Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle
Seema Mital, Wendy K Chung, Steven D Colan, Lynn A Sleeper, Cedric Manlhiot, Cammon B Arrington, James F Cnota, Eric M Graham, Michael E Mitchell, Elizabeth Goldmuntz, Jennifer S Li, Jami C Levine, Teresa M Lee, Renee Margossian, Daphne T Hsu, Pediatric Heart Network Investigators, Gail Pearson, Victoria Pemberton, Mario Stylianou, Marsha Mathis, Lynn Mahony, Lynn Sleeper, Steven Colan, Lisa Virzi, Lisa Wruck, Victor Zak, David F Teitel, Leslie Kalish, Patty Connell, Jane W Newburger, Roger Breitbart, Jami Levine, Ellen McGrath, Carolyn Dunbar-Masterson, Daphne Hsu, William Hellenbrand, Ashwin Prakash, Seema Mital, Darlene Servedio, Victoria L Vetter, Chitra Ravishankar, Sarah Tabbutt, Meryl Cohen, Katherine Lee, Marisa Nolan, Stephanie Piacentino, Michelle Toms, D Woodrow Benson, Catherine Dent Krawczeski, Lois Bogenschutz, Teresa Barnard, Steven Schwartz, David Nelson, Page A W Anderson, Jennifer Li, Wesley Covitz, Kari Crawford, Michael Hines, James Jaggers, Theodore Koutlas, Charlie Sang Jr, Lori Jo Sutton, Mingfen Xu, J Philip Saul, Andrew Atz, Girish Shirali, Eric M Graham, Teresa Atz, L LuAnn Minich, John A Hawkins, Richard V Williams, Linda M Lambert, Marian E Shearrow, Brian McCrindle, Elizabeth Radojewski, Nancy Slater, Svetlana Khaikin, Susan McIntyre, Nancy Ghanayem, Kathy Mussatto, Michele Frommelt, Lisa Young-Borkowski, Albert Rocchini, Laurie Rodgers Augustyniak, Steven Colan, Renee Margossian, Wendy Chung, Liyong Deng, Patricia Lanzano, Michael Artman, Judith Massicot-Fisher, Timothy Feltes, Julie Johnson, Thomas Klitzner, Jeffrey Krischer, G Paul Matherne, John Kugler, Rae-Ellen Kavey, David J Driscoll, Mark Galantowicz, Sally A Hunsberger, Thomas J Knight, Holly Taylor, Catherine L Webb, Seema Mital, Wendy K Chung, Steven D Colan, Lynn A Sleeper, Cedric Manlhiot, Cammon B Arrington, James F Cnota, Eric M Graham, Michael E Mitchell, Elizabeth Goldmuntz, Jennifer S Li, Jami C Levine, Teresa M Lee, Renee Margossian, Daphne T Hsu, Pediatric Heart Network Investigators, Gail Pearson, Victoria Pemberton, Mario Stylianou, Marsha Mathis, Lynn Mahony, Lynn Sleeper, Steven Colan, Lisa Virzi, Lisa Wruck, Victor Zak, David F Teitel, Leslie Kalish, Patty Connell, Jane W Newburger, Roger Breitbart, Jami Levine, Ellen McGrath, Carolyn Dunbar-Masterson, Daphne Hsu, William Hellenbrand, Ashwin Prakash, Seema Mital, Darlene Servedio, Victoria L Vetter, Chitra Ravishankar, Sarah Tabbutt, Meryl Cohen, Katherine Lee, Marisa Nolan, Stephanie Piacentino, Michelle Toms, D Woodrow Benson, Catherine Dent Krawczeski, Lois Bogenschutz, Teresa Barnard, Steven Schwartz, David Nelson, Page A W Anderson, Jennifer Li, Wesley Covitz, Kari Crawford, Michael Hines, James Jaggers, Theodore Koutlas, Charlie Sang Jr, Lori Jo Sutton, Mingfen Xu, J Philip Saul, Andrew Atz, Girish Shirali, Eric M Graham, Teresa Atz, L LuAnn Minich, John A Hawkins, Richard V Williams, Linda M Lambert, Marian E Shearrow, Brian McCrindle, Elizabeth Radojewski, Nancy Slater, Svetlana Khaikin, Susan McIntyre, Nancy Ghanayem, Kathy Mussatto, Michele Frommelt, Lisa Young-Borkowski, Albert Rocchini, Laurie Rodgers Augustyniak, Steven Colan, Renee Margossian, Wendy Chung, Liyong Deng, Patricia Lanzano, Michael Artman, Judith Massicot-Fisher, Timothy Feltes, Julie Johnson, Thomas Klitzner, Jeffrey Krischer, G Paul Matherne, John Kugler, Rae-Ellen Kavey, David J Driscoll, Mark Galantowicz, Sally A Hunsberger, Thomas J Knight, Holly Taylor, Catherine L Webb
Abstract
Background: We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle.
Methods and results: Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05).
Conclusions: Renin-angiotensin-aldosterone system-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact.
Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.
Figures
Source: PubMed