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Heart Failure Reviews (Springer)2022ReviewNon-viral Gene Delivery

Treatment of cardiac fibrosis: from neuro-hormonal inhibitors to CAR-T cell therapy

Paolo Morfino, Alberto Aimo, Vincenzo Castiglione, Carolina Galvez-Montón, Michele Emdin, Antoni Bayes-Genis

Summary

Cardiac fibrosis contributes to the pathogenesis of heart failure, myocardial infarction, and arrhythmias, but no primarily anti-fibrotic drug has been approved for cardiovascular disease. Many candidate anti-fibrotic strategies have shown promise in preclinical models yet failed to demonstrate clear clinical benefit. There is a need to summarize current and emerging therapeutic options and to evaluate a new approach: targeting cardiac. RAAS inhibitors: Lisinopril reduced collagen volume fraction (CVF) vs. hydrochlorothiazide; losartan reduced CVF and PICP; spironolactone/eplerenone reduced PICP/PIIINP and improved diastolic function in some trials. -.

Keywords

CAR-T cellsT cellsLipid nanoparticlemRNANanoparticlesEndosomal escapeEndocytosis
Purpose: Cardiac fibrosis contributes to the pathogenesis of heart failure, myocardial infarction, and arrhythmias, but no primarily anti-fibrotic drug has been approved for cardiovascular disease. Many candidate anti-fibrotic strategies have shown promise in preclinical models yet failed to demonstrate clear clinical benefit. There is a need to summarize current and emerging therapeutic options and to evaluate a new approach: targeting cardiac myofibroblasts directly using CAR-T cells.
Hypothesis: As a review article, this work does not test a single hypothesis. Its central thesis is:

If cardiac myofibroblasts—the key effector cells in fibrosis—are selectively targeted and eliminated, then myocardial fibrosis can be reduced and cardiac function improved. In particular, if T cells are engineered in vivo using lipid nanoparticles containing mRNA encoding a receptor against fibroblast activation protein (FAP), then transient FAP-targeted CAR-T cells can safely reduce fibrosis and improve cardiac function in mouse models, potentially overcoming limitations of current anti-fibrotic drugs and ex vivo CAR-T cell therapy.

Aims: Primary Aim: To review the therapeutic options for cardiac fibrosis, from neuro-hormonal inhibitors to emerging CAR-T cell therapy.
  • Secondary Aims:
  • To summarize the pathophysiology and clinical significance of cardiac fibrosis.
  • To evaluate drugs without primarily anti-fibrotic action (RAAS inhibitors, inflammation modulators, anti-TGF-β antibodies, pirfenidone, MMP inhibitors, adrenergic receptor modulators).
  • To discuss the rationale and preclinical evidence for CAR-T cell therapy targeting FAP-expressing cardiac myofibroblasts.
  • To assess the feasibility, limitations, and future directions of CAR-T cell therapy in cardiovascular disease.
Delivery system:

Component: CAR-T platform; Details: In vivo engineered CAR-T cells using CD5-targeted lipid nanoparticles (CD5/LNP-FAPCAR)

Component: Nanoparticle; Details: Lipid nanoparticle (LNP) coated with anti-CD5 antibodies

Component: Payload; Details: Modified mRNA encoding a chimeric antigen receptor directed against fibroblast activation protein (FAPCAR)

Component: Target cell (delivery); Details: CD5+ T cells (CD5 is a membrane glycoprotein expressed on T cells)

Component: Target cell (therapeutic effect); Details: FAP-expressing cardiac myofibroblasts

Component: Mechanism; Details: LNP binds CD5 on T cells → endocytosis → endosomal escape → mRNA release → translation of FAPCAR on T cell surface → FAPCAR+ T cells recognize and eliminate FAP+ myofibroblasts

Component: Other drugs discussed; Details: RAAS inhibitors (lisinopril, losartan, spironolactone, eplerenone, sacubitril/valsartan), inflammation modulators (etanercept, infliximab, colchicine, statins), pirfenidone, MMP inhibitors (PG-116800), β3-AR agonists (mirabegron)

Approach: This is a narrative review synthesizing preclinical and clinical literature. No primary experimental data are presented.
  • Clinical studies summarized: RAAS inhibitor trials (Brilla et al., López et al., Díez et al., RALES, EPHESUS, ALDO-DHF, PARAMOUNT, PIROUETTE), inflammation modulator trials (RENEWAL, ATTACH, COLCOT, COVERT-MI), statin trials (GISSI-HF, CORONA), MMP inhibitor trial (PREMIER), β3-AR trial (BEAT-HF).
  • Preclinical CAR-T model: C57BL/6 mice received Ang II + phenylephrine infusion for 28 days to induce pressure-overload cardiac damage. After 1 week of damage, mice received a single dose of CD5/LNP-FAPCAR. Mice were analyzed 2 weeks after treatment.
  • Ex vivo CAR-T model: FAP-targeted CAR-T cells tested in a mouse model of Ang II/phenylephrine-induced fibrosis.
  • Disease contexts: Cardiac fibrosis, heart failure, myocardial infarction, hypertension, aging.
Key methods: Histology: Endomyocardial biopsy with trichromatic and Sirius Red staining; Picrosirius red staining for collagen quantification. - Cardiac magnetic resonance (CMR): Late gadolinium enhancement, extracellular volume (ECV) quantification. - Echocardiography: Left ventricular end-diastolic and end-systolic volumes, LV mass index, ejection fraction, E/e′ ratio, global longitudinal strain. - Circulating biomarkers: PICP, PIIINP, PINP, TIMP-1, sST2, CITP, galectin-3. - In vitro CAR-T assays: T cell culture, FAPCAR expression detection, target cell elimination. - In vivo CAR-T detection: FAPCAR expression in T cells (reported as 17.5–24.7% of T cells 48 h after injection).
Key results: RAAS inhibitors: Lisinopril reduced collagen volume fraction (CVF) vs. hydrochlorothiazide; losartan reduced CVF and PICP; spironolactone/eplerenone reduced PICP/PIIINP and improved diastolic function in some trials. - Pirfenidone (PIROUETTE phase II): In 94 HFpEF patients with extended fibrosis, pirfenidone reduced ECV by 0.7% vs. an increase of 0.5% in placebo (p = 0.009), but without significant improvement in diastolic function. - MMP inhibitor (PREMIER): PG-116800 did not prevent LV remodeling or improve mortality/re-infarction at 90 days. - Anti-TNF therapy: Etanercept (RENEWAL) showed no benefit; infliximab (ATTACH) increased mortality and was discontinued. - Ex vivo FAP CAR-T cells: Reduced fibrosis in all 7 treated mice, with almost total elimination in 5/7, and maintained normal systolic and diastolic function; safety profile was favorable with mild inflammatory response. - In vivo CD5/LNP-FAPCAR: FAPCAR expression detected in 17.5–24.7% of T cells 48 h after injection. Treated mice showed improved LV size, systolic and diastolic function, and LV mass. Histology showed significant reduction in ECM fraction; 5 of 12 treated mice were indistinguishable from sham animals. - CAR-T limitations: Cytokine release syndrome incidence: mild 70–90%, severe 20–50%; cardiovascular events include symptomatic heart failure, acute coronary syndrome, ischemic stroke, and arrhythmia.
Interpretation: The authors conclude that the pathophysiological heterogeneity of myocardial fibrosis and the complexity of fibroblast responses complicate anti-fibrotic drug development. RAAS inhibitors reduce ECM deposition but no primarily anti-fibrotic drug has demonstrated clear clinical regression of fibrosis. Targeting myofibroblasts directly—rather than single molecular pathways—is a promising new approach. In vivo engineered CAR-T cells using LNP-mRNA are particularly promising for conditions with intense pro-fibrotic activation, such as myocardial infarction or myocarditis. Clinical trials are required to test this approach in humans.
Limitations: Limitations inherent to the review:
  • No primary experimental data; conclusions are synthesized from existing literature.
  • No systematic search strategy or meta-analysis.
  • Focus is primarily on preclinical and early clinical studies; no human CAR-T data for cardiac fibrosis.
  • Heterogeneity of fibrosis mechanisms and animal models limits direct comparisons.

Limitations of the field highlighted by the authors:

  • No approved anti-fibrotic drug for cardiovascular disease; clinical evidence for anti-fibrotic efficacy is extremely limited.
  • Biomarker limitations: Circulating collagen biomarkers do not reliably reflect the extent of myocardial fibrosis.
  • Anti-TGF-β therapy: Associated with serious adverse effects, including LV dilation and increased mortality.
  • CAR-T limitations: Ex vivo production is long, expensive, and associated with persistent activation; cytokine release syndrome and cardiovascular toxicities are concerns; antigen escape may limit efficacy.
  • In vivo CAR-T limitations: Long-term safety, durability, and off-target effects remain unknown; clinical feasibility in humans has not been tested.
  • Heterogeneity of fibrosis: Different forms (reparative vs. reactive) and disease stages may require different therapeutic strategies.
  • Clinical translation: Dedicated clinical trials are needed to verify efficacy and safety of CAR-T cell therapy for cardiac fibrosis.

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Treatment of cardiac fibrosis: from neuro-hormonal inhibitors to CAR-T cell therapy | Brilliant Blue Biosciences