Cardiac Fibrosis in HFpEF: Emerging Therapeutic Targets
Cardiac fibrosis drives diastolic dysfunction in HFpEF. We review pathophysiology and novel therapies: SGLT2 inhibitors and GLP-1 receptor agonists.
Introduction
HFpEF (Heart Failure with preserved Ejection Fraction) accounts for approximately half of all heart failure patients, yet effective treatments have long been elusive. Recently, cardiac fibrosis has been identified as playing a central role in HFpEF pathophysiology, gaining attention as a novel therapeutic target.
This article explores the mechanisms linking cardiac fibrosis and HFpEF, along with the latest therapeutic approaches.
The Connection Between HFpEF and Cardiac Fibrosis
HFpEF Pathophysiology
HFpEF is a condition where heart failure symptoms occur due to diastolic dysfunction despite preserved left ventricular ejection fraction (LVEF≥50%).
Key Pathological Features:
- Increased left ventricular stiffness
- Elevated left atrial pressure
- Reduced exercise tolerance
- Systemic microvascular dysfunction
Role of Cardiac Fibrosis
Cardiac fibrosis is a major contributor to diastolic dysfunction in HFpEF:
| Fibrosis Type | Characteristics | Impact on HFpEF |
|---|---|---|
| Interstitial | Collagen deposition between cardiomyocytes | Reduced ventricular compliance |
| Perivascular | Remodeling around coronary arteries | Decreased coronary reserve |
| Replacement | Scarring after cardiomyocyte necrosis | Relatively less impact on contractile function |
Biomarker Assessment
| Biomarker | Measurement Target | Clinical Significance |
|---|---|---|
| sST2 | IL-33/ST2 pathway | Indicator of fibrosis/inflammation, prognostic value |
| Galectin-3 | Macrophage activation | Pro-fibrotic, correlates with poor prognosis |
| PICP, PINP | Collagen synthesis markers | Assessment of collagen turnover |
| CITP | Collagen degradation marker | Assessment of ECM remodeling |
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Role of Cardiac Fibroblasts
Differentiation from Fibroblasts to Myofibroblasts
In response to cardiac injury or chronic stress (hypertension, diabetes, obesity), cardiac fibroblasts differentiate into α-SMA-positive myofibroblasts.
Activating Factors:
- TGF-β1 (most important)
- Angiotensin II
- Endothelin-1
- Mechanical stress
- Inflammatory cytokines (IL-6, IL-1β)
Cardiac-Specific Features
Cardiac fibroblasts differ from fibroblasts in other organs:
- Electrical coupling: Form gap junctions with cardiomyocytes, potentially causing arrhythmias
- Paracrine signaling: Influence cardiomyocyte hypertrophy and metabolism
- Matrix production: Increased production of type I and III collagen
Latest Therapeutic Approaches
SGLT2 Inhibitors
Following the success of EMPEROR-Preserved and DELIVER trials, SGLT2 inhibitors have become standard treatment for HFpEF.
Anti-fibrotic Mechanisms:
- Reduction of cardiac sodium overload
- Suppression of inflammatory pathways (NLRP3 inflammasome)
- Promotion of autophagy
- Improvement of cardiac metabolism (enhanced ketone utilization)
| Drug | Trial | Primary Composite Endpoint Reduction |
|---|---|---|
| Empagliflozin | EMPEROR-Preserved | 21% (CV Death + HF Hospitalization) |
| Dapagliflozin | DELIVER | 18% (CV Death + HF Hospitalization) |
GLP-1 Receptor Agonists
Semaglutide has shown efficacy in HFpEF patients with obesity.
STEP-HFpEF Trial Results:
- Improvement in symptom scores in addition to weight loss
- Direct effects on cardiac fibrosis under investigation
MR Antagonists (Finerenone)
The FINEARTS-HF trial (2024) demonstrated efficacy of the non-steroidal MR antagonist Finerenone in HFpEF.
Mechanism of Action:
- Inhibition of aldosterone-induced collagen synthesis
- Suppression of cardiac fibrosis progression
- Reduction of inflammation
Preclinical Models
Selection of HFpEF Models
| Model | Induction Method | Features | Limitations |
|---|---|---|---|
| ZSF1 Rat | Genetic obesity + hypertension | Comorbidities similar to human HFpEF | Single strain only |
| DOCA-Salt Hypertension | Salt-sensitive hypertension | Rapid cardiac hypertrophy and fibrosis | Extreme model |
| HFD+L-NAME | High-fat diet + NOS inhibition | Metabolic abnormality + endothelial dysfunction | Complex intervention required |
| TAC | Aortic constriction | Pressure overload-induced hypertrophy | May transition to HFrEF |
Evaluation Endpoints
Functional Assessment:
- Echocardiography (E/e', left atrial volume index)
- Hemodynamic measurement (LVEDP)
- Exercise stress testing
Histological Assessment:
- Masson Trichrome staining
- Sirius Red staining (collagen quantification)
- α-SMA immunostaining (myofibroblasts)
Molecular Markers:
- Collagen I/III mRNA/protein
- TGF-β1, CTGF expression
- MMP/TIMP ratio
Summary
Cardiac fibrosis is central to HFpEF pathophysiology, and novel therapeutics such as SGLT2 inhibitors and Finerenone have demonstrated efficacy. Future development of treatments that more directly target fibrosis (e.g., anti-TGF-β therapy, Senolytics) is anticipated.
Selecting appropriate HFpEF models in preclinical research and quantitatively evaluating cardiac fibrosis is key to translational success.
References
- Anker SD, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461.
- Solomon SD, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098.
- Kosmala W, et al. Effect of Aldosterone Antagonism on Myocardial Fibrosis and Function in Heart Failure With Preserved Left Ventricular Ejection Fraction. JACC. 2022.
- Pitt B, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024.