Environmental causes of congenital heart defects?

Congenital heart defects are the most common type of birth defect (at least in the United States). Around 1% of all babies that born in each year have some type of a heart defect, though that percentage halves (0.6%) if you only consider moderate to severe heart defects like tricuspid atresia or hypoplastic left heart syndrome (Hoffman and Kaplan 2002 J American College of Cardiology 39, 1890-1900; Reller et al., 2008 J of Pediatrics 153, 807-813).

As you can see, many parents or friends/relatives of patients with heart defects are left wondering why this happened to them if it is so rare. Sadly, some more recent studies have noticed an upward trend in the incidence of heart defects. For example, from 1968-1997 the incidence of moderate-severe congenital heart defects was 6.2/1000 births (0.62%) but from 1995-1997, the incidence was 9/1000 births (0.9%: Botto et al., Pediatrics 107). Some of this increase is obviously because our ability to detect minor or major congenital heart defects has increased over this period of time. But other features about our environment have changed and they are an easy target to blame the incidence or rise in the incidence of congenital heart defects.

In a new paper by Liu et al. (2013, Environmental Health 12) titled “Association between maternal exposure to housing renovation and offspring with congenital heart disease: a multi-hospital case-control study”, the authors report the correlation/association between being exposed to housing renovation during pregnancy and the incidence of congenital heart defects in the resulting children. We tend to worry more about the level of pollution outside our home than inside our home, yet we spend most of our days inside. Also, during a home renovation or after moving into a new house, occupants can be exposed to a variety of synthetic substances that are released from the materials used in the housing renovation or construction of the new home (e.g., volatile organic compounds, formaldehyde, heavy metals). This form of “indoor pollution” can arise from new paint on the walls, new caulk, new carpet or plastic flooring  (volatile organic compounds) or from cabinets or other furniture made from pressed wood (formaldehyde). Basically, bad stuff that people should avoid but especially pregnant women.

A few recent studies have looked at how such exposure to these renovation materials may increase in the incidence of congenital heart defects in children. A recent study concluded that exposure to new paint (volatile organic compounds) may be associated with the formation of congenital heart defects (Hjortebjerg et al., 2012, Environmental Health 11, 54). In the present study by Liu et al., the authors identified patients in four hospitals in China and screened their babies for fetal defects with ultrasound. They identified a group carrying babies with congenital heart defects and a control group from the same hospital during the same study period. They then gave both groups a questionnaire about their perceived non-occupational exposure to organic solvents or other such compounds. They excluded individuals who stated that they thought they had high occupational exposure to these toxins or if they had chromosomal abnormalities. Finally, they had a face-to-face interview with these pregnant women and asked about their exposure to housing renovations during three time periods: 7-12 months before pregnancy, 4-6 months before pregnancy, 0-3 months before pregnancy, or during the first trimester. Their criteria for housing renovation was that it involved installing at least one or more of the following list: marble surfaces, laminated board, plywood, carpets, ceramic tiles, paints, or wallpapers.

What did this study show about environmental causes of congenital heart defects?

1) Women with a fetus with a congenital heart defect were more likely to have been exposed to a housing renovation. Around 30% of the women that were pregnant with a fetus with a congenital heart defect had been exposed to a housing renovation project compared to 19% of the women without a fetus with a congenital heart defect. Not huge effect sizes but a statistical difference.

2) Mothers that smoke were more likely to be carrying a baby with a congenital heart defect (CHD). Around 46% of women carrying a fetus with a CHD smoked or were exposed to smoke compared to 30% of women carrying a fetus without a CHD.

3) Mothers living near a factory or landfill were more likely to be carrying a baby with a congenital heart defect. Around 30% of women carrying a fetus with a CHD lived near a factor/landfill whereas about 18% of women carrying a fetus without a CHD did so.

4) The overall risk of fetus developing a congenital heart defect was increased with exposure to indoor housing renovations. The odds of a fetus developing a CHD were on average 1.89 times higher if they were exposed to indoor housing renovations prior to or soon into pregnancy compared to mothers not exposed to such indoor pollution. These results are similar to a previous study in Denmark where being exposed to paint fumes during the first trimester was associated with an increased (though very slight) risk of producing a fetus with a congenital heart defect (Hjortebjerg et al., 2012 Environmental Health 11, 54-61).

5) The timing of exposure to housing renovations was important in affecting the risk of a fetus developing a congenital heart defect. Mothers exposed to a housing renovation that occurred within i) 3 months before pregnancy or ii) during the first trimester had an increased risk of producing a fetus with a CHD but only if they had moved into a house that had had a renovation within 1 month previous. Given that much of the heart development happens during the first trimester (e.g., both of the ventricles and atria are formed by 32 days after conception: Bruneau, 2008 Nature 451, 943-948), it is not necessarily surprising that being exposed to such indoor pollution in the first trimester was associated with an increased incidence of CHD. However, it is surprising that women that were exposed to indoor pollution (renovation) 3 months before pregnancy had a higher incidence of producing a fetus with a CHD. The second interesting point was that mothers (either 3 months prior to conception or 1st trimester) that moved in to a house that had been renovated within the previous month had a higher incidence of producing a fetus with a CHD. The authors discuss how this is also not surprising given that the amount of volatile organic compounds and other substances declines as the amount of time since renovation increases.

Conclusion: First, this is of course a correlational study and can only suggest associations between environmental variables and the incidence of congenital heart defects. However, recent studies suggest that ~12% of patients with a congenital heart defect have a chromosomal abnormality (e.g., Hartman et al., 2011 Pediatric Cardiology 32, 1147-1157), so there may also be a genetic basis to the development of some CHDs. However, it is important to emphasize that 1) such genetic studies are also associations and 2) this doesn’t necessarily mean that ~88% of patients with a CHD have an environmental (rather than genetic) basis. Most genes have small effects on the characteristics of an individual such that there could be many genes of small effect that interact to increase the incidence of CHD. However, this study by Liu et al. and others (Hjortebjerg et al., 2012 Environmental Health 11, 54-61) clearly provide quantitative support for common sense. That is, don’t paint your house while you are pregnant and consider the consequences of indoor pollution. This study supports the idea that effective campaigns for preventing CHD’s should involve promoting awareness of the negative consequences of indoor pollution produced by housing renovations.

Link to this paper:

http://www.ehjournal.net/content/12/1/25/abstract

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Lateral tunnel versus extracardiac conduit Fontan procedure: a concurrent comparison

In this paper by Kumar et al. (2003, Ann Thorac Surg 76, 1389-1397), the authors compare the outcomes of patients that underwent the Fontan procedure either using the intra-cardiac (lateral tunnel) or extra-cardiac conduit method. I have previously discussed the differences of these two types of the Fontan procedure here. and how the use of each type has changed over time here. In brief, the intra-cardiac or lateral tunnel method is the ‘older’ method (introduced in 1987) and the extra-cardiac method was more recently developed (1990). The lateral tunnel/intra-cardiac method involves sewing a piece of plastic inside the right atrium to route all blood from the lower part of the body (via the inferior vena cava) to the lungs whereas the extra-cardiac method involves placing a tube (either a tissue graft or plastic) outside the heart so that all blood from the lower part of the body (again via inferior vena cava) goes to the lungs. Regardless, some hospitals still perform the intra-cardiac method is the preferred option (see here).

The first thing to point out that this study was published over 10 years ago and uses data from patients that underwent the Fontan procedure from 1995-2002. As I have discussed elsewhere, there have been significant improvements in patient care and outcomes from the Fontan procedure. The other issue that these authors indicate is that most institutions only use one of the types of Fontan or they have suddenly changed over time. As such, it is hard to compare the outcomes of a lateral tunnel vs. extra-cardiac Fontan at a single hospital over the same time period. This study presents data where they performed both lateral tunnel (37 patients) and extra-cardiac (33 patients)  Fontan procedures at the same institution (Medical University of South Carolina) at the same time period.

Summary of Major Points of this Paper:

1) Theoretical advantages of extra-cardiac method. The lateral tunnel or intra-cardiac method requires placing a piece of plastic (“baffle”) inside of the atrium. The lateral tunnel/intra-cardiac method has had good early, medium, and long-term outcomes as well in previous follow-up studies. However, this requires sewing the piece of plastic (Gore Tex) inside the heart, which may increase the risk of atrial arrhythmias. The extra-cardiac method avoids having to sew this piece of plastic inside of the heart and so a theoretical advantage is that this method may decrease risk of future heart rhythm issues. However, note that this generally requires that the surgery be performed later in life because you are placing a piece of plastic in the heart that will not grow with the patient. Another possible advantage of the extra-cardiac method is that it can allow surgeons to perform the procedure without aortic cross-clamping (where they prevent the blood from leaving the heart) and even without cardiopulmonary bypass, which may have some advantages for short- and long-term outcomes (discussed here). For example, in this study, aortic cross clamping was always used for the lateral tunnel/intra-cardiac method but used in ~51% of patients for the extra-cardiac method.

2) No difference in time on cardiopulmonary bypass between intra-cardiac and extra-cardiac method but patients undergoing intra-cardiac method were on aortic cross clamping longer than those using extra-cardiac method. Patients undergoing the lateral tunnel/intra-cardiac method were on bypass (mean = 134 min) nearly the same amount of time as those undergoing the extra-cardiac method (mean = 145 min). However, 100% of patients undergoing the lateral tunnel/intra-cardiac method had aortic cross-clamping and for a longer period of time (mean = 55 min) than those that had the extra-cardiac method (52% of patients, mean = 26 min).

3) No difference in time on ventilator, time in intensive care unit, duration of chest tube drainage, and hospital stay between those having the lateral tunnel/intra-cardiac method vs. those undergoing the extra-cardiac method. This is an interesting result given that the lateral tunnel/intra-cardiac method is theoretically supposed to improve short-term outcome (that soon after the surgery) because of decreased chest tube drainage, etc. However, here they didn’t find any differences between the two methods.

4) No difference in type or frequency of medications given to patients that underwent intra-cardiac vs. extra-cardiac Fontan ~3 years previous. Though this probably attributable to the hospital itself and how they treat their patients, most of the patients were on asprin (94%) and there were no other differences between the type of frequency of medications taken between patients that underwent intra-cardiac or extra-cardiac method ~3 years previous.

5) No difference in heart rhythm problems between patients that had underwent intra-cardiac vs. extra-cardiac Fontan at ~3 years after the surgery. This is somewhat surprising that 15% of patients that had underwent the intra-cardiac Fontan ~3 years previous had heart rhythm issues (sinus node dysfunction) whereas MORE (28%) of patients that had underwent the extra-cardiac Fontan had heart rhythm issues ~3 years previous. Although this is not statistically different, this is opposite than what would be expected. Two patients underwent permanent pacemaker implantation (1 lateral tunnel and 1 extra-cardiac method) and in one case for slow junctional rhythm.

6) No difference in the post-operative blood pressure in various parts of the atrium and in the Fontan pathway (“Fontan pressure” and transpulmonary gradient) between patients that underwent the intra-cardiac vs. extra-cardiac Fontan. The authors provide brief discussion how these pressures can be predictive of early Fontan failure but they found no difference between these two methods in the first 24 hours after the Fontan.

Summary: This study highlights the lack of any real differences between the intra-cardiac/lateral tunnel vs. extra-cardiac Fontan in both the short- and long-term. This study also highlights the low rates of mortality or Fontan takedown (4.3%) around and soon after the actual surgery and high rates of survival 3-5 years after the Fontan for both the intra-cardiac (97%) and extra-cardiac (91%) methods.

The authors discuss their results in light of other studies that were contemporary at the time of this publication (2003). There results are similar to those of Gaynor et al. (2001, J Thorac Cardiovasc Surg 121, 28-41) who reported results from patients undergoing either intra- or extra-cardiac Fontan at Children’s Hospital of Philadelphia (1992-1999) and who again found no real differences between the methods. However, in another previous study that did a similar comparison between patients that underwent the intra-cardiac or extra-cardiac method at the Hospital for Sick Children in Toronto (data from 1994-1998), there was a significantly higher incidence of heart rhythm problems for patients undergoing the lateral tunnel/intra-cardiac method (45%) than those that underwent the extra-cardiac method (15%) at the post-operative period. Why the differences? The authors indicate that it may come from how the Fontan procedure was staged. The second surgery prior to the Fontan is either the hemi-Fontan procedure or the bidirectional Glenn shunt. The authors indicate that they selectively perform the hemi-Fontan for patients that were to undergo the lateral tunnel/intra-cardiac Fontan and perform the bidirectional Glenn shunt for patients that are due to undergo the extra-cardiac Fontan. In contrast, the patients at the hospital in Toronto were all staged with the bidirectional Glenn shunt regardless of whether they were to undergo the intra-cardiac or extra-cardiac Fontan (well, all patients except 1). The authors discuss how the hemi-Fontan (2nd surgery) prior to the lateral tunnel Fontan is a preferred option than doing the bidirectional Glenn shunt prior to the lateral tunnel Fontan (as the surgeons in Toronto did) because the latter involves making incisions in the same area where the previous incisions for the bidirectional Glenn shunt were made. Cutting into the same places where previous incisions were made in the sinus node region is probably not a preferable option. Interesting result. These findings confirm other studies that the risk of heart rhythm issues is higher for patients that underwent the bidirectional Glenn shunt prior to the lateral tunnel/intra-cardiac Fontan than if they had underwent the hemi-Fontan prior to the lateral tunnel/intra-cardiac Fontan. I wonder if all hospitals now always do the hemi-Fontan before the lateral tunnel/intra-cardiac method now?

Finally, the authors discuss how sometimes one method has to be done over another because of other issues with the heart anatomy. In other words, the choice of an intra-cardiac vs. extra-cardiac Fontan is not randomized among patients. For example, the lateral tunnel Fontan is often done for patients with hypoplastic left-heart syndrome but the extra-cardiac method is preferred for patients with heterotaxy syndrome. This makes it difficult to assess whether the short-, medium, or long-term outcomes are a result of the surgical procedure itself (i.e., which Fontan method) or the actual underlying condition.

Link to this paper:

https://www.sciencedirect.com/science/article/pii/S0003497503010105

Intra- or extracardiac Fontan operation? A simple strategy when to do what

In this paper, Kuroczynski et al. (Arch Med Sci 2013) reviewed the records of patients that had undergone intra-cardiac or extra-cardiac Fontan after the bidirectional Glenn surgery (the second one in staged surgeries). It is a relatively small dataset (72 patients) from one institution/hospital in Germany over a number of years (1995-2008) but I think this question is interesting and important. Understanding the potential risks and benefits of both an intra-cardiac or extra-cardiac Fontan is important. We should expect that medical science should improve outcomes and sometimes this requires paradigm shifts. For example, if an institution/hospital only performs intra-cardiac Fontan procedure, if presented with overwhelming evidence that the extra-cardiac route is “better” in the long-term (which this study does not necessarily show!), they should reconsider their methods.

Here are the major points:

As I have discussed before, two routes are commonly used in the Fontan procedure. Remember that the Fontan procedure is the 3rd step for a univentricular heart and generally comes after a 2nd open heart surgery (often the bidirectional Glenn).

1) What is the intra-cardiac Fontan method? The first potential Fontan method is to use the intra-cardiac route (also called ‘lateral tunnel’) where the blood from the lower part of the body (inferior vena cava) is routed directly to the pulmonary arteries through a ‘tunnel’ in  the atrium (generally the right atrium), which involves sewing a patch (‘baffle’) inside the heart. As its name implies (‘intra-cardiac’), this happens inside the heart. One potential caveat of the intra-cardiac Fontan is that it requires aortic cross-clamping (preventing blood from leaving the heart to the rest of the body) and stopping the heart so the surgical procedure can be completed. The intra-cardiac method also typically involves placing a fenestration in the baffle, which I have discussed in other blogs. Here is a diagram of the intra-cardiac method from Khairy et al. (2007, Circulation 115, 800-812):

Screen shot 2013-03-19 at 7.09.48 AM

2) What is the extra-cardiac Fontan method? The extra-cardiac method differs from the intra-cardiac method mostly in that it happens outside of the heart. Outside of the heart, a tunnel made of polytetrafluroethylene (type of plastic also used in non-stick cookware) connects the blood flow from the lower part of the body (again the inferior vena cava) directly to the right pulmonary artery. Here is an image of the extra-cardiac method from the Boston Children’s Hospital

Image

3) Do the extra-cardiac and intra-cardiac methods differ in their short- and long-term outcomes? The authors suggest that the extra-cardiac method has become the method of choice more recently because i) improved blood flow, ii) less risk of thrombosis (blood clots), iii) lower chance of heart rhythm problems in the short- and long-term, iv) surgically speaking, it is easier and requires less aortic clamping, which may be advantageous (see my other posts). However, this is actually narrow view and, while the extra-cardiac method is preferred at some pediatric cardiology hospitals, the intra-cardiac method is preferred at others. Furthermore, this is definitely not all pediatric cardiologists agree that the extra-cardiac method is preferred over the intra-cardiac method based upon follow-up studies such as this one (Khairy et al., 2012 Circulation 126, 2516-2525).

4) What do the data show presented in this study? Although the sample sizes were extremely small (e.g., for patients with tricuspid atresia, they performed 9 intra-cardiac Fontan and 10 extra-cardiac Fontan), the results are still interesting. However, keep these small sample sizes in mind as well as the fact that these data were collected from 1995-2008 and the type and level of treatment has likely improved for patients undergoing the Fontan procedure over that time period.

5) Patients undergoing the intra-cardiac method spend MORE time on cardiopulmonary bypass than patients undergoing the extra-cardiac method. The amount of time spent on cardiopulmonary bypass for the intra-cardiac Fontan was greater (median = 170 min, range = 50-399 min) than the extra-cardiac Fontan (median 104 min, range = 53-247 min). Most studies (including this one) generally show that spending more time on bypass is not good in the short- and long-term. However, it is again hard to identify cause and effect here given that patients with more complex heart defects will necessarily spend more time on bypass.

6) Patients undergoing the intra-cardiac method (median = 39 hours) spend MORE time on a ventilator after the Fontan procedure than patients undergoing the extra-cardiac method (median = 21 hours). These numbers (the median # of hours spent on ventilator) seem crazy high. A predictor of the length of time spent on the ventilator was the amount of time with aorta cross-clamped (which might reflect a more complicated surgical procedure so not surprising longer time on ventilator). Age and weight at which the Fontan was performed did not impact amount of time on ventilator.

7) Patients undergoing the intra-cardiac method (median = 19.5 days) spent MORE time in the intensive care unit recovering from the Fontan than patients undergoing the extra-cardiac method (median = 14 days). Again, it would be important to know how these values changed over the years as this may have gone down from what it was in the mid 1990’s. Age and weight at which the Fontan was performed did not impact amount of time in intensive care unit.

8) Patients undergoing the intra-cardiac method (median = 48 hours) had to receive greater inotropic support with catecholamines (basically how long they received drugs like dopamine to help their heart beat properly) than patients undergoing the extra-cardiac method (median = 10 hours).

Summary: Taken together, this study shows that there were major advantages for performing the extra-cardiac method over the intra-cardiac method. Patients that underwent the intra-cardiac method spent MORE time i) on cardiopulmonary bypass, ii) on a ventilator, iii) on drugs that helped heart contract, iv) in the intensive care unit. All of this is interesting but it doesn’t prove that intra-cardiac method is worse than extra-cardiac method as this is one study with a small sample size of patients from one institution over a long period of time where how patients needing the Fontan procedure are treated has changed.

Caveats: Why the authors did not report presence/absence of heart rhythm problems is unknown but would have been interesting. Although they found that age and weight at Fontan completion didn’t affect the outcomes, the authors also discuss that they prefer to do the Fontan at a later age (median patient age of Fontan completion was 3.2 years in this study). Using the extra-cardiac method generally requires patients to be older so that changing the length of the conduit (extra-cardiac tunnel) can be avoided as the patient gets older and grows. However, this has to be balanced with the fact that performing the Fontan at a later age can damage the normal ventricle (Mair et al., 2001).

Link to this paper:http://www.termedia.pl/Clinical-research-Intra-or-extracardiac-Fontan-operation-A-simple-strategy-when-to-do-what,19,20334,0,1.html

Fontan circulation: success or failure?

In this paper by Mondesert et al. (2013, Canadian Journal of Cardiology) critically review the putative success of the Fontan procedure that is commonly used to treat children (and adults) with complex congenital heart defects such as hypoplastic right or left heart syndrome and so on. This is a fantastic review and opinion by these Canadian researchers that highlights the difficulties associated with the Fontan circulation and discusses avenues for future research. What I found most revealing is that they highlight the “bad news” or potential complications, which is a big contrast to our experience with pediatric cardiologists or cardiothoracic surgeons that sometimes highlight only the “good news” of the Fontan procedure. Success can favor those who are prepared and it is important to be aware of these potential complications resulting from the Fontan circulation and also emphasize the need for more research in treating congenital heart defects.

I also think that this paper has a great overview (with diagrams) of the Fontan circulation showing the different variations of the Fontan procedure: 1) modified classic version, 2) intracardiac lateral tunnel, and 3) extracardiac tunnel.

Here are some interesting points from this paper:

1) The Fontan does not cure patients with congenital heart defects. The Fontan procedure was first introduced in 1971 and it is obviously a life saving procedure that many children (and parents) have benefited from. However, as you would suspect given that the Fontan procedure is a type of “palliative care”, it doesn’t “cure” or “fix” the congenital heart defect. You might almost view it as a bridge to another surgery or even another health complication. However, it is quite amazing that the current rate of death around the time of the Fontan (soon after) is <2%.

2) Those with the Fontan circulation do not have ‘normal’ heart physiology or functioning. Two major complications that might have many “downstream” effects are the following effects on increasing (“hypertension”) and decreasing (“hypotension”) blood pressure depending upon its location (veins or arteries). First, with Fontan circulation, there is “systemic venous hypertension”, which means that the blood pressure in the veins (blood going back to the heart) in the body is higher than in individuals with normal heart function (not Fontan circulation). There are many negative consequences that may be caused by systemic venous hypertension (congestive heart failure, edema or swelling, dysfunction of the liver, potentially protein-losing enteropathy) that are basically related to the distribution of fluids in the body. A second complication is “pulmonary arterial hypotension” where the blood pressure in arteries going towards or in the lungs (hence pulmonary) is lower than in individuals with normal heart function. There are also a number of negative consequences associated with pulmonary arterial hypotension such as cyanosis (blue lips!) or lack of exercise capacity. As this paper summarizes, many of the subsequent medical conditions and deaths that follow the Fontan procedure (either in the short- or long-term) are thought to originate from this change in systemic and pulmonary blood pressure.

3) Patients that undergo the Fontan procedure have limited lifespans (enjoy them now). In those that survive the Fontan procedure (and probably released from the hospital), 90% survive or do not need a heart transplant 10 years post-Fontan, whereas these numbers drop to 83% 20 years post-Fontan, and 70% 25 years post-Fontan. This study declares that one type of Fontan (i.e., modified classic, intracardiac lateral tunnel, or extracardiac tunnel) has not been associated with higher survival or success of patients. But surely because some of these techniques have been used for varying amounts of time we need more study to confirm this. All of this information about the causes of death following the Fontan procedure is reported in Khairy et al. (2008, Circulation 2008;117:85-92)

4) Individuals that had the Fontan procedure most often die from heart failure, stroke (thrombosis), or some unexplained sudden death. Of note is the fact that the risk of death from heart failure is quite low within 10 years of the Fontan procedure but increases with time after 10 years post-Fontan.

5) A few risk factors associated with increased risk of death or need for heart transplant are highlighted. A) One risk factor that seems to be important in predicting death or need for a heart transplant is the development of atrial tachycarrhythmias (meaning some heart rhythm problem where the heart is beating too fast), patients with these rhythm problems may have a higher risk of death. B) Second, the risk of death from a stroke or thrombosis increases dramatically 15 years post-Fontan yet the use of antiplatlet or anticoagulation therapy (asprin or warfarin, respectively) was associated with a decrease in the risk of death from stroke. C) Patients that developed protein-losing enteropathy, only had the right ventricle (e.g., hypoplastic left heart syndrome), or had increase blood pressures had a higher risk of death.

6) Not surprisingly, as time passes from the date of the Fontan procedure, the risk of death or need from a heart transplant increases. The authors note that this could be from some sudden death or heart failure, but it could also be from a gradual decline in heart function that is hard to document. Obtaining detailed health profiles from patients with Fontan circulation over their lifetime might help reveal early indicators associated with a heightened risk of death later in life.

How does the Fontan fail? The authors describe and summarize three different ways or categories in which the Fontan can “fail” (that is the patient dies or needs a heart transplant). Here is a summary:

1) The first category that they use is “ventricular dysfunction” where the ejection of the blood out of the heart (remember, ventricles eject blood!) or the blood pressure inside the heart becomes abnormal. This maybe is not surprising given that patients with the Fontan circulation have only one ventricle that is doing the work of two. This is a good reason why heart catheter procedures are performed so that these blood pressures inside the heart can be documented. One way to treat such ventricular dysfunctions is through drugs such as enalapril that can affect ventricular function. However, these authors indicate that benefits for administering enalapril are not entirely clear and they may actually depend upon whether the patient has hypoplastic right or left heart. A more recent drug that has been proposed to treat this ventricular dysfunction is sildenafil (viagra). In trials with adults that had heart failure and children that had the Fontan procedure, administering sildenafil increased some measures of ventricular performance. However, more studies are needed here.

2) The second category in which the Fontan can fail is through “systemic complications”, which are those where the altered Fontan circulation affects other parts of the body negatively. i) First, patients that need the Fontan often have low oxygen saturations in their blood (cyanosis) and this can persist even after the Fontan. In particular, in fenestrated Fontan procedure where a small hole is made in the patch of material put inside the heart to alter circulation (which can increase survival soon after the Fontan), oxygen saturations may remain lower for some time after the Fontan. This chronic cyanosis could have other pervasive effects on the body. The authors suggest that surgical intervention to close the fenestration might be necessary in some cases. It does seem like much more work about the long-term complications of the fenestrated Fontan are needed.

ii) Because of the altered Fontan circulation, many patients develop liver (hepatic) dysfunction. As was indicated above, patients with Fontan circulation have systemic venous hypertension and what a few studies have found summarized in this paper is that patients with Fontan circulation have venous pressures in or near their liver that may be 3-4 times higher than normal. Over the long-term, this hepatic dysfunction may have some major negative consequences but this is far from understood. However, in the autopsy of patients with Fontan circulation, many of them show signs of liver cirrhosis or other characteristics associated with liver dysfunction. In many cases, the authors indicate, the negative effects of hepatic dysfunction (which start right after the Fontan) are not apparent until 10 years after the Fontan. One future area of research is to identify early signs of hepatic dysfunction potentially using non-invasive measures such as levels of particular metabolites in the blood ore presumably also in the urine or feces. Unfortunately, there is as of yet no real promising avenues to treat hepatic dysfunction in patients with Fontan circulation. However, the authors do indicate that drugs that lower systemic venous pressure could be beneficial and also that combined heart and liver transplant is an option.

iii) Patients with Fontan circulation often die from stroke or thrombosis. This is likely caused by many factors such as changes in blood flow or even the placement of a synthetic material in the heart. Identifying all of the risk factors associated with death from thrombosis is another area of research. Interestingly, the authors state that another study shows that risk of death from thrombosis is similar for patients with the intra-cardiac lateral tunnel or extra-cardiac tunnel (Robbers-Visser et al., 2010 Eur J Cardiothorac Surg 2010;37:934-41) yet there is still no consensus on whether the use of anticoagulation (warfarin) or antiplatelet (asprin) substances are necessary (Canter 2011, J Am Coll Cardiol 2011;58:652-3).

iv) Protein-losing enteropathy has to be the worst diagnosis a patient with the Fontan circulation can receive. PLE essentially means that important proteins are lost and there are many swellings of particular areas of the body. The worst part about it is that it can come on very quick but it can also develop slowly.  The authors indicate that the most common early symptom of PLE is that a child complains their clothes or shoes don’t fit and sometimes they have diarrhea. Doctors than confirm PLE by finding low levels of protein or albumin in the blood and finally showing that a particular protein produced by the liver is excreted in the feces at a high concentration. Why it occurs in some patients with Fontan circulation but not others is not really clear but nonetheless 3-10% of patients with Fontan circulation develop PLE. The causes of PLE are not really known but the low oxygen saturations in the gut may underlie PLE. Treating PLE is complicated and include increasing cardiac output, administration of drugs that are anti-inflammatory (heparin, steroids), or a combination of budesonide (steroid) and sildenafil (again, viagra).

v) Similar to PLE, plastic bronchitis is also a scary but rare side-effect of the Fontan circulation (<1-2% of patients develop it). Airways become obstructed by debris and other substances and the linings of the lungs become inflamed and swell. The cause of plastic bronchitis is also unknown but might be similar to the cause of PLE. Treating plastic bronchitis is still largely experimental and involves drugs used for asthma (inhaled steroids) or mechanical clearing of the obstructions. Cardiac transplantation can also improve the outcome.

vi) Many patients have heart arrhythmias afther the Fontan procedure (the authors say up to 40% of patients). Normal sinus rhythm is disrupted by the Fontan procedure and a fast (tachyarrhythmias) or slow (bradyarrhythmias) can result. The obvious treatment for these heart rhythm problems is to implant a pacemaker or treat through other means such as ablation or drugs (for tachyarrhythmias). The authors indicate that the current consensus indicate that patients with an intra-cardiac lateral tunnel Fontan have a similar risk of developing an arrhythmia as patients with the extra-cardiac Fontan (cite a variety of studies especially Khairy and Poirier, 2012, Circulation 126,2516-2525). Patients that are older at their Fontan procedure tend to have a higher risk of developing heart rhythm problems. Somewhat scarily, atrial tachyarrhythmias may not be very obvious and may cause sudden death, so surveillance for these rhythm problems is important.

3) Now we come to the final category of how patients with the Fontan circulation can die. The final way that may be the most pernicious is through chronic deterioration. As the years tick by after the Fontan procedure, heart function gets worse, which is reflected in the decline in the ability to do aerobic exercise. For example, for patients that had the Fontan early in life, they may have exercise capacity that is highly reduced (44%) compared to normal patients and this capacity to do exercise tends to decline in a linear fashion each year (declines 2.6% each year). At thirty years of age, patients with Fontan circulation have much reduced exercise capacity (55% less than normal) and the number of health problems and hospitalization rates increase dramatically. This is probably not surprising since, again, one ventricle is doing the work of two. How could we increase or preserve cardiac function with age? One way is through drugs such as a recent study showing that children given sildenafil (viagra) for 6 weeks have improved exercise capacity compared to those not given the drug (Goldberg et al., 2011, Circulation 2011;123:1185-93). The obvious solutions are heart transplantation, but again, because the Fontan circulation has already wreaked havoc in the body such as negatively affecting hepatic or kidney function. So patients with Fontan circulation may still be in poor shape even after a heart transplant. The final, seemingly far-fetched, option is to use a mechanical device that assists the heart. As mentioned above, ventricular dysfunction increases with time since Fontan, which could cause chronic failure of the Fontan. One way to improve survival is to use mechanical devices (“Fontan assist device”) that assist blood flow out or into the heart. For example, mechanical devices that increase arterial blood pressure or decrease venous pressure. This is an interesting topic but the authors say that these devices hold promise but only in the distant future.

Link to this paper:

http://dx.doi.org/10.1016/j.cjca.2012.12.009

Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial?

In this article by Silvetti et al. (Europace, in press), the authors report on the results from one hospital in which pacemakers were implanted in 287 patients (1-11 years of age). All of these patients had a congenital heart defect and nearly all of them had underwent at least one heart surgery.

As I will examine in future posts, open heart surgeries (particularly the Fontan using the lateral tunnel approach) may increase the risk of heart rhythm problems such as sinus node dysfunction or atrioventricular block (though the empirical data do not always support these predictions). All of the patients in this study had a pacemaker implanted because of sinus node dysfunction or atrioventricular block. Sinus node dysfunction is a broad term for a variety of abnormal heart rhythm conditions (arrhythmias such as bradycardia or tachycardia where the heart beats too slow or too fast, respectively) associated with a general abnormal functioning of the hearts main internal pacemaker (the sinus node or sinoatrial node located in the right atrium of the heart). The sinus node generates the electrical pulses required for proper heart function. Unfortunately, during many heart surgeries, the sinus node can be scarred and function abnormally after surgery. For example, during the Fontan surgery using the lateral tunnel technique, the sinus node may be damaged because of sewing a baffle within the right atrium. In an older retrospective study, Manning et al. (1996, Journal of Thoracic and Cardiovascular Surgery 111, 833-840) found that patients undergoing the multistaged Fontan (i.e., what is done in practice today for most children) have a higher probability of having some sinus node dysfunction following the Fontan.

Patients in this study also had atrioventricular block, which occurs when the electrical signals generated in the right atrium (again in the sinus node) do not travel to the ventricles. The ventricles can still beat on their own using their own intrinsic pacing capacity, though at a lower rate.

To treat the sinus node dysfunction or atrioventricular block, a pacemaker was implanted in these patients. Pacemakers can either be implanted through an endocardial (or transvenous) system (117/287 patients, or 40.1% of patients), where the leads for the pacemaker are inserted into a vein and guided to the heart (like a heart catheter procedure). The lead(s) are inserted into the heart (leads on the inside of the heart) and the other end of the wire is placed into a pacemaker, which is placed in a ‘pocket’ of skin that is created in the chest. The endocardial system is common in adults but less so in children. Its advantages are that it can be performed under local anaesthetic. However, the endocardial method may be more risky with children because they have smaller veins (again, this method threads the leads up the veins).

The second way to implant a pacemaker is the epicardial method, which is more common in children (in this study 170/287 patients, or 59%). The epicardial method involves placing the leads into the heart on the outside of the heart (hence ‘epi’) and putting the pacemaker in a ‘pocket’ of skin created in the abdomen. The epicardial method was initially chosen because the lead implantation procedure could compensate for growth in the child without the leads becoming dislodged. The endocardial system is generally chosen for children that have undergone the Fontan procedure because the actual Fontan procedure can make the area requiring pacing inaccessible through the endocardial (transvenous method). The epicardial method requires general anaesthesia and is generally a more complicated procedure (e.g., requiring partial or full sternotomy or thoracotomy) or more unpleasant experiences…

The main results from this study are below. Though remember that this is the experience of one hospital and we need to compare the epicardial vs. endocardial pacemaker techniques among all hospitals performing these approaches to really compare if one approach is ‘better’ than another.

1) Pacemakers fail about 1/3 of the time! They followed these patients 2-10 years after pacemaker implantation. In that time, the pacing system failed 29% of the time. That means 1/3 of all pacemakers implanted failed at some point!

2) The rate of failure for the two different methods over this 2-10 period differed. Pacemakers implanted using the endocardial technique (i.e,. the transvenous technique) failed 13% of the time whereas those using the epicardial technique failed 40% of the time. That is interesting because the epicardial technique is supposedly preferred for implanting pacemakers in infants and children.  The mechanism by which these pacemakers implanted using the epicardial technique is not clear but appears to be because of lead malfunction.

3) Pacemakers implanted at an earlier age tended to fail more often.

Link to this article:

doi: 10.1093/europace/eut029

18 years of the Fontan operation at a single institution

In this study by Dr. Lindsay S. Rogers et al. (2012, Journal of the American College of Cardiology 60, 1018-1025), the authors report their experiences of performing the Fontan operation (palliation) on 771 patients from 1992-2009 at the Children’s Hospital of Philadelphia. The authors recorded a variety of variables about the patient (demographic and anatomical) and the actual surgical procedure (e.g, time on cardiopulmonary bypass, amount of drainage from the pleural – chest – tubes, length of stay, readmission to the hospital following the procedure) and report their findings here.

The interesting part of this study is that they split their analysis into 3 different ‘eras’. Era 1 were Fontan operations performed from 1992-1997 (6 years), Era 2 was 1998-2002 (5 years), and Era 3 was 2003-2009 (7 years). This is important because how patients with a congenital heart defect born in 1992-1993 that had the Fontan procedure may have been treated much differently than those born in 2007-2008 that exhibited the same defect and had the same Fontan procedure. Obviously we hope that science and medical research in general should advance how we treat human diseases and how we perform operations and so it is predicted that outcomes for those born in Era 3 (2003-2009) that had the Fontan procedure may have higher survival rates than those born in Era 1 (1992-1997). This study highlights the shift in treating children with congenital heart defects among these three eras. For example, as the authors indicate, Era 1 (1992-1997) represents a time period when most children were treated with the lateral tunnel type of Fontan (see #1 below for an introduction to this point) , during Era 2 (1998-2002), there was a shift towards using the extra-cardiac conduit method (but still relatively equal number of both method) and routine use of the “modified ultrafiltration” method of cardiopulmonary bypass (see link below) started during this Era 2 (in 1996), and in Era 3 most Fontan operations were performed using the extra-cardiac conduit method (though note that this differs from other hospitals such as C.S. Mott Children’s Hospital – see below). Again, this study highlights the importance of allowing researchers to use such data gathered from children having the Fontan procedure as it allows these types of analyses.

Here are the major findings or those that I find interesting:

1) As Fig. 1 indicates, the number of Fontan procedures performed per year at this hospital ranges from 25-70, not terribly high and somewhat surprising to me. It also shows how the type of Fontan performed has changed dramatically across these years. In Era 1 (1992-1997), most Fontan procedures had the lateral tunnel method whereas in the modern era (2003-2009), most Fontan procedures used the extra-cardiac conduit method. From what I understand, the lateral tunnel method is older (well, introduced in 1987) than the extra-cardiac conduit method (introduced in 1990). The lateral tunnel (LT) procedure involves placing a ‘baffle’ (piece of Gore-tex) inside the atrium. One predicted risk of the LT procedure is an increased chance of developing heart rhythm problems, which might not be surprising given that you are sewing something inside of the atrium. The LT procedure is still used by many major hospitals (e.g., at C.S. Mott Children’s Hospital at the University of Michigan, 92% of Fontan procedures performed from 1992-2007 used the LT method: Hirsch et al. 2008, Annals of Surgery 248, 402-410). The extra-cardiac conduit (literally outside the heart tunnel…) or ECC method basically does not involve sewing this baffle into the atrium and is theoretically associated with decreased postoperative complications. This topic (lateral tunnel vs. ECC) should clearly be a focus of a future blog post as I have a major interest in this area. Moving on…

2) From Era 1 (1992-1997), the median age at Fontan was 2.3 years, whereas it was 2.8 years in Era 3 (2003-2009). This is somewhat surprising given our personal experiences that the age of Fontan has been steadily decreasing over the years. Also, as these authors show, the age at stage 2 surgery (e.g., “hemi-Fontan”) decreased from Era 1 (6.4 months) to Era 3 (5.9 months). It would be interesting to conduct a more fine-grained analysis where we look at how differences in age at Fontan affect other parameters (e.g., do children that have Fontan at 18 months have a different outcome than those at 36 months?). As far as I can tell, most studies that have looked at this break the data up into larger chunks (e.g., Fontan performed >3 years or ❤ years as in Shiraishi et al. (2009, Annals Thoracic Surgery 87, 555-561). In this study by Shiraishi et al. (2009), they found that patients with dominant left ventricle (e.g., having Tricuspid atresia or a very small/reduced right ventricle) that had the Fontan procedure performed before 3 years of age had a higher cardiac index (basically heart performance corrected for variation in body size) at 5 and 10 years after operation and higher peak oxygen consumption (might view this as exercise capacity).

On the other hand, this increase in age at Fontan from Era 1 to Era 3 is likely due to the observation that body weight at the time of the Fontan procedure is a predictor of short- and long-term outcomes. Indeed, weight at Fontan from Era 1 (12 pounds) has increased to Era 3 (12.9 pounds).

3) Perhaps the most important part of this paper is the “outcomes” section. The good news is that only 3.5% of the patients that underwent the Fontan procedure died from 1992-2009 (27/771) and the probability of death of the individual <30 days after the Fontan procedure has declined significantly from Era 1 (9.3% died) to Era 3 (1.2%), though there hasn’t been any improvement in increasing survival <30 days after the Fontan from Era 2 (1.0%) to Era 3 (1.2%).

4) More good news is that duration in the ICU, total time in the hospital, and the frequency of lengthy (>14 days)  pleural effusions (drainage from the chest tubes) has declined from Era 1 to Era 3. Though the average i) ICU duration (2-3 days across Era 1 to Era 3) has not changed from 1992-2009, the variation has changed such that were fewer lengthy stays in the ICU in Era 3 (range of stay was 1-45 days) compared to Era 1 (0-181 days). Similarly, the duration of chest tube drainage in Era 1 (mean was 3 days) was similar to Era 3 (4 days) but again the frequency of chest tube drainage that lasted >14 dyas has declined from Era 1 (28.6%) to Era (17.5%). Moreover, the length of hospital stay has declined from Era 1 (12 days) to Era 3 (8 days) and the frequency of lengthy hospital stays (>14 days) after the Fontan has declined from Era 1 (46.7% of Fontan procedures performed here involved patients staying >14 days after procedure) compared to Era 3 (19.5% patients stayed >14 days after Fontan).

5) The final and important part of this paper is indicating the risk factors that predicted whether patients that had the Fontan procedure died, had lengthy hospital stays or chest tube drainage after the Fontan. For death or Fontan takedown within 30 days of the Fontan procedure, those patients that had longer times on deep hypothermic circulatory arrest had an increased probability of dying or Fontan takedown. However, the use of modified ultrafiltration during cardiopulmonary bypass has decreased the risk of death or Fontan takedown, which again is good news and evidence that progress in surgical techniques has benefited patients having the Fontan procedure performed in the modern era. This also highlights the importance of asking your surgeon or their support team how long your child was on cardiopulmonary bypass as it provides some potentially useful information about the future or risks for the future. Also of note, whether patients had the i) lateral tunnel or extra-cardiac conduit method of the Fontan and ii) whether fenestration was or was not used did not affect the risk of death or Fontan takedown within 30 days of the Fontan, though this is again only 30 days after the Fontan and we need to know more about the long-term outcomes of these different procedures.

6) Because the authors found that those patients with longer support times (basically longer cardiopulmonary bypass time) had longer hospital stays and longer periods of chest tube drainage after the Fontan, they also investigated what factors of the patient affected total support time. They found that patients that were larger at the Fontan had longer total support times and that those patients that had the extra-cardiac conduit method also had longer total support times. These are interesting results when comparing the benefits and costs of the lateral tunnel vs. extra-cardiac conduit method as well as the age (and weight) at which to perform the Fontan procedure. However, the longer total support time and the longer time on deep hypothermic circulatory arrest (see above) likely just reflect that the surgery was more complicated because of a complex heart defect. The authors do indicate that their results suggest that the extra-cardiac conduit method is associated with greater short-term complications (longer chest tube drainage and hospital stay duration because of longer total support time) but the preferential use of this procedure over the lateral tunnel method is because it is thought to lower the risk of long-term complications (heart rhythm problems associated with lateral tunnel methods). Yet, we need to see those data showing a reduction in heart rhythm problems in order to justify the conclusion that the extra-cardiac conduit method has long-term benefits compared to the lateral tunnel method!

7) The final and interesting point of this paper is found in Table 9, which summarizes the post-operative outcomes from several similar studies using data collected from several hospitals that commonly perform these procedures (e.g., Children’s Hospital of Philadelphia, C.S. Mott Children’s Hospital at the University of Michigan, Children’s Mercy Hospitals and Clinics in Kansas City, Children’s Hospital of Wisconsin, Children’s Hospital in Boston,  etc.). What is interesting here is that you might make some comparisons among the different studies (and really hospitals) for mortality rates, hospital stay times, bypass times, etc. Though I will resist making comparisons here because really it isn’t good science to make comparisons when the hospitals and surgeons take in different numbers of patients (some do more than others) and take in patients with varying degrees of difficulty (who may have higher mortality rates). For example, at the Children’s Mercy Hospitals and Clinics in Kansas City, surgeons performed 145 Fontan procedures (all nonfenestrated, extra-cardiac conduit method) from 1997-2008 and 5.5% of those patients died and 2.8% of those patients had Fontan takedown. In contrast, at Children’s Hospital of Wisconsin in Milwaukee, surgeons performed 256 Fontan procedures (fenestration used selectively) from 1994-2007, 2.0% of those patients died and 0.8% of those patients had Fontan takedown. These differences may or may not be statistically different from one another and we do not know if the degree of complexity of the defects treated at the two hospitals differ from one another.

Link to this paper:

http://dx.doi.org/10.1016/j.jacc.2012.05.010

Link to information about Modified Ultrafiltration during cardiopulmonary bypass:

http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/anesthesia/site/content/v04/040064r00.htm