- Email: [email protected]
Paediatric acute heart failure—from deck chairs to lifeboats
COMMENTARY
COMMENTARY
Paediatric acute heart failure—from deck chairs to lifeboats See page 1967 Children with acute heart failure have been candidates for heart transplantation for almost 20 years. Analysis of outcomes by era shows a steadily improving survival after transplantation over the past 20 years.1 Yet many children with acute heart failure die while waiting on a transplant list. In the USA, children have a three-fold greater risk of dying compared with adults awaiting transplantation.2 Children with acute heart failure generally fall into two categories: those with an established diagnosis of cardiomyopathy, and acute cardiac failure in a previously healthy child. Traditional medical therapy for children with acute heart failure has been empirical and symptomatic. The usual spectrum of inotropic, vasodilating, and diuretic therapies have been tried with few, if any, data to recommend one regimen over another. Immunotherapy for presumed myocarditis has also been tried in paediatric patients.3 Case reports and institutional series have generally reported a therapeutic bias in favour of the drug for improved survival.4 However, the reality that a quarter of children with acute heart failure will die has not changed over the past 40 years.5 Extracorporeal membrane oxygenation and ventricularassist devices have been used as a bridge to transplantation in children.6 Long-term support on a circuit with extracorporeal membrane oxygenation is cumbersome and associated with substantial morbidity and mortality.7 In children, unlike in adults, mechanical circulatory support can reduce the risk of death in the short term but has not proven useful for long-term support. Hence the sense of futility that paediatricians feel for children with progressive acute heart failure. The use of urgent listing for patients on mechanical support allowed an algorithm for nationwide sharing such that these patients received the next available suitable heart for transplantation. A strategy of combining mechanical circulatory support and an urgent listing-status for transplantation is reported by Allan Goldman and colleagues in this issue of The Lancet. These investigators analyse a multi-institutional series that began in 1998 and was retrospectively reviewed after 2002. Both extracorporeal membrane oxygenation and pulsatile ventricular-assist devices were used. With this urgent listing the median waiting time for a donor heart was only 7·5 days compared with 18 days in children who did not receive mechanical support as a bridge towards transplantation, and only short periods of mechanical support were required. Goldman and colleagues report impressive results in terms of reduced mortality from 10 deaths in 1998, to 1 death in 2002, while patients with cardiomyopathy and acute heart failure were waiting on the list. In a fully used donor-organ pool, moving patients on mechanical support to an urgent status would be expected to have a detrimental effect on other patients awaiting transplantation. One could even imagine a scenario in 1948
which only patients who had been moved onto mechanical support would receive donor organs. However, in the UK as reported by Goldman and in the USA,2 a large proportion of paediatric donor organs are not successfully matched with a paediatric recipient, and potential donor organs go to waste. Goldman and colleagues report 137 heart-transplant procedures out of 257 donor hearts offered for transplantation, leaving 120 potential donors unused. A potential donor can become available at a time when no suitable recipient is listed and thus go unused, while a potential recipient could be listed and die within weeks. This mismatch can lead to a dual worst-case scenario of patients dying on the waiting list and donor hearts going unused. Goldman and colleagues present data to support an alternative scenario that potentially converts this dismal outcome into a win-win situation. In Goldman and colleagues’ report, children supported with extracorporeal membrane oxygenation had an 85% long-term survival compared with 45% for children on a ventricular-assist device. The differences in survival between extracorporeal membrane oxygenation and ventricular-assist devices reported by Goldman are concerning and surprising, but are based on only 22 mechanically assisted children. Perhaps the short time on mechanical support favoured extracorporeal membrane oxygenation. Other reports of successful transplantation after ventricular-assist devices in paediatric recipients were not compared with outcomes with extracorporeal membrane oxygenation.8 Children with congenital heart disease also seem to be a higher risk group for mechanical support.7 Our ability to immunise against the infectious agents that can lead to acute heart failure is limited.9 Additionally, patients with familial and non-familial cardiomyopathy are also at risk. At present, we are not able to prevent acute heart failure in children. Goldman and colleagues’ use of a dual strategy of mechanical circulatory support and urgent listing for transplantation offers a lifeboat for occupants of a rapidly sinking ship. But of course a lifeboat does not guarantee rescue. Only a more readily available supply of donor organs can provide the assurance of a rescue procedure for children with acute heart failure. I have no conflict of interest to declare.
Mark Boucek Section of Cardiology, Children's Hospital, Denver, CO 80218, USA (e-mail: [email protected]) 1
2
3
Boucek MM, Edwards LB, Keck BM, et al. The registry of the international society for heart and lung transplantation: sixth official pediatric report—2003. J Heart Lung Transplant 2003; 22: 636–52. Colombani PM, Dunn SP, Harmon WE, Magee JC, McDiarmid SV, Spray TL. Pediatric transplantation. Am J Transplant 2003; 3 (suppl 4): 53–63. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 1994; 89: 252–57.
THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
COMMENTARY
4
5 6
7
8
9
Kleinert S, Weintraub RG, Wilkinson JL, Chow CW. Myocarditis in children with dilated cardiomyopath: incidence and outcome after dual therapy immunosuppression. J Heart Lung Transplant 1997; 16: 1248–54. Lewis AB, Chabot M. Outcome of infants and children with dilated cardiomyopathy. Am J Cardiol 1991; 68: 365–69. Ibrahim AE, Duncan BW, Blume ED, Jonas RA. Long-term follow-up of pediatric cardiac patients requiring mechanical circulatory support. Ann Thorac Surg 2000; 69: 186–92. Kulik TJ, Moler FW, Palmisano JM, et al. Outcome-associated factors in pediatric patients treated with extracorporeal membrane oxygenator after cardiac surgery. Circulation 1996; 94 (suppl 9): II63–68. Stiller B, Hetzer R, Weng Y, et al. Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device. J Heart Lung Transplant 2003; 22: 1201–08. Baboonian C, McKenna W. Eradication of viral myocarditis. J Am Coll Cardiol 2003; 42: 473–76.
Atherosclerosis: infection-induced involvement of mitochondrial chaperonins See page 1971 The role of human cytomegalovirus (HCMV) in atherogenesis is disputed. One potential pathomechanism is induction of autoimmunity against heat-shock protein 60 (hsp60), an intramitochondrial protein, which is also found in the serum of healthy human beings.1 Because aminoacid sequences of hsp60 are highly homologous between different species, from prokaryotes to human beings, antibodies against hsp60 (anti-hsp60) of exogenous pathogens can crossreact with human hsp60 due to this molecular mimicry. Hsp60 is highly expressed in endothelial cells stressed by heat, infections, mechanical stress, oxidants, cytokines, oxidised LDL, and nicotine.2 Previously a cross-reaction between anti-hsp60 and hsp60 has been described on the surface of stressed endothelial cells.3 In this issue of The Lancet Caterina Bason and colleagues report an in-vitro study that provides evidence that, during HCMV infection, human antibodies against two HCMV peptides cross-react with human hsp60 (anti-hsp60-hsp60 reaction) and also cause apoptosis of non-stressed endothelial cells through interaction with integrin, connexin 45, and CD151 on the endothelial cell surface. These investigators identified an 11-aminoacid hsp60 sequence that was recognised by the sera of 71% of 270 patients with coronary artery disease but not by the sera of 98 participants without such disease. These findings raise several questions. First, why is hsp60 released from the mitochondrium to the extracellular space? HCMV infection could lead to dissociation of hsp60 and bax, a pro-apoptotic protein mediating the release of cytochrome c to the cytosol; cytotoxic cell death with disintegration of the mitochondrial membranes; or hsp60 release to the extracellular space to support intravascular defence mechanisms. Released hsp60 is known to bind to Toll-like receptors on the endothelial cell surface, reacts with anti-hsp60, and induces endothelial cell lysis in the presence of complement or peripheral blood mononuclear cells.2,3 Second, does the immune system react against endogenous or HCMV hsp60? Probably there is no autoimmune reaction, but antibodies against antigens of infectious agents cross-react with hsp60. This hypothesis is substantiated by several studies,4,5 including that of Bason and colleagues. Anti-hsp60 is associated with severity of coronary artery disease in cross-sectional studies. However, in case-control studies, the association of anti-hsp60 titres with coronary artery disease was weak in the absence of cardiovascular risk factors.6 Additionally, anti-hsp60 are also found in healthy human beings, and might protect against arthritis or diabetes mellitus.2,5,7,8 THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
Third, is the protective effect of hsp60 abolished by binding to anti-hsp60? A protective effect of hsp60 has been reported in transgenic SOD1 mice exposed to ischaemia and in diseased muscle cells exposed to oxidative stress. The protective effect of hsp60 could be explained by hsp60 forming a complex with bax or bak, thus blocking the ability of bax and bak to initiate apoptosis.3 Fourth, how does the anti-hsp60-hsp60 reaction induce apoptosis and atherosclerosis? Increased consumption of hsp60 could lead to a reduction of intra-mitochondrial hsp60. Since hsp60 protects mitochondrial housekeeping, release of hsp60 may reduce available energy or activate inducers of apoptosis. Apoptosis of endothelial cells is considered an initial step in atherogenesis since it increases vascular permeability, proliferation and migration of smooth-muscle cells, and blood coagulation.9 Fifth, do these results apply to both sexes, since only 22% of patients in Bason and colleagues study were women? Furthermore, in women the relation between anti-HCMV seropositivity and cardiac death is stronger than in men.10 Sex differences could also exist in the relation between HCMV infection and coronary artery disease.10 Furthermore, in female apolipoprotein-E knockout mice CMV infection induced larger atherosclerotic lesions than in males.11 Finally, is the observed anti-hsp60-hsp60 reaction associated with early or advanced coronary artery disease? Assuming that the described autoimmune reaction has a role in initiating atherosclerosis, reactivity to the 11-aminoacid sequence of hsp60 can be expected in at least some of the participants who did not have angiographic evidence of coronary artery disease, since angiography may be normal in early stages of atherosclerosis.12 The observed reaction could simply be a consequence of ischaemic myocardial cell necrosis with subsequent hsp60 release.13 Furthermore, the reaction could be related to plaque erosion and thrombus formation in advanced atherosclerosis, in which endothelial apoptosis also has an important role.14 To assess the clinical relevance of the antihsp60-hsp60 reaction, it would be necessary to know in which stage of coronary artery disease the investigated patients were, whether they had stable or unstable angina pectoris, or had had a myocardial infarction. Despite some evidence that HCMV infection contributes to the pathogenesis of atherosclerosis, a clear causal relation is still missing. Endothelial cell death in early or advanced atherosclerosis might be due not only to viral toxicity but also to apoptosis induced by impaired mitochondrial metabolism. We have no conflict of interest to declare.
*Claudia Stöllberger, Josef Finsterer Second Medical Department, and Department of Neurology, Krankenanstalt Rudolfstiftung, A-1030 Vienna, Austria (e-mail: [email protected]) 1
2 3
4
5
Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A. Circulating human heat shock protein 60 in the plasma of British civil servants. Relationship to physiological and psychosocial stress. Circulation 2002; 106: 196–201. Xu Q. Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 2002; 22: 1547–59. Schett G, Xu Q, Amberger A, Van der Zee R, et al. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 1995; 96: 2569–77. Perschinka H, Mayr M, Millonig G, et al. Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 1060–65. Uray K, Hudecz F, Füst G, Prohászka Z. Comparative analysis of linear antibody epitopes on human and mycobacterial 60-kDa heat shock proteins using samples of healthy blood donors. Int Immunol 2003; 15: 1229–36.
1949
COMMENTARY
Paediatric acute heart failure—from deck chairs to lifeboats See page 1967 Children with acute heart failure have been candidates for heart transplantation for almost 20 years. Analysis of outcomes by era shows a steadily improving survival after transplantation over the past 20 years.1 Yet many children with acute heart failure die while waiting on a transplant list. In the USA, children have a three-fold greater risk of dying compared with adults awaiting transplantation.2 Children with acute heart failure generally fall into two categories: those with an established diagnosis of cardiomyopathy, and acute cardiac failure in a previously healthy child. Traditional medical therapy for children with acute heart failure has been empirical and symptomatic. The usual spectrum of inotropic, vasodilating, and diuretic therapies have been tried with few, if any, data to recommend one regimen over another. Immunotherapy for presumed myocarditis has also been tried in paediatric patients.3 Case reports and institutional series have generally reported a therapeutic bias in favour of the drug for improved survival.4 However, the reality that a quarter of children with acute heart failure will die has not changed over the past 40 years.5 Extracorporeal membrane oxygenation and ventricularassist devices have been used as a bridge to transplantation in children.6 Long-term support on a circuit with extracorporeal membrane oxygenation is cumbersome and associated with substantial morbidity and mortality.7 In children, unlike in adults, mechanical circulatory support can reduce the risk of death in the short term but has not proven useful for long-term support. Hence the sense of futility that paediatricians feel for children with progressive acute heart failure. The use of urgent listing for patients on mechanical support allowed an algorithm for nationwide sharing such that these patients received the next available suitable heart for transplantation. A strategy of combining mechanical circulatory support and an urgent listing-status for transplantation is reported by Allan Goldman and colleagues in this issue of The Lancet. These investigators analyse a multi-institutional series that began in 1998 and was retrospectively reviewed after 2002. Both extracorporeal membrane oxygenation and pulsatile ventricular-assist devices were used. With this urgent listing the median waiting time for a donor heart was only 7·5 days compared with 18 days in children who did not receive mechanical support as a bridge towards transplantation, and only short periods of mechanical support were required. Goldman and colleagues report impressive results in terms of reduced mortality from 10 deaths in 1998, to 1 death in 2002, while patients with cardiomyopathy and acute heart failure were waiting on the list. In a fully used donor-organ pool, moving patients on mechanical support to an urgent status would be expected to have a detrimental effect on other patients awaiting transplantation. One could even imagine a scenario in 1948
which only patients who had been moved onto mechanical support would receive donor organs. However, in the UK as reported by Goldman and in the USA,2 a large proportion of paediatric donor organs are not successfully matched with a paediatric recipient, and potential donor organs go to waste. Goldman and colleagues report 137 heart-transplant procedures out of 257 donor hearts offered for transplantation, leaving 120 potential donors unused. A potential donor can become available at a time when no suitable recipient is listed and thus go unused, while a potential recipient could be listed and die within weeks. This mismatch can lead to a dual worst-case scenario of patients dying on the waiting list and donor hearts going unused. Goldman and colleagues present data to support an alternative scenario that potentially converts this dismal outcome into a win-win situation. In Goldman and colleagues’ report, children supported with extracorporeal membrane oxygenation had an 85% long-term survival compared with 45% for children on a ventricular-assist device. The differences in survival between extracorporeal membrane oxygenation and ventricular-assist devices reported by Goldman are concerning and surprising, but are based on only 22 mechanically assisted children. Perhaps the short time on mechanical support favoured extracorporeal membrane oxygenation. Other reports of successful transplantation after ventricular-assist devices in paediatric recipients were not compared with outcomes with extracorporeal membrane oxygenation.8 Children with congenital heart disease also seem to be a higher risk group for mechanical support.7 Our ability to immunise against the infectious agents that can lead to acute heart failure is limited.9 Additionally, patients with familial and non-familial cardiomyopathy are also at risk. At present, we are not able to prevent acute heart failure in children. Goldman and colleagues’ use of a dual strategy of mechanical circulatory support and urgent listing for transplantation offers a lifeboat for occupants of a rapidly sinking ship. But of course a lifeboat does not guarantee rescue. Only a more readily available supply of donor organs can provide the assurance of a rescue procedure for children with acute heart failure. I have no conflict of interest to declare.
Mark Boucek Section of Cardiology, Children's Hospital, Denver, CO 80218, USA (e-mail: [email protected]) 1
2
3
Boucek MM, Edwards LB, Keck BM, et al. The registry of the international society for heart and lung transplantation: sixth official pediatric report—2003. J Heart Lung Transplant 2003; 22: 636–52. Colombani PM, Dunn SP, Harmon WE, Magee JC, McDiarmid SV, Spray TL. Pediatric transplantation. Am J Transplant 2003; 3 (suppl 4): 53–63. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 1994; 89: 252–57.
THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
COMMENTARY
4
5 6
7
8
9
Kleinert S, Weintraub RG, Wilkinson JL, Chow CW. Myocarditis in children with dilated cardiomyopath: incidence and outcome after dual therapy immunosuppression. J Heart Lung Transplant 1997; 16: 1248–54. Lewis AB, Chabot M. Outcome of infants and children with dilated cardiomyopathy. Am J Cardiol 1991; 68: 365–69. Ibrahim AE, Duncan BW, Blume ED, Jonas RA. Long-term follow-up of pediatric cardiac patients requiring mechanical circulatory support. Ann Thorac Surg 2000; 69: 186–92. Kulik TJ, Moler FW, Palmisano JM, et al. Outcome-associated factors in pediatric patients treated with extracorporeal membrane oxygenator after cardiac surgery. Circulation 1996; 94 (suppl 9): II63–68. Stiller B, Hetzer R, Weng Y, et al. Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device. J Heart Lung Transplant 2003; 22: 1201–08. Baboonian C, McKenna W. Eradication of viral myocarditis. J Am Coll Cardiol 2003; 42: 473–76.
Atherosclerosis: infection-induced involvement of mitochondrial chaperonins See page 1971 The role of human cytomegalovirus (HCMV) in atherogenesis is disputed. One potential pathomechanism is induction of autoimmunity against heat-shock protein 60 (hsp60), an intramitochondrial protein, which is also found in the serum of healthy human beings.1 Because aminoacid sequences of hsp60 are highly homologous between different species, from prokaryotes to human beings, antibodies against hsp60 (anti-hsp60) of exogenous pathogens can crossreact with human hsp60 due to this molecular mimicry. Hsp60 is highly expressed in endothelial cells stressed by heat, infections, mechanical stress, oxidants, cytokines, oxidised LDL, and nicotine.2 Previously a cross-reaction between anti-hsp60 and hsp60 has been described on the surface of stressed endothelial cells.3 In this issue of The Lancet Caterina Bason and colleagues report an in-vitro study that provides evidence that, during HCMV infection, human antibodies against two HCMV peptides cross-react with human hsp60 (anti-hsp60-hsp60 reaction) and also cause apoptosis of non-stressed endothelial cells through interaction with integrin, connexin 45, and CD151 on the endothelial cell surface. These investigators identified an 11-aminoacid hsp60 sequence that was recognised by the sera of 71% of 270 patients with coronary artery disease but not by the sera of 98 participants without such disease. These findings raise several questions. First, why is hsp60 released from the mitochondrium to the extracellular space? HCMV infection could lead to dissociation of hsp60 and bax, a pro-apoptotic protein mediating the release of cytochrome c to the cytosol; cytotoxic cell death with disintegration of the mitochondrial membranes; or hsp60 release to the extracellular space to support intravascular defence mechanisms. Released hsp60 is known to bind to Toll-like receptors on the endothelial cell surface, reacts with anti-hsp60, and induces endothelial cell lysis in the presence of complement or peripheral blood mononuclear cells.2,3 Second, does the immune system react against endogenous or HCMV hsp60? Probably there is no autoimmune reaction, but antibodies against antigens of infectious agents cross-react with hsp60. This hypothesis is substantiated by several studies,4,5 including that of Bason and colleagues. Anti-hsp60 is associated with severity of coronary artery disease in cross-sectional studies. However, in case-control studies, the association of anti-hsp60 titres with coronary artery disease was weak in the absence of cardiovascular risk factors.6 Additionally, anti-hsp60 are also found in healthy human beings, and might protect against arthritis or diabetes mellitus.2,5,7,8 THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
Third, is the protective effect of hsp60 abolished by binding to anti-hsp60? A protective effect of hsp60 has been reported in transgenic SOD1 mice exposed to ischaemia and in diseased muscle cells exposed to oxidative stress. The protective effect of hsp60 could be explained by hsp60 forming a complex with bax or bak, thus blocking the ability of bax and bak to initiate apoptosis.3 Fourth, how does the anti-hsp60-hsp60 reaction induce apoptosis and atherosclerosis? Increased consumption of hsp60 could lead to a reduction of intra-mitochondrial hsp60. Since hsp60 protects mitochondrial housekeeping, release of hsp60 may reduce available energy or activate inducers of apoptosis. Apoptosis of endothelial cells is considered an initial step in atherogenesis since it increases vascular permeability, proliferation and migration of smooth-muscle cells, and blood coagulation.9 Fifth, do these results apply to both sexes, since only 22% of patients in Bason and colleagues study were women? Furthermore, in women the relation between anti-HCMV seropositivity and cardiac death is stronger than in men.10 Sex differences could also exist in the relation between HCMV infection and coronary artery disease.10 Furthermore, in female apolipoprotein-E knockout mice CMV infection induced larger atherosclerotic lesions than in males.11 Finally, is the observed anti-hsp60-hsp60 reaction associated with early or advanced coronary artery disease? Assuming that the described autoimmune reaction has a role in initiating atherosclerosis, reactivity to the 11-aminoacid sequence of hsp60 can be expected in at least some of the participants who did not have angiographic evidence of coronary artery disease, since angiography may be normal in early stages of atherosclerosis.12 The observed reaction could simply be a consequence of ischaemic myocardial cell necrosis with subsequent hsp60 release.13 Furthermore, the reaction could be related to plaque erosion and thrombus formation in advanced atherosclerosis, in which endothelial apoptosis also has an important role.14 To assess the clinical relevance of the antihsp60-hsp60 reaction, it would be necessary to know in which stage of coronary artery disease the investigated patients were, whether they had stable or unstable angina pectoris, or had had a myocardial infarction. Despite some evidence that HCMV infection contributes to the pathogenesis of atherosclerosis, a clear causal relation is still missing. Endothelial cell death in early or advanced atherosclerosis might be due not only to viral toxicity but also to apoptosis induced by impaired mitochondrial metabolism. We have no conflict of interest to declare.
*Claudia Stöllberger, Josef Finsterer Second Medical Department, and Department of Neurology, Krankenanstalt Rudolfstiftung, A-1030 Vienna, Austria (e-mail: [email protected]) 1
2 3
4
5
Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A. Circulating human heat shock protein 60 in the plasma of British civil servants. Relationship to physiological and psychosocial stress. Circulation 2002; 106: 196–201. Xu Q. Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 2002; 22: 1547–59. Schett G, Xu Q, Amberger A, Van der Zee R, et al. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 1995; 96: 2569–77. Perschinka H, Mayr M, Millonig G, et al. Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 1060–65. Uray K, Hudecz F, Füst G, Prohászka Z. Comparative analysis of linear antibody epitopes on human and mycobacterial 60-kDa heat shock proteins using samples of healthy blood donors. Int Immunol 2003; 15: 1229–36.
1949