What are the diseases associated with QT prolongation and how are genetic factors involved in their pathogenesis?

Diseases Associated with QT Prolongation and Their Genetic Pathogenesis

Diseases Associated with QT Prolongation (4 marks)

QT prolongation is associated with several diseases that increase the risk of life-threatening arrhythmias, particularly torsades de pointes (TdP). The main conditions include:

• Congenital Long QT Syndrome (LQTS): A hereditary cardiac disease with prevalence of approximately 1 in 2,500-5,000 live births, characterized by prolonged QT interval and high risk of life-threatening arrhythmias 1, 2

• Electrolyte Disturbances:

  • Hypocalcemia (less than 7.5 mg/dl) produces distinctive lengthening of the ST segment 2
  • Hypokalemia decreases T wave amplitude and increases U wave amplitude 2
  • Hypomagnesemia often accompanies hypokalemia and exacerbates QT prolongation 2

• Central Nervous System Abnormalities: Can produce QT prolongation and T wave inversion 2

• Drug-Induced QT Prolongation: Caused by medications that block IKr current, including:

  • Antiarrhythmic drugs (quinidine, procainamide, disopyramide, sotalol, dofetilide, ibutilide) 2, 3
  • Macrolide antibiotics (erythromycin, clarithromycin) 2
  • Fluoroquinolones 4
  • Antipsychotics (thioridazine, haloperidol) 5, 6
  • Antidepressants (tricyclics, SSRIs) 5, 6
  • Methadone 2, 5

• Cardiac Diseases:

  • Heart failure, especially with reduced ejection fraction 2
  • Ischemic heart disease 2
  • Bradyarrhythmias (complete heart block, sick sinus syndrome) 2
  • Left ventricular hypertrophy 2

• Autoimmune-Related QT Prolongation: Neonates born to mothers with autoimmune diseases positive for anti-Ro/SSA antibodies may show transient QT prolongation 2

Genetic Factors in QT Prolongation Pathogenesis (6 marks)

Genetic mutations affecting cardiac ion channels are the primary pathogenic mechanism in congenital LQTS, while genetic polymorphisms may predispose individuals to acquired forms of QT prolongation. The genetic basis includes:

• Ion Channel Gene Mutations: LQTS is caused by mutations in genes encoding cardiac ion channel subunits or proteins that modulate ionic currents 1, 2

  • KCNQ1 (LQT1): Most prevalent LQTS variant (approximately 50% of genotyped cases) affecting the slow component of delayed rectifier potassium current (IKs) 1
  • KCNH2 (LQT2): Affects the rapid component of delayed rectifier potassium current (IKr) 1
  • SCN5A (LQT3): Affects the sodium channel, causing gain of function with persistent inward sodium current during repolarization 1, 2
  • Other genes: KCNE1, KCNE2, CACNA1c, CAV3, SCN4B also cause LQTS by encoding various ion channel components 1

• Pathophysiological Mechanism: All these mutations prolong the cardiac action potential duration by either:

  • Decreasing outward potassium currents (loss of function in potassium channels) 1, 7
  • Increasing inward sodium or calcium currents (gain of function in sodium channels) 1, 2

• Inheritance Patterns:

  • Most congenital LQTS follows autosomal dominant inheritance (Romano-Ward syndrome) 1
  • Rarer autosomal recessive forms exist (Jervell and Lange-Nielsen syndrome) with associated deafness 1
  • Approximately 30% of LQTS cases are due to de novo mutations with unaffected parents 2

• Penetrance and Expression:

  • Low penetrance exists in LQTS, meaning gene carriers may have normal QT intervals 2
  • Genetic modifiers and environmental factors influence clinical expression 1, 7

• Genetic Predisposition to Acquired LQTS:

  • Subclinical mutations or common genetic polymorphisms may predispose individuals to drug-induced QT prolongation 8, 7
  • Some cases of drug-induced LQTS may be related to previously undetected genetic variants 7
  • Pharmacogenetic interactions occur when genetic variants potentiate the QT-prolonging effect of medications 7

• Risk Stratification Based on Genotype:

  • Different genetic subtypes have varying risks and triggers for arrhythmic events 1
  • LQT1 patients are more sensitive to sympathetic stimulation (exercise)
  • LQT2 patients are more sensitive to emotional stress and auditory stimuli
  • LQT3 patients have higher risk during rest or sleep 1, 9

• Gene-Specific Therapy Approaches:

  • Beta-blockers are most effective in LQT1 patients 2
  • Sodium channel blockers may benefit LQT3 patients 9
  • Gene-based specific therapy is still in preliminary stages 8

Understanding these genetic mechanisms is crucial for diagnosis, risk stratification, and developing targeted therapies for patients with QT prolongation disorders 1, 9.