heart Surgeons Society from 1994 to 1999. Reduced left ventricular function was present in 46% of neonates. The initial procedure was SAV in 28 patients and BAV in 82 patients. Mean percent reduction in systolic gradient was significantly greater with BAV (65±17%) than SAV (41±32%;
P
<0.001). Higher residual median gradients were present in the SAV versus BAV group (36 mm Hg [range, 10 to 85 mm Hg] versus 20 mm Hg [0 to 85 mm Hg],
P
<0.001). Important aortic regurgitation was more often present after BAV (18%) than SAV (3%;
P
=0.07). Time-related survival after valvotomy was 82% at 1 month and 72% at 5 years, with no significant difference for SAV versus BAV, even after adjustment for differences in patient and disease characteristics. Independent risk factors for mortality were mechanical ventilation before valvotomy, smaller aortic valve annulus (
z
score), smaller aortic diameter at the sinotubular junction (
z
score), and a smaller subaortic region. A second procedure was performed in 46 survivors. Estimates for freedom from reintervention were 91% at 1 month and 48% at 5 years after the initial valvotomy and did not differ significantly between groups.

Conclusions

SAV and BAV for neonatal critical aortic stenosis have similar outcomes. There is a greater likelihood of important aortic regurgitation with BAV and of residual stenosis with SAV.
Evidence of Functional Myocardial Ischemia Associated With Myocardial Dysfunction in Brain-Dead Pigs
Authors: Seguin Carole , Devaux Yvan , Grosjean Sandrine , Siaghy El Medhy , Mairose Pierre , Zannad Faiez , de Talancé Nicole , Ungureanu-Longrois Dan , Mertes Paul Michel
Published: July 2021

Background

Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs.

Methods and Results

Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10±3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt
max
, rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt
max
, RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt
max
, RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism.

Conclusions

Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.
Enhanced Myocardial Angiogenesis by Gene Transfer With Transplanted Cells
Authors: Yau Terrence M. , Fung Karen , Weisel Richard D. , Fujii Takeshiro , Mickle Donald A.G. , Li Ren-Ke
Published: July 2021

Background

The combination of myocardial cell transplantation and angiogenic gene transfer may improve postinfarction left ventricular (LV) perfusion. We evaluated the angiogenic effect of heart cells transfected with vascular endothelial growth factor (VEGF) and transplanted into a myocardial scar.

Methods and Results

Donor rat heart cells were transfected with plasmids encoding VEGF
165
and green fluorescence protein. Syngeneic adult rats underwent LV cryoinjury to create a transmural scar. Three weeks later, 4×10
6
transfected heart cells (n=14), untransfected heart cells (n=13), or culture medium (n=16) were transplanted into the center of the scar. After 5 weeks, LV function, quantitative histology, and regional blood flow were evaluated. Plates of heart cells transfected with VEGF
165
produced 6.1 times more intracellular VEGF than nontransfected cells. Capillary density (mean±SEM) per high-power field in the center of the myocardial scar was 1.1±0.02 in control rats, 3.9±0.11 in untransfected rats, and 6.3±0.11 in transfected rats (
P
=0.0002). Capillary density in the border zone around the scar was 1.9±0.03 in control rats, 6.4±0.10 in untransfected rats, and 8.7±0.16 in transfected rats (
P
=0.004). Regional blood flow within the scar was 8.8±0.8% of normalized flow in control hearts, 10.4±0.7% in hearts transplanted with untransfected cells, but 17.6±1.2% in hearts transplanted with transfected cells (
P
=0.03 versus control,
P
=0.07 versus nontransfected). There was no difference in LV function attributable to transplantation with transfected cells at the time point studied.

Conclusions

Transplantation of heart cells transfected with VEGF induced greater angiogenesis than transplantation of unmodified cells. Combined gene transfer and cell transplantation strategies may improve postinfarction LV perfusion and function.
Quantitative Myocardial Cytokine Expression and Activation of the Apoptotic Pathway in Patients Who Require Left Ventricular Assist Devices
Authors: Birks Emma J. , Latif Najma , Owen Virginia , Bowles Christopher , Felkin Leanne E. , Mullen Anthony J. , Khaghani Asghar , Barton Paul J.R. , Polak Julia M. , Pepper John R. , Banner Nicholas R. , Yacoub Magdi H.
Published: July 2021

Background

Molecular mechanisms underlying the deterioration of patients undergoing LV assist device (LVAD) implantation remain poorly understood. We studied the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 and the terminal stage of the apoptotic pathway in patients with decompensating heart failure who required LVAD support and compared them with patients with less severe heart failure undergoing elective heart transplantation.

Methods and Results

Myocardial and serum samples from 23 patients undergoing LVAD implantation were compared with those from 36 patients undergoing elective heart transplantation. Myocardial TNF-α mRNA (1.71-fold;
P
<0.05) and protein (3.43±0.19 versus 2.95±0.10 pg/mg protein;
P
<0.05) were elevated in the LVAD patients. Immunocytochemistry demonstrated TNF expression in the myocytes. Serum TNF-α was also elevated (12.5±1.9 versus 4.0±0.4 pg/mL;
P
<0.0001) in the LVAD patients. IL-6 mRNA (2.57-fold higher;
P
<0.005) and protein (27.83±9.35 versus 4.26±1.24 pg/mg protein;
P
<0.001) were higher in the LVAD candidates, as was serum IL-6 (79.3±23.6 versus 7.1±1.6 pg/mL;
P
<0.0001). Interleukin-1β mRNA expression was 9.78-fold higher in the LVAD patients (
P
<0.001). iNOS mRNA expression was similar to that in advanced heart failure patients and was not further elevated in the LVAD patients. Levels of procaspase-9 (8.02±0.91 versus 6.16±0.43 oligodeoxynucleotide [OD] units;
P
<0.01), cleaved caspase-9 (10.02±1.0 versus 7.34±0.40 OD units;
P
<0.05), intact and spliced DFF-45 (4.58±0.75 versus 2.84±0.23 OD units;
P
<0.05) were raised in LVAD patients, but caspase-3 and human nuclease CPAN were not.

Conclusions

Elevated TNF-α, IL-1β, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF-α and IL-6 in serum of deteriorating patients who required LVAD support. These occurrences may have therapeutic implications and influence the timing of LVAD insertion.
Aprotinin But Not ε-Aminocaproic Acid Decreases Interleukin-10 After Cardiac Surgery With Extracorporeal Circulation
Authors: Greilich Philip E. , Okada Kuniyuki , Latham Paige , Kumar Ramaswamy Ravi , Jessen Michael E.
Published: July 2021

Background

Extracorporeal circulation induces a systemic inflammatory response, which may adversely affect organ function. One manifestation of this response is increased fibrinolysis. Antifibrinolytic drugs such as aprotinin and ε-aminocaproic acid have been effective in reducing fibrinolysis and blood loss after extracorporeal circulation; however, the effects of antifibrinolytic drugs on proinflammatory and anti-inflammatory mediators are not known. This study examined the effects of aprotinin and ε-aminocaproic acid on plasma levels of proinflammatory [interleukin-6 (IL-6)] and anti-inflammatory [interleukin-10 (IL-10)] cytokines during and after extracorporeal circulation.

Methods and Results

Seventy-two patients undergoing coronary artery bypass grafting with extracorporeal circulation were randomly assigned in a double-blind study to receive high-dose aprotinin, ε-aminocaproic acid, or saline placebo. Plasma levels of IL-6 and IL-10 were measured at 5 time points before, during, and after extracorporeal circulation. In all 3 groups, both IL-6 and IL-10 rose significantly after institution of extracorporeal circulation and remained elevated through the first postoperative day. Compared with saline, aprotinin significantly reduced IL-10 (
P
=0.02) and peak IL-6 (
P
=0.02) after extracorporeal circulation. In contrast, none of the reductions in IL-6 and IL-10 by ε-aminocaproic acid achieved statistical significance. Both aprotinin and ε-aminocaproic acid decreased blood loss compared with saline, but there was no significant difference in the number of patients receiving blood products among the treatment groups.

Conclusions

These data suggest that aprotinin and ε-aminocaproic acid differ in their effects on the inflammatory response to extracorporeal circulation. Aprotinin but not ε-aminocaproic acid appears to attenuate the rise in the proinflammatory and anti-inflammatory cytokines IL-6 and IL-10. Further studies will be required to determine if these cytokine alterations translate to changes in clinical outcomes.
Waiting for Cardiac Surgery
Authors: Ray A. Andrew , Buth Karen J. , Sullivan John A. , Johnstone David E. , Hirsch Gregory M.
Published: July 2021

Background

The Queen Elizabeth II Health Sciences Centre uses a weekly peer-review conference of cardiovascular experts to prioritize each surgical case to 1 of 4 queues with the use of standardized criteria of coronary anatomy, stress test result, and symptoms. We examined the hazard of waiting as well as the impact of waiting on surgical outcomes.

Methods and Results

Analysis was performed for 2102 consecutive patients queued for CABG, aortic valve replacement, or CABG+aortic valve replacement between January 1, 1998, and December 31, 1999. Among 1854 patients undergoing surgery, median waiting times on the respective queues were as follows: in-house urgent group, 8 days; semiurgent A group, 37 days; semiurgent B group, 64 days; and elective group, 113 days. There were 13 deaths (12 cardiac) that occurred during the waiting period (0.7% of the patients). Of the 8.7% patients upgraded to a more urgent queue, 86.1% required hospitalization before surgery. Although female sex was not associated with prolonged waiting time, it was predictive of urgent status (
P
=0.001). The incidence of postoperative complications was 25.0%, and operative mortality was 2.86%. Both were more frequent among patients undergoing surgery early (
P
=0.01); however, this difference was attributable to the in-house urgent queue. The median length of stay was 7 days for all patients and was not affected by waiting time.

Conclusions

Death and upgrades while the patients were waiting tended to occur early in the queuing process, and prolonged waiting was not associated with worse surgical outcomes. The cost of reducing waiting times could in part be offset by prevention of hospital admissions among upgraded patients.