Journal of the Saudi Heart Association (2011) 23, 13–16

King Saud University

Journal of the Saudi Heart Association

www.ksu.edu.sawww.sha.org.sa

www.sciencedirect.com

REVIEW ARTICLE

Down’s syndrome and myocardial reperfusion injury

Susheel Kumar, Richard Jonas *

Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, United States

Received 10 June 2010; revised 19 August 2010; accepted 29 August 2010Available online 9 September 2010

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KEYWORDS

Down syndrome;

Reperfusion injury;

Surgery

Corresponding author. Tel.

-mail address: rjonas@cnmc

16-7315 ª 2010 King Saud

sevier B.V. All rights reserve

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i:10.1016/j.jsha.2010.08.002

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Abstract Down syndrome is known to be an independent risk factor for mortality after surgical

repair of congenital heart anomalies. It is also associated with neurodegenerative disease and accel-

erated aging. The mechanism of the latter features has been attributed to abnormal handling of oxy-

gen-free radicals as well as mitochondrial dysfunction. These properties also place the child with

Down syndrome at a risk of an exaggerated myocardial ischemia/reperfusion injury.

A 6 month old child with Down syndrome is reported who suffered from obvious clinical ische-

mia/reperfusion injury following an uncomplicated repair of complete AV canal. Both intraopera-

tive as well as postoperative echocardiography documented a satisfactory technical repair. After

resting the heart on ECMO the child’s myocardial function returned to normal.

The mechanisms by which patients with Down syndrome are at risk of ischemia/reperfusion

injury are reviewed. Future studies should focus on specific approaches for myocardial protection

in the child with Down syndrome undergoing cardiac surgery.ª 2010 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Contents

1. Clinical summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.1. Down’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4762811.

Jonas).

y. Production and hosting by

Saud University.

lsevier

14 S. Kumar, R. Jonas

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Down’s syndrome (DS) caused by an extra copy of genes on

chromosome 21 is associated with a high incidence of congen-ital heart defects, mental retardation, early onset Alzheimer’sdisease and an accelerated aging process among other deleteri-

ous phenotypes (Tiano et al., 2008; Pallardo et al., 2006). Animbalance in redox metabolism resulting in oxidative stressand tissue injury has been shown to be the basic defect under-

lying this disorder (Tiano et al., 2008; Pallardo et al., 2006).Gene-dose effect leads to elevated levels of superoxide dismu-tase-1(SOD-1) which results in an excess of reactive oxygenspecies (ROS) formation and consequent cell injury (Zigman

and Lott, 2007). In recent years focus has shifted to abnormal-ities in mitochondrial function as an additional mechanism ofcell injury (Conti et al., 2007; Prince et al., 1994; Arbuzova

et al., 2002) in DS. Reperfusion following a period of ischemiais associated with generation of superoxide radicals and alter-ations in mitochondrial membrane (Yellon and Hausenloy,

2007). Although both redox metabolism and mitochondrialfunction are now known to be abnormal in DS, the issue ofmyocardial reperfusion injury either potential or real has not

raised before. We report a case of myocardial reperfusion in-jury following open heart surgery in an infant with DS and dis-cuss the possible mechanisms of the same.

1. Clinical summary

UL, a nearly 6 month old girl was diagnosed with Down syn-

drome and complete atrioventricular canal at birth. Althoughsurgical intervention for her congenital heart disease was ini-tially planned at 3 months, it was delayed because of serious

social reasons. She was medically managed with decongestivetherapy for heart failure and weighed 5.3 kg at the time ofoperation. CXR showed cardiomegaly with pulmonary pleth-

ora. Electrocardiogram revealed prominent biventricularforces. Echocardiogram (ECHO) showed a complete atrioven-tricular (AV) canal (Rastelli type A) with a large ventricular

septal defect (VSD) and a large atrial component. Both theAV valves were competent. There was a bridging band of tis-sue between the superior and inferior common leaflets natu-rally dividing the AV valve into right and left components.

In addition there was a moderate-sized ostium secundumdefect.

Surgical repair of her congenital defect was undertaken

under cardiopulmonary bypass. A standard midline sternot-omy approach was used. Cardiopulmonary bypass (CPB)was instituted using aortic and bicaval cannulation. The pat-

ent ductus arteriosus was ligated soon after going on bypass.The patient was cooled to 28 �C. Aorta was cross clampedand the heart arrested using antegrade cardioplegia (weuse oxygenated St. Thomas crystalloid cardioplegia solution

for myocardial arrest at our institution). The heart arrestedsatisfactorily with complete disappearance of electrical activ-ity. The caval tourniquets were tightened and right atrium

(RA) was opened by an oblique incision running parallelto the atrioventricular groove. The ECHO diagnosis ofCAVC type A was confirmed. The band of tissue between

the bridging leaflets was used as a guide to demarcate the

left from the right AV valve. Modified single patch tech-nique was used for repair of the AV canal defect. The cleftin the left AV valve was repaired and both the atrial septal

defects were closed using a single pericardial patch. The cor-onary sinus was placed on the left side of the patch. Half-dose cardioplegia was used intermittently at intervals of

20 min or earlier if there were signs of electrical activity.Rewarming was initiated towards the end of procedure.The heart was thoroughly deaired and the cross clamp wasreleased with the cardioplegia site bleeding freely. The total

cross clamp time was 39 min with two additional half dosesof cardioplegia following the first full dose. At this point wenoted that the myocardial perfusion was poor and the heart

did not appear pink as it would normally do following re-lease of cross clamp. It was hoped that this was a transientphenomenon and would rapidly improve. Epicardial pacing

was used for variable heart block with intermittent periodsof sinus rhythm. Upon complete rewarming, the child wasweaned from cardiopulmonary bypass using 7.5 mg/kg/min

of dopamine with systolic blood pressure in the 50 s and leftatrial pressure between 12 and 15 mmHg. The total durationof cardiopulmonary bypass was 70 min. However, the myo-cardial perfusion continued to look poor with ST elevation

in all the leads. There was some improvement in hemody-namics with return of sinus rhythm and escalation of dopa-mine support but with no difference in the color of the

heart. About 30 min following weaning from CPB, thehemodynamics deteriorated and the child had to be placedback on CPB. A decision was made to rest the heart on

Extracorporeal membrane oxygenation (ECMO) instead ofattempting another wean with high pressors. A left atrialvent was placed to decompress the left heart. The perfusionof the heart remained concerningly poor through all this.

There was rapid return of pulsatility on ECMO. ECHOconfirmed an adequate repair with mild to moderate left AVvalve regurgitation. At the time of removal of left atrial vent

24 h later, we noted a significant change in the color of theheart. The heart appeared pink and well perfused for the firsttime following the operation and there was also a notable

improvement in contractility. The patient could be easilyweaned off ECMO within the next 24 h. She had an unremark-able post operative course following ECMO decannulation

and was discharged home.

2. Discussion

Myocardial reperfusion injury is the injury caused to the myo-cardium by restoration of blood flow after an ischemic episode.This results in death or damage to the cardiac myocytes that

were viable immediately before myocardial reperfusion. Myo-cardial reperfusion injury was first postulated by Jennings etal. in 1960. The injury that occurs to the myocardium on re-

lease of aortic cross clamp following cardioplegic arrest ofthe heart is a form of myocardial reperfusion injury. The reper-fusion injury can manifest as four types of cardiac dysfunction

Figure 1 showing the mediators of myocardial reperfusion injury and the potential steps that could be affected in Down’s syndrome.

N = neutrophil. E = vascular endothelium. PTP = permeability transition pore. ROS = reactive oxygen species. SR = sarcoplasmic

reticulum.

Down’s syndrome and myocardial reperfusion injury 15

(Yellon and Hausenloy, 2007). Myocardial stunning denotesmechanical dysfunction that persists after reperfusion despitethe absence of irreversible damage and despite the restoration

of normal or near normal coronary flow. This is a relativelymild sublethal injury and results in global derangement ofthe mechanical properties of the heart. This heart usually

recovers from this sort of injury within a few days to weeks.The second type of injury is the ‘no reflow’ phenomenon whichrefers to the inability to reperfuse a previously ischemic regiondue to impedence of microvascular blood flow following resto-

ration of blood flow. Reperfusion arrhythmias are the thirdtype of injury and are often amenable to treatment. Lethalreperfusion injury causes death of the cardiomyocytes and is

fatal.Mediators of reperfusion injury (Fig. 1) have been well de-

scribed (Yellon and Hausenloy, 2007).

1. Oxygen paradox. The reperfusion of ischemic myocardiumgenerates harmful oxidative radicals termed reactive oxy-gen species (ROS) which can itself mediate myocardial

injury. The ROS such as O2�, H2O2 and OH� also reduces

the bioavailability of the intracellular signaling moleculelike NO which has cardioprotective affects.

2. Calcium paradox. Reperfusion results in an abrupt increasein intracellular calcium secondary to sarcolemmal mem-brane damage and oxidative stress induced dysfunction of

the sarcoplasmic reticulum. This resulting calcium overloadinduces cardiomyocyte death by causing hypercontractureof myocardial cells and opening of mitochondrial perme-

ability transition protein (PTP).3. PH paradox. The correction of pH following washout of

lactic acid and activation of membrane channels contrib-utes to reperfusion injury by activation of PTP.

4. Inflammation. Neutrophils are drawn into the injured areaby the chemoattractants released by the myocardium fol-lowing reperfusion. This is facilitated by the cell adhesion

molecules. The neutrophils inflict damage by causing vas-cular plugging and release of degradative enzymes andROS.

5. Mitochondrial PTP. The mitochondrial PTP is a nonse-lective channel of the inner mitochondrial membrane.Opening of the channel collapses the mitochondrial

membrane potential and uncouples oxidative phosphory-lation resulting in ATP depletion and death. The chan-nel is closed during ischemia and opens with reperfusionin response to mitochondrial calcium overload, oxidative

stress, restoration of physiological pH and ATPdepletion.

2.1. Down’s syndrome

Studies suggest that multiple chromosome 21 genes affect pro-tein synthesis, mitochondrial function and reactive oxygen spe-cies production, one carbon metabolism and cell adhesion(Conti et al., 2007). Mitochondrial function and ROS path-

ways have been targets of numerous studies on neurodegener-ation in DS (Tiano et al., 2008; Pallardo et al., 2006; Contiet al., 2007; Prince et al., 1994; Arbuzova et al., 2002; Busciglio

et al., 2002; Shukkur et al., 2006).SOD-1 is a key enzyme involved in the metabolism of reactive

oxygen species (ROS). Normally it protects against free radical in-

jury by converting superoxide anion (O2�) into H2O2 which is

further broken down by glutathione peroxidase to H2O. SOD-1level is markedly raised in DS as the gene for SOD-1 is located

on chromosome 21. The increased level of SOD-1, a molecular

16 S. Kumar, R. Jonas

marker of DS can lead to the accumulation of ROS like OH

which can damage DNA, RNA, proteins and lipids. This oxida-tive stress has been implicated in the neuronal injury leading tomental retardation and early onset of Alzheimer’s disease in DS(Brugge et al., 1992; Sinha, 2005). Oxidative stress also causes

accelerated aging process (Pallardo et al., 2006).On studying the gene expression profiles of the hearts of hu-

man fetuses with Down’s syndrome Conti et al. found that

chromosome 21 gene expression was globally up regulated1.5-fold. Interestingly, not all genes were equally upregulatedand genes located on other chromosomes were also signifi-

cantly dysregulated (Conti et al., 2007). Further analyses re-vealed down regulation of genes encoding mitochondrialenzymes and up regulation of genes encoding extra cellular

matrix proteins. Reduction of mitochondrial enzyme activityhas been reported in platelets from DS patients (Prince et al.,1994) as well as in astrocytes and primary cultures of fibro-blasts (Arbuzova et al., 2002; Busciglio et al., 2002). Shukkur

et al. elegantly demonstrated the contribution of mitochon-drial dysfunction to neurodegeneration in a mouse mode ofDS (Shukkur et al., 2006). Mitochondrial dysfunction has thus

come to be increasingly recognized as an additional contribut-ing factor to the pathology of DS.

Neutrophil chemotaxis and phagocytic activity have been

proven to be adversely affected in DS (Zaldivar-Chiapaet al., 2005).

Thus it is easy to see how DS patients may respond differ-ently to the reperfusion injury (Fig. 1) as ROS formation, mito-

chondria and leukocyte play a key role in it although we do notknow how theymay combine to produce a different response. Inour case, we used the same standard cardioplegia at the same

intervals as in any other patient. The heart responded well tothe cardioplegic arrest and there were no signs of electric activityon ECG during the period of aortic cross clamp. Deairing of the

heart was thorough before release of cross clamp and there wereno signs of coronary air embolism. Mechanical dysfunctionaccompanied the pale color of the heart and both improved over

a period of 24 h. The senior author of this paper has encoun-tered a similar case of reperfusion injury in a Down’s syndromewith AV canal defect. In that case too, the patient recoveredafter being placed on ECMO.

DS patients form a significant proportion of those requiringrepair of congenital heart lesions. The question of vulnerabilityof these hearts to reperfusion injury has not been raised before

probably because most of the cardioplegia in use afford goodmyocardial protection from anoxic damage in these heartstoo. It is also probable that cases of reperfusion injury in the past

have either not been reported or they have gone unrecognized.Moreover individuals with DS are affected to a variable extent,the mechanism of which is yet not understood (Wiseman et al.,

2009). Sinha has demonstrated the differential expression ofthe antioxidant genes in DS depending on age and sex (Sinha,2005). Further studies are required to understand not only themyocardial reperfusion injury in DS but also the inflammatory

response to CPB.

3. Conclusion

The underlying mechanisms operative in DS pathology may

make them vulnerable to myocardial reperfusion injury follow-ing open heart surgery as it did in our case. Awareness of this isimportant to recognize and deal with this form of reperfusioninjury. More studies and research are required in this direction

to understand this.

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