Congenital Heart Disease

• CHD ~80% idiopathic --> multifactorial (polygenic, epigenetic, environmental factors)
• Known associations with CHD

  • Chromosomal
  • Mendelian genetic syndromes
  • Non-syndromic single gene disorders
  • Idiopathic
  • Maternal diabetes
  • Toxins
  • Intrauterine viral infections
• Chromosomal associations

  • Trisomy 13
  • Trisomy 18
  • Trisomy 21
  • Turner Syndrome (Monosomy X)
  • 22q11 deletion (velocardiofacial syndrome)
• Mendelian genetic syndromes

  • Holt-Oram (TBX5 gene; 80% incidence)
  • Noonan (PTPN11, SOS1, RAF1, RIT1; 80-90% incidence)
  • Alagille (JAG1, NOTCH1; 85-95% incidence)
• Non-syndromic single gene disorders

  • Transcription factors (NKX2, GATA4)
  • Membrane-ligand receptors
  • Sarcomeric proteins
• Idiopathic associations

  • CHARGE association
  • VACTERL sequence
  • Abnormalities of position and situs (including ciliopathies)
• Maternal diabetes

  ~3x risk in outflow tract abnormalities (TOF, TA, DORV)
• Toxins associated with CHD

  • Alcohol
  • Warfarin
  • Selective serotonin reuptake inhibitors
• Intrauterine viral infections include rubella
• Acyanotic: L-->R shunt (normal/inc. pulmonary blood flow)

  Cyanotic: R-->L shunt (bypassing lungs)
• Atrial Septal Defect:


  Primum type ASD

  Failure of complete closure of septum primum with endocardial cushions. Rare in isolation, More commonly forms part of endocardial cushion defect/AV canal.

  Secundum type ASD

  Most common. incomplete closure/perforations in septum secundum --> patent foramen ovale. May be asymptomatic (BP keeps it shut).

  BOTH L-->R arteriovenous shunt - acyanotic - if large, risk of development of cardiac failure and pulmonary hypertension due to inc. pulmonary blood flow
• Atrioventricular septal defect (AV canal/endocardial cushion defect): 40-60% bc of Trisomy 21. Abnormal development of endocardial cushions = large defect --> common atrioventricular valve (5 leaflets). In complete AVSD, infants often asymptomatic during perinatal period, but large L-->R shunt --> early, severe cardiac failure + pulmonary hypertension --> high morbidity/mortality sans surgical intervention
• Ventricular Septal Defect. 80% perimembranous but can be anywhere in septum. L-->R postnatal. <1cm, symptoms may not start until 6mths-2yo. Very small defects may close spontaneously. Acyanotic. L/R shunt --> pulmonary hypertension overtime --> reverse of flow across shunt --> late cyanosis (Eisenmenger complex years later)
• Patent Ductus Arteriosus - structural abnormality of ductus arteriosus. Aorto-pulmonary shunt --> pulmonary hypertension. More common in premature infants. Unlikely to spontaneously close after 3 mo. Remains open in the presence of hypoxia. Machinery murmur over DA region o fupper chest. Closure induced through prostaglandin inhibitor administration eg Indomethacin. Can require surgery

  
• Coarctation of the Aorta.

  Preductal: tubular narrowing of the aortic arch. More likely to be symptomatic in early infancy, often associated with bicuspid aortic valve.

  Ductal: localised narrowing in the region of the closed DA - delayed symptoms. Common in Turner Syndrome (Monosomy X).

  Clinically: hypertension (reduced kidney blood flow) and differential BP between upper and lower limbs with weak femoral pulses.
• Tetralogy of Fallot. Most common form of cyanotic CHD. Abnormal spiralling of aorticopulmonary membrane --> asymmetric division with narrowing of right ventricular infundibulum. 4 components. R infundibular pulmonary stenosis. Large VSD. AOrta over-riding the VSD with dextroposition of aortic valve. Right ventricular hypertrophy (2ndary phenomenon)

  
• Tetralogy of Fallot severity depends on degree of pulmonary stenosis. Cyanosis within first 6mo.

  
• Hypoplastic left heart complex. Mitral and/or aortic valve atresia (complete absense) --> underdevelopment of left heart and ascending aorta. Most common CHD incompatible with extra-uterine life --> systemic blood flow relies on persistence of a PDA. Infant pale due to poor systemic blood flow, with weak/absent pulses and BP. Shunt procedure (NORWOOD) has some success: atrial septostomy to allow oxygenated venous return to RA, shunt systemic venous return directly into PA (SVC to PA - passive) and shunt RV flow of oxygenated blood into aorta.

  
• Tricuspid atresia with hypoplastic right ventricle. 1-3% CHD. Absence of identifiable tricuspid valve --> dilatation of right atrium and functionaly univentricular heart. Outlet from RA is via the patent foramen ovale or an ASD. Usually presents in newborn with cyanosis and pulsating liver - cyanosis becomes more pronounced with closure of ductus arteriosus. Surgical intervention --> formation of a conduit between RA and PA and litigation of main PA

  
• Transposition of the great vessels. Complete TGA --> ventricular-atrial discordance. Aorta originates anteriorly from RV, pulmonary artery from LV --> separate circulations of systemic and pulmonary blood unless a communication exists - required to sustain extra-uterine life - ASD (patent FO), VSD (~40% cases) or PDA. Otherwise die <0.5 hour. Clinical: if intact septum, require immediate atrial septostomy at birth, followed by arterial switch procedure.

  
• abnormalities of valves may be congenital or aquired. stenosis (narrowing) incompetence (regurgitation) or mixed.
• HAND1 mutation involved in right-left ventricle differentiation
• NKX2-5: involved in myocardiocyte differentiation > early on > causes atrial septal defect, tetralogy of fallot, av conduction defects
• TBX5 mutation - septal defects (R/L v and R atria septal defects). Holt-oram syndrome (septal defect, conduction disease, malformed upper limbs)
• GATA4 mutation: myocyte differentiation and cardiac gene expression --> ASD, TOF, Av conduction defects
• PTPN11 (Noonan syndrome --> pulmonary stenosis and septal defects)
• which rib is palpable at the manubriosternal junction/sternal angle?

  2nd rib
• AMyotrophic lateral sclerosis (ALS) is a Type 3 filament disorder
• sphingomyelin is a type of phospholipid
• What protein is commonly affected in Alzheimer's?

  Tau
• What type of intermediate filament disorder is Alzheimer's?

  Type 4
• What type of intermediate filament disorder are cataracts?

  Type 5
• No valves are open at the beginning of isovolumetric contraction
• 1. mitral 2. tricuspid 4. pulmonary 5. aortic (valve heart sounds at surface points). All physicians take money.
• JAG1 and PTPN11 mutations affect valve development
• TOF = pulmonary valve stenosis, overriding aorta, VSD, RV hypertrophy
• JAG1 --> alagille syndrome --> pulmonary stenosis and TOF
• PTPN11 --> Noonan syndrome --> pulmonary valve stenosis and Septal defects
• mutations in K+ channel -> cant move K effectivly -> cant regulate Cardiac cycle --> open delayed rectifier K+ channels -> restoration of membrane potential. repolarisation takes longer
• the qt interval represents the time between the depolarisation and repolarisation of ventricles