Advertisement

From genetics to prognosis

  • Can Yerebakan
    Correspondence
    Address for reprints: Can Yerebakan, MD, Cardiovascular Surgery, Children's National Heart Institute, Children's National Health System, The George Washington University School of Medicine, 111 Michigan Ave NW, Washington, DC 20010.
    Affiliations
    Division of Cardiovascular Surgery, Children's National Heart Institute, Children's National Health System, The George Washington University School of Medicine, Washington, DC
    Search for articles by this author
  • Manan Desai
    Affiliations
    Division of Cardiovascular Surgery, Children's National Heart Institute, Children's National Health System, The George Washington University School of Medicine, Washington, DC
    Search for articles by this author
Open ArchivePublished:March 27, 2018DOI:https://doi.org/10.1016/j.jtcvs.2018.03.067
      Figure thumbnail fx1
      Manan Desai, MD (left), and Can Yerebakan, MD (right).
      We are moving from early prenatal detection of cardiac diseases to an understanding of the underlying genetic disorders. Their early treatment in the prenatal period may be the future.
      See Article page e101 in the March 2018 issue.
      Cardiomyopathies in childhood are challenging cardiac disorders that carry high mortalities. Cardiac transplantation is the treatment of choice in case of intractable cardiac failure; however, the chronic shortage of donor organs hinders its unlimited application. Medical and surgical management strategies evolve steadily to improve the outcomes of our patients. Better risk stratification and novel alternatives for medical and surgical treatment options are therefore required.
      • Latus H.
      • Yerebakan C.
      • Akintuerk H.
      • Schranz D.
      Transcatheter interatrial communications for the treatment of left heart disease: application in the pediatric population.
      • Latus H.
      • Hachmann P.
      • Gummel K.
      • Recla S.
      • Voges I.
      • Mueller M.
      • et al.
      Biventricular response to pulmonary artery banding in children with dilated cardiomyopathy.
      Left ventricular noncompaction (LVNC) is an entity with still debatable classification. It has been classified as a distinct cardiomyopathy but also as a subtrait of other major cardiomyopathies.
      • Elliott P.
      • Andersson B.
      • Arbustini E.
      • Bilinska Z.
      • Cecchi F.
      • Charron P.
      • et al.
      Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on myocardial and pericardial diseases.
      • Maron B.J.
      • Towbin J.A.
      • Thiene G.
      • Antzelevitch C.
      • Corrado D.
      • Arnett D.
      • et al.
      American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      The definition differs in the guidelines of various medical societies, so the true incidence is unclear. It has been reported to affect the pediatric population the most after dilated cardiomyopathy and hypertrophic cardiomyopathy.
      • Nugent A.W.
      • Daubeney P.E.
      • Chondros P.
      • Carlin J.B.
      • Cheung M.
      • Wilkinson L.C.
      • et al.
      National Australian Childhood Cardiomyopathy Study
      The epidemiology of childhood cardiomyopathy in Australia.
      LVNC has increasingly been diagnosed in adults presenting in the echocardiographic laboratory.
      • Sandhu R.
      • Finkelhor R.S.
      • Gunawardena D.R.
      • Bahler R.C.
      Prevalence and characteristics of left ventricular noncompaction in a community hospital cohort of patients with systolic dysfunction.
      LVNC shares many of its genetic mutations with sarcomere genes. Familial inheritance as a genetic disorder has been reported in many series. One of the most common mutations occur in MYH7, the β-myosin heavy chain gene.
      • Hoedemaekers Y.M.
      • Caliskan K.
      • Michels M.
      • Frohn-Mulder I.
      • van der Smagt J.J.
      • Phefferkorn J.E.
      • et al.
      The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.
      • van Waning J.I.
      • Caliskan K.
      • Hoedemaekers Y.M.
      • van Spaendonck-Zwarts K.Y.
      • Baas A.F.
      • Boekholdt S.M.
      • et al.
      Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy.
      CD36 mutation, on the other hand, has been known to cause a wide variety of pathologic manifestations, from atherosclerosis to hypertrophic cardiomyopathy.
      • Hirano K.
      • Kuwasako T.
      • Nakagawa-Toyama Y.
      • Janabi M.
      • Yamashita S.
      • Matsuzawa Y.
      Pathophysiology of human genetic CD36 deficiency.
      In the March 2018 issue of the Journal, Hirono and colleagues
      • Hirono K.
      • Sakai T.
      • Hata Y.
      • Nishida N.
      The presence of multiple variants affects the clinical phenotype and prognosis in left ventricular noncompaction after surgery.
      describe the presence of 2 simultaneous variant of MYH7 and CD36 genes in a prenatally diagnosed case of LVNC and discusses its impact on the prognosis. Hirono and colleagues
      • Hirono K.
      • Sakai T.
      • Hata Y.
      • Nishida N.
      The presence of multiple variants affects the clinical phenotype and prognosis in left ventricular noncompaction after surgery.
      are to be congratulated on the prenatal detection of the cardiomyopathy and the coexistence of both gene variants with cardiac phenotype in the same patient. A recent retrospective study from the Netherlands in 327 patients at 4 centers showed that those with LVNC-related genes with known mutations were more likely to have cardiac symptoms, left ventricular systolic dysfunction, and high risk of major cardiac adverse events.
      • van Waning J.I.
      • Caliskan K.
      • Hoedemaekers Y.M.
      • van Spaendonck-Zwarts K.Y.
      • Baas A.F.
      • Boekholdt S.M.
      • et al.
      Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy.
      Probst and associates,
      • Probst S.
      • Oechslin E.
      • Schuler P.
      • Greutmann M.
      • Boyé P.
      • Knirsch W.
      • et al.
      Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.
      however, discussed that sarcomere mutations per se did not predict clinical phenotype.
      Whether the coexistence of the 2 described mutations in the same patient explain prolonged pleural effusions, pericardial effusions, and ascites remains debatable. The patient underwent pulmonary artery banding and continuous prostaglandin infusion as part of a hybrid stage I palliation. We need to know more details of the surgical and postoperative medical approach to be able to attribute the clinical course fully to the rare coexistence of the mutations. Abnormal long-chain fatty acid metabolism is observed in myocytes with CD36 deficiency.
      • Nozaki S.
      • Tanaka T.
      • Yamashita S.
      • Sohmiya K.
      • Yoshizumi T.
      • Okamoto F.
      • et al.
      CD36 mediates long-chain fatty acid transport in human myocardium: complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency.
      Even when the clinical significance is not clarified in the mentioned study, the described patient may be tested for this disorder.
      A prenatal detection and genetic follow-up of a cardiac disease by clarifying underlying mutations already indicates the future objectives of modern medicine, which are early detection of cardiac diseases and offering potential prenatal medical, surgical, or genetic treatment options. Accurate counseling of parents for the postnatal period in light of the clinical and genetic information may become possible early in the pregnancy. For surgeons, such information with prognostic significance may play an extremely important role in the timing and selection of different available surgical strategies. Continuous efforts to achieve this goal should therefore be strongly encouraged.

      References

        • Latus H.
        • Yerebakan C.
        • Akintuerk H.
        • Schranz D.
        Transcatheter interatrial communications for the treatment of left heart disease: application in the pediatric population.
        J Heart Lung Transplant. 2016; 35: 1274-1275
        • Latus H.
        • Hachmann P.
        • Gummel K.
        • Recla S.
        • Voges I.
        • Mueller M.
        • et al.
        Biventricular response to pulmonary artery banding in children with dilated cardiomyopathy.
        J Heart Lung Transplant. 2016; 35: 934-938
        • Elliott P.
        • Andersson B.
        • Arbustini E.
        • Bilinska Z.
        • Cecchi F.
        • Charron P.
        • et al.
        Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on myocardial and pericardial diseases.
        Eur Heart J. 2007; 29: 270-276
        • Maron B.J.
        • Towbin J.A.
        • Thiene G.
        • Antzelevitch C.
        • Corrado D.
        • Arnett D.
        • et al.
        • American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention
        Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
        Circulation. 2006; 113: 1807-1816
        • Nugent A.W.
        • Daubeney P.E.
        • Chondros P.
        • Carlin J.B.
        • Cheung M.
        • Wilkinson L.C.
        • et al.
        • National Australian Childhood Cardiomyopathy Study
        The epidemiology of childhood cardiomyopathy in Australia.
        N Engl J Med. 2003; 348: 1639-1646
        • Sandhu R.
        • Finkelhor R.S.
        • Gunawardena D.R.
        • Bahler R.C.
        Prevalence and characteristics of left ventricular noncompaction in a community hospital cohort of patients with systolic dysfunction.
        Echocardiography. 2008; 25: 8-12
        • Hoedemaekers Y.M.
        • Caliskan K.
        • Michels M.
        • Frohn-Mulder I.
        • van der Smagt J.J.
        • Phefferkorn J.E.
        • et al.
        The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.
        Circ Cardiovasc Genet. 2010; 3: 232-239
        • van Waning J.I.
        • Caliskan K.
        • Hoedemaekers Y.M.
        • van Spaendonck-Zwarts K.Y.
        • Baas A.F.
        • Boekholdt S.M.
        • et al.
        Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy.
        J Am Coll Cardiol. 2018; 71: 711-722
        • Hirano K.
        • Kuwasako T.
        • Nakagawa-Toyama Y.
        • Janabi M.
        • Yamashita S.
        • Matsuzawa Y.
        Pathophysiology of human genetic CD36 deficiency.
        Trends Cardiovasc Med. 2003; 13: 136-141
        • Hirono K.
        • Sakai T.
        • Hata Y.
        • Nishida N.
        The presence of multiple variants affects the clinical phenotype and prognosis in left ventricular noncompaction after surgery.
        J Thorac Cardiovasc Surg. 2018; 155: e110-e119
        • Probst S.
        • Oechslin E.
        • Schuler P.
        • Greutmann M.
        • Boyé P.
        • Knirsch W.
        • et al.
        Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.
        Circ Cardiovasc Genet. 2011; 4: 367-374
        • Nozaki S.
        • Tanaka T.
        • Yamashita S.
        • Sohmiya K.
        • Yoshizumi T.
        • Okamoto F.
        • et al.
        CD36 mediates long-chain fatty acid transport in human myocardium: complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency.
        Mol Cell Biochem. 1999; 192: 129-135

      Linked Article