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Drug-induced cardiovascular disease

Noncancer drugs that cause or worsen heart failure and cardiomyopathy, bradycardia and atrioventricular block, hypotension, valvular heart disease, and pericardial disease, with causality assessment, reporting, and prevention.

Scope and classification of drug-induced cardiovascular disease

Drug-induced cardiovascular disease is structural, functional, or electrical cardiac injury, or hemodynamic deterioration, that a medication, an illicit substance, or a nonprescription product causes or precipitates. The effect can be new disease in a previously normal heart, or decompensation of disease that was stable until the drug was added. The distinction matters for prognosis. After withdrawal, direct myocardial toxicity (clozapine myocarditis, chloroquine cardiomyopathy) usually leaves the injury as the dominant problem. Exacerbation of underlying dysfunction (a nondihydropyridine calcium channel blocker in a patient with an ejection fraction of 25%) usually reverses when the drug is stopped and exposes the underlying disease.

The 2016 American Heart Association (AHA) scientific statement on drugs that may cause or exacerbate heart failure classifies each drug by these two pathways. It also grades the magnitude of the effect, the strength of evidence, and the time from first dose to onset. The 2025 European Journal of Heart Failure expert consensus document on pharmacologic pitfalls updates the same catalog and adds guidance by heart failure phenotype.

Evaluation criteria from Table 3 of the 2016 AHA statement. They grade the drug’s potential to precipitate heart failure, not a class of recommendation.

Cancer therapy cardiotoxicity, drug-induced QT prolongation, drug-induced hypertension, and overdose are covered on separate pages, linked in the section on cancer therapy, QT prolongation, hypertension, and overdose.

Epidemiology and burden of drug-induced cardiovascular disease

No registry counts drug-induced cardiovascular disease as a single entity, and its frequency is estimated from the drugs that cause it. The exposures are common. The AHA statement cites survey data showing that 35% of US adults regularly use an over-the-counter medication and 38% use a complementary or alternative product, including one in four people older than 85 years. Patients with heart failure take many drugs from several prescribers, and the number of noncardiac comorbidities rises with age.

In a nested case-control study of 92,163 heart failure admissions from five databases in four European countries, current use of an NSAID increased the odds of admission by 19%. Among 169 consecutive patients with second-degree or third-degree atrioventricular (AV) block not related to infarction or digoxin, 54% were taking a beta-blocker, verapamil, or diltiazem. Methamphetamine-associated heart failure is increasing in prevalence across racial, ethnic, and socioeconomic groups. Older adults with dementia who take a cholinesterase inhibitor have more hospital visits for syncope and bradycardia and more pacemaker implantations than those who do not.

Pharmacovigilance data are the first source of most signals. Spontaneous reports to the US Food and Drug Administration (FDA) documented the heart failure signal for itraconazole, and the valvulopathy of fenfluramine-phentermine first appeared as a case series of 24 women.

Mechanisms of drug-induced cardiac toxicity

The mechanism predicts the phenotype, the time course, and whether the injury reverses. A drug can act through more than one mechanism, and the dominant one can change with dose.

Mechanistic classification compiled from the 2016 AHA statement, the 2025 European consensus, and the 2020 AHA statement on drug-induced arrhythmias.

Negative inotropy depends on reserve. A dose of diltiazem that is neutral in a normal ventricle lowers cardiac output in a ventricle that already depends on every increment of contractility. The effect is not offset by vasodilation, as it is with the dihydropyridines. Sodium retention acts through the kidney and the vasculature. Prostaglandin inhibition by NSAIDs raises systemic vascular resistance, reduces renal blood flow, and blunts the natriuretic response to loop diuretics. Thiazolidinediones expand plasma volume, and pregabalin, minoxidil, and the dihydropyridines produce edema through precapillary vasodilation as well as renal sodium retention.

Phosphodiesterase-3 inhibition raises intracellular cyclic adenosine monophosphate and calcium, increases contractility and heart rate, and promotes ventricular arrhythmia. Oral milrinone increased mortality in severe heart failure in the PROMISE trial. Cilostazol, a selective phosphodiesterase-3 inhibitor used for claudication, carries a contraindication in heart failure of any severity by extrapolation from that trial. Anagrelide shares the mechanism and has been associated with high-output heart failure.

Mitochondrial and oxidative injury underlies alcohol cardiomyopathy and the cardiomyopathy reported with zidovudine and other nucleoside analogues that inhibit mitochondrial DNA polymerase. Cationic amphiphilic drugs, chloroquine and hydroxychloroquine foremost, accumulate in lysosomes and inhibit phospholipid degradation. The resulting vacuolar myopathy, with lamellar and curvilinear bodies on electron microscopy, thickens the ventricle and damages the conduction system. Amiodarone causes phospholipidosis in lung, liver, and cornea, but clinically important cardiac storage disease from amiodarone is not an established entity.

Patient risk factors and pharmacokinetic amplifiers

These patient factors increase the probability and severity of drug-induced cardiovascular disease.

• Preexisting ventricular dysfunction. Reduced ejection fraction is the strongest modifier for negatively inotropic and proarrhythmic drugs. The risk of new or worsened heart failure with sotalol in premarketing studies was 3% in patients without heart failure and 10% in those with it.
• Age. Older adults have lower renal clearance, a smaller volume of distribution for water-soluble drugs, impaired baroreflexes, and more conduction disease. The heart failure signal with pramipexole was strongest in patients aged 80 years or older. The excess risk with tumor necrosis factor-alpha inhibitors in rheumatoid arthritis was confined to patients aged 65 years or older.
• Kidney disease. Reduced clearance raises exposure to digoxin, sotalol, dofetilide, atenolol, and lithium. Acute kidney injury combined with hyperkalemia and an AV nodal blocker produces BRASH syndrome (bradycardia, renal failure, AV nodal blockade, shock, and hyperkalemia). Kidney dysfunction also predicts minoxidil-associated pericardial effusion and hydroxychloroquine cardiomyopathy.
• Hepatic disease. Hepatically cleared drugs accumulate, and hypoalbuminemia increases the free fraction of highly bound drugs.
• Electrolyte disorders. Hypokalemia and hypomagnesemia increase digoxin toxicity and torsades de pointes. Hyperkalemia slows AV conduction and adds to nodal blockers.
• Drug interactions. Strong inhibitors of cytochrome P450 (CYP) 3A4 (clarithromycin, itraconazole, ketoconazole, ritonavir) raise exposure to verapamil, diltiazem, dronedarone, and eplerenone. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) raise metoprolol and carvedilol exposure. P-glycoprotein inhibitors (amiodarone, verapamil, dronedarone) raise digoxin concentrations. Pharmacodynamic stacking of two nodal blockers is the most frequent mechanism of drug-induced bradycardia. Interaction management is covered in Cardiovascular drug interactions, renal dosing and dosing in older adults.
• Pharmacogenetics. Slow acetylators are at higher risk of hydralazine-induced lupus. Siponimod is contraindicated in the CYP2C93/3 genotype. Variants that reduce repolarization reserve underlie a proportion of drug-induced torsades.
• Polypharmacy and multiple prescribers. Medications started by different clinicians, filled at different pharmacies, or bought over the counter escape review. A prescribing cascade, in which the adverse effect of one drug is treated with a second drug, compounds the problem.

Drugs that cause or worsen heart failure

The table below combines the 2016 AHA statement and the 2025 European consensus for noncancer drugs. The magnitude, level of evidence, and onset columns reproduce the AHA grading. Cancer drugs are listed in the AHA statement and are covered in the linked cardio-oncology pages.

Drugs that cause or worsen heart failure. Mechanism, magnitude, level of evidence, and onset are from the 2016 AHA statement (Tables 1 and 3). Guidance is from the 2022 AHA/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guideline and the 2025 European consensus, and Class 3: Harm entries are 2022 guideline recommendations.

Phenotype changes the list. The 2025 European consensus advises avoiding NSAIDs, thiazolidinediones, saxagliptin and alogliptin, and alpha-1 blockers across all ejection fraction categories. It considers nondihydropyridine calcium channel blockers generally safe in heart failure with preserved ejection fraction (HFpEF), and class IC drugs, dronedarone, and sotalol usable in selected HFpEF patients without structural heart disease or ischemia.

Thiazolidinediones and heart failure

Pioglitazone and rosiglitazone are peroxisome proliferator-activated receptor gamma agonists that improve insulin sensitivity. Their heart failure risk arises mainly from fluid retention. Peripheral edema occurs in 3% to 5% of patients on monotherapy and in 7.5% to 8% when a thiazolidinedione is combined with another glucose-lowering drug such as a sulfonylurea. Heart failure follows in patients with limited cardiac reserve.

The evidence is consistent across trials and observational data. In the DREAM trial of rosiglitazone in 5,269 people at risk for diabetes, confirmed heart failure was more frequent with rosiglitazone (hazard ratio [HR] 7.03; 95% confidence interval [CI] 1.60–30.9). In PROactive, 5,238 patients with type 2 diabetes and macrovascular disease, without NYHA class II–IV heart failure at entry, were randomized to pioglitazone or placebo. Serious heart failure occurred in 5.7% with pioglitazone and 4.1% with placebo, while heart failure mortality was similar (0.96% vs 0.84%). A 6-month randomized trial enrolled patients with NYHA class II–III heart failure and an ejection fraction of 40% or less. Pioglitazone produced earlier heart failure and more cardiovascular deaths, hospitalizations, or emergency visits for heart failure than glyburide (13% vs 8%). A Medicare analysis of 227,571 users found a higher heart failure risk with rosiglitazone than with pioglitazone (HR 1.25).

The 2022 AHA/ACC/HFSA guideline classifies thiazolidinediones as Class 3: Harm in HFrEF, and the American Diabetes Association advises avoiding them in symptomatic heart failure. The fluid retention reverses on withdrawal. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the preferred glucose-lowering drugs in heart failure.

Dipeptidyl peptidase-4 inhibitors, sulfonylureas, and metformin in heart failure

The dipeptidyl peptidase-4 (DPP-4) inhibitors differ by agent. SAVOR-TIMI 53 enrolled 16,492 patients with type 2 diabetes at high cardiovascular risk, 12.8% of whom had heart failure. Saxagliptin did not change cardiovascular death, myocardial infarction, or stroke, but hospitalization for heart failure increased (HR 1.27; 95% CI 1.07–1.51). The excess was greatest in patients with elevated natriuretic peptides, prior heart failure, or chronic kidney disease. In EXAMINE, alogliptin after acute coronary syndrome produced a nonsignificant difference in heart failure admission (3.1% vs 2.9%; HR 1.07; 95% CI 0.79–1.46). Sitagliptin in TECOS had no effect on heart failure hospitalization. A meta-analysis of randomized trials of all DPP-4 inhibitors found a small overall increase in acute heart failure (odds ratio [OR] 1.19; 95% CI 1.03–1.37), driven mainly by saxagliptin.

The 2022 AHA/ACC/HFSA guideline states that saxagliptin and alogliptin increase the risk of heart failure hospitalization and should be avoided in patients with heart failure (Class 3: Harm). The mechanism is unknown.

Sulfonylureas were associated with 20% to 30% higher heart failure risk than metformin in large retrospective cohorts, a finding not reproduced in UKPDS, ADOPT, or NAVIGATOR. Metformin is no longer contraindicated in heart failure. The FDA removed heart failure as a contraindication in 2006 after observational data showed lower mortality and no excess lactic acidosis. In 2016 it set the contraindication at an eGFR below 30 mL/min/1.73 m². Metformin is withheld in unstable or hospitalized patients with heart failure, in whom hypoperfusion and renal dysfunction coexist.

NSAIDs and COX-2 inhibitors

Nonselective NSAIDs and selective COX-2 inhibitors inhibit renal prostaglandin synthesis. In a patient with heart failure, renal blood flow and sodium excretion depend on vasodilator prostaglandins. Inhibition causes sodium and water retention, raises systemic vascular resistance, lowers glomerular filtration, and blunts the response to loop diuretics. With renin-angiotensin blockade, it also causes hyperkalemia. A single prescription can reverse decongestion achieved in hospital.

The largest dataset is a nested case-control study of 92,163 heart failure admissions matched with 8,246,403 controls. Current use of any NSAID raised the odds of admission (OR 1.19; 95% CI 1.17–1.22). The odds rose with seven traditional NSAIDs and two COX-2 inhibitors, from 1.16 for naproxen to 1.83 for ketorolac, and roughly doubled with very high doses of diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib. Celecoxib at commonly used doses did not increase the risk. Danish registry data cited in the AHA statement showed dose-related increases in heart failure hospitalization, myocardial infarction, and death with both coxibs and traditional NSAIDs in patients discharged with heart failure.

The 2022 AHA/ACC/HFSA guideline states that NSAIDs worsen heart failure symptoms in HFrEF and should be avoided or withdrawn whenever possible (Class 3: Harm; level of evidence B-NR). Acetaminophen is the analgesic of choice, and the European consensus lists topical NSAIDs as a safer alternative. Over-the-counter cold and sinus preparations often contain ibuprofen, which patients do not recognize as an NSAID. The hypertensive effect of NSAIDs is covered in Secondary hypertension.

Calcium channel blockers in heart failure

Verapamil and diltiazem reduce L-type calcium entry into myocytes and nodal cells, lowering contractility, heart rate, and AV conduction. Their vasodilation is too weak to offset the negative inotropy. In the Multicenter Diltiazem Postinfarction Trial, 2,466 patients after myocardial infarction were randomized to diltiazem or placebo. Among the 490 with pulmonary congestion at baseline, diltiazem increased adverse cardiac events (HR 1.41; 95% CI 1.01–1.96), and the risk rose with the severity of baseline heart failure. The 2022 AHA/ACC/HFSA guideline classifies nondihydropyridine calcium channel blockers as Class 3: Harm in HFrEF.

The dihydropyridines vary. Nifedipine worsened heart failure in small trials (5 of 21 patients hospitalized vs 0 of 20 with isosorbide dinitrate). Amlodipine had a neutral effect on mortality in PRAISE-2 (HR 0.97; 95% CI 0.83–1.13), with more peripheral and pulmonary edema and less uncontrolled hypertension and angina. Amlodipine and felodipine are therefore the calcium channel blockers used for hypertension or angina that persists after guideline-directed medical therapy (GDMT) is optimized.

In atrial fibrillation with rapid ventricular response and new left ventricular dysfunction, the ejection fraction may be low because of the tachycardia. The European consensus considers short-term, closely monitored use of a nondihydropyridine agent acceptable in carefully selected patients of this kind. The risk of decompensation remains, and beta-blockers, digoxin, or amiodarone are preferred for rate control in HFrEF.

Antiarrhythmic drugs that worsen heart failure

Class I antiarrhythmic drugs block sodium channels, and several are negative inotropes. Disopyramide is the most depressant. Among 100 patients started on oral disopyramide for ventricular arrhythmias, 16 developed heart failure within 48 hours, 12 of whom had prior heart failure. Flecainide lowers ejection fraction in patients with preexisting dysfunction, and in the Cardiac Arrhythmia Suppression Trial (CAST), encainide and flecainide increased mortality after myocardial infarction despite suppressing ventricular ectopy. The 2022 AHA/ACC/HFSA guideline classifies class IC drugs as Class 3: Harm in HFrEF because of increased mortality. Disopyramide retains a role in obstructive hypertrophic cardiomyopathy with preserved ejection fraction, where negative inotropy reduces the outflow gradient.

Sotalol combines beta-blockade with potassium channel block. In premarketing studies, new or worsened heart failure occurred in 3% of patients without prior heart failure and in 10% of those with it. Ibutilide causes little hemodynamic change at an ejection fraction of 35% or less, but heart failure independently increases the risk of ibutilide-induced torsades de pointes.

Dronedarone reduced cardiovascular hospitalization and death in ATHENA. In ANDROMEDA, patients hospitalized with symptomatic heart failure and severe left ventricular dysfunction had higher mortality with dronedarone than with placebo (8.1% vs 3.8%; HR 2.13; 95% CI 1.07–4.25), largely from worsening heart failure. The trial was stopped early. In PALLAS, dronedarone in high-risk permanent atrial fibrillation increased cardiovascular death, stroke, and heart failure hospitalization. The label contraindicates dronedarone in NYHA class IV heart failure, in symptomatic heart failure with recent decompensation requiring hospitalization, and in permanent atrial fibrillation. The 2022 guideline classifies dronedarone with the class IC drugs as Class 3: Harm in HFrEF.

Amiodarone and dofetilide are the antiarrhythmic drugs used for rhythm control in HFrEF. Their selection, dosing, and monitoring are covered in Antiarrhythmic drugs, and their QT effects in Long QT syndrome and QT prolongation.

Antihypertensive, vasodilator, pulmonary, and steroid drugs that worsen heart failure

Alpha-1 blockers. In ALLHAT, the doxazosin arm was stopped early because heart failure was doubled compared with chlorthalidone (relative risk 2.04; 95% CI 1.79–2.32). Proposed explanations include fluid retention from renin and aldosterone activation, less blood pressure reduction, and unmasking of heart failure when protective drugs were stopped at randomization. Prazosin did not reduce mortality in V-HeFT I, whereas hydralazine with isosorbide dinitrate did. In 388 patients with heart failure who took an alpha-1 blocker for benign prostatic hyperplasia (58% took tamsulosin), exposure was associated with more heart failure hospitalization in patients not taking a beta-blocker (HR 1.94; 95% CI 1.14–3.32). It was not associated with hospitalization in those taking one.

Central sympatholytics. In MOXCON, sustained-release moxonidine in 1,934 patients with NYHA class II–IV HFrEF lowered plasma norepinephrine by 18.8%. The trial was stopped early for excess mortality (5.5% vs 3.4%), with more heart failure hospitalization and myocardial infarction. Rapid withdrawal of sympathetic support is the presumed mechanism. Clonidine has favorable hemodynamic effects in small studies but causes sinus bradycardia and AV block, and abrupt cessation produces rebound hypertension.

Minoxidil. In a small randomized trial, minoxidil 20 mg twice daily raised ejection fraction from 29.6% to 42.7% at 3 months. It also produced more clinical events (worsening heart failure, increased diuretic requirement, death) than placebo (21 vs 7 events). Minoxidil also causes pericardial effusion, described in the section on pericardial disease.

Cilostazol and anagrelide. Cilostazol raises heart rate by 5 to 7 beats/min and increases ventricular premature beats and nonsustained ventricular tachycardia at all doses. It has never been studied in heart failure and is contraindicated in heart failure of any severity. Anagrelide-induced heart failure occurred in 2.4% of patients in one series, two of whom died suddenly, and often follows a dose increase.

Pulmonary vasodilators. In the FIRST trial, chronic epoprostenol increased mortality in NYHA class IIIB–IV HFrEF, and it is contraindicated for long-term use in that population. Bosentan caused leg edema in 5% of patients vs 1% with placebo in pulmonary hypertension studies, and in HFrEF trials (REACH, ENABLE) it produced early worsening of heart failure from fluid retention. Pulmonary vasodilators in pulmonary hypertension due to left heart disease are discussed in Pulmonary hypertension.

Beta-2 agonists. Inhaled beta-2 agonists were associated with a dose-related increase in admissions for worsening heart failure (adjusted OR 1.8 for one or two canisters per month and 2.1 for three or more). Systemic beta-2 agonists were associated more strongly with ventricular arrhythmia. Oral beta-2 agonists are avoided in heart failure. Inhaled agents are used at the lowest effective frequency, with long-acting muscarinic antagonists and inhaled corticosteroids as maintenance alternatives in coexisting chronic obstructive pulmonary disease.

Glucocorticoids and mineralocorticoids. Glucocorticoids promote sodium retention, hypertension, insulin resistance, and dyslipidemia. In observational data summarized by the European consensus, high-dose glucocorticoid therapy was associated with heart failure (OR 2.66). The OR rose from 1.95 below 7.5 mg/day of prednisolone equivalent to 3.69 above 20 mg/day. Fludrocortisone opposes mineralocorticoid receptor antagonists. Short courses in acute heart failure have not shown harm.

Ophthalmic beta-blockers. Timolol eye drops are absorbed systemically through the nasolacrimal mucosa without first-pass metabolism. Bradycardia, hypotension, bronchospasm, and pulmonary edema have been reported in patients with heart failure, and they resolve with dose reduction or withdrawal.

Beta-blockers during acute decompensation. Beta-blockers are foundational in HFrEF, but initiation or rapid up-titration in a congested patient can precipitate decompensation, and they are started once volume status is optimized. Patients admitted with decompensation who are already taking a beta-blocker usually continue it in the absence of cardiogenic shock or symptomatic bradycardia, because withdrawal is associated with worse outcomes. Titration problems are covered in Heart failure with reduced ejection fraction.

Sodium load from medications. Intravenous antibiotics and some oral formulations carry substantial sodium. In 82 patients admitted to a cardiac intensive care unit for acute heart failure, the mean nondietary sodium load was 4.0 g/day, and higher loads correlated with longer stays.

Selected high-sodium medications from Table 6 of the 2016 AHA statement.

Anti-infective, rheumatologic, and neurologic drugs that worsen heart failure

Itraconazole. Between 1992 and 2001, 58 cases of heart failure with itraconazole were reported to the FDA, with 28 hospital admissions and 13 deaths. Itraconazole is negatively inotropic, and the risk is higher at doses of 400 mg/day or more. The FDA advises against itraconazole for onychomycosis in patients with ventricular dysfunction or a history of heart failure, and reserves it for life-threatening fungal infection. Itraconazole is also a strong CYP3A4 inhibitor that raises exposure to verapamil, diltiazem, simvastatin, and eplerenone. Amphotericin B, conventional and liposomal, has caused dilated cardiomyopathy that resolved 10 days to 6 months after withdrawal, and its hypokalemia increases digoxin toxicity.

Macrolides and other antimicrobials. Clarithromycin during exacerbations of chronic obstructive pulmonary disease or pneumonia has been associated with more cardiovascular events and heart failure in observational cohorts. The European consensus prefers azithromycin when a macrolide is needed. Trimethoprim-sulfamethoxazole causes hyperkalemia with renin-angiotensin blockers and mineralocorticoid receptor antagonists.

Tumor necrosis factor-alpha inhibitors. In the ATTACH trial, 150 patients with NYHA class III–IV heart failure and an ejection fraction of 35% or less received placebo or infliximab 5 or 10 mg/kg. Neither dose improved clinical status, and the 10-mg/kg dose increased death or heart failure hospitalization (HR 2.84; 95% CI 1.01–7.97). Etanercept had no benefit in RENAISSANCE and RECOVER. In patients with rheumatoid arthritis, observational data show no overall increase in heart failure but a higher risk of hospitalization and death in those aged 65 years or older. Infliximab is avoided in moderate to severe heart failure and is not given above 5 mg/kg. The 2015 American College of Rheumatology guideline restricts tumor necrosis factor-alpha inhibitors in heart failure to compensated patients without a reasonable alternative.

Pregabalin and carbamazepine. Pregabalin causes peripheral edema in 6% of patients vs 2% with placebo, probably through calcium channel modulation. The FDA advises caution in NYHA class III–IV heart failure, especially with a thiazolidinedione. Carbamazepine, structurally related to the tricyclic antidepressants, causes hypotension, bradycardia, and AV block, and severe ventricular dysfunction with ejection fraction below 35% has been reported only in overdose. Duloxetine is a hemodynamically neutral alternative for neuropathic pain.

Dopamine agonists. In a cohort of 26,814 users of antiparkinsonian drugs, current use of any dopamine agonist was associated with heart failure (rate ratio 1.58), highest with pramipexole (1.86) and cabergoline (2.07). In 25,459 patients with Parkinson disease, pramipexole was associated with heart failure, most within the first 3 months and in patients aged 80 years or older. The FDA issued a safety communication in 2012.

Lithium. At therapeutic concentrations (0.6–1.2 mEq/L), lithium has been associated with sinus node dysfunction, AV block, ventricular premature beats, T-wave changes, interstitial myocarditis, and cardiomyopathy, most of which resolved on withdrawal. The European consensus advises against lithium in HFrEF, with valproate or lamotrigine as alternatives.

Antidepressants. Tricyclic antidepressants cause sinus tachycardia, orthostatic hypotension, QRS and QT prolongation, and second-degree or third-degree AV block through sodium channel block, alpha-adrenergic blockade, and anticholinergic effects. Selective serotonin reuptake inhibitors had minimal effect on electrocardiographic (ECG) and echocardiographic indices in prospective studies of patients with heart failure, recent infarction, or unstable angina. Citalopram prolongs the QT interval in a dose-dependent manner, and its maximum dose is 40 mg/day.

Anesthetic agents. Volatile anesthetics are negatively inotropic but are preferred for maintenance in ventricular dysfunction because of hemodynamic stability and preconditioning. Propofol lowers preload and blunts baroreflexes. Ketamine stimulates the sympathetic system but is negatively inotropic, and in severe left ventricular dysfunction with depleted catecholamine stores the net effect can be depression. Etomidate causes the least cardiovascular depression and is used for induction, not maintenance, because it suppresses adrenal steroidogenesis.

Stimulant, recreational, and anabolic drug cardiomyopathy

Methamphetamine. Methamphetamine-associated heart failure is increasing in prevalence and has a male predominance. In a systematic review of 21 observational studies, up to 44% of affected patients had preserved ejection fraction, and symptoms were worse than in heart failure from other causes. The left ventricle is dilated, and pulmonary pressures are often raised. Female sex, abstinence, and GDMT were associated with recovery, and chamber size on echocardiography and the extent of fibrosis on biopsy predicted how much the ventricle recovered after abstinence. Methamphetamine also causes pulmonary arterial hypertension, which is covered in Pulmonary arterial hypertension.

Cocaine. Cocaine blocks presynaptic catecholamine reuptake and sodium channels. It causes coronary vasospasm and thrombosis, myocarditis with contraction band necrosis, catecholamine-mediated left ventricular dysfunction, aortic dissection, and ventricular arrhythmia, and chronic use produces left ventricular hypertrophy and dilated cardiomyopathy. Cocaine-associated chest pain and acute toxicity are covered in Cardiovascular toxicology.

Prescription stimulants. Amphetamine, dextroamphetamine, and methylphenidate raise blood pressure by a few millimeters of mercury. Case reports describe sudden death, myocardial infarction, stroke, and cardiomyopathy, but large epidemiologic studies in children and adults found no increase in serious cardiovascular events. The 2016 AHA statement lists them as myocardiotoxic and not generally used in heart failure.

Alcohol. Alcoholic cardiomyopathy is a dilated cardiomyopathy attributed to heavy intake, generally more than 80 g/day for at least 5 years, after other causes are excluded. Ethanol and acetaldehyde cause oxidative stress, mitochondrial dysfunction, and impaired actin-myosin interaction. Truncating variants in the titin gene are overrepresented, consistent with a genetic predisposition. Abstinence is the central treatment, combined with GDMT for HFrEF. Some patients recover ejection fraction, and recovery carries an excellent prognosis. Alcohol and cardiovascular risk are covered in Alcohol, stimulants and substance use and the heart.

Anabolic-androgenic steroids. Long-term illicit use is associated with reduced left ventricular systolic and diastolic function and with more coronary atherosclerosis than in nonusers. The steroids also raise low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, raise blood pressure, and increase hematocrit.

Cannabis. The 2020 AHA scientific statement on cannabis describes associations between cannabis use and myocardial infarction, arrhythmia, and stroke, mainly from observational data with confounding by tobacco. Smoked cannabis delivers combustion products similar to tobacco smoke. Synthetic cannabinoids have been associated with more severe cardiotoxicity.

Decongestants and herbal stimulants. Pseudoephedrine, phenylephrine, ephedrine, and ephedra-like products raise blood pressure and heart rate and can provoke ischemia and arrhythmia at high doses or with prolonged use. The 2016 AHA statement advises that ephedra-like products be avoided in heart failure.

Clozapine and other antipsychotic myocarditis and cardiomyopathy

Clozapine is the most cardiotoxic antipsychotic. In Australian pharmacovigilance data, the incidence of clozapine myocarditis over 10 years was 0.7% to 1.2% of treated patients. Onset was within the first 2 months and was not related to dose. Of affected patients, 52% recovered and 10% died. In a series of 75 cases, onset fell between days 10 and 33, and 83% of cases began between days 14 and 21. Of about 190,000 US patients treated between 1989 and 1999, 28 cases of myocarditis with 18 deaths and 41 cases of cardiomyopathy with 10 deaths were reported to the FDA. Cardiomyopathy appears later, at an average of 6 to 9 months.

The presentation is often nonspecific: fever, tachycardia above the expected clozapine-induced rise, chest pain, dyspnea, or influenza-like symptoms, with eosinophilia in some patients. Troponin was at least twice the upper limit of normal in 90% of cases in the Australian series. The mechanism is thought to be an IgE-mediated hypersensitivity reaction, with catecholamine excess and inflammatory mediators as contributors.

Monitoring protocol for clozapine myocarditis derived from 75 cases and 94 controls. The combination of troponin and CRP thresholds had an estimated sensitivity of 100% for symptomatic myocarditis in that series; sensitivity for asymptomatic disease is unknown.

Treatment is withdrawal of clozapine and standard management of myocarditis and ventricular dysfunction. Because clozapine is often the only effective drug for treatment-resistant schizophrenia, rechallenge after complete recovery is sometimes undertaken jointly by psychiatry and cardiology with slow titration and the same troponin and CRP surveillance. Recurrence has been reported. Olanzapine and other atypical antipsychotics have been linked to isolated cases of myocarditis and cardiomyopathy. All antipsychotics cause orthostatic hypotension through alpha-1 blockade, and many prolong the QT interval.

Hypersensitivity and eosinophilic drug myocarditis

Hypersensitivity myocarditis is an idiosyncratic, delayed-type immune reaction to a drug, characterized histologically by interstitial infiltrates rich in eosinophils with little myocyte necrosis. It is independent of dose and cumulative exposure. Frequently implicated drugs include sulfonamides, beta-lactam antibiotics, minocycline, anticonvulsants (carbamazepine, phenytoin), clozapine, and dobutamine during prolonged infusion. The 2016 AHA statement lists lenalidomide as a cause of hypersensitivity myocarditis. It may occur as part of drug reaction with eosinophilia and systemic symptoms (DRESS), with rash, fever, eosinophilia, and hepatitis.

The clinical picture ranges from asymptomatic troponin elevation to fulminant myocarditis with ventricular arrhythmia. Peripheral eosinophilia supports the diagnosis but is absent in some cases. CMR shows edema and nonischemic late gadolinium enhancement, and endomyocardial biopsy confirms the diagnosis and distinguishes it from necrotizing eosinophilic myocarditis and giant cell myocarditis. Treatment is withdrawal of the drug and corticosteroids, with mechanical support for cardiogenic shock. Immune checkpoint inhibitor myocarditis has a different mechanism and course and is covered in Immune checkpoint inhibitor myocarditis. The diagnostic pathway for myocarditis is covered in Myocarditis.

Hydroxychloroquine, chloroquine, and antiretroviral drug cardiomyopathy

Chloroquine and hydroxychloroquine are cationic amphiphilic drugs that accumulate in lysosomes and inhibit phospholipid degradation. The cardiac result is a vacuolar myopathy with myelin figures and curvilinear bodies on electron microscopy, producing concentric thickening, a restrictive or hypertrophic phenotype, and conduction disease.

In a systematic review of 127 reported patients, 58% had taken chloroquine and 39% hydroxychloroquine. Treatment had lasted a median of 7 years, and the median cumulative dose was 1,235 g for hydroxychloroquine and 803 g for chloroquine. Conduction disorders affected 85%, heart failure 27%, ventricular hypertrophy 22%, and valvular dysfunction 7%. Of 78 patients withdrawn from treatment, 45% recovered normal function, 13% had irreversible damage, and 31% died. Risk factors include older age, female sex, long duration, high daily dose per kilogram, preexisting cardiac disease, and renal insufficiency.

Bundle branch block, fascicular block, or AV block in a patient taking long-term hydroxychloroquine is an early warning sign, even without symptoms. CMR may show late gadolinium enhancement. The lamellar bodies resemble those of Fabry disease, and normal alpha-galactosidase A activity distinguishes the drug toxicity from Fabry disease. Endomyocardial biopsy with electron microscopy is the diagnostic standard. Treatment is withdrawal of the drug, pacing for advanced conduction disease, and GDMT. Short-term hydroxychloroquine therapy also prolongs the QT interval, a separate effect covered in Long QT syndrome and QT prolongation.

Antiretroviral drugs. Zidovudine and other early nucleoside reverse transcriptase inhibitors inhibit mitochondrial DNA polymerase gamma and have been associated with mitochondrial myopathy and cardiomyopathy. Some protease inhibitors prolong the PR interval. In contemporary regimens, the cardiovascular concern is mainly atherosclerotic risk and drug interactions through CYP3A4 inhibition by ritonavir and cobicistat.

Tachycardia-mediated, bradycardia-mediated, and stress cardiomyopathy from drugs

Some drugs injure the ventricle through the heart rate. Sustained drug-induced tachycardia, from theophylline, excess thyroid hormone, sympathomimetics, or beta-2 agonists, can produce tachycardia-mediated cardiomyopathy that recovers with rate control. Class IC drugs slow atrial flutter enough to permit 1:1 AV conduction with a very fast ventricular rate, which is why they are given with an AV nodal blocker.

Bradycardia-mediated heart failure is underrecognized. Excess nodal blockade, especially beta-blocker combined with diltiazem, verapamil, or digoxin, produces chronotropic incompetence and a fixed low cardiac output. In a patient with a stiff ventricle that cannot raise stroke volume, the result is congestion that responds to reducing the nodal blocker, not to more diuretic. When a nodal blocker is indispensable and bradycardia limits it, pacing permits the drug to continue.

High-dose catecholamines and stimulants, including epinephrine given by error, dobutamine, and some chemotherapy, trigger takotsubo syndrome, covered in Takotsubo syndrome.

Recognition and treatment of drug-induced cardiomyopathy

Drug-induced cardiomyopathy is a diagnosis of exclusion with a time course. The evaluation establishes the temporal relationship between exposure and onset, excludes ischemic, valvular, hypertensive, genetic, inflammatory, and infiltrative causes, and looks for features specific to the suspected drug.

Clinical patterns that point to a specific drug cause.

Echocardiography establishes the phenotype. CMR characterizes edema, fibrosis, and infiltration and helps distinguish myocarditis from storage disease. Endomyocardial biopsy is indicated when the diagnosis changes treatment, as in suspected hypersensitivity or giant cell myocarditis and in suspected antimalarial toxicity, where electron microscopy is diagnostic. Coronary evaluation follows standard indications.

Treatment combines withdrawal of the drug with GDMT according to ejection fraction, as for any cardiomyopathy. The four foundational drug classes for HFrEF are started even when recovery is expected, because recovery is not assured and GDMT promotes it. Ejection fraction is reassessed after withdrawal and titration, and defibrillator decisions for primary prevention are deferred while recovery is possible. Patients whose ejection fraction recovers meet criteria for heart failure with improved ejection fraction, in which GDMT is continued. Management is covered in Heart failure with reduced ejection fraction and Dilated cardiomyopathy.

Drug-induced bradycardia and atrioventricular block

Drugs slow the heart by suppressing sinus node automaticity, prolonging AV nodal conduction and refractoriness, or blocking conduction in the His-Purkinje system. Sinus node and AV node action potentials depend on calcium current and autonomic tone, so beta-blockers, calcium channel blockers, digoxin, and cholinergic drugs act there. Sodium channel blockers act mainly below the node and widen the QRS complex. Drugs are the most common reversible cause of bradycardia, usually as a combination of two or more nodal blockers in an older patient whose kidney function has declined.

Drugs that cause sinus bradycardia, sinus pauses, and AV block, compiled from the 2018 ACC/AHA/Heart Rhythm Society (HRS) bradycardia guideline, the 2020 AHA statement on drug-induced arrhythmias, and the 2016 AHA statement. Antidote doses for acute toxicity are listed in Bradycardia and atrioventricular block.

Drug effects interact with the level of block. Nodal blockers prolong the PR interval and produce Mobitz I block, and they rarely cause isolated infranodal block. Sodium channel blockers, hyperkalemia, and storage disease produce bundle branch block, Mobitz II block, and complete heart block with a wide escape rhythm. A wide-QRS escape rhythm in a patient taking only beta-blockers points to intrinsic His-Purkinje disease, not drug effect. Bradycardia also lengthens the QT interval of the following beat, so a QT-prolonging drug given during sinus bradycardia or AV block predisposes to pause-dependent torsades de pointes.

Prognosis of drug-related atrioventricular block and the decision to pace

Attribution of AV block to a drug is often wrong. Among 169 consecutive patients with second-degree or third-degree AV block not caused by infarction, digoxin toxicity, or vasovagal syncope, 92 (54%) were taking a beta-blocker, verapamil, or diltiazem. Their clinical and ECG features matched those of patients with block and no drug. Withdrawal of the drug resolved the block in 41%, compared with spontaneous improvement in 23% of patients with block who took no drug. Among patients whose block resolved after withdrawal, 56% had recurrence of AV block without the drug. AV block truly caused by the drug was found in only 15% of patients who developed block on these agents.

Prognosis of AV block related to nodal blocking drugs after discontinuation of the drug.

The 2018 ACC/AHA/HRS guideline reflects these data. For selected patients with symptomatic second-degree or third-degree AV block on chronic stable doses of a medically necessary antiarrhythmic drug or beta-blocker, permanent pacing without further observation for drug washout or reversibility is reasonable (Class 2a; level of evidence B-NR). In sinus node dysfunction, symptomatic bradycardia that results from clinically necessary guideline-directed drug therapy with no alternative is an indication for permanent pacing (Class 1; level of evidence C-EO). AV block from transient or reversible causes, including drug toxicity, is managed with medical therapy, supportive care, and temporary pacing when necessary before the need for permanent pacing is determined (Class 1; level of evidence B-NR). Permanent pacing is not performed when acute AV block from a known reversible and nonrecurrent cause resolves completely with treatment of that cause (Class 3: Harm; level of evidence C-LD).

An acute presentation with block after a newly started or recently increased dose, a supratherapeutic drug level, or kidney injury that raised exposure is managed with withdrawal and temporary support, followed by ambulatory monitoring after recovery. Block on long-standing stable doses, block with a wide QRS or infranodal level, and recurrence after rechallenge favor intrinsic conduction disease and pacing. Indications, pacing mode, and acute management are covered in Bradycardia and atrioventricular block. Overdose with hemodynamic collapse is covered in Cardiovascular toxicology and digoxin toxicity in Digoxin.

Cholinesterase inhibitors, sphingosine-1-phosphate modulators, ticagrelor, and other specific causes of bradycardia

Cholinesterase inhibitors. In 19,803 community-dwelling older adults with dementia treated with a cholinesterase inhibitor and 61,499 controls, users had more hospital visits for syncope (31.5 vs 18.6 per 1,000 person-years; HR 1.76), bradycardia (6.9 vs 4.4; HR 1.69), permanent pacemaker insertion (4.7 vs 3.3; HR 1.49), and hip fracture (22.4 vs 19.8; HR 1.18). Donepezil, rivastigmine, and galantamine are therefore reviewed in any older patient with syncope, falls, or bradycardia, and a pacemaker is not implanted for bradycardia that resolves after the drug is stopped. A prescribing cascade follows when the syncope is attributed to intrinsic conduction disease and treated with a pacemaker while the drug continues.

Sphingosine-1-phosphate receptor modulators. Fingolimod and related drugs for multiple sclerosis activate atrial G protein–gated potassium channels at the first dose, slowing the sinus rate within hours and occasionally producing AV block. The US label for fingolimod requires 6 hours of observation after the first dose, with hourly pulse and blood pressure and an ECG before the dose and at the end of observation. Overnight monitoring is required when drug treatment for bradycardia is needed. First-dose monitoring is repeated when therapy restarts after an interruption of 1 day or more in the first 2 weeks, more than 7 days in weeks 3 and 4, or more than 14 days after the first month. Contraindications include myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, and class III–IV heart failure within the previous 6 months. Mobitz type II second-degree AV block, third-degree AV block, and sick sinus syndrome without a functioning pacemaker are also contraindications. A baseline corrected QT interval (QTc) of 500 ms or more and treatment with class Ia or class III antiarrhythmic drugs are contraindications as well. Siponimod, ozanimod, and ponesimod are started with dose titration to blunt the first-dose effect.

Ticagrelor. In the continuous ECG substudy of PLATO (2,908 patients), ventricular pauses of 3 seconds or more in the first week occurred in 5.8% with ticagrelor and 3.6% with clopidogrel (relative risk 1.61). Most pauses were asymptomatic, nocturnal, and sinoatrial in origin. At 1 month, pauses were similar with the two drugs (2.1% vs 1.7%), and syncope, pacemaker implantation, and cardiac arrest did not differ. The mechanism is thought to involve adenosine, whose cellular reuptake ticagrelor inhibits.

Ivabradine. Ivabradine slows the sinus node only and does not affect AV conduction. It is used in stable, symptomatic chronic heart failure with an ejection fraction of 35% or less, sinus rhythm, and a resting heart rate of 70 beats/min or more on maximally tolerated beta-blocker doses or with a contraindication to beta-blockers. It is contraindicated in acute decompensated heart failure, clinically significant hypotension or bradycardia, sick sinus syndrome, sinoatrial block, or third-degree AV block without a functioning demand pacemaker. Pacemaker dependence, severe hepatic impairment, and use with strong CYP3A4 inhibitors are also contraindications. Its use and dosing are covered in Heart failure with reduced ejection fraction.

Lithium and antiepileptic drugs. Lithium causes sinus node dysfunction, sinoatrial exit block, and occasionally AV block, usually at therapeutic levels and reversibly. Lacosamide prolongs the PR interval in a dose-related manner, and AV block has been reported, especially with other PR-prolonging drugs or in conduction disease. Carbamazepine causes sinus bradycardia and AV block, mainly in older patients.

Ophthalmic and perioperative drugs. Timolol eye drops cause bradycardia, AV block, and syncope in older adults, and the effect is often missed because eye drops are not recorded as medications. Dexmedetomidine causes bradycardia and hypotension in a dose-related manner, most often with a loading dose.

BRASH syndrome

BRASH syndrome is bradycardia, renal failure, AV nodal blockade, shock, and hyperkalemia occurring together. Hyperkalemia and an AV nodal blocking drug act synergistically, so the bradycardia is more severe than either would produce alone. The usual precipitant is hypovolemia or a drug that promotes hyperkalemia or kidney injury, often a renin-angiotensin blocker or a mineralocorticoid receptor antagonist. Bradycardia lowers renal perfusion, which worsens hyperkalemia and raises the concentration of renally cleared nodal blockers such as atenolol, nadolol, sotalol, and digoxin, and the cycle progresses to shock.

Potassium is often only moderately elevated, so the syndrome is mistaken for isolated nodal blocker overdose or isolated hyperkalemia. Treatment addresses all components at once: intravenous calcium, insulin with dextrose, and beta-agonist therapy for hyperkalemia; volume resuscitation when the patient is hypovolemic; diuresis to remove potassium; and chronotropic support, often with an epinephrine infusion. Glucagon, high-dose insulin, or lipid emulsion are used in refractory cases, and dialysis or transvenous pacing when these fail. The nodal blocker and the potassium-retaining drug are withheld, and the regimen is rebuilt after recovery with doses matched to kidney function.

Drug-induced hypotension and orthostatic hypotension

Orthostatic hypotension is defined as a sustained fall in systolic blood pressure of at least 20 mm Hg or in diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing or of head-up tilt to at least 60 degrees. In patients with supine hypertension, a fall in systolic pressure of 30 mm Hg is the accepted criterion. Drug-induced hypotension results from vasodilation, volume depletion, sympathetic blockade, or impaired heart rate response, and it presents as dizziness, falls, syncope, angina, acute kidney injury, or, in preload-dependent states, shock. Older adults, patients with autonomic failure from diabetes or Parkinson disease, and those taking several antihypertensive and psychotropic drugs are most susceptible. Many drugs that lower blood pressure are not prescribed as antihypertensives.

Drugs that cause hypotension and orthostatic hypotension, compiled from the consensus definition of orthostatic hypotension, a review of drug-related orthostatic hypotension beyond antihypertensive drugs, and the 2016 AHA statement.

Preload-dependent and afterload-fixed physiology turns modest vasodilation into shock. In severe aortic stenosis, obstructive hypertrophic cardiomyopathy, right ventricular infarction, cardiac tamponade, and severe pulmonary hypertension, nitrates, phosphodiesterase-5 inhibitors, and potent arterial vasodilators can lower blood pressure abruptly and without compensatory rise in output.

Evaluation measures supine and standing blood pressure at 1 and 3 minutes and reviews every drug, including over-the-counter sleep aids with antihistamine activity and alpha blockers prescribed for prostatic symptoms. Management is deprescribing or dose reduction, moving antihypertensive doses to bedtime when supine hypertension is not a concern, separating vasodilators in time, and correcting volume depletion. Pharmacologic treatment of neurogenic orthostatic hypotension and the evaluation of autonomic failure are covered in Orthostatic hypotension, POTS and autonomic disorders, and the evaluation of syncope in Syncope.

Drug-induced valvular heart disease: mechanism and pathology

Drug-induced valvular heart disease is a fibrotic, restrictive valvulopathy caused by drugs or metabolites that stimulate serotonin 5-HT_2B receptors on valvular interstitial cells. Stimulation activates mitogenic signaling, and myofibroblasts proliferate and deposit extracellular matrix. Norfenfluramine (the active metabolite of fenfluramine and dexfenfluramine), pergolide, cabergoline, ergotamine, methylergonovine (the active metabolite of methysergide), and MDMA are 5-HT_2B agonists. This receptor mechanism explains why structurally unrelated drugs produce an identical valve disease.

Pathologically, the leaflets and chordae are encased in plaque-like fibrous tissue with intact underlying architecture, giving the valves a glistening white appearance. The histology is identical to that of carcinoid valve disease and of ergotamine valvulopathy. Because carcinoid syndrome releases serotonin into the venous circulation and the lung inactivates it, carcinoid disease affects mainly the tricuspid and pulmonary valves. Drugs reach both sides of the heart through the circulation, so drug-induced disease affects the mitral and aortic valves at least as often as the right-sided valves.

Distinguishing drug-induced valvulopathy from carcinoid and rheumatic disease.

Drugs that cause valvular heart disease

Drugs associated with serotonergic valvulopathy and the evidence for each. The FDA case definition of drug-associated valvulopathy is aortic regurgitation of mild or greater severity or mitral regurgitation of moderate or greater severity.

Echocardiographic criteria, screening, and natural history of drug-induced valve disease

In November 1997 the US Department of Health and Human Services defined fenfluramine-associated valvulopathy as aortic regurgitation of mild or greater severity or mitral regurgitation of moderate or greater severity after exposure. The thresholds exclude trace or mild mitral regurgitation and trace aortic regurgitation, which are common in the general population. Early uncontrolled echocardiographic surveys of exposed patients reported prevalences around 30%, but controlled studies found lower and more variable excess risk. The 2016 AHA statement cites valvular regurgitation in 12% of patients treated for more than 90 days compared with 5.9% of unexposed patients (OR 2.2). Risk was concentrated in patients with longer exposure.

The echocardiographic appearance is diffuse leaflet thickening without commissural fusion, restricted leaflet motion, and apical displacement of the coaptation point. The mitral tenting area is increased and correlated with regurgitant severity in patients taking pergolide or cabergoline. Regurgitation is graded with the standard integrated methods, and transesophageal echocardiography defines the subvalvular apparatus when repair is considered. Severity determines management through the stages of the 2020 ACC/AHA valvular heart disease guideline, which apply to drug-induced primary regurgitation as they do to other causes. Valve-specific grading and indications are covered in Mitral regurgitation and Tricuspid regurgitation and tricuspid stenosis.

After withdrawal, regurgitation stabilizes or improves in some patients and progresses in others, and patients have required valve surgery years after the drug was stopped. Surgical specimens show the same plaque-like encasement of leaflets and chordae.

Echocardiographic screening is performed in three settings. Low-dose fenfluramine for epilepsy is prescribed through a REMS program with echocardiography before, during, and after treatment. Ergot-derived dopamine agonists, when used, are monitored with baseline and periodic echocardiography and stopped if restrictive valve disease develops. For cabergoline in hyperprolactinemia, regulatory recommendations, most stringent in Europe, call for baseline and periodic echocardiography. The higher prevalence of tricuspid regurgitation in the meta-analysis supports surveillance in long-term or high-cumulative-dose treatment. A patient with a past exposure to fenfluramine, benfluorex, or pergolide and a new murmur, dyspnea, or unexplained regurgitation undergoes echocardiography, and the exposure is recorded as a cause once other causes are excluded.

Appetite suppressants, methamphetamine, and dasatinib also cause pulmonary arterial hypertension. Drug-induced pulmonary arterial hypertension is classified in group 1 and is covered in Pulmonary arterial hypertension.

Drug-induced pericarditis, pericardial effusion, and lupus-like syndromes

Drugs cause pericardial disease by inducing a lupus-like autoimmune syndrome, by direct hypersensitivity, by fluid retention, by fibrosis, or by bleeding into the pericardium.

Drug causes of pericarditis and pericardial effusion.

Drug-induced lupus resembles idiopathic systemic lupus erythematosus but usually lacks its major complications. Serositis, arthralgia, myalgia, and fever predominate, and renal and central nervous system disease are uncommon with the classic drugs. Antihistone antibodies are present in most cases from procainamide and hydralazine, whereas anti-double-stranded DNA antibodies are uncommon except with tumor necrosis factor-alpha inhibitors. The mechanism probably involves drug metabolites that enhance neutrophil activation and neutrophil extracellular trap formation, exposing autoantigens. Symptoms resolve within weeks to months of withdrawal, and pericarditis is treated with an NSAID or a short course of glucocorticoid when needed. Hydralazine-associated vasculitis requires withdrawal of the drug and often immunosuppression, and tamponade requires drainage.

The general approach to pericarditis, effusion, and tamponade is covered in Acute and recurrent pericarditis and constriction in Constrictive pericarditis.

Cancer therapy, QT prolongation, drug-induced hypertension, and overdose

Cancer therapy cardiotoxicity. Anthracyclines cause dose-dependent, largely irreversible cardiomyopathy, and human epidermal growth factor receptor 2 (HER2)–targeted therapy causes dysfunction that is often reversible. These are covered in Cancer therapy-related cardiac dysfunction. Fluoropyrimidine vasospasm, vascular endothelial growth factor (VEGF) inhibitor hypertension and heart failure, and tyrosine kinase inhibitor arrhythmia are covered in Cardiovascular toxicity of targeted cancer therapies, and immune checkpoint inhibitor myocarditis in its own page.

Drug-induced QT prolongation and torsades de pointes. Block of the rapid delayed rectifier potassium current underlies most drug-induced QT prolongation. Risk depends on the drug, the dose, interactions, electrolytes, bradycardia, female sex, and heart failure. Drug lists, QTc thresholds, monitoring, and treatment of torsades are covered in Long QT syndrome and QT prolongation.

Drug-induced hypertension. NSAIDs, glucocorticoids, calcineurin inhibitors, VEGF inhibitors, erythropoietin, stimulants, decongestants, serotonin-norepinephrine reuptake inhibitors, oral contraceptives, and licorice raise blood pressure, and abrupt clonidine withdrawal produces rebound hypertension. These are covered in Secondary hypertension.

Overdose and poisoning. Beta-blocker and calcium channel blocker overdose, sodium channel blocker poisoning, local anesthetic toxicity, and cocaine-associated chest pain are covered in Cardiovascular toxicology.

Herbal, over-the-counter, and complementary products

Over-the-counter and complementary products are a frequent and often undisclosed cause of cardiovascular adverse effects, and many patients believe that the government regulates them as it does prescription drugs. The 2016 AHA statement recommends asking specifically about them at every visit. Cold and sinus preparations contain NSAIDs and the vasoconstrictors phenylephrine or pseudoephedrine, which can cause ischemia, stroke, and arrhythmia at high doses. Topical nasal decongestants (oxymetazoline, phenylephrine) used beyond labeled limits have caused hypertension, stroke, and bradycardia. Some antacids and effervescent products carry a large sodium load.

Complementary and alternative products with cardiovascular effects or interactions, from Tables 7 and 9 of the 2016 AHA statement.

Establishing causality: temporal relationship, dechallenge, and rechallenge

Attribution of a cardiovascular event to a drug rests on five lines of evidence: a plausible time from exposure to onset, a known mechanism or prior reports, improvement after withdrawal (positive dechallenge), recurrence on re-exposure (positive rechallenge), and the absence of a better explanation. Concentration and dose-response add support. The time to onset in the AHA statement, from immediate for NSAIDs and negative inotropes to delayed for valvulopathy and antimalarial cardiomyopathy, defines the plausible window for each drug.

Dechallenge is informative only when the expected recovery time is known. Fluid retention from a thiazolidinedione or an NSAID resolves within days to weeks, sinus node effects of amiodarone take weeks to months, and valve fibrosis may never regress. Persistence after withdrawal does not exclude a drug cause, and recovery after withdrawal does not prove one, because conditions such as AV block, myocarditis, and atrial fibrillation fluctuate on their own.

Rechallenge provides the strongest evidence and carries the most risk. It is not used for life-threatening reactions such as hypersensitivity myocarditis, clozapine myocarditis with ventricular dysfunction, or high-grade AV block without pacing, unless the drug is essential, no alternative exists, and the patient is monitored. Unintentional rechallenge, when a patient restarts a drug or receives a related agent, is documented because it often settles causality.

The Naranjo adverse drug reaction probability scale scores ten questions and classifies the reaction as definite, probable, possible, or doubtful. It was designed for clinical trials and case reports, its agreement between observers is modest for some reactions, and it does not replace clinical judgment. It structures documentation and reporting.

Scoring: 9 or more, definite; 5 to 8, probable; 1 to 4, possible; 0 or less, doubtful. Pioglitazone-associated congestion that resolved after withdrawal, with objective weight gain and edema and no competing cause, scores 7 (probable).

Reporting adverse drug reactions: MedWatch and FAERS

Postmarketing surveillance in the United States depends on spontaneous reports. Health professionals and patients report serious adverse events voluntarily to the FDA MedWatch program, online or on Form 3500, whereas manufacturers are required to report adverse events they learn about. Reports enter the FDA Adverse Event Reporting System (FAERS), where they are coded and analyzed for disproportionate reporting signals. A report does not require proof of causality, and a suspected association is sufficient.

Spontaneous reporting detects rare and unexpected reactions that trials are too small or too short to find, such as itraconazole-associated heart failure and clozapine myocarditis. Its limits are underreporting, the absence of a denominator, reporting stimulated by publicity, and confounding by indication. Signals are tested in observational databases and, when possible, in trials, as with the dopamine agonist and NSAID heart failure signals. The results are labeling changes, safety communications, boxed warnings, restricted distribution programs such as the low-dose fenfluramine REMS, and market withdrawal, as with fenfluramine and pergolide.

A useful report records the drug, dose, start and stop dates, indication, concomitant drugs, the time to onset, the event with objective evidence (ECG, echocardiogram, troponin, biopsy), the response to withdrawal and any rechallenge, and the outcome.

Prevention: medication reconciliation and deprescribing

Recommendations for minimizing polypharmacy and improving drug safety in heart failure from the 2016 AHA statement.

Safer alternatives exist for most drugs that worsen heart failure, and substitution is the usual intervention.

Alternatives to drugs that cause or worsen heart failure, adapted from the 2025 European consensus and the 2022 AHA/ACC/HFSA guideline.

Deprescribing is done by tapering where withdrawal phenomena occur. Beta-blockers are reduced gradually to avoid rebound tachycardia and ischemia, clonidine is tapered to avoid rebound hypertension, and antipsychotic or antidepressant changes are coordinated with the prescribing psychiatrist. Computer-based clinical decision support with drug-interaction alerts reduced prescriptions of QT-prolonging drugs in studies summarized in the 2020 AHA statement on drug-induced arrhythmias.

Older adults, kidney disease, pregnancy, and heart failure phenotype

Older adults. Drug-induced orthostatic hypotension, bradycardia, and falls concentrate in older adults, in whom alpha-1 blockers, cholinesterase inhibitors, antipsychotics, tricyclic antidepressants, and combinations of nodal blockers are common. Doses are adjusted to kidney function estimated by formula, because serum creatinine alone overestimates clearance in small or frail patients.

Kidney disease. Renally cleared nodal blockers accumulate, and hyperkalemia predisposes to BRASH syndrome. Metformin is contraindicated below an eGFR of 30 mL/min/1.73 m², and NSAIDs accelerate loss of kidney function in heart failure.

Pregnancy. ACE inhibitors, angiotensin receptor blockers, sacubitril-valsartan, and mineralocorticoid receptor antagonists are withheld in pregnancy for fetal toxicity, and their withdrawal is planned before conception in women with cardiomyopathy.

Heart failure phenotype. In HFpEF, fluid-retaining drugs (NSAIDs, thiazolidinediones, glucocorticoids, pregabalin, dihydropyridines) matter more than negative inotropes, and nondihydropyridine calcium channel blockers are generally tolerated. In HFrEF, negative inotropes and proarrhythmic drugs add mortality risk beyond congestion.

Sources of error in attributing cardiovascular disease to a drug

• Attributing AV block to a beta-blocker or calcium channel blocker and discharging the patient after withdrawal, when more than half of patients whose block resolves have recurrence off the drug.
• Implanting a pacemaker for bradycardia caused by a cholinesterase inhibitor, ophthalmic timolol, or lithium while the drug continues.
• Missing BRASH syndrome because potassium is only moderately raised and the drug doses are standard.
• Omitting over-the-counter NSAIDs, decongestants, eye drops, and complementary products from the medication history.
• Treating pregabalin-, thiazolidinedione-, or dihydropyridine-induced edema with more diuretic as if it were cardiac congestion, or attributing true congestion to the drug.
• Labeling a dilated cardiomyopathy as idiopathic without asking about methamphetamine, alcohol, or anabolic steroid use.
• Attributing new mitral or aortic regurgitation to degenerative disease in a patient with past exposure to fenfluramine, benfluorex, pergolide, or high-dose cabergoline.
• Confusing drug-induced valvulopathy with carcinoid heart disease when left-sided valves are involved and serotonin metabolites are normal.
• Delaying troponin and CRP surveillance during the first 4 weeks of clozapine, when most myocarditis occurs.
• Overlooking conduction disease in long-term hydroxychloroquine therapy as an early sign of cardiomyopathy.
• Giving a nitrate within 12 hours of avanafil, 24 hours of sildenafil or vardenafil, or 48 hours of tadalafil.
• Stopping clonidine or a beta-blocker abruptly during deprescribing.
• Withholding GDMT in drug-induced HFrEF because recovery is expected after the drug is stopped.

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