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:

A 43- to 54-year follow-up of 1000 patients with congenital heart disease

In this paper by Drs. James H. Moller and Ray C. Anderson (The American Journal of Cardiology, 2013, in press, see link below), the authors followed the survival of 994 patients with various congenital heart defects that were evaluated in 1952-1963. These patients were seen by these doctors early in life (infancy or childhood) and then they were followed into adulthood, which is now a time period of 43-54 years! The authors have published similar follow-up studies in the past such as a follow-up ranging from 26-37 years following the initial diagnosis.

This study is not an experiment but simply an observational study where they simply measure various health metrics at regular checks. It may be helpful in predicting what trajectory your child or adult might follow depending upon their condition but remember that in this study, these children were diagnosed in 1952-1963. Luckily for children born more recently that have similar heart defects today, their treatment and diagnosis may be much more advanced and refined than the children that were diagnosed in 1952-1963. I enjoy these types of ‘follow-up’ papers because they help to remove some of the cloud of confusion or lack of clarity on the future for children born today with congenital heart defects.

As the authors indicate, it is surprising and encouraging that ~64% of these patients that were born from 1952-1963 were still alive >50 years after their initial diagnosis. This is encouraging because we can only hope that the treatment for children with the same conditions that are born today will have even higher probabilities of survival due to improved and refined treatment. These types of papers are also important for parents with children with congenital heart defects as well as adults living with congenital heart defects because they demonstrate the importance of voluntarily enrolling in such follow-up studies so that more data and patterns can be identified.

Here is a quick summary of some of the major results of this paper:

1) Around 63% of patients were alive almost 50 years later and risk of death declines after surviving first 10 years of life. This study was based at the Departments of Medicine and Pediatrics at the University of Minnesota in Minneapolis. The authors report information about survival from 994 patients that were diagnosed with a congenital heart defect from 1952-1963. Of these 994 patients, 63.6% (632) were alive as of 31 December 2006 (apparently the date of the last evaluation). For those patients that had died, most of the deaths (57.7% or 209/362 patients) occurred in the first 10 years of life with many (34.5% or 125/362 patients) occurring in their first year of life. For those that survived past 10 years of age, the rate of death was relatively equal for patients in their 20’s, 30’s, 40’s, 50’s, and 60’s (7-10% died in each decade of life). Although it would be preferable to have even lower rates of death, it is interesting to note that the rate of death is about equal for those that reached 20 years of age.

2) Around 1/3 of patients died from cardiac issues. The authors report the cause of death for 130 adult patients (I think this means those that survived until at least 20 years of age, though this is not clear). Perhaps importantly, 40% of these deaths were from non-cardiac issues (cancer, accidents, diabetes, suicide, etc.). For those patients that died through cardiac issues, sudden death was the most common cause (~27%) with congestive heart failure, death while waiting for heart transplant, myocardial infarction (heart attach), cardiac reoperation, etc. having similar frequencies.

3) The probability of survival from birth to 10, 20, 30, 40, 50, 60 years of age was markedly lower for patients that are cyanotic (low oxygen saturations). How cyanosis was measured and the cut-off for the cyanotic group versus the other group is not clear to me.

4) Patients with only a ventricular septal defect, patent ductus arteriosus, or an atrial septal defect (no other condition) actually had a similar probability of survival to normal patients from 0-60 years of age. However, patients that had one of these three conditions plus another defect (not clear what they mean by ‘other anomalies’ here) had a much lower probability of survival from 0-60 years of age.

Link to this paper: