Causes, Diagnosis, Treatment, and Prognosis of Cardiac Fibrosis: A Systematic Review

Abstract

Cardiac fibrosis, characterized by excessive extracellular matrix deposition, contributes to heart failure, arrhythmias, and myocardial dysfunction. Despite advances in understanding its mechanisms, targeted antifibrotic therapies remain limited. This review examines the causes, molecular mechanisms, diagnostic approaches, and therapeutic strategies for cardiac fibrosis. A systematic review of peer-reviewed studies was conducted, focusing on the etiology, diagnosis, treatment, and prognosis of cardiac fibrosis with no specific timeframe. The condition is driven by fibroblast activation, inflammatory pathways, and mechanical stress, with key contributing factors including ischemic heart disease, hypertension, diabetes, and aging. Diagnostic tools such as cardiac magnetic resonance imaging with T1 mapping and biomarkers play a crucial role, with natriuretic peptides offering both diagnostic and prognostic value. Galectin-3 has also shown promise as a prognostic marker. Current therapies, including RAAS inhibitors and beta-blockers, help prevent fibrosis progression but do not reverse established fibrosis. Emerging strategies such as plant-based compounds, gene therapy, fibroblast-targeting vaccines, and stem cell reprogramming show potential in preclinical studies. However, cardiac fibrosis remains a major driver of heart disease progression, and existing treatments remain limited. Major gaps include the lack of validated antifibrotic agents and challenges in translating preclinical findings into clinical applications. Further research is essential to develop effective targeted interventions.

Keywords: antifibrotic therapies; cardiac biomarker; cardiac fibrosis; fibroblast activation; heart failure.

Figure 1. Flowchart depicting the literature search and selection process

The initial search yielded 1,981 studies. The selection process involved screening titles and abstracts, followed by assessing articles that met the inclusion criteria for methodological quality and relevance. After resolving discrepancies through discussion, 68 studies were selected for qualitative synthesis.

Figure 2. Progression from injury to fibrosis

This figure illustrates the key cellular and molecular processes involved in cardiac fibrosis. In response to myocardial injury (e.g., ischemia, hypertension, and diabetes), fibroblasts become activated and differentiate into myofibroblasts, which subsequently secrete excessive ECM [1,9]. ECM, extracellular matrix Image credits: Hasan A. BaniHani

Figure 3. Diagnostic algorithm for cardiac fibrosis

Patients with suspected cardiac fibrosis are evaluated based on symptoms (e.g., heart failure and arrhythmias) and risk factors (e.g., hypertension, diabetes, and aging) before undergoing biomarker testing. Blood biomarkers such as Galectin-3, BNP, NT-proBNP, and TIMP-1 are measured. If results are normal, fibrosis is unlikely, and the patient is monitored. If abnormal, further evaluation is required. Imaging studies, including CMR with T1 mapping/LGE or PET scans (68Ga-FAPI), are then used to assess fibrosis severity. Positive findings lead to treatment consideration, while inconclusive cases necessitate additional testing. For uncertain cases, histological confirmation via endomyocardial biopsy is performed as the gold standard to confirm fibrosis [45,46,52,53]. BNP, B-type natriuretic peptide; CMR, cardiac magnetic resonance imaging; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TIMP-1, tissue inhibitor of metalloproteinases-1 Image credits: Hasan A. BaniHani