1p36 and the Heart John Lynn Jefferies, MD, MPH, FACC, FAHA Director, Advanced Heart Failure and Cardiomyopathy Services Associate Professor, Pediatric Cardiology and Adult Cardiovascular Diseases Associate Professor, Division of Human Genetics The Heart Institute Cincinnati Children s Hospital
1p36 and the Heart Multiple organ systems can be effected in 1p36 Cardiovascular system is frequently involved As with all organ systems, there is a broad range of clinical findings Screening and surveillance is important to assess for structural heart defects as well heart muscle disease
1p36 and the Heart Typical diagnostic strategy would include an echocardiogram An echocardiogram (ultrasound of the heart) will either rule in or rule out congenital (structural) heart disease This means that this cannot be acquired over time If not present, will never be present
1p36 and the Heart Cardiomyopathy is a term that denotes abnormal heart muscle This can also be diagnosed by echocardiography However, the heart muscle can change over time Having a normal echocardiogram does not rule out the development of disease in the future
Cardiovascular Findings in 1p36 Syndrome Gajecka et al. 2007. Am J Med Genet C Semin Med Genet;145C(4):346-356.
Congenital Heart Disease Lesions Associated with 1p36 Deletion Gajecka et al. 2007. Am J Med Genet C Semin Med Genet;145C(4):346-356.
Cardiovascular Findings in 1p36 Syndrome 60 patients with 1p36 deletion syndrome 41 female One of the largest cohorts reported 71% of the patients had heart defects 23% had cardiomyopathy Left ventricular noncompaction (LVNC) Battaglia et al. 2008. Pediatrics;121:404-410.
Cardiovascular Findings in 1p36 Syndrome Congenital heart defects in 34/48 (71%) Septal defects, patent ductus arteriosus (PDA), valve abnormalities, tetralogy of Fallot, coarctation of the aorta, Ebstein s anomaly Cardiomyopathy in 13/48 (27%) LVNC in 11/13 Dilated cardiomyopathy in 2/13 Battaglia et al. 2008. Pediatrics;121:404-410.
Congenital Heart Defects Atrial Septal Defect (ASD) Ventricular Septal Defect (VSD) Patent Ductus Arteriosus (PDA) Tetralogy of Fallot (TOF) Coarctation of the Aorta Ebstein s Anomaly
Congenital Heart Disease Treatment Treatment depends on severity of lesion and potential long-term impacts Some resolve spontaneously Some can be treated with a catheter Some require surgery If spontaneous resolution does not occur, life-long cardiac evaluation is recommended
Cardiomyopathies Left Ventricular Noncompaction (LVNC) Dilated Cardiomyopathy (DCM) Hypertrophic Cardiomyopathy (HCM) Restrictive Cardiomyopathy (RCM) Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
Dilated Cardiomyopathy (DCM)
Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is a heart disease characterized by ventricular chamber enlargement and a reduction in contractile performance. 1 DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation. 1 Maron BJ, Towbin JA, Thiene G, et al. Circulation. 2006;113:1807-1816.
Left Ventricular Noncompaction (LVNC)
Left Ventricular Noncompaction LVNC is a cardiomyopathy characterized by abnormal, deep trabeculations in the LV myocardium. 1 LV systolic dysfunction, heart failure (and some cases of heart transplantation), thromboemboli, arrhythmias, sudden death, and extensive cardiac remodeling are associated with LVNC. 2 1. Maron BJ, Towbin JA, Thiene G, et al. Circulation. 2006;113:1807-1816. 2. McNally E, Dellefave L.Trends Cardiovasc Med. 2009;19:17-21.
Left Ventricular Noncompaction LVNC has been classified as a primary cardiomyopathy with a genetic origin Morpholigically characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses Clinically and genetically a very heterogeneous disorder Symptomatic versus asymptomatic at presentation may be predictive of outcome Oechslin et al. J Am Coll Cardiol. 2000;36:493-500.
Left Ventricular Noncompaction During cardiac development, myocardium initially trabeculated Period before coronary development Adaptation to provide coronary blood flow to the developing myocardium Development of the coronary vasculature associated temporally with the loss of LV trabeculations Between gestational weeks 5-8, trabeculae regress and myocardium compacts
Noninvasive Imaging Echocardiography remains most commonly used imaging modality Availability Portability Duration of study Anesthesia Insurance approval
Noninvasive Imaging Cardiac MRI Numerous advantages to use of serial MRI Reproducibility Reconstruction Myocardial characterization Chamber sizes (atria) Late gadolinium enhancement (fibrosis) Response to therapy Progression of disease
Left Ventricular Noncompaction
Nucifora et al. Eur J Heart Fail Myocardial Fibrosis in Left Ventricular Noncompaction
Left Ventricular Noncompaction Clinical manifestations Heart failure Embolic events Arrhythmias Sudden cardiac death
Mortality and SCD in LVNC The presence of heart muscle dysfunction was strongly associated with mortality (p<0.001) Repolarization abnormalities were associated with increased mortality (HR 2.1; p=0.02) Presence of arrhythmias was associated with mortality (HR 2.8; p=0.002) Brescia et al. Circulation 2013; April 30 [Epub ahead of print].
Left Ventricular Noncompaction Kobza et al. PACE. 2008;31:461-467.
Heart Failure Defined Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. Hunt SA et al. Circulation. 2001;104:2996
Heart Failure in Children Heart failure in childhood may present in the first days of life or anytime thereafter Signs and symptoms of heart failure in children may include: Breathlessness Tachypnea or tachycardia Diaphoresis Failure to thrive None
Jessup et al. Circulation 2009;119:1977-2016.
Sites of Action for HF Therapies Beta blockers Heart Digoxin, inotropes ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists Diuretics, aldosterone antagonists, nesiritide Cardiacresynchronization therapy Peripheral Arteries Kidney ACE inhibitors, angiotensin receptor blockers, vasodilators, alpha blockade, nesiritide, exercise Jessup M, Brozena S. N Engl J Med. 2003;348:2007
The Heart Failure Syndrome Myocardial Injury Fall in LV Performance Activation of RAAS and SNS (endothelin, AVP, cytokines) Myocardial Toxicity Change in Gene Expression ANP BNP Peripheral Vasoconstriction Sodium/Water Retention Morbidity and Mortality Remodeling and Progressive Worsening of LV Function HF Symptoms Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2
Ventricular Remodeling Ventricular Remodeling Initial infarct Global remodeling (days to months) Ventricular Remodeling in Diastolic and Systolic HF Normal heart Dilated heart (systolic HF) Hypertrophied heart (diastolic HF) Jessup M et al. N Engl J Med. 2003;348:2007
Pharmacologies in Heart Failure Management Cardiac Lusitropic Antifibrotic Antiremodeling Hemodynamic (balanced vasodilation) Veins Arteries Coronary arteries Neurohormonal aldosterone endothelin norepinephrine Renal sodium and water excretion Abraham WT et al. J Card Fail. 1998;4:37 Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67 Marcus LS et al. Circulation. 1996;94:3184 Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239 Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049
Cardiomyopathy Diagnosis and Treatment Careful attention to the echocardiogram required Often this is best achieved by seeing a Cardiologist who specializes in heart muscle disease More advanced imaging such as an MRI may be needed in select patients to see the heart muscle adequately
Cardiomyopathy Diagnosis and Treatment Treatment depends on the type of cardiomyopathy, disease severity, and symptoms Many patients with LVNC do not need treatment Medicines are indicated for patients with DCM or with LVNC and abnormal heart function Advanced therapies exist for patients with severe disease
Conclusions Screening for cardiac disease should occur at the time that initial diagnosis of 1p36 is made Evidence of structural/congenital heart disease should prompt referral to a Cardiologist Intervention may or may not be necessary depending on the findings
Conclusions The diagnosis of a cardiomyopathy should trigger referral to a Cardiologist, preferably someone with expertise in that area Treatment will be defined by the type and severity of disease DCM has been associated with 1p36 and can develop at different ages in life This warrants life-long echocardiographic screening