Drug-Induced Cardiotoxicity & QT Prolongation

Drug-induced long QT and torsades de pointes

The common target. Ventricular repolarization (phase 3) depends mainly on the rapid and slow delayed-rectifier K+ currents, IKr and IKs. IKr flows through the channel encoded by KCNH2 (hERG), whose unusually large inner cavity traps many structurally unrelated drugs. IKr blockade therefore underlies most acquired long QT: the action potential plateau lengthens and the QT interval follows.

From long QT to torsades. During a prolonged plateau, L-type Ca2+ channels recover and reopen, producing early afterdepolarizations (EADs) in phase 2 or 3. EADs that reach threshold trigger beats, and uneven repolarization across the ventricular wall sustains a polymorphic VT whose QRS peaks twist around the baseline — torsades de pointes. It is typically pause-dependent (short-long-short sequence), often self-terminates with syncope, and can degenerate into ventricular fibrillation.

Judging the QT. The QT is corrected for rate, most often with Bazett's formula (QTc = QT/√RR). A QTc above about 450 ms in men or 460 ms in women is prolonged; above 500 ms, or a rise of more than 60 ms from baseline, torsades risk climbs steeply and the offending drug is usually stopped.

Risk amplifiers. Hypokalemia (low extracellular K+ itself reduces IKr conductance and enhances drug block), hypomagnesemia, bradycardia or pauses, female sex, older age, congenital long-QT variants, structural heart disease and impaired renal or hepatic clearance. CYP3A4 inhibitors (clarithromycin, erythromycin, ketoconazole, grapefruit juice) raise levels of QT-prolonging substrates, and two QT-prolonging drugs are additive.

Why amiodarone is different. Amiodarone lengthens the QT markedly, but it also blocks Na+ and L-type Ca2+ currents, which suppresses EADs and keeps repolarization more uniform, so torsades is uncommon.

Do not treat torsades with class IA or III antiarrhythmics such as procainamide or sotalol; they prolong the QT further.

Cardiomyopathy and myocarditis from cancer drugs

Anthracyclines. Doxorubicin and daunorubicin cycle between quinone and semiquinone forms, generating reactive oxygen species with iron, and poison topoisomerase IIβ in cardiomyocytes. Injury can be acute (arrhythmias, myopericarditis) but is classically a late dilated cardiomyopathy. Dexrazoxane, an iron chelator that also interferes with topoisomerase II, reduces the damage; mediastinal radiation adds risk.

Trastuzumab. HER2 signaling helps cardiomyocytes survive stress. Blocking it lowers EF, often without symptoms, but because myocytes are not killed, function usually recovers after trastuzumab is paused, and many patients can be rechallenged.

Checkpoint inhibitor myocarditis. Anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 and anti-CTLA-4 (ipilimumab) antibodies release brakes on T cells, which can infiltrate the myocardium. It is uncommon but among the most lethal immune-related events, usually arises within the first three months, is more frequent with combination therapy, and often overlaps with myositis and myasthenia-like weakness. Troponin rises, and heart block or ventricular arrhythmias may follow. Treatment is to stop the drug and give high-dose glucocorticoids. Other direct myocardial toxins include high-dose cyclophosphamide (hemorrhagic myocarditis) and clozapine (myocarditis in the first weeks of therapy).

Vasospasm, ischemia and sodium-channel toxicity

Fluoropyrimidines. 5-FU and its oral prodrug capecitabine can cause coronary vasospasm — angina, ST elevation, occasionally MI or arrhythmia — typically during or soon after an infusion, with no fixed stenosis on angiography.

Triptans and ergots. Triptans are 5-HT1B/1D agonists, and 5-HT1B receptors on coronary smooth muscle mediate constriction; they are contraindicated in CAD, prior MI or stroke, Prinzmetal angina and uncontrolled hypertension. Ergot alkaloids (ergotamine, methylergonovine) constrict vessels through serotonin and α-adrenergic receptors and can cause coronary or limb ischemia, especially with CYP3A4 inhibitors.

Cocaine. Blocking reuptake of norepinephrine, dopamine and serotonin produces α1-mediated coronary vasospasm, tachycardia and hypertension that raise O2 demand, and platelet activation with thrombosis — MI even in young patients with normal coronaries. Aortic dissection and Na+ channel blockade with a wide QRS also occur. Benzodiazepines come first to blunt sympathetic outflow, then aspirin, nitrates and calcium channel blockers; classic teaching avoids β-blockers because unopposed α-stimulation may worsen vasospasm. Wide-complex rhythms respond to sodium bicarbonate.

TCA overdose. Tricyclics block fast Na+ channels, slowing phase 0 conduction. A QRS above 100 ms predicts seizures and above 160 ms ventricular arrhythmias; a tall terminal R wave in aVR is characteristic. Anticholinergic signs (dilated pupils, dry flushed skin, tachycardia) and α1-blockade hypotension accompany it. IV sodium bicarbonate is the antidote for the cardiotoxicity: the Na+ load overcomes channel blockade and alkalemia reduces drug binding. Physostigmine is avoided because it can precipitate bradyarrhythmias and asystole.

Drugs that worsen heart failure or damage valves

• Verapamil and diltiazem — negative inotropes; avoid in HFrEF.
• Thiazolidinediones (pioglitazone, rosiglitazone) — PPAR-γ increases collecting-duct Na+ reabsorption, causing fluid retention; contraindicated in NYHA III–IV HF.
• NSAIDs — block renal prostaglandins, causing Na+ and water retention and blunting diuretics.
• Dronedarone — increased mortality in advanced or recently decompensated HF.
• Cilostazol — a PDE3 inhibitor like milrinone; contraindicated in HF of any severity.

Serotonergic valvulopathy. 5-HT2B receptors on valvular interstitial cells are mitogenic. Agonists — fenfluramine (the "fen" of fen-phen), the ergot-derived dopamine agonists pergolide and cabergoline at high doses, MDMA and methysergide — cause fibrous plaques that thicken and retract leaflets, producing regurgitation, most often mitral and aortic. The lesions resemble carcinoid heart disease, which is right-sided because the lungs inactivate serotonin before it reaches the left heart; circulating drugs reach left-sided valves directly.