Long QT syndrome

Pathophysiology and Genetics

Long QT syndrome (LQTS) is a genetic abnormality affecting ventricular repolarization, with an estimated incidence ranging from 1 in 2,500 to 1 in 10,000 births,.
The underlying pathophysiology involves a net decrease in the repolarizing current during the cardiac action potential, which can occur either due to an increased inward positive current or a reduced outward positive current.
This prolongation of ventricular repolarization causes oscillations in the membrane potential known as early after-depolarizations (EADs).
If EADs reach a critical threshold, they can trigger ectopic beats and initiate the life-threatening polymorphic ventricular tachycardia known as Torsades de Pointes (TdP).
The disease is broadly categorized into two historical phenotypes: Romano-Ward syndrome (autosomal dominant, normal hearing) and Jervell and Lange-Nielsen syndrome (autosomal recessive/homozygous variants, associated with congenital sensorineural deafness),.

Subtype	Gene and Channel	Pathophysiologic Mechanism	Characteristic Triggers
LQT1	KCNQ1 (Potassium channel, IKs)	Loss of function leading to reduced outward potassium current	Swimming, physical exertion, emotional stress,
LQT2	KCNH2 (Potassium channel, IKr)	Loss of function leading to reduced outward potassium current	Auditory triggers (e.g., alarm clocks), postpartum period,
LQT3	SCN5A (Sodium channel, INa)	Gain of function causing an increased "late" inward sodium current during phases 2 and 3	Sleep, rest (carries the highest probability for sudden death),

Patients often present with syncope brought on by exercise, fright, sudden startle, or occurring during sleep.
Other initial presentations include generalized seizures, presyncope, or episodic palpitations.
Approximately 10% of patients present initially with sudden cardiac arrest.
In the fetal and neonatal period, LQTS can present as fetal bradycardia, second-degree heart block, or unexplained intrauterine fetal demise/stillbirth.

Modality	Specific Findings and Utility
Electrocardiogram (ECG)	A resting heart rate-corrected QT interval (QTc) > 0.47 seconds is highly indicative of LQTS, while >0.44 seconds is suggestive. Additional hallmark findings include notched T waves in at least three leads, macroscopic T-wave alternans, and a disproportionately low resting heart rate for the patient's age. During acute arrhythmic events, the ECG classically demonstrates Torsades de Pointes,.
Exercise Stress Testing	Used to unmask concealed LQTS and differentiate genotypes. In LQT1, the QTc paradoxically prolongs during exercise and remains prolonged into recovery. In LQT2, the QTc may lengthen in early exercise but normalizes at higher heart rates. The modified "Schwartz score" utilizes a QTc ≥ 480 milliseconds at the 4th minute of exercise recovery as a highly predictive diagnostic criterion.
Echocardiography	The echocardiogram typically demonstrates normal biventricular size and systolic function, as LQTS is a primary electrical channelopathy occurring in a structurally normal heart. It is primarily utilized to exclude other structural or cardiomyopathic causes of ventricular arrhythmias and syncope.
Ambulatory (Holter) Monitoring	A 24-hour Holter monitor is utilized as a diagnostic adjunct to evaluate for intermittent T-wave alternans, macroscopic T-wave changes, and occult episodes of non-sustained ventricular tachycardia or Torsades de Pointes.

The clinical diagnosis is frequently established using the Schwartz score, which integrates ECG findings, clinical history, and family history.
ECG criteria include: QTc ≥ 480 ms (3 points), 460–479 ms (2 points), Torsades de pointes (2 points), T-wave alternans (1 point), notched T-wave in 3 leads (1 point), and low heart rate for age (0.5 points).
Clinical criteria include: Syncope with stress (2 points) or without stress (1 point), and congenital deafness (0.5 points).
Family history criteria include: Definite LQTS in a family member (1 point) or unexplained sudden cardiac death below age 30 (0.5 points).
A total score of ≥ 3.5 indicates a high probability of LQTS.

Patients must strictly avoid all medications known to prolong the QT interval (e.g., macrolide antibiotics like erythromycin, antifungals like fluconazole, tricyclic antidepressants, and certain antihistamines).
Electrolyte derangements, specifically hypokalemia, hypocalcemia, and hypomagnesemia, must be promptly identified and aggressively corrected to prevent proarrhythmic states.
Patients should be instructed to avoid specific genotype-related triggers (e.g., swimming in LQT1, loud alarm clocks in LQT2) and acquire a personal automated external defibrillator (AED) for sports safety,.

Beta-adrenergic blocking agents are universally recommended as the first-line therapy for all LQTS patients, including asymptomatic individuals who are genotype-positive.
Nonselective beta-blockers with long-acting properties, specifically nadolol or sustained-release propranolol, are preferred and have been shown to be more effective than cardioselective agents like atenolol or metoprolol in reducing cardiac events.
In patients with the LQT3 subtype, the sodium channel blockers mexiletine or flecainide may be utilized to actively shorten the QT interval and reduce cardiac events,.

Implantable cardioverter-defibrillator (ICD) placement is a Class I indication for patients who have survived a prior cardiac arrest.
ICD therapy is also indicated for secondary prevention in patients who continue to experience recurrent syncope or ventricular arrhythmias despite maximum tolerated beta-blocker therapy.
Left cardiac sympathetic denervation is recommended for high-risk patients who either cannot tolerate beta-blockers, fail beta-blocker therapy, or in whom an ICD is strictly contraindicated or refused.
Permanent pacemaker implantation may occasionally be required to manage severe, drug-induced bradycardia resulting from high-dose beta-blocker therapy.