A. Morphology and types

Polymorphic VT is a VT that has two or more QRS morphologies:

1. The most common polymorphic VT is a polymorphic VT without baseline QT prolongation. In other words, the sinus rhythm’s QTc interval is normal or only mildly prolonged. It is related to:
   
   
   
   • Acute ongoing ischemia, from an acute coronary event or from severe shock of any origin
     
   • Decompensated HF, with secondary ischemia and cellular stretch
     
   • Channelopathies, metabolic abnormalities or drug toxicity (class I agents, tricyclics)
     
   • Pseudo-TdP: triggered by very short-coupled PVCs (<400 ms) atop a reasonable QTc (<500 ms), with no acute ischemia
     

     Acutely, polymorphic VT is treated similarly to any sustained VT. The underlying metabolic abnormalities are treated, and urgent ischemic evaluation and revascularization are performed. As opposed to TdP, amiodarone may be used; quinidine is used for pseudo-TdP.

   
   
2. Torsades de pointes is a polymorphic VT with changing QRS polarity occurring in the context of a prolonged baseline QTc interval (often > 500 ms) or abnormal U wave. VT with twisting QRS polarity similar to Figure 9.5, but normal baseline QTc interval, is a non-TdP polymorphic VT and is usually an ischemic rhythm. TdP typically occurs in short runs < 20 seconds interceded with baseline rhythm but may become persistent or degenerate into VF (Figures 9.5–9.8).
   

   There are two types of TdP:

   
   
   
   
   • TdP secondary to congenital QT prolongation, where TdP is often dependent on increased catecholaminergic tone. The long QT is sec- ondary to a genetic channelopathy affecting potassium channels (LQT1 and 2), or, less often, sodium channels (LQT3), and leading to prolongation of repolarization with early afterdepolarizations. It is often inherited in an autosomal dominant fashion.
     
   • TdP secondary to acquired QT prolongation, where TdP is related to a combination of:
     
     
     
     • Bradycardia, which further prolongs and disperses repolarization (pause-dependent TdP).
       
     • Long–short R–R sequences: a pause is followed by an early PVC that falls in the ventricular repolarization period and triggers TdP.
       
     • One of four factors prolonging QT:
       
       
       
       1. Electrolyte disorders (↓ K, ↓ Ca, ↓ Mg)
          
       2. Drugs (AAD class I and III, neuroleptics, macrolides, cocaine)
          
       3. Ischemia
          
       4. Other: any cardiomyopathy, hypothyroidism, diabetic autonomic neuropathy, or cerebrovascular event (with tall or inverted T waves). Acquired TdP is three times more common in women than men.
   
   
3. Even without QT prolongation, bradycardia and long pauses may lead to early afterdepolarizations and spontaneous action potentials that initiate reentry in a patient with underlying myocardial disease (acute ischemia, myocardial scar). Bradycardia not only prolongs but disperses repolarization across the myocardium, allowing the sustainment of reentry. Thus, bradycardia may trigger polymorphic VT or monomorphic VT even without QT prolongation. In fact, in a patient with acute MI, frank bradycardia < 50 bpm can trigger VT/VF.²²

   

   

   

   

   
   

   As opposed to a steady-state bradycardia, acute bradycardia that occurs after a period of tachycardia is associated with a more striking prolongation of repolarization that facilitates the induction of polymorphic VT.²³ For instance, this is seen when AV nodal ablation is performed in patients with AF. As a result, the latter patients are paced at a rate of 80–90 bpm for ~1 week to prevent VT.

A. Types

The most common LQT syndromes are LQT1 (~35%), LQT2 (25%), and LQT3 (~5–10%). LQT1 and 2 are related to loss of function of K channels (I_Ks and I_Kr respectively), leading to prolongation of repolarization with a broad and long T wave in LQT1, and a broad and notched T wave in LQT2 (Figure 9.9).²⁵ LQT3 is related to a gain of function of Na channels, leading to increased depolarization and thus prolongation of the plateau phase of repolarization, i.e., prolongation of the ST segment with a normal-width T wave. The prolongation of repolarization (QT) elicits two untoward processes: (i) afterdepolarizations, and (ii) increased transmural dispersion of repolarization, which allows afterdepolarizations to propagate and sustain reentry and arrhythmias.

In LQT1 and 2, TdP is triggered by catecholaminergic activity, which increases the amplitude of early afterdepolarizations. In particular, swimming or physical or emotional stress may trigger TdP in LQT1. Sudden noise or emotion as well as postpartum may trigger TdP in LQT2 (not exercise), whereas sleep may trigger TdP in LQT3.

LQT is mainly autosomal dominant with variable penetrance (Romano–Ward syndrome).

B. Problems with the definition of long QT and with the diagnosis

A prolonged QT is defined as a QTc > 460 ms in women and > 450 ms in men. In the absence of reversible metabolic, drug, or ischemic causes, LQT syndrome is suspected, particularly if QTc > 480 ms. Up to 10% of normal individuals have QTc that is mildly prolonged (up to 480 ms), and 10–15% of patients with long QT syndrome have normal baseline QTc (mainly 400–460 ms).²⁶ Furthermore, 24-hour ambulatory monitoring of QTc has shown that the QTc of healthy individuals varies throughout the day by an average of 76 ms and may reach 480–490 ms at night or in the early morning.²⁷

In patients with QTc prolongation, rule out the transient causes (e.g., drugs) and perform an echo to rule out underlying cardiomyo- pathy (any cardiomyopathy may prolong QT). If QTc > 480–500 ms without any reversible cause, the diagnosis of LQT is virtually established. In patients with borderline QTc prolongation of 450–480 ms, further testing may need to be performed, particularly in case of syncope or family history of sudden death: further prolongation of QTc with exercise testing (measurement performed a few minutes into recovery, as the heart rate slows down), epinephrine infusion, Valsalva, immediate standing, or post-PVC implies LQT1. QTc >445–470 ms at 2–4 min of recovery is predictive of long QT syndrome.¹¹ In normal individuals, QTc is reduced with exercise or epinephrine infusion.²⁸ In addition, the presence of macroscopic T wave alternans supports the diagnosis of LQT. Other supportive features in case of borderline QTc prolongation: syncope, family history of LQT or sudden death, familial screening with ECG (marked prolongation of QTc in a family member may confirm the diagnosis in the index patient).

QT interval is best measured in the lead that shows a distinct T-wave termination with the best separation of T and U waves.²⁹ The QT interval may be artificially shortened in some leads, because an isoelectric segment may be recorded at the beginning of the QRS complex

or at the end of the T wave in those leads. On the other hand, QT is often longest in leads V₂–V₃, but those leads show the least separation between the T wave and the normal U wave and may therefore overestimate the length of the QT interval. Leads I, aVR, and aVL do not have the normal diastolic U wave but do not always show a distinct T wave. Thus, QT interval is often best measured in leads II and V₅ or V₆.

A normal U wave (<25% of T wave) or an abnormal U wave that is not merging with the T wave should not be used in QT calculation. In practice, a wave that exceeds 25% of the T wave and that merges with the T wave giving a “bifid” T-wave appearance should be taken into account; this is a part of the T wave (TU wave) rather than a true diastolic U wave.

QT interval shortens with increasing heart rate (17.5 ms for every 10 beats). The corrected QT corresponds to the patient’s predicted QT interval had the heart rate been 60 bpm; it is often calculated using the Hodges formula: QTc = QT + 1.75 × (rate – 60).

C. Epidemiology and risk of sudden death

The long QT syndrome phenotype is more common in women than men (~1.5:1).

Sudden death and syncope mainly occur in childhood or early adulthood before the age of 40 (Table 9.1). QTc > 500 ms, female sex with LQT2, or male sex with LQT3 confer the highest lifetime risk.³⁰ Female sex confers a higher risk of sudden death in adulthood, including LQT1, whereas male sex is a risk factor for sudden death in childhood.³¹ Overall, ~ 50% of LQT syndrome patients experience TdP with syncope or sudden death during their lifetime.

Patients with long QT syndrome genotype but normal phenotype (normal QTc) have a real risk of sudden death, albeit smaller than patients with prolonged QTc, and should be treated with β-blockers.

While the risk of sudden death attributed to long QT syndrome is highest in the first 40 years of life, this syndrome remains associated with a 2.65-fold increased risk of sudden death in patients 41–60 years of age, particularly with LQT2 or 3, according to an LQT registry. The risk beyond the age of 60 is attenuated, partly because the risk of death from other illnesses increases at this stage.³²

D. Genetic testing

Genetic testing is negative in 20–25% of patients with LQT1–3, because of unidentified mutations of identified genes. Thus, testing is not useful to rule out the diagnosis, but may rule it in when positive in a patient with borderline clinical criteria. Testing is useful for two more reasons: (i) identify the type of LQT, which has prognostic implications; (ii) once a mutation is identified in a proband, family members are checked for that same mutation with a very high rule-out yield.

E. Therapy

The mainstay of therapy of congenital LQT1 is β-blockade, the efficacy of which is assessed by blunting of the exertional heart rate and mild reduction of QTc (~20 ms). β-blockers should be prescribed to all patients, including silent carriers. β-blockade reduces the risk of cardiac events by ~70% in LQT1 and LQT2, but is less effective in LQT3, especially men with LQT3.^33,34 In patients with prior syncope, β-blockers reduce the 5-year risk of recurrent syncope to 30%, and the 5-year risk of sudden death from long QTc to 3%.³⁴ In addition to β-blockade, long-term therapy of symptomatic or asymptomatic congenital LQT includes the maintenance of a normal electrolyte balance, avoidance of drugs that prolong the QT interval, and restriction from participation in athletic activities. LQT type is identified by genetic testing or by the effect of exercise or epinephrine on the QTc (in LQT1, QTc prolongs with exercise or epinephrine, while in LQT2 or 3, QTc shortens). Mexiletine, a class Ib antiarrhythmic, shortens QT and may be considered in all types of LQT when β-blocker is ineffective, particularly LQT3. Left cardiac sympathetic denervation, consisting of removing the left paravertebral stellate ganglion, may also be used for recurrent cardiac events despite β-blockade.¹¹

ICD is indicated in patients with LQT syndrome and prior cardiac arrest (class I indication). In patients with syncope, β-blockade therapy may be enough, with the use of ICD if syncope recurs. Note that TdP is self-terminating, so ICD may not be very helpful in patients with syncope; in fact, the ICD shock triggers anxiety and further catecholamine surge, which may provoke more TdP and VF. Hence, ACC gives a class I ICD recommendation for syncope only in case of recurrence despite β-blockade, intolerance to β-blockade, or other high-risk features (QTc >500, LQT 2-3, age <40).11 ICD implantation may be considered in asymptomatic patients with the highest risk of sudden death, such as those with QTc > 500 ms, or LQT 2 (women) or 3, the latter two being less responsive to β-blockade and having a high residual risk of cardiac events despite β-blockade (class IIb recommendation). Women with LQT2 have a particularly high risk of sudden death in the 9 months post-partum, 7 times higher than their pre-pregnancy and pregnancy risks, and may receive Lifevest during that period, if not ICD.^11,35

A. Secondary prevention

ICD is indicated for any sustained VT, regardless of EF (AVID, CIDS trials),^36,37 except:

• Polymorphic VT or VF occurring the first 48 hours after a large MI or STEMI.
  
• Polymorphic VT secondary to active ischemia that can be treated with revascularization. The revascularization is urgent in this context.
  
• Idiopathic monomorphic VT, with no structural heart disease, and no specific channelopathy/ electrical disease.

VT occurring in a patient with CAD but without acute MI or with only low-level troponin elevation qualifies for ICD regardless of EF and of the potential for complete revascularization.³⁸ VT that is monomorphic, or even polymorphic with no acute MI, usually signals an underlying scar and its inducibility is unaffected by revascularization.³⁹ According to the ACC guidelines: “In patients with ischemic heart disease and sustained monomorphic VT, coronary revascularization alone is an ineffective therapy to prevent recurrent VT.”¹¹

B. Primary prevention means ICD implantation in a patient without a history of sustained VT or sudden death

It is indicated in ischemic or non-ischemic cardiomyopathy if EF is ≤ 35% and the patient is symptomatic, NYHA functional class II or III, despite optimal medical therapy (ACC class I recommendation). The following waiting periods are required before implanting the ICD:

• >40 days after acute MI.
  
• > 3 months after revascularization for chronic ischemia.
  
• > 3 months of guideline-directed medical therapy for non-ischemic cardiomyopathy. This ensures the cardiomyopathy is not reversible before proceeding with ICD implantation.³⁸

Note that, in ischemic cardiomyopathy with EF ≤ 30%, ICD is indicated even if the functional class is I, i.e., if the patient is asymptomatic (class I recommendation). Also, in ischemic cardiomyopathy, ICD is indicated if EF is 36–40%, NSVT is present, and VT is inducible on EP study (class I recommendation).

Those recommendations are based on the MADIT II and SCD-HeFT trials^*.^20,40 The absolute yearly reduction in mortality was 3.5% in MADIT II, and 2% in SCD-HeFT. In these two trials, the survival curves of ICD therapy and placebo progressively diverged with time; how- ever, in both trials, the curves did not begin to diverge until 12 months, indicating that the benefit from ICD in primary prevention is a long-term benefit that is seen in patients healthy enough to survive several years. The yearly number needed to treat (NNT) to prevent one death is 25 in the MADIT II trial.

While the risk of sudden death is highest in the first 40 days after MI, ICD implantation is not beneficial during this time frame. One hypothesis is that, during this early period, patients at highest risk of VT/VF are patients with large infarctions and severe heart failure who may eventually succumb to pump failure even if resuscitated from VF (DINAMIT, IRIS trials).^41,42 Thus, ICD simply converts arrhythmic death into pump failure death or pulseless electrical activity (PEA) in many of those patients and does not prevent the eventual mortality. Also, the untoward effects of the periprocedural stress of ICD implantation may hinder the benefit. Building on this data, an analysis of the MADIT II trial has suggested that the benefit of ICD is mainly seen in patients whose MI is older than 1.5 years; while sudden death is highest in the early MI period, pump failure death, HF events, and recurrent acute coronary events are also highest during this period, reducing the effect of ICD on the overall mortality.⁴³ ICD is mainly effective in patients who have been stable for a prolonged duration after their MI, wherein the risk of isolated arrhythmic death from the arrhythmogenic scar becomes a relatively bigger concern.