Sepsis-associated myocarditis: Epidemiology, pathophysiology, diagnosis, management, and future directions

Abstract

Sepsis-associated myocarditis is a major challenge in critical care, driving global morbidity and mortality through cardiac dysfunction. Despite advances in diagnostics, consensus on optimal management remains lacking. This review explores epidemiology, clinical complexities, and research gaps. A systematic search of OVID MEDLINE and Scopus (2000–2025) using terms “sepsis,” “myocarditis,” “cardiac dysfunction,” and “inflammatory cardiomyopathy” identified 10,344 records. After removing duplicates (2323) and applying filters for human studies (1840), English language (1775), and publication year (1340), 87 articles were eligible. Thirty were excluded for lacking outcome data, leaving 57 studies for final analysis, supplemented by 13 additional articles that highlight therapeutic strategies, emerging directions, and supportive evidence. Study quality was assessed using PRISMA 2020 guidelines. Sepsis-associated myocarditis is characterized by myocardial inflammation and impaired cardiac function, often worsened by systemic inflammatory responses. Left ventricular dysfunction is frequent, influenced by infectious agents, immune dysregulation, and drug toxicities. While diagnostic modalities have improved, therapeutic approaches remain inconsistent, with no standardized protocols established. Current management typically involves intravenous fluids, antibiotics, and vasopressors, yet patient outcomes vary widely. The absence of consensus highlights an urgent need for targeted research to clarify mechanisms, define effective interventions, and improve survival in this high-risk population.

Introduction

Sepsis-Associated Myocarditis is increasingly recognized as a critical complication of sepsis, characterized by transient myocardial dysfunction and impaired contractility. Initially described as reversible left ventricular depression, its definition has broadened to encompass diverse patterns of systolic and diastolic impairment. This evolving terminology reflects the complexity of distinguishing Sepsis-Associated Myocarditis from other sepsis-related cardiac dysfunctions, fueling ongoing debate about whether it represents a distinct pathological entity or a heterogeneous manifestation of systemic inflammation. ¹

Despite advances in diagnostic tools such as echocardiography, cardiac biomarkers, and imaging modalities, consensus on SIC remains elusive. Some studies emphasize its reversibility, while others highlight persistent dysfunction and poor outcomes, challenging the notion of a uniform clinical course. The lack of standardized diagnostic thresholds and agreed-upon criteria complicates both clinical recognition and research comparability, leaving clinicians uncertain about its prognostic significance and therapeutic implications.^1–3

Core dilemmas persist in current practice and research. Pathophysiological mechanisms remain incompletely defined, with immune dysregulation, mitochondrial injury, and microvascular dysfunction all implicated.^4–6 Management strategies are equally controversial: while supportive care with fluids, antibiotics, and vasopressors remains the norm, questions linger about the role of targeted cardioprotective interventions. These uncertainties underscore the urgent need for unified definitions, mechanistic clarity, and evidence-based treatment protocols to improve outcomes in critically ill patients with sepsis-associated cardiac dysfunction.

Methods

Search strategy and study selection

A systematic search was conducted in OVID MEDLINE and Scopus (2000–2025) using sepsis-related terms combined with myocarditis descriptors and cardiac dysfunction parameters. Boolean operators were applied in MEDLINE, while Scopus used the same strategy within TITLE/ABS/KEY fields. Filters restricted results to human, English-language, peer-reviewed articles, with open access prioritized. The search yielded 10,344 records (10,277 MEDLINE; 67 Scopus (after screening)). After removing 2323 duplicates, 8021 records were screened. Exclusions included 1840 non-human studies, 65 non-English publications, and 435 outside the date range. Of 87 full texts assessed, 30 lacked outcome data, leaving 57 studies for synthesis, supplemented by 13 additional articles that highlight therapeutic strategies, emerging directions, and supportive evidence (Figure 1).

Figure 1.

PRISMA 2020 flow diagram illustrating the study selection process for the systematic review of sepsis-associated myocarditis (2000–2025).

Included studies were peer-reviewed human research on sepsis-associated myocarditis or myocardial dysfunction published between 2000 and 2025. Eligible designs comprised observational cohorts, case series, randomized controlled trials, and diagnostic accuracy studies with extractable outcomes such as echocardiography, biomarkers, cardiac MRI, biopsy findings, and therapeutic interventions. Excluded were animal studies, pediatric case reports with fewer than five patients, non-English publications, editorials or letters without data, and studies lacking outcome measures (mortality, recovery, ventricular function, arrhythmias, or major adverse cardiovascular events).

Methodological quality was assessed using JBI Checklists and the Newcastle–Ottawa Scale, with dual independent review and consensus resolution. Key domains were demographics, diagnostic criteria, intervention details, and outcome reporting. Case reports/series showed low–moderate bias from incomplete diagnostics and follow-up, while observational studies were generally stronger but sometimes lacked standardized outcomes.

Results: Risk of bias varied by study type. Case reports and small series (e.g. E. coli, echovirus, Salmonella myocarditis) showed moderate bias, mainly from incomplete diagnostics, limited follow-up, and lack of standardized outcomes—especially in bacterial cases restricted to acute presentations. In contrast, observational cohorts and pooled reviews demonstrated lower bias, with clearer demographics, diagnostic methods, and survival data. Viral myocarditis series (enteroviruses, influenza) provided more systematic evidence, though outcome heterogeneity persisted.

Overall, rare case reports offered novel pathogen insights but limited interpretive strength, while multicenter and pooled studies yielded more reliable prognostic estimates. This synthesis balances novelty from rare cases with robustness from larger datasets, highlighting 30 clinically relevant articles (Supplementary Tables S1–S2).

Sepsis-induced cardiac dysfunction and myocarditis: mechanisms, pathogenesis, and clinical implications

Sepsis-associated myocarditis is a significant complication in critically ill adults, with variable incidence due to inconsistent diagnostic criteria. It arises from complex pathogen–immune–metabolic interactions that impair contractility through cytokine storms, nitric oxide excess, mitochondrial dysfunction, calcium imbalance, microvascular hypoperfusion, autonomic dysregulation, and direct myocardial injury. Central to this process is NLRP3 inflammasome activation by PAMPs and DAMPs, driving caspase-1–mediated release of IL-1β and IL-18, which trigger pyroptosis, oxidative stress, and organelle dysfunction—effects mitigated experimentally by its inhibition. Overall, sepsis-related myocardial injury reflects overlapping pathways of apoptosis, necroptosis, pyroptosis, autophagy, and emerging mechanisms such as regulated necrosis and RNA methylation, whose clinical relevance remains to be fully defined.

Clinically, sepsis-associated myocarditis is underdiagnosed due to transient or subclinical presentations and limitations of routine tools such as biopsy or cardiac MRI. Right ventricular dysfunction is common and prognostically significant, while left ventricular diastolic dysfunction worsens outcomes.^7,8 Animal models with LPS exposure replicate hypotension, impaired relaxation, and myocarditis-like changes.^7,9 Myocarditis may arise from infections, autoimmune disease, or drugs, with pathological features ranging from abscesses, ¹⁰ necrotic changes linked to GBS, ¹¹ infarction-like ECG patterns, ¹² and conduction blocks requiring pacemakers. ¹³ Other reported complications include pericardial effusion, ¹⁴ meningococcal myocarditis, ¹⁵ leptospirosis-related systolic dysfunction, ¹⁶ eosinophilic myocarditis with refractory VT,^17,18 lupus myocarditis, ¹⁹ BCG-induced granulomas,^20,21 giant cell myocarditis, ²² myocardial edema, ²³ fulminant myocarditis linked to hypophysitis, ²⁴ catecholamine toxicity, ²⁵ TNF-mediated dysfunction, ²⁶ bacterial lactate-driven injury, ²⁷ septic cardiomyopathy with distinct hemodynamics, ²⁸ and drug-induced myocarditis such as clozapine. ²⁹ These diverse mechanisms highlight the complexity of sepsis-related cardiac involvement and its impact on patient outcomes.

Viral etiology

Viral myocarditis is a significant complication that can co-occur with sepsis, as seen in cases of young patients presenting with respiratory distress and bacterial sepsis.^30,31 Coxsackie myocarditis may progress to chronic dilated cardiomyopathy in up to 10% of cases, while enterovirus infections often mimic sepsis, requiring clinicians to consider myocarditis in infants with shock and test for enteroviruses.^32–36 COVID-19 is strongly linked to myocardial injury, with myocarditis contributing to acute heart failure and shock,^37–39 and post-SARS-CoV-2 multisystem inflammatory syndromes (MIS-A, MIS-C) manifesting as cardiogenic shock, sometimes requiring ventilation. Pediatric viral sepsis can cause myocardial calcification and necrosis, leading to acute heart failure, while myocarditis has also been reported following mRNA COVID-19 vaccination and as a fatal complication of severe COVID-19 infection. ³⁷ Neonates are particularly vulnerable, with echoviruses and coxsackie B viruses causing sepsis, meningitis, and myocarditis, confirmed in autopsy findings. Clinically, myocarditis may mimic sepsis with heart failure, shock, arrhythmias, and infarction-like necrosis, while other viral causes include yellow fever, human parechovirus, and H1N1 influenza (Figure 2), which can present as fulminant myocarditis.^40,41

Figure 2.

Viral infections leading to myocarditis.

Bacterial etiology

Bacterial cardiomyopathy (BCM) is a rare myocardial infection without endocarditis, most often caused by Staphylococcus aureus, and typically arises as a complication of severe bacteremia or sepsis, presenting with flu-like symptoms, arrhythmias, heart failure, or death.^10,42 Pathological findings include multiple abscesses in the left ventricle, purulent pericarditis, and necrotic or suppurative changes linked to group B Streptococcus. Diagnostic overlap with myocardial infarction complicates recognition, as seen in Escherichia coli sepsis mimicking infarction or causing acute myocarditis, including cases of complete atrioventricular block requiring pacemaker implantation.^13,43 Other bacterial causes include Salmonella typhi myocarditis with multi-organ failure, prostatitis-associated myocarditis, and pediatric S. aureus sepsis with 20% cardiac involvement and 25% mortality.^14,44 Rising incidence of serogroup W meningococcal disease has also been linked to myocarditis, with cardiac MRI recommended for early diagnosis.^15,45 Myocardial inflammation is frequent in leptospirosis, with systolic dysfunction rates comparable to sepsis and ST-segment elevation plus troponin predicting reduced ejection fraction. ¹⁶ Rare forms include eosinophilic myocarditis causing refractory ventricular tachycardia and shock,^17,18 and melioidosis-related myocarditis from Burkholderia pseudomallei, often fatal (Figure 3).

Figure 3.

Bacterial aetiology and factors leading to myocarditis.

Miscellaneous etiology

Systemic lupus erythematosus (SLE) can cause severe cardiovascular complications such as cardiogenic shock from SLE myocarditis, demonstrated in a young patient who recovered after targeted therapy.^19,46 Intravesical Bacillus Calmette–Guérin (BCG) therapy for urothelial cancer has been linked to fatal myocarditis with necrotizing granulomas,^20,47,48 while severe colitis can trigger giant cell myocarditis (GCM) and acute left ventricular failure. ²² Myocarditis is also a rare complication of inflammatory bowel disease (IBD), as seen in ulcerative colitis with reduced cardiac function and pericardial effusion, requiring management of both IBD and heart failure. ⁴⁹ Additionally, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, though rare, may lead to severe myocarditis (Figure 4).

Figure 4.

Miscellaneous aetiology and factors leading to myocarditis.

Clinical presentations

Myocarditis often presents with nonspecific symptoms and lacks sensitive clinical markers for etiology, ³² making advanced investigations such as echocardiography, cardiac CT, MRI, and biopsy essential for diagnosis. Its variable presentations, including viral myocarditis with respiratory distress or neonatal cases mimicking sepsis, ³⁰ contribute to underdiagnosis, though early recognition is critical given risks of rapid deterioration, especially in viral causes like COVID-19 that can lead to acute heart failure and shock. Severe pediatric viral sepsis may cause cardiogenic shock, respiratory failure, and widespread myocardial calcification with necrosis, while neonates face high mortality from hepatitis, meningoencephalitis, and myocarditis, often resembling bacterial sepsis with heart failure and infarction-like necrosis. Other viral etiologies include yellow fever, causing fibrosis and hypertrophy, and fulminant myocarditis linked to encephalitis. Bacterial cardiomyopathy (BCM), though rare, involves myocardial abscesses and dysfunction with outcomes ranging from flu-like illness to arrhythmias, infarction, ¹² purulent pericarditis, ¹⁰ or atrioventricular block in E. coli bacteremia, ¹³ while Salmonella myocarditis can cause multi-organ failure. Uncommon but severe causes include eosinophilic myocarditis,^17,18 SLE myocarditis, BCG-related myocarditis, giant cell myocarditis,^19,20 and fulminant myocarditis associated with lymphocytic hypophysitis. ²⁴

Diagnostic criteria and challenges

Diagnostic evaluation of sepsis-related myocardial dysfunction relies on a multimodal approach: echocardiography remains the bedside cornerstone, with global longitudinal strain offering greater sensitivity than conventional indices but limited by operator variability and software access; biomarkers such as troponin and NT-proBNP provide rapid adjuncts for risk stratification though lack specificity,^50,51 while emerging inflammatory mediators remain investigational; cardiac magnetic resonance (CMR) enables superior tissue characterization when echocardiographic findings are inconclusive, but logistical barriers restrict its use to stable patients; and endomyocardial biopsy, the histopathologic gold standard, offers etiologic precision but is reserved for select cases of refractory shock, unexplained arrhythmias, or suspected immune-mediated myocarditis due to procedural risks.^52–58

No single modality suffices in defining sepsis-associated myocarditis. Echocardiography offers accessibility, biomarkers provide prognostic context, CMR delivers tissue specificity, and biopsy ensures etiologic confirmation. The challenge lies in balancing diagnostic yield against feasibility in critically ill patients. A tiered approach—starting with echocardiography and biomarkers, escalating to CMR when feasible, and reserving biopsy for select cases—offers the most pragmatic pathway.^57,59 Ultimately, the lack of consensus on definitions and thresholds underscores the need for standardized protocols and multicenter validation to improve diagnostic accuracy and therapeutic decision-making (Table 1).

Table 1.

Comparative overview of cardiac diagnostic modalities: advantages, limitations, and optimal use cases.

Modality	Advantages	Limitations	Best use cases
Echocardiography (including strain)	Bedside, repeatable; detects global & regional function	Load-dependent; operator variability; limited tissue characterization	Initial assessment; serial monitoring; guide therapy
Biomarkers (Troponin, NT-proBNP, Inflammatory markers)	Rapid, scalable; prognostic value; useful when imaging not available	Non-specific in sepsis; affected by renal function	Risk stratification; triage; adjunct to imaging
Cardiac MRI	Tissue characterization (edema, fibrosis); non-invasive	Limited availability; not feasible in unstable patients	Ambiguous cases; suspected myocarditis
Endomyocardial Biopsy	Histopathologic gold standard; definitive diagnosis	Invasive; sampling error; procedural risk; limited availability	Refractory shock; suspected fulminant or giant cell myocarditis

Evidence-based assessment of management

Management of sepsis-associated myocarditis extends beyond standard sepsis care, requiring tailored pharmacological and immunomodulatory strategies. Positive inotropes such as dobutamine are commonly used for persistent dysfunction, though survival benefit remains uncertain, while agents like Levosimendan, ivabradine, and short-acting beta-blockers show mixed or context-dependent results, underscoring the need for individualized therapy guided by echocardiographic phenotyping. Immunomodulation is central in select phenotypes: glucocorticoids are standard for immune checkpoint inhibitor–related myocarditis, IVIG has shown benefit in infants, and IL-1 blockade with anakinra plus steroids has demonstrated rapid improvement in refractory cases. Adjuncts such as aspirin and colchicine have been reported with positive outcomes, though evidence remains largely observational, and randomized trial data are lacking.^53,54

For fulminant myocarditis with cardiogenic shock or refractory arrhythmias, mechanical circulatory support (MCS) provides critical rescue. VA-ECMO improves survival when initiated early under multidisciplinary shock team coordination, with predictors including ST-segment changes, elevated troponin, low LVEF, hypotension, and ventilatory support needs. Pacemakers may be required for advanced conduction block, while invasive ventilation supports respiratory failure. Despite technological advances, mortality remains high, and survivors often face long-term complications, highlighting both the progress in supportive care and the ongoing gaps in defining optimal timing, patient selection, and integration with pharmacological and immunomodulatory therapies^53,54,60,61 (Table 2).

Table 2.

Potential treatment options for management of sepsis-associated myocarditis.

Prognosis and long-term outcomes

Prognosis in Sepsis-Associated Myocarditis is strongly influenced by ventricular function. Right ventricular (RV) dysfunction is a key predictor of poor outcomes, correlating with hemodynamic instability, multi-organ failure, and higher short-term mortality, while persistent RV impairment beyond the acute phase increases one-month mortality risk. Left ventricular (LV) diastolic dysfunction also emerges as a reliable marker of adverse outcomes, contributing to pulmonary congestion, reduced cardiac reserve, and long-term vulnerability to recurrent heart failure. Advanced imaging with cardiac magnetic resonance (CMR) further refines prognostication by distinguishing reversible edema from irreversible fibrosis, with edema-only patterns suggesting potential recovery and fibrosis indicating risk for chronic dysfunction.

Long-term outcomes for sepsis survivors with myocardial involvement remain guarded. Persistent RV or biventricular dysfunction predisposes to chronic heart failure, arrhythmias, and diminished quality of life, while ongoing inflammation and endothelial senescence may accelerate atherosclerosis and major adverse cardiac events. Beyond cardiovascular sequelae, survivors often face impaired physical function, cognitive decline, and psychological morbidity. ⁶² These findings underscore the importance of routine biventricular assessment, incorporation of diastolic indices, and selective use of CMR, alongside structured long-term follow-up, rehabilitation, and multidisciplinary care to improve survival and quality of life.

Future directions

Sepsis-associated myocarditis remains underdiagnosed and undertreated due to its heterogeneous presentation and limited diagnostic consensus. Future research must prioritize the validation of novel biomarkers that can differentiate septic cardiomyopathy from true myocarditis. Candidates include inflammatory mediators (e.g. IL-6, ST2, galectin-3), endothelial injury markers, and multi-omics signatures that integrate transcriptomic, proteomic, and metabolomic data. These biomarkers should be evaluated in prospective cohorts with standardized imaging and clinical endpoints to establish diagnostic thresholds and prognostic relevance.^62,63

Equally critical is the design of targeted clinical trials for pharmacologic and immunomodulatory therapies. Trials should stratify patients by echocardiographic phenotype (e.g. RV vs LV dysfunction, preserved vs reduced EF), biomarker profiles, and CMR findings to identify responders to agents such as beta-blockers, IVIG, anakinra, and corticosteroids. Adaptive trial designs and platform studies may accelerate discovery while accommodating the complexity of sepsis. Additionally, phenotypic stratification frameworks—combining imaging, biomarkers, and clinical severity scores—should be developed to guide personalized therapy and mechanical circulatory support decisions. These efforts will require multicenter collaboration, integration of AI-driven analytics, and harmonization of definitions to transform care for this high-risk population.

Discussion

Sepsis-associated myocarditis is increasingly recognized across diverse pathogens and patient populations. Case reports demonstrate bacterial etiologies such as Escherichia coli, ⁶⁴ Staphylococcus aureus, ¹⁴ and Salmonella, alongside viral causes including echoviruses.^5,30,65 These reports highlight the broad epidemiologic spectrum, with neonates and children particularly vulnerable to enteroviral myocarditis, while adults often present with fulminant courses in influenza and resistant bacterial infection.

Mechanistic studies reveal that sepsis-induced myocardial depression arises from cytokine surges, nitric oxide overproduction, mitochondrial dysfunction, and endothelial injury. Viral sepsis adds further complexity, with influenza and COVID-19 triggering hyperinflammatory cascades.^5,66 Toll-like receptor 4 (TLR4) activation and endothelial cross-talk have been implicated in SARS-CoV-2 myocarditis,^67,68 while persistent inflammation and calcification have been documented in bacterial cases.^6,69 These findings underscore the dual contribution of direct pathogen invasion and systemic immune dysregulation.

Clinically, sepsis-associated myocarditis often mimics acute coronary syndromes, with troponin elevation and ECG changes complicating differentiation. ⁷ Echocardiography remains central, with 3D and strain imaging improving detection of myocardial dysfunction and abscess formation.^53,64 Autopsy studies provide definitive confirmation in fulminant cases. ⁷⁰ Integration of biomarkers, imaging, and microbiologic testing is essential to distinguish sepsis-related myocardial injury from ischemic or inflammatory mimics.

Supportive care with antimicrobials and hemodynamic stabilization remains the cornerstone. Advanced mechanical support has shown promise in refractory cases: temporary ventricular assist devices and ECMO/ECPR have improved survival in fulminant myocarditis. ⁷⁰ Pediatric and adult cohorts confirm that the timely initiation of extracorporeal support is critical. Case reports also highlight the need for pacemaker implantation in conduction abnormalities and surgical intervention for myocardial abscesses. Emerging research emphasizes immunomodulatory pathways as therapeutic targets. Cholinergic anti-inflammatory signaling and endothelial-focused interventions may attenuate hyperinflammation and microthrombosis. Standardized diagnostic criteria, pathogen-stratified registries, and integration of advanced imaging with biomarker profiling are urgently needed to refine management. Ultimately, bridging clinical case evidence with mechanistic insights will be key to improving outcomes in sepsis-associated myocarditis.

Conclusion

Sepsis-associated myocarditis is increasingly recognized as a critical complication with major short- and long-term consequences. Despite advances in imaging and biomarker profiling, diagnostic uncertainty persists, particularly in differentiating reversible inflammation from irreversible myocardial injury. Current management remains largely supportive, though targeted therapies such as immunomodulators, inotropes, and mechanical circulatory support show promise in select cases. Future priorities include validating novel biomarkers, refining phenotypic stratification, and conducting personalized clinical trials, alongside establishing standardized diagnostic criteria and multidisciplinary care pathways to improve outcomes and reduce cardiovascular sequelae in sepsis survivors.