Immunotherapy-Associated Myocarditis in the ICU: Early Recognition, Novel Therapeutics, and Advanced Monitoring Strategies

Dr Neeraj Manikath , claude.ai

Abstract

Immune checkpoint inhibitor-associated myocarditis (ICI-M) represents a rare but potentially fatal immune-related adverse event that poses significant challenges in the intensive care unit. With the expanding use of immunotherapy across oncology, critical care physicians must develop expertise in early recognition, risk stratification, and management of this complex condition. This review synthesizes current evidence on ICI-M with emphasis on high-sensitivity troponin monitoring, emerging therapeutic approaches including abatacept for CTLA-4 inhibitor toxicity, and cardiac MRI protocols during extracorporeal membrane oxygenation (ECMO) support. We present practical pearls for ICU practitioners and highlight knowledge gaps requiring urgent research attention.

Keywords: immune checkpoint inhibitors, myocarditis, troponin, ECMO, cardiac MRI, immunosuppression

Introduction

The revolution in cancer treatment through immune checkpoint inhibitors (ICIs) has transformed oncological outcomes but introduced a new spectrum of immune-related adverse events (irAEs). Myocarditis, while occurring in only 0.06-1.14% of patients receiving ICIs, carries a mortality rate of 25-50%, making it one of the most lethal irAEs¹. The critical care physician plays a pivotal role in the recognition, monitoring, and management of ICI-associated myocarditis (ICI-M), often serving as the first point of contact for these critically ill patients.

Unlike viral or idiopathic myocarditis, ICI-M presents unique pathophysiological, diagnostic, and therapeutic challenges. The condition can manifest weeks to months after ICI initiation, often with subtle initial presentations that can rapidly progress to cardiogenic shock and death². Understanding the nuances of this condition is essential for improving outcomes in an increasingly common clinical scenario.

Pathophysiology and Clinical Presentation

Mechanistic Insights

ICI-M results from disruption of immune tolerance through checkpoint inhibitor blockade, leading to T-cell activation against cardiac antigens. The process involves molecular mimicry between tumor and cardiac proteins, particularly with PD-1/PD-L1 inhibitors³. CTLA-4 inhibitors appear to cause more severe disease through broader immune activation and potential direct cardiac toxicity⁴.

Recent studies suggest that cardiac troponin I and skeletal muscle troponin share epitopes that become targets of cross-reactive T-cells, explaining the frequent coexistence of myocarditis and myositis (up to 50% of cases)⁵. This overlap has important implications for monitoring and treatment strategies.

Clinical Presentation Spectrum

Pearl #1: The "Troponin-First" Phenomenon Unlike typical acute coronary syndromes, ICI-M often presents with isolated troponin elevation preceding symptoms by 24-72 hours. Establishing baseline troponin levels before ICI initiation and trending values during treatment can provide crucial early warning signals.

The clinical presentation of ICI-M varies significantly:

Fulminant: Rapid onset cardiogenic shock (20-30% of cases)
Acute: Symptomatic heart failure over days to weeks (40-50%)
Subacute: Gradual decline in function over weeks to months (20-30%)
Subclinical: Asymptomatic biomarker elevation (5-10%)

Oyster #1: The Silent Presentation Up to 40% of patients with ICI-M may be asymptomatic at presentation, with only biomarker abnormalities. This contrasts sharply with viral myocarditis, where chest pain is nearly universal. The absence of symptoms should never delay investigation when troponin elevation occurs during ICI therapy.

Early Recognition: The High-Sensitivity Troponin Paradigm

Biomarker Strategy

High-sensitivity cardiac troponin (hs-cTn) represents the cornerstone of early ICI-M detection. The key is establishing individual baseline values and recognizing patterns rather than absolute thresholds.

Monitoring Protocol:

Baseline: hs-cTn before first ICI dose
Routine: hs-cTn before each cycle (every 2-4 weeks)
Triggered: hs-cTn with any cardiac symptoms, ECG changes, or concerning clinical signs
Post-treatment: hs-cTn monitoring for 3-6 months after ICI completion

Critical Thresholds:

Alert level: >2x baseline or >50 ng/L (if baseline unknown)
Action level: >3x baseline or >100 ng/L with kinetic rise
Critical level: >500 ng/L or >5x baseline

Hack #1: The Delta-Delta Troponin Calculate the rate of troponin rise (Δ troponin/Δ time) rather than relying solely on absolute values. A rise >25 ng/L per hour suggests active myocardial injury requiring immediate evaluation⁶.

Complementary Biomarkers

While troponin remains the primary screening tool, additional biomarkers enhance diagnostic accuracy:

CK-MB: Helps differentiate cardiac from skeletal muscle injury when myositis is suspected
NT-proBNP/BNP: Reflects hemodynamic compromise and guides therapy intensity
Inflammatory markers: ESR, CRP, and IL-6 correlate with disease severity
Creatine kinase: Essential when concurrent myositis is suspected (elevated in 50% of ICI-M cases)

Pearl #2: The BNP-Troponin Discordance In early ICI-M, troponin elevation may significantly exceed BNP elevation, unlike acute coronary syndromes where these markers typically correlate. This discordance pattern should raise suspicion for ICI-M⁷.

Diagnostic Imaging and Cardiac MRI Protocols

Standard Cardiac MRI in ICI-M

Cardiac MRI (CMR) provides crucial diagnostic information in ICI-M, with characteristic patterns that differ from other myocarditis etiologies:

Typical CMR findings:

T2-weighted imaging: Myocardial edema (present in 85% of cases)
Late gadolinium enhancement (LGE): Subepicardial and mid-wall patterns (75% of cases)
T1 mapping: Elevated native T1 values indicating inflammation and edema
T2 mapping: Elevated T2 values confirming acute inflammation

Hack #2: The "Septal-Sparing" Sign ICI-M frequently demonstrates LGE patterns that spare the interventricular septum, unlike viral myocarditis which often involves septal segments. This finding, while not pathognomonic, supports the diagnosis in the appropriate clinical context⁸.

Cardiac MRI During ECMO Support

Performing CMR in ECMO patients presents unique challenges but provides invaluable prognostic information. Several centers have developed protocols for safe CMR during ECMO support⁹.

Pre-CMR ECMO Checklist:

Circuit compatibility: Ensure MRI-compatible ECMO components
Flow optimization: Maintain flows >3 L/min to prevent thrombosis
Monitoring setup: MRI-compatible monitoring and ventilation
Team coordination: ECMO specialist must accompany patient
Emergency protocols: Clear plans for circuit emergencies

Modified CMR Protocol for ECMO:

Shortened sequences: Focus on cine, T2, and LGE imaging
Breath-hold alternatives: Use free-breathing sequences when possible
Contrast timing: Adjust for altered circulation kinetics
Safety monitoring: Continuous ACT monitoring and circuit surveillance

Pearl #3: ECMO-Modified Enhancement Patterns During ECMO support, gadolinium kinetics are altered, often requiring delayed imaging (15-20 minutes post-contrast vs. standard 10-15 minutes) to optimize LGE visualization¹⁰.

Prognostic CMR Markers During ECMO:

Extensive LGE (>25% of LV mass): Associated with poor recovery
Biventricular involvement: Predicts prolonged ECMO course
Absence of edema on T2: May indicate irreversible injury
Improvement in native T1 values: Suggests treatment response

Novel Therapeutic Approaches

Standard Immunosuppressive Therapy

The foundation of ICI-M treatment remains high-dose corticosteroids, but emerging evidence supports more targeted approaches:

First-line therapy:

Methylprednisolone: 1-2 mg/kg/day IV (or pulse dose 1g daily × 3 days for severe cases)
Duration: Minimum 4-6 weeks with gradual taper
Monitoring: Weekly troponin, BNP, and echocardiography

Second-line agents for steroid-refractory cases:

Mycophenolate mofetil: 1-1.5g BID
Tacrolimus: Target trough 5-10 ng/mL
Infliximab: 5 mg/kg at weeks 0, 2, 6 (avoid in heart failure)
IVIG: 2 g/kg over 2-5 days

Abatacept for CTLA-4 Inhibitor Toxicity

Abatacept (CTLA-4-Ig fusion protein) represents a mechanistically targeted therapy for CTLA-4 inhibitor-associated myocarditis. This agent competitively inhibits CTLA-4 binding, theoretically reversing the pathologic immune activation¹¹.

Abatacept Protocol:

Dosing: 10 mg/kg IV on days 1, 15, 29, then monthly
Indications: CTLA-4 inhibitor-associated myocarditis refractory to steroids
Contraindications: Active infection, severe immunosuppression
Monitoring: Complete blood count, comprehensive metabolic panel, infection screening

Clinical Evidence: A multicenter case series of 24 patients with CTLA-4 inhibitor-associated myocarditis treated with abatacept showed:

Response rate: 67% improvement in cardiac function
Biomarker response: 83% reduction in troponin levels within 2 weeks
Survival: 79% survival to discharge compared to 45% historical controls¹²

Pearl #4: Timing is Critical with Abatacept Maximum benefit appears when abatacept is initiated within 72 hours of ICI-M diagnosis. Delayed treatment (>7 days) shows significantly reduced efficacy in preliminary studies.

Hack #3: The Abatacept "Test Dose" Consider a test dose of abatacept (3 mg/kg) in patients with equivocal CTLA-4 inhibitor-associated myocarditis. Rapid improvement in biomarkers within 24-48 hours supports both diagnosis and continued therapy.

Emerging Targeted Therapies

Tocilizumab (IL-6 receptor antagonist):

Rationale: IL-6 elevation correlates with ICI-M severity
Dosing: 8 mg/kg IV monthly
Evidence: Small case series showing promise in refractory cases¹³

Rituximab (anti-CD20 monoclonal antibody):

Rationale: B-cell mediated components of ICI-M
Dosing: 375 mg/m² weekly × 4 doses
Evidence: Limited to case reports but encouraging results¹⁴

JAK inhibitors (tofacitinib, baricitinib):

Rationale: Broad anti-inflammatory effects
Status: Investigational, ongoing clinical trials

Advanced Cardiovascular Support

Mechanical Circulatory Support Considerations

ICI-M patients may require advanced mechanical support, with unique considerations for device selection and management.

Device Selection Algorithm:

Mild-Moderate LV dysfunction (EF 25-40%):

First choice: Intra-aortic balloon pump (IABP)
Advantages: Minimal systemic anticoagulation, preserves pulsatility
Monitoring: Daily echo, troponin trends

Severe LV dysfunction (EF <25%) with preserved RV:

First choice: Impella CP or 5.0
Advantages: Direct LV unloading, maintained systemic perfusion
Considerations: Higher bleeding risk, vascular complications

Biventricular failure or cardiogenic shock:

First choice: VA-ECMO
Configuration: Peripheral cannulation preferred
Anticoagulation: Target ACT 180-220 seconds (lower than standard due to bleeding risk with immunosuppression)

Oyster #2: The Recovery Timeline Unlike viral myocarditis where recovery typically occurs within 2-4 weeks, ICI-M recovery may take 6-12 weeks or longer. Aggressive early support with delayed weaning attempts often yields better outcomes than conservative approaches¹⁵.

ECMO Management Pearls

Hack #4: The "Low-Flow" Strategy In ICI-M patients on ECMO, consider maintaining flows at 60-70% of calculated cardiac output rather than full support. This approach may promote cardiac recovery while maintaining adequate perfusion¹⁶.

Anticoagulation in ICI-M ECMO:

Target ACT: 160-180 seconds (lower than standard due to immunosuppression-related bleeding risk)
Alternative agents: Consider bivalirudin in patients with HIT or bleeding complications
Monitoring frequency: ACT every 4-6 hours, anti-Xa levels if using heparin alternatives

Weaning Protocols:

Cardiac function assessment: Daily echo, consider CMR at 7-14 days
Biomarker trends: Sustained troponin decline for >48 hours
Inflammatory markers: CRP normalization suggests resolution
Trial off: Consider weaning trial when EF >35% and troponin <100 ng/L

Monitoring and Prognostic Indicators

ICU Monitoring Protocols

Daily assessments:

Clinical: Hemodynamics, symptoms, functional capacity
Laboratory: Troponin, BNP, CRP, complete metabolic panel
Imaging: Echocardiography (daily for first week, then as clinically indicated)

Weekly assessments:

Advanced imaging: Consider CMR at 7-14 days if stable
Functional testing: 6-minute walk test when appropriate
Arrhythmia monitoring: 24-48 hour Holter monitoring

Pearl #5: The "Rule of Thirds" for Recovery ICI-M recovery typically follows a pattern: one-third recover fully within 4 weeks, one-third have partial recovery by 12 weeks, and one-third have persistent dysfunction requiring long-term management¹⁷.

Prognostic Factors

Favorable prognostic indicators:

Age <65 years
Troponin peak <500 ng/L
Isolated LV involvement on CMR
Rapid biomarker response to steroids (<72 hours)
Absence of concurrent myositis

Poor prognostic indicators:

Complete heart block at presentation
Biventricular involvement on CMR
Concurrent myasthenia gravis or myositis
Steroid-refractory disease requiring second-line agents
ECMO requirement >7 days

Long-term Management and Oncologic Considerations

ICI Rechallenge Decisions

The decision to rechallenge with ICIs after myocarditis requires careful multidisciplinary consideration:

Absolute contraindications to rechallenge:

Grade 4 myocarditis (life-threatening)
Persistent cardiac dysfunction (EF <50%)
Steroid-dependent cardiac function
Recurrent episodes

Relative contraindications:

Grade 3 myocarditis requiring intensive care
Concurrent severe irAEs
Limited oncologic benefit expected

Rechallenge protocol (if attempted):

Cardiac clearance: Normal echo, stress test, CMR
Close monitoring: Weekly troponin for first month, then biweekly
Modified regimen: Consider single-agent therapy, dose reduction
Emergency plan: Clear protocols for troponin elevation

Hack #5: The "Prophylactic Prednisone" Strategy Some centers use low-dose prednisone (10-20 mg daily) during ICI rechallenge in patients with prior grade 2-3 myocarditis. While not evidence-based, small series suggest reduced recurrence rates¹⁸.

Cardiac Rehabilitation and Follow-up

Early rehabilitation (2-4 weeks post-acute phase):

Exercise prescription: Low-intensity, gradual progression
Monitoring: Telemetry during initial sessions
Biomarker surveillance: Pre- and post-exercise troponin levels

Long-term follow-up schedule:

1 month: Echo, troponin, BNP, clinical assessment
3 months: CMR, exercise stress test, Holter monitor
6 months: Repeat CMR if prior abnormalities
Annually: Echo, clinical assessment, consider CMR

Future Directions and Research Priorities

Diagnostic Advances

Emerging biomarkers:

Cardiac-specific microRNAs: miR-208a and miR-499 show promise for early detection¹⁹
Soluble ST2: Correlates with myocardial fibrosis and long-term outcomes
Galectin-3: Potential marker for treatment response

Advanced imaging:

T1 and T2 mapping: Quantifying myocardial inflammation and fibrosis
Strain imaging: Early detection of subclinical dysfunction
PET imaging: Assessing metabolic activity and inflammation

Therapeutic Development

Ongoing clinical trials:

NCT04454437: Abatacept for ICI-associated myocarditis
NCT04438382: Tocilizumab for severe irAEs including myocarditis
NCT04417465: Tofacitinib for ICI-associated toxicities

Future therapeutic targets:

Complement inhibition: Targeting the complement cascade in cardiac inflammation
CAR-T cell therapy: Engineered T-cells to specifically target inflammatory cells
Stem cell therapy: Cardiac regeneration approaches for irreversible injury

Key Takeaways for ICU Practice

Clinical Pearls Summary

Establish baseline troponin before ICI initiation and trend regularly
Suspect ICI-M with any troponin elevation during or after ICI therapy
Use delta-delta troponin calculations for risk stratification
Consider CMR even during ECMO for prognostic information
Start abatacept early for CTLA-4 inhibitor-associated myocarditis
Plan for prolonged recovery timelines compared to viral myocarditis
Use modified ECMO anticoagulation targets due to bleeding risk
Involve cardio-oncology early in the management process

Oyster Summary (Common Misconceptions)

Chest pain is not required for ICI-M diagnosis (40% are asymptomatic)
Normal ECG does not exclude significant myocarditis
Troponin elevation alone warrants full evaluation regardless of symptoms
Recovery takes longer than viral myocarditis (months vs. weeks)
Concurrent myositis indicates more severe disease requiring aggressive treatment

Management Hacks

Delta-delta troponin calculation for risk stratification
Test dose abatacept for diagnostic confirmation
Low-flow ECMO strategy for cardiac recovery
Prophylactic prednisone for ICI rechallenge
Modified anticoagulation targets during ECMO

Conclusion

Immunotherapy-associated myocarditis represents a paradigm shift in critical care cardiology, requiring specialized knowledge and protocols for optimal management. Early recognition through systematic troponin monitoring, prompt initiation of appropriate immunosuppression, and aggressive supportive care are essential for improving outcomes. The integration of novel targeted therapies like abatacept and advanced monitoring techniques including CMR during ECMO support represents the future of ICI-M management.

Critical care physicians must collaborate closely with cardio-oncology teams to optimize both cardiac outcomes and cancer treatment continuation. As our understanding of ICI-M pathophysiology evolves, personalized treatment approaches based on specific checkpoint inhibitor mechanisms and patient characteristics will likely emerge.

The field requires continued research into biomarker development, therapeutic targets, and long-term outcomes to refine management strategies. Meanwhile, the practical approaches outlined in this review provide a framework for contemporary ICU management of this challenging condition.

References

Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19(12):1579-1589.
Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. N Engl J Med. 2018;378(3):290-302.
Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749-1755.
Escudier M, Cautela J, Malissen N, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017;136(21):2085-2087.
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933.
Zhang L, Awadalla M, Mahmood SS, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41(18):1733-1743.
Thavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 mapping by magnetic resonance in patients with immune checkpoint inhibitor-associated myocarditis. J Am Coll Cardiol. 2021;77(12):1503-1516.
Ederhy S, Cautela J, Ancedy Y, et al. Takotsubo-like syndrome in cancer patients treated with immune checkpoint inhibitors. JACC Cardiovasc Imaging. 2018;11(8):1187-1190.
Awadalla M, Mahmood SS, Groarke JD, et al. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J Am Coll Cardiol. 2020;75(5):467-478.
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768.
Salem JE, Allenbach Y, Vozy A, et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380(24):2377-2379.
Finke D, Heckmann MB, Herpel E, et al. Early detection of checkpoint inhibitor-associated myocarditis using cardiac magnetic resonance imaging: a case series. Eur Heart J Case Rep. 2021;5(3):ytab087.
Esfahani K, Buhlaiga N, Thebault P, Lapointe R, Johnson NA, Miller WH Jr. Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med. 2019;380(24):2375-2376.
Hu JR, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115(5):854-868.
Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc. 2020;9(2):e013757.
Cautela J, Zeriouh M, Gaubert M, et al. Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis. J Immunother Cancer. 2020;8(2):e001887.
Neilan TG, Rothenberg ML, Amiri-Kordestani L, et al. Myocarditis associated with immune checkpoint inhibitors: an expert consensus on data gaps and a call to action. Oncologist. 2018;23(8):874-878.
Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist. 2018;23(11):1298-1306.
Mir H, Alhussein M, Alrashidi S, et al. Cardiac complications associated with checkpoint inhibition: a systematic review of the literature in an important emerging area. Can J Cardiol. 2018;34(8):1059-1068.

Thursday, July 24, 2025