Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy

Hok, Kathryn D.; Rich, Haydn E.; Shadid, Anthony; Gunamalai, Lavanya; Weng-Mills, Tingting; Thandavarayan, Rajarajan A.; Banda, Nirmal K.; Doursout, Marie-Francoise; Restrepo, Marcos I.; Shivshankar, Pooja

doi:10.3390/ijms26209931

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Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy

by

Kathryn D. Hok

^1,†

,

Haydn E. Rich

^1,†,

Anthony Shadid

¹

,

Lavanya Gunamalai

²,

Tingting Weng-Mills

³

,

Rajarajan A. Thandavarayan

⁴

,

Nirmal K. Banda

⁵,

Marie-Francoise Doursout

⁶,

Marcos I. Restrepo

⁷

and

Pooja Shivshankar

^1,*

¹

Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA

²

Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA

³

Department of Biochemistry and Molecular Biology, UTHealth-McGovern Medical School, Houston, TX 77030, USA

⁴

Department of Cardiology, DeBakey Heart & Vascular Center, Houston Methodist Weill Cornell Medical College, Houston, TX 77030, USA

⁵

Division of Rheumatology-Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA

⁶

Department of Anesthesiology, UTHealth-McGovern Medical School, Houston, TX 77030, USA

⁷

VA-San Antonio Geriatric Research Education and Clinical Center (GRECC)-South Texas Veterans Health Care System Audie L. Murphy Division, UTHealth San Antonio, San Antonio, TX 78229, USA

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(20), 9931; https://doi.org/10.3390/ijms26209931 (registering DOI)

Submission received: 6 August 2025 / Revised: 28 September 2025 / Accepted: 10 October 2025 / Published: 12 October 2025

(This article belongs to the Special Issue Cardioimmunology: Inflammation and Immunity in Cardiovascular Disease)

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Abstract

Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation—classical, lectin, and alternative—are implicated in developing cardiac damage, inflammation, and hypertrophy due to infectious and non-infectious causes, autoimmune diseases, genetic polymorphisms, and forms of complement dysregulation. Of interest in this review is the role of the complement system, a collection of soluble and membrane-bound proteins that mediate inflammatory processes through interactions with signaling molecules and immune cells. This review comprehensively discusses the roles of these complement pathways in contagious, chronic inflammatory, genetic, and metabolic diseases. An overview of the completed and terminated clinical trials aimed at preventing cardiovascular mortality by targeting various aspects of the complement system and inflammatory reaction is included. Most current treatments for cardiac inflammation and remodeling primarily target the renin–angiotensin–aldosterone system (RAAS), which prevents further remodeling by reducing myocardial workload. However, moving forward, there may be a place for emerging anti-complement therapeutics, which impair the inflammatory response that generates hypertrophy itself.

Keywords: complement immune system; complement anaphylatoxins; cardiac inflammation; cardiac hypertrophy; cardiac remodeling; autoimmune diseases; cardiovascular events; infectious diseases; genetic defects in complement genes; complement in metabolic diseases; cardiovascular adversities; cardiovascular diseases; cardiac arrhythmias

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MDPI and ACS Style

Hok, K.D.; Rich, H.E.; Shadid, A.; Gunamalai, L.; Weng-Mills, T.; Thandavarayan, R.A.; Banda, N.K.; Doursout, M.-F.; Restrepo, M.I.; Shivshankar, P. Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy. Int. J. Mol. Sci. 2025, 26, 9931. https://doi.org/10.3390/ijms26209931

AMA Style

Hok KD, Rich HE, Shadid A, Gunamalai L, Weng-Mills T, Thandavarayan RA, Banda NK, Doursout M-F, Restrepo MI, Shivshankar P. Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy. International Journal of Molecular Sciences. 2025; 26(20):9931. https://doi.org/10.3390/ijms26209931

Chicago/Turabian Style

Hok, Kathryn D., Haydn E. Rich, Anthony Shadid, Lavanya Gunamalai, Tingting Weng-Mills, Rajarajan A. Thandavarayan, Nirmal K. Banda, Marie-Francoise Doursout, Marcos I. Restrepo, and Pooja Shivshankar. 2025. "Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy" International Journal of Molecular Sciences 26, no. 20: 9931. https://doi.org/10.3390/ijms26209931

APA Style

Hok, K. D., Rich, H. E., Shadid, A., Gunamalai, L., Weng-Mills, T., Thandavarayan, R. A., Banda, N. K., Doursout, M.-F., Restrepo, M. I., & Shivshankar, P. (2025). Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy. International Journal of Molecular Sciences, 26(20), 9931. https://doi.org/10.3390/ijms26209931

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Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy

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