If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

If you are one who avoids giving iron to patients with infection, you will be interested in knowing why Daoud et al argue that giving iron is OK. If you hadn’t thought about it recently, this is an excellent opportunity to consider why there has been concern. And why does the serum iron level drop with infection?

Patients with hemochromatosis, characterized by total body overload of iron, are reported to be at risk of overwhelming infection from Vibrio vulnificus. This may well hold true for patients with chronic severe liver disease of other etiologies as well. Vibrio and certain other bacteria (Listeria, Yersinia, Legionella) can demonstrate rapid growth and increased intracellular resistance to killing in the setting of excess iron. Macrophages, in the setting of chronic infection or inflammation, retain excess iron, which may reduce their bactericidal functions. Thus, there has been concern about iron supplementation (including transfusion) in the setting of infection, even in patients with low iron levels and anemia.

The circulating level of the liver protein hepcidin increases as part of the acute-phase response to infection, perhaps with the physiologic “goal” of reducing the availability of free iron to microbial invaders. Hepcidin binds and blocks the function of the membrane iron exporter ferroportin, and iron is functionally trapped within intestinal enterocytes (reducing its absorption) and macrophages (reducing its availability to erythrocyte precursors).

For some of us out of medical school for more than 10 years, the work of Ganz and others^1,2 describing the seminal role of hepcidin in iron metabolism may be only partially known. The short article by Daoud and colleagues may urge us to read more about the pathophysiologic foundation of a clinical conundrum. I hope so, for it is that urge to understand that helps define our professional identity as physicians.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.¹

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.^2,3 Other important causes include nutritional deficiencies (iron, vitamin B₁₂, and folic acid)⁴ and blood loss.^5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.¹

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards⁷ to 95% in intensive care units.⁸

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.⁹ Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.^10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.² The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.^1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.^10,12 Pieracci et al¹³ documented these benefits in critically ill surgical patients, whereas van Iperen et al¹¹ did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors^1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.¹⁵

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.¹⁶ Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.¹

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.¹⁶

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,¹⁵ while chronically it might be related to enhanced atherosclerosis and cardiac disease.¹⁶

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.¹⁵ Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.^17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.^15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.²⁰ A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.^21–26 Multiple studies^{13,19,21,22,25–27} found no relation between iron therapy and risk of infection or death.

Canziani et al²³ found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al²⁴ found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,²⁷ in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.^15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.²⁸

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors^{1,15,16,18,19,29} that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - More and more patients with congenital heart disease are surviving into adulthood, resulting in a growing number of operations performed to repair adult congenital heart disease (ACHD). Many of these patients also have atherosclerotic coronary artery disease that may need to be addressed at the time of ACHD surgery, but data on the prevalence of coronary artery disease in this population, as well as outcomes after such surgery, are limited.

To address this issue, Dr. John M. Stulak of the Mayo Medical School, Rochester, Minn., and his associates conducted a study of 122 patients (77 male) who underwent concomitant coronary artery bypass grafting (CABG) for atherosclerotic coronary artery disease (CAD) at the time of ACHD repair. Dr. Stulak presented the results at the annual meeting of the Society of Thoracic Surgeons.

Dr. Stulak noted that, based on his findings, "Concomitant CABG may be required at the time of repair of ACHD. Disease of the LAD [left anterior descending coronary artery] is most common, and survival is higher when a LIMA [left internal mammary artery] graft is used. Late functional outcome is good with a low incidence of late angina, MI, or the need for percutaneous coronary intervention."

The patients, mean age 64 years, had surgery between February 1972 and August 2009. A total of 25% had angina, 6% had prior myocardial infarction, and 5% had previous percutaneous intervention.

The most common primary cardiac diagnoses were secundum atrial septal defect (ASD) in 60%, Ebstein anomaly in 11%, partial anomalous pulmonary venous connection (PAPVC) in 7%, and ventricular septal defect (VSD) in 6%. A total of 17% of the patients had a prior cardiac operation.
 
The most common operations included ASD repair in 64%; tricuspid valve surgery (11%), pulmonary valve surgery (8%), VSD repair (8%), and PAPVC repair (7%). A single bypass graft was performed in 69 patients, 2 grafts in 32 patients, 3 grafts in 14 patients, 4 grafts in 5 patients, and 5 grafts in 2 patients. The LIMA was used in 57 of 82 patients (70%) with LAD disease.

The median follow-up was 6 years for 111 available patients. During that time, recurrent CAD was reported in 9 patients (8%); 8 patients (7%) had angina, and 5 (4%) had an MI. Six (5%) patients underwent intervention. All but 11 patients achieved NYHA functional class 1 or 2. The overall survival observed was 76% at 5 years, 56% at 10 years, and 33% at 15 years. In those patients with LAD disease, 10-year survival was significantly higher when LIMA was used (66% vs. 36%).

Dr. Stulak added the importance of this study is also to stress that each treatment approach should be individualized whether it is conventional CABG, off-pump CABG, or a staged hybrid technique with percutaneous coronary intervention for CAD.

Dr. Stulak and his colleagues had no disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

SAN DIEGO - Over the past 24 years, the prevalence of indications for pediatric heart transplantation resulting from congenital heart disease has changed. Transplantation for failed SV palliation, including failed Fontan procedure, has now become the predominant indication, according to the observations of a single-center experience reported in the J. Maxwell Chamberlain Memorial Paper for Congenital Heart Surgery at the annual meeting of the Society of Thoracic Surgeons.

Heart transplantation is the only viable treatment for children with end-stage heart failure resulting from either congenital heart disease (CHD) or cardiomyopathy. The purpose of this study by Dr. Rochus K. Voeller and his colleagues at Washington University in St. Louis was to review the trends in the indications for transplant and survival following transplant, using a retrospective review of all 307 orthotopic heart transplants performed at St. Louis Children's Hospital from January 1986 to December 2009. Combined heart-lung transplants were excluded from the study.

The indications for transplantation in 1986-2009 were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 174 patients with CHD, 80% had single-ventricle anomalies (SV). In the CHD group, transplantation for failed SV palliation, including the failed Fontan procedure, became the predominant indication in the latest 8-year interval of their program (increasing from 11% in the 1984-1993 period to 60% in the 2002-2009 period). The rate of retransplantation remained low and unchanged across the various time periods, according to Dr. Voeller.

The mean recipient age was 6.1 years, with 41% of the recipients aged younger than 1 year at the time of transplantation. Nearly one-third of all patients had prior surgical procedures or surgery ranging from banding to Fontan operations; 55% of the patients were boys; 8% of patients were bridged with either ECMO (extracorporeal circulation membrane oxygenation) or VAD (ventricular assist devices).

Overall survival of transplant patients was 81%, 76%, 72%, and 65% at 1, 3, 5, and 10 years, respectively. Survival was best in those patients who were transplanted for cardiomyopathy (1-, 3-, 5-, and 10-year survival of 90%, 84%, 81%, and 81%, respectively) and worst in patients with failed palliations for SV anomalies, especially failed Fontan procedures (1-, 3-, 5-, and 10-year survival of 66%, 61%, 61%, and 53%, respectively).

"Our results demonstrate the high-risk nature of transplants in patients with failed palliations for SV anomalies, including Fontan procedures performed during infancy. As the survival with early palliation for SV anomaly patients improves, more centers will be referred with these patients who will require transplantation at some point," said Dr. Voeller in an interview.

"This will not only impact pediatric heart transplant programs, but it will also influence adult transplant programs as well. Patients following SV palliation, including Fontan procedure, are much more difficult patients to transplant because of a variety of factors. Risk factor analysis will be needed to determine which patients might benefit from earlier transplant referral and how to better prepare these patient for transplant in order to reduce the risk of the procedure," he concluded.

Dr. Voeller reported that none of the authors had any financial disclosures.

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”