Circulation. 2005 May 31;111(21):2783-91. 

From stem cells to viable autologous semilunar heart valve.

Sutherland FW, Perry TE, Yu Y, Sherwood MC, Rabkin E, Masuda Y, Garcia GA,
McLellan DL, Engelmayr GC Jr, Sacks MS, Schoen FJ, Mayer JE Jr.

Department of Cardiothoracic Surgery, Children's Hospital, Boston, Mass, USA.
fraser.sutherland@northglasgow.scot.nhs.uk

BACKGROUND: An estimated 275,000 patients undergo heart valve replacement each
year. However, existing solutions for valve replacement are complicated by the
morbidity associated with lifelong anticoagulation of mechanical valves and the
limited durability of bioprostheses. Recent advances in tissue engineering and
our understanding of stem cell biology may provide a lifelong solution to these
problems. METHODS AND RESULTS: Mesenchymal stem cells were isolated from ovine
bone marrow and characterized by their morphology and antigen expression through
immunocytochemistry, flow cytometry, and capacity to differentiate into multiple
cell lineages. A biodegradable scaffold was developed and characterized by its
tensile strength and stiffness as a function of time in cell-conditioned medium.
Autologous semilunar heart valves were then created in vitro using mesenchymal
stem cells and the biodegradable scaffold and were implanted into the pulmonary
position of sheep on cardiopulmonary bypass. The valves were evaluated by
echocardiography at implantation and after 4 months in vivo. Valves were
explanted at 4 and 8 months and examined by histology and immunohistochemistry.
Valves displayed a maximum instantaneous gradient of 17.2+/-1.33 mm Hg, a mean
gradient of 9.7+/-1.3 mm Hg, an effective orifice area of 1.35+/-0.17 cm2, and
trivial or mild regurgitation at implantation. Gradients changed little over 4
months of follow-up. Histology showed disposition of extracellular matrix and
distribution of cell phenotypes in the engineered valves reminiscent of that in
native pulmonary valves. CONCLUSIONS: Stem-cell tissue-engineered heart valves
can be created from mesenchymal stem cells in combination with a biodegradable
scaffold and function satisfactorily in vivo for periods of >4 months.
Furthermore, such valves undergo extensive remodeling in vivo to resemble native
heart valves.

Eur J Anaesthesiol. 2005 May;22(5):353-8. 

The influence of xenon, nitrous oxide and nitrogen on gas bubble expansion
during cardiopulmonary bypass.

Grocott HP, Sato Y, Homi HM, Smith BE.

Duke University Medical Center, Division of Cardiothoracic Anesthesiology and
Critical Care Medicine, Department of Anesthesiology, Durham, NC 27710, USA.
h.grocott@duke.edu

BACKGROUND AND OBJECTIVE: Xenon may have favourable applications in the setting
of cardiac surgery. Its advantages include a desirable haemodynamic profile as
well as potential cardiac and neuroprotective properties. However, its low
solubility may lead to enhanced diffusion into enclosed gas spaces. The purpose
of this study was to compare the effects of xenon (Xe), nitrous oxide (N2O) and
nitrogen (N2) on gas bubble size during cardiopulmonary bypass (CPB). METHODS:
Rats were randomized to receive 70% Xe, 26% oxygen (O2), 4% carbon dioxide (CO2)
(xenon group); 70% N2O, 26% O2, 4% CO2 (nitrous oxide group) or 70% N2, 26% O2,
4% CO2 (nitrogen group) during 90 min of normothermic CPB. Small gas bubbles
(300-500 microL; n = 12 per group) were injected into a bubble chamber on the
venous side of the bypass circuit. After 10 min of equilibration, they were
removed for volumetric analysis. RESULTS: The increase in bubble size was 2 +/-
2% with nitrogen, 17 +/- 6% with xenon (P = 0.0192 vs. nitrogen) and 63 +/- 23%
with nitrous oxide (P = 0.0001 vs. nitrogen). The nitrous oxide group had
significantly increased bubble size compared to the xenon group (P = 0.0001).
CONCLUSIONS: During CPB, xenon anaesthesia produced a small increase in gas
bubble size compared to nitrogen. Nitrous oxide resulted in significantly larger
bubbles compared to both nitrogen and xenon.

Eur J Anaesthesiol. 2005 May;22(5):347-52. 

Cerebral inflammatory response during and after cardiac surgery.

Mielck F, Ziarkowski A, Hanekop G, Armstrong VW, Hilgers R, Weyland A, Quintel
M, Sonntag H.

University of Gottingen, Department of Anaesthesiology, Gottingen, Germany.
fmielck@gwdg.de

BACKGROUND AND OBJECTIVE: Neurological dysfunction is a common problem after
cardiac surgery with cardiopulmonary bypass (CPB). Cerebral ischaemia associated
with the use of CPB may result in a release of neuronal-ischaemic markers and a
subsequent cerebral inflammatory response which may additionally release
inflammatory cytokines. In order to locate the origin and to quantify the
release of neuronal-ischaemic markers and cytokines we investigated
arterial-cerebral venous concentration gradients during and after CPB in a
clinical setting. METHODS: In twenty-five patients scheduled for coronary artery
bypass grafting surgery we measured the plasma concentration of neuron-specific
enolase, S-100beta protein as well as interleukins (IL) IL-6, IL-8 and IL-10
from arterial and cerebral venous blood samples prior to surgery (baseline),
during hypothermic CPB at 32 degrees C, after termination of bypass, as well as
2, 4 and 6 h after admission to the intensive care unit. RESULTS:
Arterial-cerebral venous concentration gradients of neuron-specific enolase,
S-100beta, IL-6, IL-8 and IL-10 were neither detectable during nor after CPB.
Compared to the baseline period, S-100beta and neuron-specific enolase
significantly increased during hypothermic CPB. After termination of CPB,
neuronal-ischaemic markers as well as cytokines were increased and remained
elevated during the investigated time course without reaching baseline values.
CONCLUSIONS: Although we found an overall increase in plasma concentrations of
neuronal-ischaemic markers, IL-6, IL-8 and IL-10 during and after CPB,
arterial-cerebral venous gradients were not detectable for any of these
parameters. Our results suggest that the increase of investigated parameters
associated with the use of CPB are not primarily caused by a cerebral
inflammatory response but rather reflect a release from other sources in the
systemic circulation.

Braz J Med Biol Res. 2005 May;38(5):713-21. Epub 2005 May 25. 

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients
undergoing cardiac surgery.

Carmona MJ, Malbouisson LM, Pereira VA, Bertoline MA, Omosako CE, Le Bihan KB,
Auler Jr JO, Santos SR.

Disciplina de Anestesiologia, Servico de Anestesiologia e Terapia Intensiva
Cirurgica, Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina,
Universidade de Sao PauloSao Paulo, SP, Brasil.

The pharmacokinetics of propranolol may be altered by hypothermic
cardiopulmonary bypass (CPB), resulting in unpredictable postoperative
hemodynamic responses to usual doses. The objective of the present study was to
investigate the pharmacokinetics of propranolol in patients undergoing coronary
artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11
patients, 4 women and 7 men (mean age 57 +/- 8 years, mean weight 75.4 +/- 11.9
kg and mean body surface area 1.83 +/- 0.19 m(2)), receiving propranolol before
surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol
levels were measured before and after CPB by high-performance liquid
chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the
pharmacokinetic parameters after administration of the drug pre- and
postoperatively. There was an increase of biological half-life from 4.5 (95% CI
= 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of
distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P <
0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7
ml min-1 kg-1 (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in
drug distribution could be explained in part by hemodilution during CPB. On the
other hand, the increase of biological half-life can be attributed to changes in
hepatic metabolism induced by CPB under moderate hypothermia. These alterations
in the pharmacokinetics of propranolol after CABG with hypothermic CPB might
induce a greater myocardial depression in response to propranolol than would be
expected with an equivalent dose during the postoperative period.

J Am Coll Cardiol. 2005 May 17;45(10):1691-9. 

Impact of pulmonary hypertension on the outcomes of noncardiac surgery:
predictors of perioperative morbidity and mortality.

Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD.

Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo
Clinic College of Medicine, Rochester, Minnesota 55905, USA.

OBJECTIVES: We sought to determine the predictors of short-term morbidity and
mortality (< 30 days) after noncardiac surgery in patients with pulmonary
hypertension (PH). BACKGROUND: Pulmonary hypertension is considered to be a
significant preoperative risk factor. METHODS: The PH and surgical data bases
were matched from 1991 to 2003. Patients were excluded if PH was secondary to
left heart disease, not present before surgery, or the procedure involved
cardiopulmonary bypass. Univariate and multivariate logistic regression analyses
were used to identify variables associated with short-term morbidity and
mortality. RESULTS: Of 1,276 patients in the PH database, 145 patients (73%
female) met all study criteria. The mean age (+/-SD) was 60.1 +/- 16.0 years.
Right ventricular systolic pressure (RVSP) (mean +/- SD) on the two-dimensional
echocardiogram was 68 +/- 21 mm Hg. There were 60 patients (42%) who experienced
one or more short-term morbid event(s) (1.8 events/patient experiencing any
event). A history of pulmonary embolism (p = 0.01), New York Heart Association
functional class > or = II (p = 0.02), intermediate- to high-risk surgery (p =
0.04), and duration of anesthesia > 3 h (p = 0.04) were independent predictors
of short-term morbidity. There were 10 early deaths (7%). A history of pulmonary
embolism (p = 0.04), right-axis deviation (p = 0.02), right ventricular (RV)
hypertrophy (p = 0.04), RV index of myocardial performance > or = 0.75 (p =
0.03), RVSP/systolic blood pressure > or = 0.66 (p = 0.01), intraoperative use
of vasopressors (p < 0.01), and anesthesia when nitrous oxide was not used (p <
0.01) were each associated with postoperative mortality. CONCLUSIONS: In
patients with PH undergoing noncardiac surgery with general anesthesia, specific
clinical, diagnostic, and intraoperative factors may predict worse outcomes.

J Thromb Haemost. 2005 May 9; [Epub ahead of print] 

Genetic factors contribute to bleeding after cardiac surgery.

Welsby IJ, Podgoreanu MV, Phillips-Bute B, Mathew JP, Smith PK, Newman MF,
Schwinn DA, Stafford-Smith M; THE PERIOPERATIVE GENETICS AND SAFETY OUTCOMES
STUDY (PEGASUS) INVESTIGATIVE TEAM.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Summary. Background: Postoperative bleeding remains a common, serious problem
for cardiac surgery patients, with striking inter-patient variability poorly
explained by clinical, procedural, and biological markers.Objective: We tested
the hypothesis that genetic polymorphisms of coagulation proteins and platelet
glycoproteins are associated with bleeding after cardiac
surgery.Patients/methods: Seven hundred and eighty patients undergoing
aortocoronary surgery with cardiopulmonary bypass were studied. Clinical
covariates previously associated with bleeding were recorded and DNA isolated
from preoperative blood. Matrix Assisted Laser Desorption/Ionization,
Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were
used for genotype analysis. Multivariable linear regression modeling, including
all genetic main effects and two-way gene-gene interactions, related clinical
and genetic predictors to bleeding from the thorax and mediastinum.Results:
Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T,
GPIbalpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor
pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE)
deletion/insertion] demonstrate significant association with bleeding (P <
0.01). Adding genetic to clinical predictors results improves the model,
doubling overall ability to predict bleeding (P < 0.01).Conclusions: We
identified seven genetic polymorphisms associated with bleeding after cardiac
surgery. Genetic factors appear primarily independent of, and explain at least
as much variation in bleeding as clinical covariates; combining genetic and
clinical factors double our ability to predict bleeding after cardiac surgery.
Accounting for genotype may be necessary when stratifying risk of bleeding after
cardiac surgery.

Pediatr Crit Care Med. 2005 May;6(3):319-326. 

Low postoperative hematocrit increases cerebrovascular damage after hypothermic
circulatory arrest.

Shum-Tim D, Macdonald D, Laliberte E, Chen J, Jamal AM, Philip A, Platt R.

Divisions of Cardiac Surgery (DS-T, DM, ST, EL, A-MJ), Plastic Surgery (JC, AP),
Department of Surgery and Department of Epidemiology and Biostatistics, The
Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec,
Canada E-mail: dominique.shum-tim@muhc.mcgill.ca.

OBJECTIVE: The objective of this study was to evaluate the systemic and cerebral
effects of different postoperative hematocrit management following
cardiopulmonary bypass and deep hypothermic circulatory arrest. DESIGN: Animal
case study. SETTING: Laboratory. SUBJECTS: Four-week-old Yorkshire piglets.
INTERVENTIONS: Twelve piglets were subjected to cardiopulmonary bypass
(hematocrit = 25%) and 100 mins of deep hypothermic circulatory arrest (15
degrees C). After weaning cardiopulmonary bypass, they were randomized to either
group L or H, in which the postoperative hematocrit was maintained approximately
20% vs. approximately 30%, respectively, and survived for 6 hrs. MEASUREMENTS
AND MAIN RESULTS: Changes in body weight, bioimpedance, and colloid oncotic
pressure were assessed. Near-infrared spectroscopy and immunohistochemical
assays for cerebral transforming growth factor-beta(1) and caspase-3 were
performed. Postoperative weight gain (kg) and decreases in bioimpedance (ohms)
were significantly less in group H (1.5 +/- 0.2 [H] vs. 2.4 +/- 0.6 [L], p =
.01; 39.3 +/- 15.5 [H] vs. 89.1 +/- 29.6 [L], p = .01). Mean colloid oncotic
pressure (mm Hg) was significantly higher in group H (10.8 +/- 1.6 [H] vs. 8.2
+/- 0.8 [L], p = .01) at 6 hrs postoperatively. Oxyhemoglobin, oxidized
cytochrome aa(3) (muM x differential path-length factor), and tissue oxygenation
index (%) were significantly better in group H (65.7 +/- 31.8 [H] vs. -104.7 +/-
55.2 [L], p = .0001; 0.52 +/- 4.1 [H] vs. -12.8 +/- 6.1 [L], p = .0001, and 55.7
+/- 4.6% [H] vs. 45.3 +/- 6.4% [L], p = .004, respectively). Cerebral
transforming growth factor-beta(1) and caspase-3 scores were significantly
better in group H (3.0 +/- 0.6 [H] vs. 1.9 +/- 0.9 [L], p = .04 and 1.8 +/- 0.5
[H] vs. 3.2 +/- 0.8 [L], p = .02, respectively). Mean arterial pressure (mm Hg)
was consistently higher with group H (94.7 +/- 13.0 [H] vs. 78.3 +/- 11.5 [L], p
= .003) despite comparable central venous pressure ( approximately 11 mm Hg).
CONCLUSIONS: Lower postoperative hematocrit was associated with increased fluid
retention, lower perfusion pressure, and worse cerebrovascular injury following
deep hypothermic circulatory arrest. Postoperative hematocrit management may
have profound systemic and cerebral effects after deep hypothermic circulatory
arrest and merits further investigation.

J Card Surg. 2005 May-Jun;20(3):241-5. 

Effects of ischemic preconditioning in human heart.

Buyukates M, Kalaycioglu S, Oz E, Soncul H.

Department of Cardiovascular Surgery, Gazi University Faculty of Medicine,
Ankara, Turkey.

BACKGROUND: The aim of this study is to investigate the effects of ischemic
preconditioning (IP) on myocardium and the level of nitric oxide (NO) in
patients undergoing aorta-coronary bypass surgery. METHODS: Twenty consecutive
patients with coronary artery disease were subjected into two equal groups; the
IP group and the control group. Following the onset of cardiopulmonary bypass in
the study group, hearts were preconditioned with two 3-minute periods of
cross-clamping separated by 2 minutes of reperfusion. In the control group,
cardiopulmonary bypass was continued for 10 minutes without using cross-clamp.
Arterial and coronary sinus blood samples were used to determine serum NO,
malondialdehyde (MDA), creatine phosphokinase-MB (CKMB), and lactate
dehydrogenase (LDH) levels. Need for defibrillation after cross-clamp removal,
ECG changes, postoperative arrhythmias, ejection fraction, and fractional
shortening rates were recorded as hemodynamic data. RESULTS: Serum NO level was
higher in the study group 5 minutes after aortic clamp removal (199.3 +/- 92.7
vs. 112.2 +/- 35.8 micromol; p = 001). Serum MDA (2.55 +/- 0.4 vs. 4.06 +/- 0.5;
etamol/ml; 5 minutes after the aortic clamp removal; p = 0.0002); CK-MB (22.8
+/- 2.5 vs. 37.4 +/- 4.1; U/L 12 hours after the operation, p < 0.0001), and LDH
(501.8 +/- 46.7 vs. 611.4 +/- 128.3; IU/L 48 hours after the operation, p =
0.02) levels were significantly lower in the preconditioned group when compared
with the control group. Also, need for electrical defibrillation was
significantly lower in the study group; Ejection fraction (64.3 +/- 6.3 vs. 57.6
+/- 7.6; p = 0.04) and fractional shortening (31.7 +/- 3.9 vs. 26.2 +/- 4.0; p =
0.04) rates were better in the study group postoperatively. CONCLUSIONS: These
data may suggest that cardioprotection by ischemic preconditioning offers higher
NO production, a lower myocardial ischemia, and better functional recovery of
the hearts in coronary artery surgery patients.

J Card Surg. 2005 May-Jun;20(3):212-7. 

Survival and quality of life after cardiac surgery complicated by prolonged
intensive care.

Bapat V, Allen D, Young C, Roxburgh J, Ibrahim M.

Department of Cardiothoracic Surgery, St. Thomas' Hospital, London, UK.
vnbapat@yahoo.com

AIM: To determine survival, factors determining survival and evaluate quality of
life (QOL) after 1 year, in patients who had prolonged intensive care unit (ICU)
stay after cardiac surgery. METHODS: In the year 2001, 804 patients underwent
various cardiac procedures utilising cardiopulmonary bypass (CPB). Eighty-nine
consecutive patients requiring ICU stay of > or = 5 days constituted the study
group, majority of these suffered from multiorgan failure (> 2 organ systems).
Survival was determined in the study group after 1 year. Patients with an
uncomplicated postoperative course were matched to the survivors in the study
group with respect to age, gender, type of surgery, risk scores, and duration of
follow-up and constituted the control group. The, Short Form Health Survey was
used to assess QOL at the end of 1 year in these patients. QOL was compared
between the study group and the control group and to that of general population.
RESULTS: Seventy percent of the patients in the study group suffered from
failure of at least three organ systems. Mean ICU stay was 13 +/- 3 days (median
nine, maximum 53). At the end of 1 year the mortality in the study group was
34%. The independent predictors of mortality were: preoperative cardiac support,
lower ejection fraction, higher Parsonnet score, higher Euroscore, pulmonary
complications, renal failure necessitating hemofiltration, CNS complications,
and failure of three or more organ systems. The QOL was lower in the study group
than the control group in all eight dimensions measured (significant in five p <
0.05): Physical function, Role physical, Vitality, Mental health, General
health, and Bodily pain. CONCLUSION: One year mortality in patients with
prolonged ICU stay after cardiac surgery remains high. Identification of risk
factors will help to reduce the mortality with help of regular follow up. The
QOL remains low in all dimensions especially those measuring physical aspects
and pain.

Anesth Analg. 2005 May;100(5):1276-82, table of contents. 

An evaluation of the effects of a standard heparin dose on thrombin inhibition
during cardiopulmonary bypass in neonates.

Guzzetta NA, Miller BE, Todd K, Szlam F, Moore RH, Tosone SR.

Department of Anesthesiology, Children's Healthcare of Atlanta at Egleston, 1405
Clifton Road NE, Atlanta, GA 30322, USA. nina_guzzetta@emoryhealthcare.org

We compared the adequacy of heparinization in neonates and older children
undergoing cardiopulmonary bypass (CPB) by measuring heparin activity, thrombin
formation, and thrombin activity. Ten neonates and 10 older children were
administered 400 U/kg of heparin before CPB. Heparin anti-Xa activity,
prothrombin fragment 1.2 (F1.2), and fibrinopeptide A (FPA) were measured at
baseline, after 30 min on CPB, immediately post-CPB, and 3 and 24 h post-CPB.
Heparin anti-Xa activity was significantly decreased during and immediately
post-CPB in the neonatal group. F1.2 and FPA levels in neonates were
significantly higher at baseline, decreased with the commencement of CPB, and
increased to levels higher than those in older children after CPB. Our data show
that with standard heparin doses, neonates exhibit less heparin anti-Xa activity
during CPB. Higher baseline levels of F1.2 and FPA present in neonates indicate
preoperative activation of their coagulation systems as compared with older
children. Although F1.2 and FPA levels initially decrease with the commencement
of CPB, probably representing hemodilution, the subsequent increase in these
markers indicates significantly more thrombin formation and activity during and
after CPB. These results raise the concern that 400 U/kg of heparin may not
adequately suppress thrombin formation and activity in neonates undergoing CPB.