Expert consensus on the diagnosis and treatment of immunoinflammation in heart failure

Heart failure (HF) represents a multifaceted clinical syndrome featured by cardiac structural or functional abnormalities secondary to diverse etiologies. Neurohormonal activation, including sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), is one of the most important mechanisms underlying the pathogenesis of HF. Since the 1990s, a growing number of experimental and clinical studies have shown that immunoinflammation makes an important contribution to the pathogenesis of HF. Recently, the immunoinflammation mechanisms of HF have been highlighted by clinical studies showing that interleukin (IL)-1β antagonists can prevent HF in patients with coronary heart disease (CHD) and acute ST-segment elevation myocardial infarction (STEMI).[1,2] To update the understanding of HF pathophysiology and standardize the diagnosis and treatment of the immunoinflammation in HF, the Cardiovascular Immunology Committee, Chinese Society of Immunology, together with the Chinese Collaboration Group of Immunoinflammation in Heart Failure, organized experts to jointly formulate the world’s first expert consensus on the diagnosis and treatment of immunoinflammation in HF. Consensus development methodology: This consensus was formulated based on the guidelines and methods of the World Health Organization, and with reference to the Basic Methods and Procedures for Formulating/Revising the Clinical Diagnosis and Treatment Guidelines issued by the Chinese Medical Association. This consensus is registered on the International Practice Guidelines Registration and Transparency Platform (http://www.guidelines-registry.cn, registration number: PREPARE-2023CN787). In June 2024, the consensus working group was established. The co-chairs (Xiang Cheng and Yuhua Liao) identified a core group of 72 experts from 43 institutions to generate items. The Population, Intervention, Comparison, and Outcome (PICO) format was used to identify key clinical questions. The certainty of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and evidence-to-decision (EtD) framework [Supplementary Table 1, https://links.lww.com/CM9/C640].[3] This consensus was reported according to the Accurate Consensus Reporting Document (ACCORD) checklist.[4] In a series of online meetings, the experts discussed one or more topics in a structured and organized manner to reach a consensus. The panelists non-anonymously rank each filtered statement on a nine-point scale (1–3 not essential, 4–6 neutral, 7–9 essential) with comments. The final statements were included if they received a median score ≥7. Another online interactive consensus meeting was conducted to review and agree upon the final statements. The panelists non-anonymously ranked the appropriateness of each filtered statement on three-level recommendations (strong recommendation, conditional recommendation, and not recommended) with comments. The recommendation with the highest voting percentage was selected within each statement. The literature search encompassed both English (PubMed, EMBASE, and The Cochrane Library) and Chinese (China Biology Medicine disc [CBM], China National Knowledge Infrastructure [CNKI], VIP Chinese Science and Technology Periodical Database [VIP], and WanFang) databases. The retrieval started from the inception of each database to October 2024. We discussed the proposed contents and statements at the online meeting on October 13, 2024, and March 17, 2025. Throughout October 2024 and March 2025, we completed the initial draft and the revisions according to the feedback of co-authors. This consensus is applicable to HF patients over 18 years old, and can be referred by clinicians, nurses, technicians, as well as related teachers and scientific researchers engaged in HF-related work in the hospitals. Consensus recommendations and clinical practice highlights:Statement 1: Inflammatory factor detection is recommended in HF. Class of recommendation: Conditional recommendation; Quality of evidence: B.CHD, especially acute myocardial infarction [AMI], is a common cause of HF. In the process of infarct repair, inflammatory cells infiltrate and release inflammatory factors, participating in adverse ventricular remodeling. The inflammatory factor detection is helpful for the diagnosis and prognosis evaluation of HF. The consensus recommends the detection of blood inflammatory factors (suppression of tumorigenicity-2 [sST2], galectin-3 [Gal-3], growth differentiating factor-15 [GDF-15], hypersensitive C-reaction protein [hsCRP], IL-6 and myeloperoxidase [MPO]) in HF patients. Supplementary Table 2, https://links.lww.com/CM9/C640 lists the optimal cut-off values for predicting the risk of all-cause death or HF hospitalization, i.e., sST2 >28 ng/mL in patients with chronic heart failure (CHF) and >65 ng/mL in those with acute decompensated heart failure (ADHF); Gal-3 >16.15 ng/mL in CHF patients and >9.42 ng/mL in ADHF patients; GDF-15 >1200 ng/L in HF patients; hsCRP ≥2 mg/L in HF patients; IL-6 >5.2 pg/mL in CHF patients and >11.1 pg/mL in ADHF patients; MPO >271 pmol/L in CHF patients and >99 pmol/L in ADHF patients.Statement 2: Anti-heart autoantibody (AHA) detection is recommended in HF. Class of recommendation: Strong; Quality of the evidence: A.AHA is the generic term for autoantibodies to myocardial injury. The consensus includes AHA that have been confirmed to be associated with the prognosis of HF, such as dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), and acute myocarditis [AMC]. AHA detection is helpful in the diagnosis and prognosis evaluation of HF. The consensus recommends anti-β1-adrenergic receptor (β1-AR) and anti-L-type calcium channel (L-CaC) antibody testing in HF patients, especially those with DCM, ICM, and AMC [Supplementary Table 2, https://links.lww.com/CM9/C640]. Indirect enzyme-linked immunosorbent assay (ELISA) is advised in testing of anti-β1-AR and anti-L-CaC antibodies. The serum to be tested is diluted starting at 1:20, and the AHA positivity is defined as optical density 2.5 times the background, using a microplate reader with a range of 405–492 nm.Statement 3: Epicardial adipose tissue (EAT) detection is recommended in heart failure with preserved ejection fraction (HFpEF). Class of recommendation: Strong; Quality of the evidence: A.In patients with HFpEF (left ventricular ejection fraction ≥50%), immunoinflammatory factors (IL-1β, IL-6, etc.) produced by EAT promote macrophage infiltration, cause damage to the coronary microvascular system, and induce myocardial fibrosis. The consensus recommends the measurement of EAT volume index and thickness as a diagnostic indicator of immunoinflammation in patients with HFpEF [Supplementary Table 2, https://links.lww.com/CM9/C640]. Reference value for EAT in predicting adverse cardiovascular events: EAT volume index >106 mL/m2 (cardiac magnetic resonance imaging [CMRI]) predicts the risk of all-cause mortality; EAT density ≤−76.2 HU (computed tomography [CT]) predicts the risk of hospitalization for HF; EAT thickness ≥9.45 mm (echocardiography, Echo) predicts the risk of hospitalization for HF; ECV >29% (CMRI) predicts the risk of a composite cardiovascular endpoint.Statement 4: Existing HF guideline-recommended drugs can inhibit the immunoinflammation in HF patients. Class of recommendation: Strong; Quality of the evidence: A.Existing HF guideline-recommended drugs have immune-modulatory effects. The consensus recommends guideline-directed medical therapy (GDMT) for HF, which can not only counteract aberrant SNS-RAAS activation and enhance natriuretic peptide system function, but also inhibit the immunoinflammation in HF. These pharmacological properties have expanded the understanding of the pathophysiological mechanisms of HF. There is sufficient evidence for treating HF with GDMT. Angiotensin receptor neprilysin inhibitor (ARNI)/angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), mineralocorticoid receptor antagonists (MRAs), β-adrenergic receptor blockers (BBs), and sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been listed as recommended drugs by domestic and international HF guidelines.Statement 5: Targeting innate immunity may be a new approach in HF. Class of recommendation: Conditional recommendation; Quality of evidence: B.Targeting innate immunity may be a novel approach for preventing and treating immunoinflammation in HF. The consensus recommends that targeting IL-1β pathway can prevent new-onset HF and reduce hospitalization for HF in CHD patients with inflammation risk. Semaglutide is recommended for the treatment of obese patients with HFpEF, improving HF-related symptoms and exercise capacity, along with the reduction of bodyweight and hsCRP. The ongoing trials on IL-6 inhibitor Ziltivekimab, colchicine, and MPO inhibitor AZD4831 will provide more in-depth evidence concerning the treatment of HF immunoinflammation.Statement 6: Targeting AHA through the specific drug is recommended in CHF. Class of recommendation: Conditional recommendation; Quality of the evidence: BTargeting anti-β1-AR antibodies and anti-L-CaC antibodies with specific drugs is an effective method in treating DCM and CHF. This consensus recommends the usage of BBs in DCM and CHF patients with positive anti-β1-AR antibodies and diltiazem in DCM patients with positive anti-L-CaC antibodies in early stages of HF. Contraindications include hypotension, bradycardia, and atrioventricular block. Diltiazem is contraindicated in patients with LVEDd ≥7.0 cm or New York Heart Association (NYHA) functional classes III–IV symptoms. Usage: BBs should be given at a low dose and gradually escalated to the maximum tolerated dose. The dose range of metoprolol is 23.75–190.00 mg/day, and that of carvedilol is 2.50–20.00 mg, three times a day. Diltiazem (90 mg/day) is mainly used for the treatment of HF in DCM at an early stage.Statement 7: Targeting AHA by immunoadsorption (IA) is recommended in DCM patients with sustained AHA positivity. Class of recommendation: Conditional recommendation; Quality of the evidence: BIA can effectively eliminate AHA in HF patients. The consensus recommends that DCM patients with sustained AHA positivity who are resistant to standard therapy of HF for at least 3 months may consider IA. The temporary right internal jugular vein catheterization is established for IA therapy, and 0.5 g/kg of immunoglobulin is intravenously administered after IA therapy. Regular rechecks of AHA are necessary following IA therapy.Statement 8: Immunomodulatory therapy is recommended in specific types of HF. Class of recommendation: Conditional recommendation; Quality of the evidence: BImmunomodulatory therapy is used for specific types of HF, including fulminant myocarditis and immune checkpoint inhibitor (ICI)-associated myocarditis. The consensus recommends that patients with fulminant myocarditis should receive timely and adequate dosage of glucocorticoids (GC). Meanwhile, it is recommended that immunoglobulin treatment should be initiated as soon as possible for these patients. The consensus recommends that GC should be used in mild, severe and critical, severe and critical ICI-associated myocarditis patients with HF. Routine use of GC for the prevention of ICI-related adverse effects is not recommended. In conclusion, the experimental and clinical studies have linked the immune system to the pathogenesis of HF since the original description in 1990. Immunoinflammation is common in patients with HF. The diagnosis of immunoinflammation in HF should be evaluated comprehensively [Supplementary Figure 1, https://links.lww.com/CM9/C640]. In the treatment and long-term management of immunoinflammation in HF, patients should be treated from the perspective of etiology first [Supplementary Figure 2, https://links.lww.com/CM9/C640]. A deeper understanding of immunoinflammation responsible for disease onset and progression may lead to new therapeutic opportunities to improve the outcomes of those with or at risk of developing HF [Supplementary Table 3, https://links.lww.com/CM9/C640]. Consensus Steering Committee: Experts are listed in Supplementary materials, https://links.lww.com/CM9/C640. Cardiovascular Immunology Committee, Chinese Society of Immunology: Experts are listed in Supplementary materials, https://links.lww.com/CM9/C640. Chinese Collaboration Group of Immunoinflammation in Heart Failure: Experts are listed in Supplementary materials, https://links.lww.com/CM9/C640. Funding The Noncommunicable Chronic Diseases—National Science and Technology Major Project (Nos. 2025ZD0548400, No. 2023ZD0504600), the National Key Research and Development Program (No. 2022YFC2503501), Hubei Technology Innovation Project (No. 2024BCB046), and Key Research and Development Program of Wuhan (No. 2024020702030092). Conflicts of interest None.