Long QT syndrome (inherited)

References: Circulation 2014, HRS/EHRA/APHRS 2013 guidelines

Clinical presentation

  • Symptoms:
    • Cardiac arrest / sudden death before age 40
    • Syncope (often misdiagnosed as seizures due to twitching)
  • EKG
    • Prolonged QTc
    • T-wave alternans (marker of high cardiac electrical instability)
  • Arrhythmia triggers, specific to type (not always)
    • LQT1 = Exercise (especially swimming) or emotional stress
    • LQT2 = Sudden noise (esp on waking) or at rest
    • LQT3 = Rest or sleep

DDx

  • Inherited
  • Acquired (secondary causes)
    1. Drugs
    2. Lyte abnormalities (K, Mg, Ca)
    3. CNS event
    4. Ischemia
    5. Hypothyroid
    6. Hypothermia

Investigations

  • Goals: 
  • 12-lead EKG
  • +/- standing test, exercise stress test, or epinephrine challenge to identify concealed QTc prolongation
  • Echo to R/O structural heart disease
  • Genetic testing +/- EKG/mutation cascade testing

Diagnostic criteria

  • LQTS risk score 3.5 or more after R/O secondary causes of QT prolongation
    • Hx
      • Syncope: With stress (2), without stress (1)
      • Congenital deafness (0.5)
    • FHx
      • Family member with LQTS (1)
      • Sudden death in family member >30 y with no identifiable cause (0.5)
    • EKG
      • QTc >480 msec (3), 460-470 msec (2), 450 msec (male; 1)
      • TdP (2)
      • T-wave alternans (1)
      • Notched T-wave in 3 leads (1)
      • Low HR for age (0.5)
  • Presence of unequivocally pathogenic mutation in a LQTS gene
  • QTc (Bazett's formula) 500 msec or greater in at least 2 12-lead EKGs (R/O secondary causes of QT prolongation)
  • QTc 480-499 msec + hx of unexplained syncope in absence of a pathogenic mutation

Prognosis

  • Strongly associated with underlying cause
  • Factors associated with greater risk of cardiac events:
    • Sex
      • Males at higher risk during childhood (QTc shortens by ~20 msec with puberty)
      • Females at higher risk from adolescence onward
    • Syncope/cardiac arrest before age 7 (esp before 1 y)
    • Hx of syncope
    • EKG
      • QT interval >500 msec (esp >600 msec)
      • T-wave alternans
    • Genotype (mean QT interval, risk of cardiac event, cardiac event by 40 y)
      • LQT1 (~465 msec, 30%, 0.3%/y)
      • LQT2 (~490 msec, 46%, 0.6%/y)
      • LQT3 (~495 msec, 42%, 0.56%/y)
      • Mutation-positive individuals with no QTc-prolongation @ rest have ~10% risk of arrhythmia before age 40 in the absence of tx

Management

All

  1. Avoid QTc-prolonging drugs
  2. Correct electrolyte abnormalities (esp K, Mg)
  3. Beta-blockers
    • Indications
      • Hx of syncope or documented VT/VF
      • Asymptomatic, QTc 470 msec or greater
      • Preferred: Nadolol or propranolol extended-release
      • Also consider in genetically-diagnosed LQTS with no symptoms & QTc <470 msec
  4. Cardiac sympathectomy
    • Indications: Beta-blockers contraindicated or not effective in preventing syncope/arrhythmia; ICD contraindicated/refused
  5. ICD
    • Indications:
      • Hx of cardiac arrest
      • Recurrent syncope on beta-blocker
    • Not for 1o prevention in asymptomatic LQTS not tried beta-blocker (unless high-risk features)

Genotype-specific:

  • LQT1 or exercise-induced symptoms: Avoid vigorous exercise
  • LQT2: Avoid abrupt loud noises (e.g. alarm clock, phone ringing)
  • LQT3: Consider adding Na-channel blocker (e.g. mexiletine) for QTc >500 msec (if shortens QTc by >40 msec during monitored drug test)

Pathophysiology

  • LQTS typically displays autosomal-dominant Mendelian inheritance with variable penetrance (~25%); also rarely recessive inheritance with sensorineural deafness
  • Caused by mutations in potassium, sodium, or other ion channels
    • LQT1 = KCNQ1 gene mutation, resulting in abnormal I(ks) (slow K channel)
    • LQT2 = KCNH2 gene mutation, resulting in abnormal I(kr) (fast K channel)
    • LQT3 = SCN5A gene mutation, resulting in abnormal I(Na)
    • LQT1, 2, & 3 make up 92% of genetically-confirmed LQTS; 15-20% of LQTS patients have no known genetic mutation
    • LQT7 (Andersen-Tawil syndrome) = KCNJ2 mutation (also results in neuro-MSK symptoms)
  • Ion channel gene mutation -> increased transmural repolarization dispersion across myocardium -> triggers fluxes in transmembrane gradient -> early after depolarization (EAD) during phase 2/3 of action potential -> TdP

Right-sided heart failure

Also known as isolated right ventricular (RV) failure, or simply RV failure

References: Circulation 2008 [1][2], Rev Esp Cardiol 2010

Clinical presentation

  • Mechanisms of clinical manifestations: Decreased CO, fluid retention, atrial/ventricular arrhythmias
  • Complications: Congestive hepatopathy/cardiac cirrhosis
  • Symptoms
    • Fatigue & exercise intolerance
    • Peripheral edema, ascites, weight gain
  • P/E
    • Vitals: Hypotension
    • Head & Neck: Elevated JVP
    • Chest: Palpable RV impulse, TR murmur, clear lungs
    • Limbs: Edema

DDx

  • Causes of RV dysfunction
    1. Pressure overload
      1. Left-sided HF (most common, presents with left-sided HF s/sx)
      2.  Pulmonary hypertension (PH), chronic (e.g. PAH, cor pulmonale) or acute (e.g. PE)
      3. PS
      4. RVOT obstruction
    2. Volume overload (TR, PR, ASD, other [e.g. carcinoid])
    3. RVMI or ischemia
    4. Cardiomyopathy (e.g. ARVD)
    5. Pericardial (e.g. constrictive pericarditis)
    6. Inflow limitation (TS, SVC stenosis)
    7. Congenital heart disease (may include 1+ of above mechanisms, e.g. Eisenmenger syndrome, tetralogy of Fallot, transposition of the great arteries)

Investigations

  • Goals: Characterize etiology, severity & function class, & presence/extent of end-organ damage (cardiorenal syndrome & congestive hepatopathy)
  • Echo (TTE)
    • Most commonly done 1st to assess RV function, presence/extent of TR, as well as assess for PH, congenital heart defects, valvular heart disease or left-sided disease
    • RVEF measured by 2D echo has moderate correlation (0.65-0.80) with cMRI-derived RVEF
  • cMRI
    • Most accurate way of measuring RV volume & RVEF
    • RV volume (dilatation is >101 mL/m^2)
    • RVEF (normal ~60%, >40-45%) - note: dependent on loading conditions & therefore may not reflect contractility
    • RV mass (hypertrophy is >35 g/m^2)
  • Right heart cath
    • To evaluate pulmonary pressures, PVR, CO & pulmonary vasoreactivity (in the context of PH)
  • EKG to assess rhythm, QRS duration & presence of AV block
  • Labs
    • SCr
    • ALT, albumin
    • BNP

Prognosis

  • Strongly associated with underlying cause
  • Factors associated with poor prognosis:
    • Decreased exercise tolerance
    • Severity of measures of RV systolic dysfunction (e.g. RVEF <35%), diastolic dysfunction
    • Chronotropic incompetence
    • Arrhythmias
    • LV systolic dysfunction
    • Serum uric acid
    • Bilirubin

Management

Acute

  1. General principles
    • Fluid & sodium restriction
    • If using positive-pressure ventilation, avoid inspiratory pressures >30 mm Hg
  2. Treat underlying etiology, e.g.
    • Left-sided HF: Treat as per HFrEF/pEF
    • RVMI: Revasc
    • Acute PE: Anticoagulant +/- thrombolytic
    • PAH: iNO, epoprostenol & other PAH-specific agents
  3. Maintain NSR
    • Tachyarrhythmia: DC cardioversion
    • Bradyarrhythmia: Pacemaker +/- CRT
  4. Optimize RV preload (avoid hypotension as may worsen dysfunction via myocardial ischemia)
    • Low JVP/CVP/RAP? Trial 500 mL IV crystalloids
    • High? Gradual diuresis 0.5-1 kg/day, dialysis (CRRT/IHD)
  5. Not responsive to preload optimization?
    1. Optimize RV afterload: Inhaled nitric oxide, IV/inhaled epoprostenol
    2. Optimize RV contractility: IV inotropes (e.g. dobutamine) & vasopressors
    3. Others: RVAD, heart +/- lung transplant

Chronic

  1. Treat underlying etiology
  2. Symptom control
    • Diuresis to manage fluid retention
  3. Maintain NSR & AV synchrony (e.g. cardioversion & rhythm control, pacemaker, RV CRT)
  4. Prevent sudden death
    • Evaluate for ICD
  5. Role of drugs used in HFrEF:
    • ACEI/BB/MRA: Unknown
    • Digoxin: No improvement in RVEF; no benefit in absence of LV systolic dysfunction
  6. Others: Cardiac rehab, RVAD, heart +/- lung transplant
  • Maximize RV preload & contractility, minimize RV afterload
  • Maintain NSR

Pathophysiology

  • "End-stage" process of impaired RV filling or systolic function caused by RV pressure/volume overload, ischemic/infarct, cardiomyopathy or pericardial disease
    • RV tolerates volume overload better than pressure overload
  • Decreased RV forward flow leads to:
    • Reduced LV preload & therefore reduced cardiac output = fatigue, exercise intolerance
    • Systemic venous fluid retention = peripheral edema, ascites, anasarca (generalized edema)
  • Ventricular interdependence is also an important feature of RV failure
    • Diastolic ventricular interdependence contributes to secondary LV systolic dysfunction in RV failure; RV enlargement shifts the interventricular septum & increases pericardial constract on the LV, leading to decreased LV preload & contractility (via reduced elastance)

Specific etiologies

  • RVMI:

    • Constellation of hypotension, elevated JVP, & clear lungs
    • Present in 20-50% of inferior-wall MI, hemodynamically significant in 10%
  • Cor pulmonale
    • RVH 2o to pulmonary disease (most commonly COPD) without left-sided HF
    • Related to hypoxemic vasoconstriction