Highlights
- The HYPIC trial is the first multicenter randomized study to demonstrate that adding Hydroxychloroquine (HCQ) to Prednisolone (PDN) significantly reduces major adverse cardiovascular events (MACE) in chronic inflammatory cardiomyopathy (infl-CMP).
- Combination therapy achieved a 72% reduction in the risk of the primary composite outcome (HR = 0.28, 95% CI 0.11-0.71) compared to steroid monotherapy.
- Treatment for 12 months led to significant improvements in Left Ventricular Ejection Fraction (LVEF) and reduction in cardiac remodeling (LVIDd) and biomarkers (NT-proBNP, hs-cTnI).
- HCQ demonstrated a profound immunomodulatory effect, normalizing 16 different plasma cytokines to levels seen in healthy individuals, with a favorable safety profile.
Background: The Challenge of Post-Fulminant Myocarditis Recovery
Chronic inflammatory cardiomyopathy (infl-CMP) represents a critical clinical challenge in the spectrum of heart failure. It is frequently identified as a long-term sequela of acute myocarditis, particularly fulminant myocarditis (FM). While FM is characterized by sudden, severe cardiac dysfunction and a life-threatening systemic inflammatory storm, patients who survive the acute phase often transition into a chronic phase where “smoldering” inflammation persists. This persistent inflammation leads to progressive myocardial fibrosis, adverse ventricular remodeling, and ultimately, refractory heart failure or lethal arrhythmias.
Historically, the management of infl-CMP has relied on standard heart failure therapies (beta-blockers, ACE inhibitors/ARBs, and MRA) combined with varying regimens of corticosteroids. However, steroid monotherapy often yields inconsistent results and carries significant long-term side effects. There remains an urgent clinical need for targeted immunomodulatory strategies that can suppress the specific inflammatory pathways driving disease progression without inducing excessive immunosuppression. Hydroxychloroquine (HCQ), a well-established lysosomotropic agent used in rheumatology, has emerged as a candidate for repurposing due to its ability to modulate Toll-like receptor signaling and reduce cytokine production.
Key Content
Mechanistic Rationale for HCQ in Myocardial Inflammation
Hydroxychloroquine’s potential in treating inflammatory cardiomyopathy stems from its multifaceted mechanism of action. Unlike broad-spectrum immunosuppressants, HCQ interferes with the acidification of lysosomes, thereby inhibiting the processing and presentation of autoantigens. More importantly, it acts as an antagonist for endosomal Toll-like receptors (specifically TLR7 and TLR9), which are known to play a pivotal role in the innate immune response and the subsequent activation of the “cytokine storm” in myocarditis. By stabilizing the lysosomal membrane and reducing the secretion of pro-inflammatory cytokines such as IL-6 and TNF-alpha, HCQ may prevent the transition from acute inflammation to chronic fibrotic remodeling in the heart.
The HYPIC Trial: Study Design and Methodology
The HYPIC trial (NCT05961202) was a multicenter, randomized, open-label, blinded-endpoint trial designed to evaluate the efficacy and safety of HCQ in patients with chronic infl-CMP secondary to FM. The study recruited fifty patients who were randomized in a 1:1 ratio to receive either HCQ (200 mg twice daily) combined with Prednisolone (PDN) or PDN monotherapy for a duration of 12 months. All patients received standard-of-care heart failure treatments. The primary endpoint was a composite of cardiovascular death, heart transplantation, hospitalization for heart failure, recurrence of myocarditis, or the need for permanent pacemaker or ICD implantation.
Clinical Efficacy: Improved Prognosis and Function
The results of the HYPIC trial provide compelling evidence for the superiority of combination therapy. At the 12-month follow-up, the HCQ + PDN group demonstrated a significantly lower incidence of the primary composite outcome compared to the PDN group (HR = 0.28; 95% CI 0.11-0.71; P < 0.05). This suggests that HCQ provides substantial protection against the most severe complications of inflammatory cardiomyopathy.
Secondary outcomes further supported these findings. Patients in the HCQ group showed a more pronounced increase in LVEF and a greater reduction in left ventricular internal diastolic diameter (LVIDd) compared to those receiving PDN alone. This indicates that HCQ not only prevents adverse events but also actively promotes structural and functional recovery of the myocardium. Furthermore, significant decreases in high-sensitivity cardiac troponin I (hs-cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels suggest reduced myocardial injury and wall stress, respectively.
Immunological Synthesis: Cytokine Normalization
One of the most striking findings of the HYPIC trial was the impact on the systemic inflammatory milieu. Infl-CMP is characterized by a persistent imbalance of cytokines. The study analyzed a panel of plasma cytokines and found that HCQ + PDN therapy significantly reduced the levels of 16 different pro-inflammatory markers. Notably, these levels were brought down to a range comparable to that of healthy controls. This biochemical “reset” highlights HCQ’s role as a potent immunomodulator capable of quenching the chronic inflammatory fire that drives cardiac deterioration. The reduction in hs-CRP and erythrocyte sedimentation rate (ESR) further validated the systemic anti-inflammatory effect.
Safety and Tolerability Profile
Safety is a paramount concern when introducing long-term immunomodulatory therapy. In the HYPIC trial, both groups reported an acceptable safety profile. No serious drug-related adverse events—such as retinopathy, significant QTc prolongation, or severe myelosuppression—were recorded. The incidence of common side effects was low and manageable, confirming that the dosage of 400 mg/day of HCQ is well-tolerated in this patient population over a 12-month period.
Expert Commentary
The HYPIC trial represents a significant step forward in the precision management of inflammatory cardiomyopathy. For decades, clinicians have grappled with the “grey zone” of post-myocarditis treatment, where standard heart failure meds often prove insufficient. The trial’s findings suggest that the pathophysiology of infl-CMP is driven by a persistent immune dysregulation that can be successfully targeted with HCQ.
From a clinical perspective, the 72% reduction in risk is profound, though the relatively small sample size (n=50) necessitates caution. The trial’s reliance on patients specifically following fulminant myocarditis is a strength, as this population represents the highest-risk group for developing chronic infl-CMP. However, the applicability of these findings to other forms of inflammatory cardiomyopathy (e.g., giant cell myocarditis or sarcoidosis) remains to be determined. Furthermore, while the 12-month data is robust, the long-term durability of this effect after treatment cessation is an area that requires further investigation.
The integration of cytokine profiling in the HYPIC trial provides a mechanistic “gold standard” for monitoring therapy. It shifts the treatment paradigm from symptom management toward biological remission. Experts suggest that future guidelines may consider HCQ as a class IIa or IIb recommendation for infl-CMP, particularly in patients who show persistent markers of inflammation despite standard therapy.
Conclusion
The HYPIC trial successfully demonstrates that 12 months of HCQ combined with PDN therapy significantly improves cardiac function and prognosis in patients with chronic inflammatory cardiomyopathy after fulminant myocarditis. By effectively suppressing the systemic cytokine storm and promoting reverse remodeling of the left ventricle, this combination therapy offers a new horizon for patients who previously faced a poor prognosis. Future research should focus on larger-scale Phase III trials to confirm these results and explore the optimal duration of therapy.
References
- He W, Cui G, Chen J, Chen M, Li R, Wang L, Yu T, Li G, Jiang J, Wang DW. The efficacy and safety of hydroxychloroquine in patients with chronic inflammatory cardiomyopathy: a multicenter randomized study (HYPIC trial). BMC Med. 2025 Aug 8;23(1):467. doi: 10.1186/s12916-025-04301-w. PMID: 40781621.
- Caforio AL, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(33):2636-2648.
- Tschöpe C, et al. Management of Myocarditis-Related Cardiomyopathy in Adults. Circ Res. 2019;124(11):1568-1583.
