Drug-induced Myocarditis Research Articles

Drug-induced myocarditis: a real-world pharmacovigilance study using the FDA adverse event reporting system database

ABSTRACT Background Myocarditis is a rare but potentially life-threatening inflammation of the heart muscle that can be caused by various drugs. This study aimed to comprehensively evaluate the risk of drug-induced myocarditis using data from the FDA Adverse Event Reporting System (FAERS) database. Methods We queried the FAERS database for reports of myocarditis from Q1 2004 to Q4 2023. The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were calculated to detect disproportionality signals for drugs associated with myocarditis. Results A total of 8,212 myocarditis-related reports were identified in the FAERS database. The most frequently reported drugs were clozapine (N = 1269), followed by nivolumab (N = 621), pembrolizumab (N = 358), mesalazine (252), and olanzapine (N = 191). Disproportionality analysis revealed strong signals for the top 50 drugs, including mesalazine (ROR 48.01, 95% CI 42.29-54.49), cemiplimab (ROR 38.84, 95% CI 26.71-56.47), clozapine (ROR 35.21, 95% CI 33.13-37.39), nivolumab (ROR 23.21, 95% CI 21.38-25.2), atezolizumab (ROR 20.75, 95% CI 17.91-24.05) and pembrolizumab (ROR 19.90, 95% CI 17.89-22.13). Conclusions Our findings suggest a potential risk of drug-induced myocarditis associated with various medications. Close monitoring for signs and symptoms of myocarditis is crucial, especially in patients with risk factors or those receiving these drugs. Further investigations are warranted to establish causality and identify risk factors.

The cellular mechanism of antipsychotic-induced myocarditis: A systematic review.

Antipsychotic drug-induced myocarditis is a serious and potentially fatal adverse drug reaction characterized by inflammation of the heart muscle (myocardium) that typically develops within the first month after commencing an antipsychotic drug. Although the precise mechanism of this severe adverse drug reaction is unknown, multiple theories have been proposed with varying levels of support from cellular or animal studies. We conducted a systematic review, in accordance with PRISMA guidelines, of published preclinical and clinical studies investigating the cellular mechanism by which antipsychotic drugs induce myocarditis. A literature search including all studies available before December 10, 2022, yielded 15 studies that met our inclusion criteria. Antipsychotics examined in the included studies included clozapine (n=13), ziprasidone (n=1), amisulpride (n=1), haloperidol (n=1), levomepromazine (n=1), olanzapine (n=1), and sertindole (n=1). The evidence suggests several overlapping mechanistic cascades involving: (1) increased levels of catecholamines, (2) increased proinflammatory cytokines, (3) increased reactive oxygen species (ROS), (4) reduced antioxidant levels and activity, and (5) mitochondrial damage. Notable limitations such as, a focus on clozapine, sample heterogeneity, and use of supratherapeutic doses will need to be addressed in future studies. Discovery of the mechanism by which antipsychotic drugs induce myocarditis will allow the development of clinically-useful biomarkers to identify those patients at increased risk prior to drug exposure. The development or repurposing of therapeutics to prevent or treat drug-induced myocarditis will also be possible and this will enable increased and safe use of antipsychotics for those patients in need.

Ketiapine Bağlı Myokardit

This article reports myocarditis related to overdose of quetiapine. An 18-year-old female patient who used 25 mg of quetiapine for anxiety disorder attempted suicide with twenty quetiapine pills. The patient developed palpitations, shortness of breath, pleuritic chest pain, and confusion in the emergency room. ST-elevation and right bundle branch block were detected on D1-aVL lead in the patient's ECG. The cardiac markers were significantly elevated. The patient was hospitalized and treated in the internal medicine intensive care unit. Drug-induced myocarditis was resolved by two weeks of treatment. This case report presents a case of myocarditis induced by quetiapine overdose.

Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.

Abstract IA10: Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans

Abstract Immune checkpoint inhibitors (ICI) have transformed cancer therapy, with regulatory approval now in 16 distinct cancer types. These agents include monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 receptor (PD-1), and its ligand (PD-L1), and work by activating the immune system (1). ICI can also lead to immune-related adverse events (irAE) including colitis, dermatitis, pneumonitis, endocrinopathies, and other irAE (2). Cardiovascular toxicities including myocarditis have emerged as uncommon but often fatal toxicities associated with ICI (3). Our group initially described cases of fulminant and fatal myocarditis after treatment with ICI (4). These patients presented with refractory electrophysiologic disturbances and concomitant myositis, with pathology confirming T-cell and macrophage infiltration into the myocardium (4). Since then other case series of myocarditis have described an estimated incidence of 0.3% to greater than 1% when ICI are used in combination (5-8). We published the largest such case series including 122 patients with ICI-associated myocarditis; these patients had early onset of symptoms (median 30 days after initial exposure to ICI), frequent deaths (50% mortality), and dramatically increased reporting of cases in 2017, the latter perhaps consistent with growing recognition of this new clinical syndrome as well as more widespread use of ICI (8). More recently, we have demonstrated association of ICI with other cardiovascular complications including myocarditis, pericarditis, vasculitis, and arrhythmias (8). Existing clinical practice extrapolates from general myocarditis literature for diagnosis of ICI-associated myocarditis, with diagnosis being made using a combination of biomarkers (specifically troponin), cardiac imaging, and biopsy (9). We have recently developed case definitions for drug-induced myocarditis, especially in oncology clinical trials (10). To better define mechanisms of ICI-associated myocarditis, our group has developed several mouse models. These include pharmacologic models (where mice in various genetic backgrounds are treated with antibodies) and genetic mouse models (where one or more immune checkpoints are genetically deleted) and recapitulate the syndrome of myocarditis observed in humans treated with ICI. The mice have sudden cardiac death, electrocardiographic perturbations, and macrophage and T-cell infiltrations in the heart, all consistent with human disease (Moslehi et al., unpublished). Importantly, the early data suggest a critical role for CTLA-4 in the development of myocarditis. Treatment with abatacept attenuates the myocarditis in mice. We have extended these observations to humans where in at least one case, severe ICI-associated myocarditis was successfully treated with abatacept (11). Citation Format: Javid J. Moslehi. Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA10.

Drug-induced myocarditis after nivolumab treatment in a patient with PDL-1-negative squamous cell carcinoma of the lung

Drug-induced myocarditis after nivolumab treatment in a patient with PDL-1-negative squamous cell carcinoma of the lung

A Case of Clozapine-Induced Myocarditis in a Young Patient with Bipolar Disorder.

We present a case of drug-induced myocarditis manifesting as acute heart failure in a young patient with bipolar disorder being treated for depression. The case describes a 20-year-old man being treated in the psychiatry ward for worsening depression when he started complaining of chest pain and shortness of breath. His list of medications included clozapine, lithium, lorazepam, and haloperidol. The main findings on physical examination were tachycardia, low-grade fever, crackles in both lung bases on auscultation, and the absence of any notable edema. Abnormal labs included a troponin of 0.9, with a CK of 245 and CK-MB of 3.1. An ECG revealed sinus tachycardia and left anterior fascicular block (LAFB). An echocardiogram revealed global hypokinesis, severe left ventricular dysfunction with an ejection fraction estimated at 20%. The patient had an admitting diagnosis of acute left ventricular systolic dysfunction likely secondary to drug-induced myocarditis (suspect clozapine) versus acute coronary syndrome. He was managed conservatively and transferred to another facility for endomyocardial biopsy confirming myocarditis. This case is an example of one of the most typical presentations of suspected drug-induced acute myocarditis and will hopefully prompt the reader to think of this underdiagnosed entity in the right clinical setting.

Myocarditis During Lenalidomide Therapy

To report the first case of pathologically confirmed myocarditis in a patient receiving treatment with lenalidomide for non-Hodgkin's lymphoma. An 85-year-old woman with recurrent follicular lymphoma was treated with lenalidomide 10 mg daily and low-dose dexamethasone 8 mg once weekly in a clinical trial. She had a past medical history of hypertension and breast cancer. Within 17 days of starting lenalidomide and dexamethasone, she developed symptoms and signs of congestive heart failure. Despite aggressive supportive care, she had progressive and refractory multiorgan failure and died. Postmortem examination of the heart confirmed the absence of coronary artery disease, and histopathological examination of the myocardium revealed a diffuse lymphocytic/eosinophilic inflammatory infiltrate with associated acute and chronic myocardial injury affecting all 4 chambers of the heart, consistent with myocarditis. Lenalidomide is an immunomodulatory agent derived from thalidomide and is approved for the treatment of multiple myeloma and myelodysplastic syndromes. The efficacy of lenalidomide has been reported in B-cell malignancies. Common toxicities are myelosuppression, fatigue, diarrhea, skin rash, venous thromboembolism, peripheral neuropathy, and tumor flare reaction. Cardiovascular toxicity has been limited to atrial fibrillation and an increased risk for venous thromboembolism. Autoimmune hemolytic anemia, pneumonitis, and dermatitis have been described with lenalidomide. We propose an immunological mechanism for myocarditis based on the predominantly T-cell infiltration of the myocardium. Our findings suggest that lenalidomide may be a cause of drug-induced myocarditis. When patients treated with lenalidomide present with signs and symptoms of heart failure in the absence of other obvious causes, lenalidomide hypersensitivity should be considered in the differential diagnosis and a myocardial biopsy should be considered when other common causes of heart failure have been excluded. A reasonable management approach is drug discontinuation and early institution of corticosteroid therapy. An objective causality assessment, using the Naranjo probability scale, revealed that the adverse drug event was probable.

Myocarditis due to oral flurbiprofen use

We report a 23-year-old man presenting with chest pain. He denoted skin eruptions on his hands, lips, mouth, and penis 24 to 36 hours after he had taken flurbiprofen 10 days ago. Detailed examination showed an ulcerated, pitching lesion with a dimension of approximately 2x2 cm on his penis; however, other explained skin lesions were ameliorated. ST elevations were present in the electrocardiogram. Cardiac biomarkers gradually rose. The scintigraphy showed myocardial hypoperfusion in the inferoseptal wall. This phenomenon is a rare case of myocarditis due to hypersensitivity reaction. In the case of nonspecific angina pectoris accompanied by electrocardiogram changes, drug-induced myocarditis must hold a place in differential diagnoses.

A 32‐year‐old woman with arthralgias and severe hypotension

A 32‐year‐old woman with arthralgias and severe hypotension

Clozapine-Associated Myocarditis

Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis. To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients. We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive. 116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n=93, 80.2%). For all cases with known treatment commencement and cessation dates (n=106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died. Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.

Use of amphotericin B in drug-resistant cases of visceral leishmaniasis in north Bihar, India.

Thirty-four multidrug-resistant cases of Indian visceral leishmaniasis (kala-azar) were treated with amphotericin B. A complete hemogram, liver and renal function tests, determination of serum electrolyte levels, a chest radiograph, and an electrocardiogram were done before, during, and after completion of therapy. Assessment for clinical and parasitologic cure was done weekly. Thirty-one patients who completed treatment had full cure after receiving 10-15 injections at six-months follow up. One patient died of myocarditis. A febrile reaction was observed in all cases, while thrombophlebitis was found in six cases (18.75%). Anorexia, nausea, and vomiting were found in seven cases (21.88%). No significant nephrotoxicity or electrolyte disturbances were observed. It is concluded that amphotericin B is an effective second-line drug for Indian visceral leishmaniasis, but unpredictable drug-induced myocarditis remains a problem.

Drug-induced myocarditis: A report of two cases

Two patients are reported with hypersensitivity myocarditis. One, a 71-year-old female, was being treated with methyldopa at the time of her death and the second, a 67-year-old female, was receiving tetracycline for a respiratory tract infection.