Are ACE inhibitors like enalapril and captopril beneficial?

Introduction

From our personal experiences (which of course may or may not be the norm), enalapril or captopril are drugs that are commonly prescribed following heart surgeries for children with congenital heart defects. The focus of this blog is for us to understand why these drugs are prescribed and what the evidence says about whether or not they are helpful for patients with congenital heart defects.

Enalapril and captopril are both angiotensin-converting enyzme (ACE) inhibitors. Angiotensin is an enzyme that causes blood vessels to constrict (“vasoconstriction”), which can raise blood pressure. Drugs like enalapril and captopril inhibit the action of this enzyme angiotensin and therefore prevent vasoconstriction and instead cause the blood vessels to relax or dilate (“vasodilation”). Both drugs can be prescribed to adults for high blood pressure (hypertension), are also prescribed to adults for preventing heart failure after they have had a heart attack, and are often used (successfully) for children or adults that show signs of congestive heart failure (e.g., Rosenthal et al., 2004, J Heart and Lung Transplantation 23, 1314-1333).

Why are these Drugs Prescribed?

One of the issues present with some patients with congenital heart defects, especially in patients following the Fontan procedure, 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 (discussed to some degree here). One way to increase blood flow to the lungs is to dilate the arteries going to the lungs. Because ACE inhibitors like enalapril and captopril are vasodilators, they have theoretical merit in being used for children with congenital heart defects and in those that have Fontan circulation. The theoretical merit is that they would dilate the pulmonary arteries thereby increasing blood flow to the lungs.

A second issue common in patients with Fontan physiology is that there is increased resistance in the blood flow around the body (systemic circulation). This could of course be because patients with Fontan physiology often exhibit low cardiac output where they have a lower total amount of blood flow pumped by the heart compared to those with structurally normal hearts (see here). However, it could also be because there are increased activity of substances that cause vasoconstriction. One way to relax the blood vessels and the flow of blood through the “tubes” in the body is to use ACE inhibitors like enalapril or captopril, which again should theoretically reduce the “vascular resistance” and hasten the flow of blood throughout the body.

A Helpful Solution?

Because ACE inhibitors like enalapril and captopril dilate the pulmonary arteries and should theoretically increase blood flow to the lungs (first ‘problem’ above) and decrease vascular resistance (second ‘problem’ above), they have often been prescribed to patients waiting for the Fontan procedure or with Fontan physiology.

First Study: Randomized double-blind, placebo-controlled studies (the gold standard experiment in medical research) are extremely rare in patients with congenital heart disease. However, one such study was done >15 years now regarding the effects of the use of enalapril on patients with Fontan physiology. Kouatli et al. (1997, Circulation 96, 1507-1512) used a randomized double-blind, placebo controlled study to investigate how enalapril affected the exercise capacity of patients after they had undergone the Fontan procedure. As we have discussed elsewhere, exercise capacity seems to be an extremely important trait in assessing how patients with Fontan physiology are currently doing as well as predicting how they will do in the future (see here). In addition, previous studies in adults show that ACE inhibitors in children and adults without congenital heart defects can improve their exercise capacity (e.g., Kramer et al., 1983 Circulation 67, 807-816; Lloyd et al., 1989 J. Pediatrics 114, 650-654).

In this study, patients (18 of them) were at least 8-27 years of age, had undergone the Fontan procedure from 1984-1994 and from 4-19 years before this study, and were able to exercise, did not have congestive heart failure, or protein-losing enteropathy, and were not dependent on ACE inhibitors. Before the study, they had the patients undergo a routine exercise test where they pedal a seated cycle until the point of exhaustion. They also measured characteristics of their overall heart function prior to exercise (‘baseline’ levels). They measured several variables before and during the exercise test including arterial oxygen saturation, heart rate, respiratory rate, blood pressure, and cardiac output (total volume of blood being pumped by the heart). The patients also underwent an echocardiogram. They gave patients a single dose of enalapril adjusted for weight or a placebo each morning for 10 consecutive weeks. They then did the same exercise test again 10 weeks later where they measured these characteristics of heart function at baseline and during exercise. They found that enalapril had no beneficial effects on any aspect baseline measurements or on exercise capacity or performance. Those patients that had taken enalapril did not differ in their heart rate, respiratory rate, blood pressure, arterial oxygen saturation, cardiac output, and other measures before (baseline) or during exercise compared to those taking the placebo. Somewhat surprisingly, patients that had been taking enalapril actually had reduced cardiac index (amount of blood flow pumped by heart controlled for variation in body size) during exercise compared to those taking the placebo. Basically, during exercise, the cardiac index is going to increase compared to baseline as your heart starts to work harder it pumps more blood. What they found was that the cardiac index of patients that had been taking enalapril did not increase as fast from baseline to during exercise compared to those taking the placebo. There was also no obvious improvement or change in heart function between patients taking enalapril or placebo using the echocardiogram results.

This is of course a very small study (18 patients) and the authors discuss how they may have not used a high enough dose of enalapril or administered it for long enough to detect any positive effects of enalapril on heart function. Additionally, the presence of side-effects in patients taking enalapril was similar to those taking the placebo, suggesting that taking enalapril did not have any negative effects but it also did not have any positive effects at least on these variables measured.

Second Study: Endothelial dysfunction is thought to be a sign that eventually leads to a variety of heart disorders in children and adults that do not have congenital heart defects. Moreover, patients with Fontan physiology can show endothelial dysfunction where the lining of the inside of blood vessels (‘endothelium’) acts abnormally. Patients with Fontan physiology tend to have reduced exercise capacity (see here) and a more recent study suggested that endothelium dysfunction may underlie some of this reduced exercise capacity (Inai et al., 2004, Am J Cardiol 93, 792-797). In this study by Inai et al. (2004), patients with Fontan physiology had abnormal endothelium functioning where they had an impaired ability to dilate their blood vessels. Patients with Fontan physiology with a lowered ability to properly dilate their blood vessels also fared poorly during exercise. This is of course likely because during exercise, the blood vessels dilate to saturate the working muscles with oxygen. Not being able to properly oxygenate working muscles during exercise because of endothelium dysfunction may generate the reduced exercise capacity observed in patients with Fontan physiology.

In another study, Jin et al. (2007, Int J Cardiology 120, 221-226) examined if administration of the ACE inhibitor to patients with Fontan physiology could improve their endothelium functioning (ability to dilate blood vessels during exertion) and thereby improve their exercise capacity. They enrolled 44 patients aged 5-29 years that had Fontan physiology and 25 health controls aged 5-27 years. 61% of the patients with Fontan physiology were taking an ACE inhibitor like enalapril (50%) or captopril (11%). In agreement with the previous study by Inai et al. (2004), 22% of  the patients with Fontan physiology had endothelium dysfunction (inner lining of blood vessels did not dilate appropriately) and 34% of patients with Fontan physiology had both endothelium and smooth muscle dysfunction (whole blood vessel did not dilate appropriately). In support of the idea that taking ACE inhibitors is beneficial for patients with Fontan physiology, Jin et al. (2007) found that patients taking enalapril had better endothelium functioning than those with Fontan physiology that were not taking enalapril (though the difference was not statistically significant). This study, though again a quite small study, indicates that patients with Fontan physiology can have improved functioning of circulatory performance by taking an ACE inhibitor like enalapril.

Summary

These results from only two studies are interesting but the theoretical advantages of taking enalapril and captopril seem to outweigh any negative side-effects, at least with respect to how these drugs are currently prescribed. Drugs like enalapril and captopril are commonly prescribed to patients with congenital heart defects even though there is little scientific evidence that chronic use of these substances by patients with Fontan physiology has beneficial effects. For example, in a recent survey of 546 children aged 6-18 years that had undergone the Fontan procedure at 7 major centers in North America (Pediatric Heart Network), 58% of them were taking an ACE inhibitor like enalapril or captopril upon enrollment in the study (Anderson et al., 2008 J Amer Coll of Cardiology 52, 85-98). Presumably, doctors believe that the beneficial effects of ACE inhibitors are present but undetectable or not yet discovered because of the lack of appropriate medical studies. However, apparently some doctors at some of the hospitals in the Pediatric Heart Network recognize the little evidence that there is in the use of ACE inhibitors as the prescription of ACE inhibitors by patients at these 7 major hospitals in North America can vary from ~30% of patients to ~80% of patients taking an ACE inhibitor (Anderson et al., 2010 Pediatric Cardiology 31, 1219-1228).

The relative lack of scientific evidence showing that ACE inhibitors like enalapril or captopril are beneficial for patients with Fontan physiology highlights that their use and prescription seems to be guided by other scientific evidence that these substances are beneficial for patients with heart failure caused by reasons other than a congenital heart defect. Basically, because ACE inhibitors seem to help middle-aged men with heart problems (Rosenthal et al., 2004, J Heart and Lung Transplantation 23, 1314-1333), they are prescribed for children or adults with Fontan physiology. Clearly more work needs to be done in this area to understand the costs and benefits of chronic use of ACE inhibitors and all other medications taken by patients with Fontan physiology.

This blog doesn’t suggest that patients with congenital heart defects stop taking ACE inhibitors. All it does is explore why these drugs are prescribed and what the evidence says about their effects.

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Exercise capacity: a predictor of mobidity and mortality?

In this paper by Diller et al. (2010, European Heart Journal 31, 3073-3083), the authors report the outcomes of 321 patients that underwent the Fontan procedure from 1997-2008 in four major hospitals in Europe.

The Importance of Exercise Capacity in Patients with Congenital Heart Defects

One of the major advancements of this study was that the authors not only recorded the fate of these patients but they also measured exercise capacity of these patients to see whether it affected their probability of dying, needing a heart transplant, or risk of hospitalization. This is an important advancement because recent studies have suggested that exercise capacity for patients with congenital heart defects (including those that have undergone the Fontan procedure) can be predictive of future survival as well as future medical issues.  For example, in 335 adult patients with various congenital heart defects (average age 33 years), exercise capacity was much lower than other individuals of the same age and was actually similar to adult patients that had heart failure that was not caused by a congenital heart defect (Diller et al., 2005, Circulation). By exercise capacity, I mean maximal oxygen consumption (“VO2 maximum”) that is measured during a cardiopulmonary exercise test that takes place on treadmill. Other traits during exercise are also measured of course but VO2 maximum is thought to reflect the overall physical condition (especially cardiovascular condition) and capacity for physical exertion of an individual. For example, VO2 maximum is very high in endurance athletes like runners or cyclists. This early study by Diller et al. (2005) was surprising because many adult patients with congenital heart defects did not report to the investigators that they actually experienced limitation during exercise or other periods of physical exertion yet they clearly showed it in their depressed VO2 maximum values.

In this study by Diller et al. (2010), the authors located 321 patients from Europe with various congenital heart defects that had the Fontan procedure 1997-2009 in 4 hospitals in Europe (German Heart Center in Munich, Royal Brompton Hospital in London, University Hospital in Bologna, and Great Ormand Street Hospital in London). They performed cardiopulomonary exercise testing to measure VO2 maximum and a variety of other characteristics reflecting exercise capacity during a standardized exercise trial on a treadmill. They followed these patients for an average of 21 months after exercise testing, though some patients were followed as short as <14 months and others >42 months. They recorded whether these patients were hospitalized, died, or underwent heart transplantation.

Major Findings of this Study by Diller et al. (2010)

1) Exercise capacity (VO2 maximum) was not affected by whether patients had the lateral tunnel/intra-cardiac Fontan or the extra-cardiac Fontan. Though it is important to note that a formal statistical analysis was not presented here.

2) VO2 maximum during exercise testing was highly reduced compared to normal patients. As expected and other studies have found (see below), VO2 maximum during exercise was highly reduced compared to what would be expected for a patient at that same age without the Fontan procedure. Actually only <3% of patients had what would be considered a normal exercise capacity (VO2 maximum) based upon the calculations of the authors.

3) VO2 maximum was not significantly related to probability of death or need for heart transplantation but heart rate reserve was. Unlike previous studies (see below), VO2 maximum was not related to the probability of death or need for a heart transplant but patients with lower heart rate reserve (which is the peak heart rate during exercise minus the resting heart rate) had a higher chance of dying or needing a heart transplant during follow-up. However, it is important to note that relatively few patients died (22 patients out of 321) or needed a heart transplant (6 patients out of 321) so these comparisons might not be the best given you are comparing the physiological values of one very small group (28 patients) compared to another much larger group (283 patients). Also, when the authors compared patients that were followed for a minimum of 3 years, they found that there was no effect of exercise capacity on probability of death or need for cardiac transplantation.

4) Patients with low exercise capacity (low VO2 maximum, low heart rate reserve, etc.) were more likely to be hospitalized during follow-up. The authors found that 41% of patients were hospitalized for a heart related issue during the follow-up period. Those patients with low VO2 maximum during exercise testing and low heart rate reserve (again peak heart rate during exercise minus resting heart rate) were more likely to be hospitalized for a heart related issue during follow-up.

Summary of Effects of Exercise Capacity on Survival and Health of Patients with Congenital Heart Defects

This study by Diller et al. (2010) adds to the growing number of studies showing that patients with congenital heart defects that ALSO exhibit low capacity for aerobic exercise tend to fare poorly. For example, in separate studies using different patients, Diller et al. (2005) found that adult patients with low exercise capacity (low VO2 maximum) tended to be more likely to be hospitalized or die in the year following exercise capacity testing (see also Dimopoulos et al., 2006 Circulation 113, 2796-2802). In a later study but with a longer follow-up time after testing of exercise capacity (28 months after testing), those with low exercise capacity (again low VO2 maximum) had a higher probability of dying in the subsequent 28 months (Diller et al., 2006 J American Coll of Cardiology 48, 1250-1256). In this same study by Diller et al. (2006), the authors also found that patients whose heart rates didn’t respond appropriately to exercise (i.e., dramatically increase immediately following the start of exercise) had a higher probability of dying in the subsequent 28 months. These studies along with the results from Diller et al. (2010) that I discussed above strongly link the  inability of the heart to perform properly during exercise for patients with congenital heart defects is unfortunately linked with an increased risk of future medical complications (reflected in increased hospitalization rates for heart related issues) or death.

Obviously these results don’t suggest that a low VO2 maximum or low heart rate reserve or other marker of exercise capacity is equivalent to an increased risk of death for ALL patients. One question that I have based upon these studies is what is known about the effects of preventative care for patients with congenital heart defects? For example, to conclusively test that exercise capacity does in fact contribute itself to increased risk of death or hospitalization rather than simply reflecting overall poor condition, future studies would need to identify groups of patients with variable exercise capacity. If half of these patients did moderate and regular exercise like walking that might increase exercise capacity, would they fare better than the other half that did not engage in such moderate exercise? I don’t know but that would be interesting to identify if we can improve outcomes by increasing exercise capacity. The major goal here would be to see how we can increase exercise capacity and that has beneficial outcomes in the short- and long-term. Interestingly, recent studies where patients with the Fontan physiology were provided with sildenafil (viagra) showed increased exercise capacity (e.g., Giardini et al., 2008 European Heart Journal 29, 1681-1687). Obviously this needs much more study to understand the costs and benefits of administering sildenafil to patients with Fontan physiology. However, this is currently a promising and interesting start to understanding if increasing exercise capacity lowers the risk of hospitalization or probability of death.

Costs and Benefits of the Fenestrated vs. Non-fenestrated Fontan Procedure

Introduction

The Fontan procedure was developed so that the heart could function and distribute oxygenated blood around the body without the need for two ventricles. As I have discussed previously (see here and here), today the Fontan procedure is done through a lateral tunnel/intra-cardiac route or an extra-cardiac route. Here is a nice image depicting what these two procedures look like.

The Fontan Operation
Extra-cardiac Fontan on the right and Fenestrated intra-cardiac/lateral tunnel Fontan on the left.
In the lateral tunnel/intra-cardiac route for the Fontan procedure, a piece of plastic (‘baffle’)  is built in the right atrium to direct the deoxygenated blood coming from the lower part of the body (via the inferior vena cava) to go directly to the lungs. One major development that was first described in 1990 to refine the lateral tunnel/intra-cardiac Fontan was the creation of a small hole called a ‘fenestration’ in the baffle during the Fontan procedure (Bridges et al., 1990, Circulation 82, 1681-1689). As the image below shows, a small hole/fenestration is created in the baffle in the right atrium (indicated by the arrow with #2)..

diagram 2.23 - Stage 3 of hypoplastic left heart syndrome reconstruction

This image highlights the fenestration (small hole) created in the baffle in the right atrium (indicated by #2 with arrow).

This ‘fenestrated Fontan’ as it is commonly called today was described by Bridges et al. (1990). The goal of the fenestration was to try and lower the risk of mortality in the period of time soon after the Fontan surgery. At that time, high blood pressure in the right atrium (where the baffle was placed) and low cardiac output (basically the total amount of blood pumped by the heart) was a predictor of mortality in the post-operative period. That is, patients with high blood pressure in the right atrium or low cardiac output were more likely to die soon after surgery. Bridges et al. (1990) proposed that some of this pressure in the right atrium could be ‘relieved’ and cardiac output increased by creating a small hole in the baffle in the right atrium. They thought that this fenestration would relieve some of this pressure and increase cardiac output, which could potentially decrease mortality rates soon after the surgery. However, of course this fenestration would also cause right-to-left shunting where deoxygenated blood in the right atrium mixes with oxygenated blood in the single ventricle, which would of course lower blood oxygen concentrations leaving the heart. Bridges et al. (1990) proposed and treated patients with these fenestrated Fontan’s by closing the hole in the baffle during a heart catheterization 3-12 months after the Fontan surgery or letting the hole close spontaneously on its own.

How Common is the Fenestrated Fontan?

The creation of a fenestration in the baffle during both lateral tunnnel/intra-cardiac or extra-cardiac Fontan procedures is now extremely common. For example, from 1992-2002, of all the Fontan procedures (using both techniques) performed in 7 different hospitals where Fontan procedures are commonly performed (part of the Pediatric Heart Network), over 80% of them created a fenestration (Atz et al., 2011, J of American College of Cardiology 57, 2437-2443). This is not surprising given that the use of a fenestration in the baffle during a Fontan procedure has many positive short-term outcomes (see list below).

Short-term Costs and Benefits of a Fenestrated Fontan

1) Patients with a fenestrated Fontan have a shorter duration of chest-tube drainage. In a well-designed randomized study by Lemler et al. (2002, Circulation 105, 207-212), the authors show that patients at the Children’s Medical Center of Dallas that underwent a fenestrated Fontan (25 patients) had significant drainage from chest tubes (that is post-operative pleural effusions) for an average of 10 days (range was 5-62 days) whereas patients that underwent a non-fenestrated Fontan (24 patients) had significant drainage from chest tubes for an average of 16 days (range 3-45). Similarly, patients that had a fenestrated Fontan had significantly less total drainage from the chest tubes (measured in volume) than those that underwent the non-fenestrated Fontan. This study supports an earlier one by Bridges et al. (1992, Circulation 86, 1762-1769) that also shows that the duration of chest tube drainage is reduced by using a fenestrated Fontan procedure in high-risk patients.

2) Patients with a fenestrated Fontan have a shorter length of hospital stay after the surgery but no difference in time spent in the intensive care unit. Bridges et al. (1992) and Lemler et al. (2002) both show that patients that underwent a fenestrated Fontan procedure stayed in the hospital after the Fontan procedure for a shorter amount of time than those that underwent the non-fenestrated Fontan. For example, Lemler et al. (2002) showed that patients that underwent the fenestrated Fontan stayed in the hospital after the surgery for an average of 12 days (range was 6-26 days) whereas those that underwent the non-fenestrated Fontan stayed in the hospital after the surgery for an average of 23 days (range was 5-64 days). In contrast, the use of a fenestration didn’t affect how long patients spent in the intensive care unit after the Fontan.

3) Patients with a fenestrated Fontan have lower oxygen saturations after the surgery. As mentioned above, a major benefit of the fenestrated Fontan is that cardiac output (amount of blood pumped by the heart) is increased but this comes at a cost of the mixing of deoxygenated blood from the right atrium with oxygenated blood in the single ventricle. For example, Lemler et al. (2002) found that patients with a fenestrated Fontan had significantly lower oxygen saturations in the post-operative period (average of 90%) compared to those with a non-fenestrated Fontan (average of 93%). Though, it should be noted that the range of oxygen saturations in the non-fenestrated group was quite high (66-98%) compared to the fenestrated group (81-96%) suggesting that the difference when looking at averages was much higher if the patient with an oxygen saturation of 66% was dropped from the analysis.

5) Patients with a fenestrated Fontan were taking more medications at hospital discharge compared to those with a non-fenestrated Fontan. Atz et al. (2011) found that patients with a fenestrated Fontan (361 patients) were more likely to be taking an ACE inhibitor (e.g., captopril or enalapril) and anti-thrombotic drugs (e.g., asprin, warfarin) at hospital discharge after the Fontan than those that had a non-fenestrated Fontan (175 patients). However, this could be because of differences among the hospitals such as one hospital always performing fenestrated Fontan’s and always providing patients with an ACE inhibitor and asprin at discharge.

6) Do patients with a fenestrated Fontan have an increased risk of stroke? It has been suggested that patients with a fenestrated Fontan may have an increased risk of stroke, though this hasn’t been supported by previous studies. For example, one of the first studies (du Plessis et al. 1995 Pediatric Neurology 12, 230-236) documenting this potential increased risk of stroke from a fenestrated Fontan showed that of the total of 314 that underwent the Fontan procedure at the Boston Children’s Hospital from 1989-1993, a total of 209 patients had a fenestrated Fontan. Out of all of these patients, 10 of them had a stroke where 9 out of 209 patients with a fenestrated Fontan (4.3%) compared to only 1 patient with a non-fenestrated Fontan having a stroke (1/105 patients or 0.95%). This difference was not statistically significant and it also reflects that patients in the fenestrated Fontan group may have already been at a higher risk for stroke prior to the procedure. More recent studies, however, do not find that patients with a fenestrated Fontan have an increased risk of stroke compared to patients with a non-fenestrated Fontan (e.g., Coon et al., 2001, Annals Thorac Surg 71, 1990-1994; Atz et al., 2011).

Long-term Costs and Benefits of a Fenestrated Fontan?

Although the fenestrated Fontan is commonly used today, whether or not it is used seems to be highly dependent upon where the Fontan procedure is done. For example, the percentage of patients that had a fenestrated Fontan can vary from 13-91% at 7 major hospitals in North America  (Atz et al., 2011). That is highly variable! Why might some surgeons always perform fenestrated Fontan’s while others choose not to create a fenestration during the Fontan procedure especially when there are such obvious short-term benefits during the post-operative period?

Well, what do we actually know about the long-term costs and benefits of a fenestrated Fontan? As mentioned above, the creation of the fenestration allows the deoxygenated blood from the right atrium to mix with the oxygenated blood in the single ventricle, which consequently can lower blood oxygen concentrations that leave the heart. Some researchers have suggested that the use of a fenestration is not a preferred option for some surgeons because there is little scientific evidence that it is beneficial in the long-term (Gersony (2008, Circulation 117, 13-15; de Laval and Deanfield 2010, Nature Reviews Cardiology 7, 520-527). This is primarily because the long-term impacts of a fenestrated Fontan are relatively unknown. Let’s look at what we do know about the long-term impacts of a fenestrated Fontan. In a recent study by Atz et al. (2011), they compared the medical status of patients that had underwent a fenestrated Fontan where the fenestration was either still open or had been closed (either spontaneously or during a heart catheterization).

1) Patients with a fenestrated Fontan may have an increased risk of death, stroke, heart transplant, etc. from 1-10 years after the Fontan procedure compared to those with a non-fenestrated Fontan. Tweddell et al. (2009, Ann Thorac Surg 88, 1291-1299) compared the fate of patients that underwent either a fenestrated Fontan (217 patients) or a non-fenestrated Fontan (38 patients) from 1994-2007 at the Children’s Hospital of Wisconsin. For these 38 patients, the fenestration that was originally present was closed in the operating room based upon the judgement of the surgeon. Interestingly, Tweddell et al. (2009) found that the patients with the fenestrated Fontan had a higher incidence of Fontan failure compared to those with a non-fenestrated Fontan. Here, Fontan failure was basically defined as the patient dying, needing a heart transplant or pacemaker, developing protein-losing enteropathy, or having a stroke. From 0-4 years of after the Fontan procedure, the incidence of Fontan failure was similar between patients with fenestrated and non-fenestrated Fontan’s. However, around 4 years after the Fontan procedure had been performed, patients with a fenestrated Fontan tended to have a higher incidence of Fontan failure. Although this study cannot confirm that fenestration resulted or caused this increase in Fontan failure, it is a highly interesting result given how often the fenestrated Fontan is performed.

2) Patients with a fenestrated Fontan have lower resting oxygen saturations than those in which the fenestration is closed. Atz et al. (2011) showed that of patients with a fenestrated Fontan (hole did not spontaneously close or wasn’t closed during a heart catheterization) had significantly lower oxygen saturations (average was 89%) compared to patients in which the fenestration was closed (average of 95%). This suggests that in terms of increasing blood oxygen saturations, closing the fenestration may be beneficial (see also Goff et al., 2000, Circulation 102, 2094-2099).

3) Few other long-term costs of a fenestrated Fontan have been documented. Atz et al. (2011) found that patients with a current fenestration compared to those with a closed fenestration did not differ in their overall health status, exercise performance, occurrence of stroke or protein-losing enteropathy, or body growth. Moreover, a previous study supports some of these results where patients with a fenestrated Fontan had a similar exercise capacity as did those with a non-fenestrated Fontan (Meadows et al., 2008, J Am Coll Cardiol 52, 108-113). This contrasts those results from Tweddell et al. (2009) at least in terms of documenting why patients with a fenestrated Fontan may have a higher incidence of Fontan failure. Essentially, there were few differences between patients with fenestrated and non-fenestrated Fontan’s.

Should the Fenestration be Closed?

Atz et al. (2011) found that around 40% of 361 patients that underwent a fenestrated Fontan had their fenestration close spontaneously. Many doctors recommend closing the fenestration at some time interval after the Fontan procedure. There may be specific benefits for closing the fenestration related to blood oxygen saturations. For example, Goff et al. (2000) found that 154 patients that underwent successful closure of the fenestration during a heart catherization had an increase (9.4% on average) in oxygen saturation when measured from 0.4-10.3 years after the fenestration closure. As indicated above, Atz et al. (2011) also found that patients in which the fenestration was closed also had higher blood oxygen saturations. These increases in blood oxygen saturations may be associated with favorable outcomes for body growth. For example, Goff et al. (2000) found that patients in which the fenestration was closed rose in their height and weight percentiles compared to what they were prior to closing the fenestration suggesting that closing the fenestration is associated with an increased rate of body growth. On the other hand, Atz et al. (2011) did not really find that there was many benefits associated with closing the fenestration other than increasing blood oxygen saturations. So is it worth it to have the fenestration closed? The current evidence suggests that there are some major benefits in terms of increasing blood oxygen saturations but few other benefits. Obviously this needs more study and we cannot make conclusions based upon one study.

Conclusion. It is somewhat surprising that most patients that undergo the Fontan procedure now have a fenestrated Fontan regardless of whether they have an intra-cardiac/lateral tunnel or extra-cardiac Fontan. This is surprising because although a fenestrated Fontan obviously has beneficial outcomes in the short-term (reducing duration and amount of chest tube drainage, reduced hospital stay), we still know very little about the long-term consequences of a fenestrated Fontan. In fact, some have now questioned whether fenestrations should always be performed and advocated the adoption of a patient-specific approach where only ‘high-risk’ patients undergo a fenestrated Fontan (Gersony, 2008). Second, the evidence is not clear regarding whether we should always be closing the fenestration later in life or even when the fenestration should be closed (i.e., how many years after the Fontan?). Some have even argued that closing the fenestration during a heart catheterization is not worth the risks even if they are low (discussed in Goff et al., 2000) and this is not surprising because the evidence at present doesn’t show that there are substantial benefits of closing the fenestration other than increases in blood oxygen saturations (Atz et al., 2011). Not discussed at length here is the fact that the presence of a fenestration can increase cardiac output (Bridges et al., 1990), which could decrease after the fenestration is closed. Given that the use of a fenestrated Fontan is highly variable among different hospitals (Atz et al., 2011), it seems wise to be informed about the potential short- and long-term costs and benefits of having a fenestrated vs. non-fenestrated Fontan. Clearly more work needs to be done here.

A genetic basis for congenital heart defects?

In a previous blog, I discussed some of the potential environmental causes of congenital heart defects (see here). Is there also a genetic basis to congenital heart defects? Surely there is some genetic component given that ~13% of patients with a congenital heart defect have a chromosomal abnormality (Hartman et al., 2011 Pediatric Cardiology) and congenital heart defects appear to be inherited within families (Oyen et al., 2009 Circulation 120,295-301). Yet, there is still very little known about the genetic or environmental causes of congenital heart defects.

Here is a brief review of what we know now about the genetic causes of congenital heart defects:

1) Chromosomal abnormalities are associated with congenital heart defects. Perhaps the most well known and most understood of the potential ’causes’ of congenital heart defects are chromosomal abnormalities. In humans, all of our cells have 23 pairs of chromosomes (so a total of 46). The different pairs of chromosomes can be ordered from largest to smallest and are numbered (1-22) plus the XX or XY chromosomes (the sex chromosomes or chromosome 23). When sperm or egg cells are being produced by the process of meiosis, each sperm or egg cell (‘germ cells’) should get 23 chromosomes (so the pairs split in half). However, sometimes the pair of chromosomes won’t split and the sperm/egg cell gets an extra chromosome or one of the sperm/egg cells is missing that specific chromosome. These extra (trisomy) or missing (monosomy) chromosomes are called ‘aneuploidies’ and they are the most well known type of chromosomal abnormality that is associated with congenital heart defects are aneuploidies. For example, Trisomy 21 (Down’s Syndrome) is caused by having 3 chromosomes at the 21st position. There are also other types of chromosomal abnormalities that do not involve the addition or subtraction of whole chromosomes. For example some chromosomal abnormalities, such as 22q11.2 deletion, only involve the subtraction of specific parts of a chromosome, in this case a small part of the 22 chromosome.

The exact proportion of individuals with a congenital heart defect that also exhibit a chromosomal abnormality is not entirely known with exact clarity but recent studies estimate that it is around 12% (e.g., Hartman et al., 2011 Pediatric Cardiology 32, 1147-1157). There are, of course, many different types of chromosomal abnormalities and different types of congenital heart defects may be associated with different types of chromosomal abnormalities. For example, in a study of 547 patients with congenital heart defects born near Atlanta, Georgia from 1994-2005 that also exhibited a chromosomal abnormality, ~53% had trisomy 21, ~13% had trisomy 18, ~12% had 22q11.2 deletion (also called DiGeorge Syndrome), and ~6% had trisomy 13 (Hartman et al., 2011). Moreover, there were associations between the congenital heart defect and whether the patient also exhibited a congenital heart defect. For example, for patients with an interrupted aortic arch or atrioventricular septal defect, 67-69% of them also had a chromosomal abnormality (Hartman et al., 2011).

Chromosomal abnormalities are associated with congenital heart defects, yet only around 12% of congenital heart defects appear to be ’caused’ by them. However, it is also possible that some of these chromosomal abnormalities underlying a congenital heart defect were missed. We have known approximately how many chromosomes humans have for ~100 years now and have been able to visualize and count (a karyotype) the number of pairs of chromosomes for around the same period of time. This can be done in an elementary science laboratory and observing extra or missing chromosomes is quite obvious (the classic cytogenetic techniques). But what about these other types of chromosomal abnormalities such as chromosomal deletions (22q11.2 deletion) or so called microdeletions (7q11.23. or Williams syndrome) that may underlie other congenital heart defects yet they are undetected? New molecular methods that are applied in a clinical setting may improve our ability to detect how often patients with congenital heart defects also exhibit chromosomal abnormalities other than aneuplodies (discussed in Pierpont et al., 2007 Circulation 1015, 3015-3038). Regardless, it would be interesting to know how often patients or the parents of patients with a congenital heart defect are offered more than just a genetic consultation to assess the possibility that a chromosomal abnormality us behind a congenital heart defect.

2) Some congenital heart defects appear to be inherited as they can reoccur within families. In addition to the relatively uniform distribution of wealth, Scandinavian countries have a lot of great things going for them. For example, every child born with a congenital heart defect is registered into a nationwide database, which allows researchers to follow these individuals throughout their lifetime and potentially identify the environmental or genetic risk factors associated with congenital heart defects. One area of research that has benefited from this large database of patients born with congenital heart defects is understanding the recurrence of congenital heart defects within families. If you have a child with a congenital heart defect, is your next child more likely to have a congenital heart defect? Well, it seems to depend on the type of congenital heart defect the first child exhibits. In a large survey of Danish people born from 1977-2005 (nearly 2 million patients!), 18,708 were born with some type of congenital heart defect (Oyen et al., Circulation 2009, 120, 295-301). What was interesting about these data was that within the families of individuals with specific types of congenital heart defects (e.g., heterotaxia, conotruncal defects, atrioventricular septal defects) there was an increased risk of recurrence of that type of congenital heart defect if another family member had also exhibited that congenital heart defect. This study estimated the ‘recurrence risk ratio’, which is a statistical measure of the recurrence of a specific type of disease (in this case congenital heart defect) within a family. You can use the presence/absence of a congenital heart defect within a family (siblings, cousins, etc.) to estimate the recurrence risk ratio. A high recurrence risk ratio means that the disease or congenital heart defect clusters within a family (so it occurs within a family more often than chance). In this study, they found that the recurrence risk ratio for congenital heart defects such as heterotaxia, atrioventricular septal defects, and right ventricular outflow tract obstruction (which includes pulmonary atresia and hypoplastic right heart syndrome) were quite high meaning that families that had one individual with such a congenital heart defect had a higher risk of producing another individual with the same congenital heart defect. However, overall, having a family history within first-degree relatives (that is your parents or older siblings had a congenital effect) was actually quite a low predictor of whether or not the child produced by the parents or the next child (with the older sibling having a congenital heart defect) would also exhibit a congenital heart defect. Only around 2% of patients with a congenital heart defect were attributed to a family history (parents or older sibling having a congenital heart defect). In other words, most families with one individual having a congenital heart defect did NOT produce another child having the same or different congenital heart defect (though sadly some did).

This study by Oyen et al. (2009) suggests two things. 1) There is some clustering within families of congenital heart defects, which could suggest either a shared genetic OR shared environmental cause. It doesn’t necessarily reflect that is inherited genetically as these types of statistical analyses cannot separate the effects of shared genes from a shared environment (e.g., Guo 2002, Am J Hum Genet. 79, 818–819), though as a side note this is likely possible using quantitative genetic analyses if a genetic pedigree was available. 2) The fact that a low proportion of the congenital heart defects (~2%) were attributed to a parent or older sibling also having a congenital heart defect again suggests the role of the early environment in causing congenital heart defects, which the authors discuss.

3) Does a single gene cause a congenital heart defect? There is a lot of hope that we can identify single genes that cause specific diseases (such as congenital heart defects) and somehow identify the presence of these specific genes in patients and mitigate the consequences. Although there has been much progress in this area, there are some major problems and actually few congenital heart defects have been associated with specific genes. Finding a single gene that causes a congenital heart defect relies on the expectation that a single gene has a large effect on some characteristic or trait. This isn’t necessarily true and more and more some have argued that this single gene approach has lost its luster. Most characteristics or traits of individuals are affected by many many different genes all with small effects on that specific characteristic. That makes it difficult to target a specific gene because a mutation in some gene might have a small effect on that characteristic and therefore can be difficult to detect by researchers. However, there are some gene mutations that appear to be highly associated with specific congenital heart defects. For example, a mutation of the gene PROSIT240 that causes changes in the expression of that specific gene in specific areas of the body (heart) may be associated with an increased risk of developing transposition of the great arteries (Muncke et al., 2003 Circulation 108, 2843-2850). Even in this example, however, the evidence implicating this gene being involved in the development of this congenital heart defect is quite weak. Of 97 patients with transposition of the great arteries, only 3 patients had a specific type of mutation in this gene PROSIT240, though admittedly this specific type of mutation wasn’t found in 400 patients without transposition of the great arteries. Clearly there is more work to do in this area but its impact on understanding the development of congenital heart defects remains to be seen.

4) Changes in the expression of genes that ‘build’ the heart early in life? A growing area of research in all scientific disciplines that may help address some of the genetic causes of congenital heart defects is developmental genetics. Developmental genetics focuses on understanding how genes or the interactions of genes and their products affect the growth and differentiation of cells and how these cells become tissues and organs. Basically, how do the cells that eventually become the heart tissue develop? A second area of growing research is how the early environment affects the expression of genes early in life. That is, we know that the production of proteins from specific genes during development that ‘builds’ tissues/organs like the heart, but we also know that the environment experienced early in life can alter the rate of production of those specific proteins during development. These could be broadly called gene (nature) by environment (nurture) interactions. However, there really is no longer a debate about whether a trait is caused by nature or nurture but it is more the interaction of the two (both genes and the environment). Amazingly, the four chambers of the human heart are formed around 32 days into pregnancy and much of the heart anatomy is formed <60 days into pregnancy (for a great animation of this see here). This means that there is ample opportunity for the early environment (that is the environment before most people know that they are actually pregnant) to affect heart development.

An interesting feature of a recent paper about this subject by Bruneau (2008, Nature 451) is describing recent developments in developmental genetics regarding heart formation. That is, our understanding of how the heart develops early in life, including the genes responsible for this development, has recently grown exponentially. The development of the heart involves the complex signaling of many genes early in life. One particularly fruitful area of research in the developmental genetics of congenital heart defects comes from understanding how the transcription rates of genes are involved in heart development. Transcription of a gene is the first step in the expression of a protein from a gene. The details are beyond this blog but if the transcription rate of the specific gene is increased, the amount of protein it produces generally also increases. The opposite is true when transcription of a gene is decreased. There are also genes that produce transcription factors, which can decrease or increase the expression of another gene. Currently, most of our understanding about the developmental genetics of congenital heart defects comes from identifying genes that produce transcription factors that cause structural changes in heart development. For example, the gene TBX5 is a transcription factor that appears to regulate the expression of specific genes involved in early heart development (Bruneau, 2008). Patients with Holt-Oram syndrome that also exhibit congenital heart defects (such as atrial or ventricular septal defects) have a mutation in the TBX5 gene that may alter the expression of genes in the heart during early development that actually causes the congenital heart defect. The important thing here is that these studies and others (reviewed in Bruneau 2008) identify that mutations in transcription factor genes that regulate the expression of other genes involved in early heart development may be important in identifying the causes of congenital heart defects. So it isn’t necessarily a mutation in a specific gene involved in the production of the tissue that forms the heart (discussed above in #3) but it could be a mutation in another gene that regulates the expression of many different genes involved in early heart development. What is even more interesting is that these mutations to transcription factor genes can be inherited but they can also be caused by the environment. I hope to expand on this area in a future blog post.

Conclusion: My conclusion from what I have discussed above is that chromosomal abnormalities are of course associated with congenital heart defects yet the use of more modern detection methods that detect more than just missing/absent chromosomes needs to be increased to fully recognize the importance of chromosomal abnormalities in causing congenital heart defects. Second, the recurrence of some specific types of congenital heart defects within families can be quite high but being a parent with a congenital heart defect or producing a child with a congenital heart defect doesn’t necessarily mean that the child or next child will have a congenital heart defect or the same defect. Third, identifying single genes that ’cause’ a congenital heart defect will be a challenge but identifying how the expression of specific genes that produce the heart early in life is an important future area of research. This is predominately because alterations in the expression of these specific genes can be caused by genetic factors that are inherited but also by environmental factors that disrupt gene expression early in life.

Links to these papers:

http://link.springer.com/article/10.1007/s00246-011-0034-5

http://circ.ahajournals.org/content/115/23/3015.short

http://circ.ahajournals.org/content/120/4/295.short

http://circ.ahajournals.org/content/108/23/2843.full

http://www.nature.com/nature/journal/v451/n7181/abs/nature06801.html

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

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