Unmasking the Hidden Burden: Inflammation and Cardiovascular Disease JAHA Spotlight on the Role of the Immune System in Cardiovascular Health and Disease

The domain of cardioimmunology is an ever‐evolving multidisciplinary field that works to understand the complex relationship between the cardiovascular system and the immune system in health and pathogenesis. Once thought to be 2 distinct entities, both the adaptive and innate immune system are now understood to be critical in the descent into pathogenesis for a wide range of cardiovascular conditions, ¹ from heart failure ² to hypertension ³ to atherosclerosis. ⁴ Through both experimental and clinical data, inflammation has been shown as an independent risk factor for the development of cardiovascular disease. Within the last decade, a multitude of clinical trials have tested the efficacy of immunomodulatory treatments in reducing cardiovascular disease (Table1), ⁵ with mixed outcomes, demonstrating the need for more basic and translational mechanistic approaches to fully understand the complex pathways at play to maximize benefit and minimize side effects. The CANTOS trial (Cardiovascular Risk Reduction Study, NCT01327846), for example, showed that modulating the innate immunity pathway with a monoclonal antibody blocking interleukin‐1β, canakinumab, significantly lowered the rate of recurrent cardiovascular events. ⁶ Unfortunately, enthusiasm for its application in atherosclerosis was tempered due to an increase in fatal infection and sepsis, highlighting the need for further refinement of immune targets to prevent unacceptable side effects. A subsequent trial (Phase II VCUART3 study [Interleukin‐1 Blockade in Acute Myocardial Infarction], NCT01950299), using a receptor antagonist Anakinra in patients with ST‐segment–elevation myocardial infarction, demonstrated a reduction in the incidence of death and new heart failure hospitalization (9% versus 25%), but the sample size was small and only 1 death was reported. ⁷ Despite modest results from the aforementioned studies, trialists have continued down these avenues, with the ARAMIS anakinra trial (Anakinra Versus Placebo for the Treatment of Acute Myocarditis, NCT03018834) to assess the interleukin‐1β blockade in an acute myocarditis setting and VA‐ART4 study using anakinra in the context of myocardial infarction (Interleukin‐1 Blockade in Acute Myocardial Infarction to Prevent Heart Failure, NCT05177822), further highlighting the continuing interest in innate blockades as a method of modulating inflammatory driven cardiac pathogenesis. ⁸

Table 1.

Landmark Studies for Inflammatory Modulation in ardiovascular Disease Within the Past 10 Years

Study title	Study ID	Intervention	Phase	Year	Population	Primary end point	Outcome
Coronary artery disease
POSIBIL6ESKD	NCT05485961	Clazakizumab (anti‐IL‐6)	Phase 2/3	2029	Diagnosed end‐stage kidney disease with diabetes or ASCVD	Time to first occurrence of MACE and change in circulating inflammatory markers	Recruiting
ZEUS	NCT05021835	Ziltivekimab (anti‐IL‐6)	Phase 3	2026	Stage 3+ chronic kidney disease with evidence of ASCVD	Time to first occurrence of 3‐point MACE	Active, not recruiting
DFV890 in CAD	NCT06031844	DFV890 (NLRP3 inhibitor)	Phase 2a	2024	Known CAD and hs‐CRP ≥2 mg/L	Change in serum levels of IL‐6 and IL‐18	No results posted
PAC‐MAN	NCT04148833	Paclitaxel	Phase 2/3	2023	Stable CAD	Change in coronary and aortic plaque size	Unknown status
Methotrexate Associated to LDL‐Like Nanoparticles Study	NCT04616872	Methotrexate	Phase 2b	2023	Multivessel coronary artery disease and hs‐CRP >2 mg/L	Change to low attenuation plaque volume	Unknown status
GOLDILOX	NCT04610892	MEDI6570 (lectin‐like oxidized low‐density lipoprotein receptor‐1, inhibitor)	Phase 2a	2023	Previous MI and hs‐CRP >1 mg/L	Change in noncalcified plaque volume	No change in plaque volume, global longitudinal strain, LVEF, or NT‐proBNP levels in treatment to placebo
LoDoCo2	EudraCT 2015–005568‐40	Colchicine	Phase 3	2020	Chronic coronary disease	Time to first occurrence of MACE	Risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo
CHANGAN	NCT02874287	Clazakizumab (anti‐IL‐6)	Phase 4	2019	Diagnosed coronary artery disease with hypertension, diabetes, or hyperlipemia	Change of fasting hs‐CRP	Completed, no results posted
CIRT	NCT01594333	Methotrexate	Phase 3	2019	Secondary prevention in CAD with diabetes/metabolic syndrome	Time to first occurrence of MACE	Low‐dose methotrexate did not reduce levels of IL‐1β, IL‐6, or CRP and did not result in fewer cardiovascular events than placebo
Acute myocardial infarction
Virginia‐ART4	NCT05177822	Anakinra (IL‐1Ra)	Phase 2	2027	STEMI	Peak VO2	Recruiting
RITA‐MI2	NCT05211401	Rituximab (anti‐CD20)	Phase 2	2027	Clinical presentation of STEMI with no history of MI	Change in LVEF by CMR	Recruiting
ARTEMIS	NCT06118281	Ziltivekimab (anti‐IL‐6)	Phase 3	2026	STEMI or NSTEMI	Time to first occurrence of MACE	Recruiting
Doxycicline in STEMI	NCT03508232	Doxycycline	Phase 2	2025	STEMI	Change in left ventricular end‐systolic volume index	Recruiting
CLEAR SYNERGY	NCT03048825	Colchicine	Phase 3	2024	STEMI or NSTEMI	Time to first occurrence of MACE	No results posted
IVORY	NCT04241601	Aldesleukin (rIL‐2)	Phase 2	2023	ACS	Change in vascular inflammation	No results posted
CLEVER‐ACS	NCT01529554	Everolimus (mechanistic target of rapamycin complex 1, inhibitor)	Phase 1/2	2021	STEMI undergoing percutaneous coronary intervention	Myocardial infarct size	No results posted
ASSAIL‐MI	NCT03004703	Tocilizumab (anti‐IL‐6R)	Phase 2	2021	Acute STEMI	Myocardial salvage index by CMR	No results posted
RITA‐MI	NCT03072199	Rituximab (anti‐CD20)	Phase 1/2	2021	Clinical presentation of STEMI with no history of MI	Adverse and serious events, biochemistry and hematological changes and clinically significant ECG changes	No results posted
CANTOS	NCT01327846	Canakinumab (anti‐IL‐1b)	Phase 3	2019	MI and hs‐CRP ≥2 mg/L	Time to first occurrence of MACE	150 mg canakinumab every 3 months resulted in significantly lower cardiovascular events compared with placebo, independent of lipid level
COLCOT	NCT02551094	Colchicine	Phase 3	2019	Acute MI	Time to first occurrence of MACE	0.5 mg colchicine daily led to a significantly lower risk of ischemic cardiovascular events than placebo
VCU‐ART3	NCT01950299	Anakinra (IL‐1Ra)	Phase 2/3	2018	Clinical presentation of STEMI	Change in hs‐CRP	Anakinra significantly reduced CRP compared with placebo
Peripheral vascular diseases
LEADER‐PAD	NCT04774159	Colchicine	Phase 3	2029	Symptomatic PAD	Time to first occurrence of MACE	Recruiting
CASPER	ACTRN12621001408875	Colchicine	Phase 3	2027	Ischemic stroke and hs‐CRP ≥2 mg/L	Time to first occurrence of MACE and change in hs‐CRP
RIISC‐THETIS	NCT05476991	Colchicine	Phase 3	2027	Noncardioembolic stroke with evidence of atherosclerotic stenosis	Recurrent stroke, new vascular event, and vascular death	Recruiting
CONQUER‐DVT	NCT06440694	Colchicine	Phase 3	2027	Acute proximal deep vein thrombosis of the lower extremity	Postthrombotic syndrome, recurrent vascular events, bleeding and QoL	Recruiting
Mechanistic Clinical Trial of Colchicine in Patients Undergoing Femoral Endarterectomy	NCT06212271	Colchicine	Phase 1	2026	Symptomatic PAD undergoing endarterectomy	NLRP3 inflammasome expression in femoral artery plaque, plaque macrophage activity, and plasma IL‐6 and hs‐CRP	Recruiting
CONCISE	NCT06062277	Colchicine	Phase 2	2025	History of stroke or transient ischemic attack, ASCVD, and hs‐CRP ≥2 mg/L	Change in inflammatory biomarkers, tolerability, adherence, and acceptability	Unknown status
COLCHIDA	NCT06102720	Colchicine	Phase 4	2025	Acute atherothrombotic ischemic stroke	Recurrent stroke, neurological deterioration, functional outcomes, new vascular events, bleeding	Recruiting
PANDA VI	NCT06195267	Sivelestat (ELA2 inhibitor)	Not applicable	2025	Type A acute aortic syndrome	All‐cause mortality	Recruiting
IRIS	NCT06238024	Tocilizumab (anti‐IL‐6R)	Phase 2/3	2024	Acute ischemic stroke	Change in infarct‐core volume, neurological deficit, change in hs‐CRP and IL‐6	No results posted
Heart failure
Colchicine in ADHF	NCT06286423	Colchicine	Phase 4	2028	Acutely decompensated HFrEF and hs‐CRP >2 mg/L & elevated BNP/NT‐proBNP	Change in hsCRP, all‐cause death, or HF hospitalization	Recruiting
COLT‐HF	NCT05873881	Colchicine	Phase 3	2027	Stable NYHA II–IV HFrEF secondary to ischemic heart disease	Time to first occurrence of MACE	Recruiting
ATHENA	NCT06200207	Ziltivekimab (anti‐IL‐6)	Phase 3	2027	Symptomatic HFpEF and hs‐CRP, >2 mg/L and elevated NT‐proBNP	Change in KCCQ, 6‐min walk distance, NYHA class, hs‐CRP, NT‐proBNP, and renal function	Recruiting
HERMES	NCT05636176	Ziltivekimab (anti‐IL‐6)	Phase 3	2027	Symptomatic HFpEF and hs‐CRP >2 mg/L & elevated NT‐proBNP	Time to first occurrence cardiovascular death, HF hospitalization or urgent HF visit, nonfatal MI, and nonfatal stroke	Recruiting
COLHEART‐PRESERVED	NCT06081049	Colchicine	Phase 2	2026	NYHA II–IV HFpEF and elevated NT‐proBNP	Change in KCCQ, blood pressure, biomarkers, and Doppler echocardiographic parameters	Recruiting
LoDoCo	NCT06130059	Colchicine	Phase 2	2026	Chronic stable HFpEF and hs‐CRP >2 mg/L	Change in peak VO2, hs‐CRP, 6‐min walk distance, QoL, and Doppler echocardiographic parameters	Recruiting
COL‐Micro‐HF	NCT06217120	Colchicine	Phase 2/3	2026	Chronic stable NYHA II–IV HFpEF and hs‐CRP, ≥5 mg/L	Change in coronary flow reserve	Not yet recruiting
Colchicine in HFpEF	NCT05637398	Colchicine	Phase 1/2	2025	Symptomatic HFpEF with body mass index, >30 mg/m2 or diabetes	Change in soluble suppression of tumorigenicity 2 and inflammatory biomarkers, change in Doppler echocardiographic parameters	Recruiting
AID‐HEART	NCT06062966	Anakinra (IL‐1Ra)	Phase 1	2025	End‐stage HFrEF on chronic stable inotrope therapy and hs‐CRP >2 mg/L	Change in hs‐CRP, inotrope dose use, and 6‐min walk test	Recruiting
REDHART2	NCT03797001	Anakinra (IL‐1Ra)	Phase 2	2024	Recently decompensated HFrEF and hs‐CRP >2 mg/L	Change in peak VO2, echocardiography indices, hs‐CRP, NT‐proBNP, and QoL, HF, or hospitalization	No change in peak VO2
ENDEAVOR	NCT04986202	Mitiperstat (myeloperoxidase inhibitor)	Phase 2b/3	2024	Symptomatic HFpEF/HF with mildly reduced EF and elevated BNP/NT‐proBNP	Change in 6‐min walk distance, QoL, NT‐proBNP levels	Reduction in CRP when treated with 5 mg AZD4831 compared with placebo
Inflammatory cardiomyopathies
MYTHS	NCT05150704	Methylprednisolone	Phase 3	2028	Acute myocarditis confirmed by CMR	Time to the first event among all‐cause death, heart transplant, long‐term left ventricular assist device implant, need for an upgrading of the temporary mechanical circulatory support, ventricular tachycardia/ventricular fibrillation treated with direct current shock, first rehospitalization due to HF or ventricular arrhythmias, or atrioventricular block	Recruiting
ARGO	NCT05855746	Colchicine	Phase 3	2028	Acute myocarditis confirmed by CMR	Extent of late gadolinium enhancement	Recruiting
CMP‐MYTHiC	EudraCT2022‐003912‐99	Colchicine	Phase 3	2026	Acute myocarditis confirmed by CMR	Clinical worsening (cardiac death, hospitalization for worsening HF or arrhythmic events, and supraventricular tachycardia) or worsening arrhythmic burden	Recruiting
CHASM CS‐RCT	NCT03593759	Prednisone	Phase 3	2025	Cardiac sarcoidosis	Measure of myocardial scarring and fibrosis	Recruiting
MAGiC‐ART	NCT04017936	Anakinra (IL‐1Ra)	Phase 2	2024	Cardiac sarcoidosis	Change in hs‐CRP	Significant reduction in CRP levels but not LVEF at 28 days
Cardiac arrhythmias
COLFIB	NCT05928728	Colchicine	Phase 3	2028	Paroxysmal/persistent AF requiring electrical cardioversion	Change in Atrial Fibrillation Effect on Quality‐of‐Life score, left atrial volume, and symptomatic AF	Recruiting
COLECTRO‐AF	NCT05890664	Colchicine	Phase 3	2027	AF undergoing electrical cardioversion	AF recurrence and antiarrhythmic drug use	Recruiting
Atibuclimab in Arrhythmogenic Cardiomyopathy	NCT06275893	Atibuclimab (anti‐CD14)	Phase 1/2	2025	Arrhythmogenic cardiomyopathy and EF >30% and hs‐CRP ≥1.5 mg/L	Treatment‐emergent adverse events and serious adverse events	Suspended
Colchicine and AF recurrence after ablation	NCT05459974	Colchicine	Phase 3	2024	Paroxysmal/persistent AF scheduled to undergo ablation	AF recurrence, AF burden, and postablation QoL	Status unknown

Some data from Potere et al. ⁵

ACS indicates acute coronary syndrome; AF, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; BNP, B‐type natriuretic peptide; CAD, coronary artery disease; CMR, cardiac magnetic resonance imaging; CRP, C‐reactive protein; EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hs‐CRP, high‐sensitivity C‐reactive protein; IL‐18, interleukin‐18; IL‐6, interleukin‐6; KCCQ, Kansas City cardiomyopathy questionnaire; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MI, myocardial infarction; NLRP3, NOD‐, LRR‐ and pyrin domain‐containing protein 3 (inflammasome); NSTEMI, non‐ST‐segment–elevation myocardial infarction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; PAD, peripheral artery disease; QoL, quality of life; STEMI, ST‐segment–elevation myocardial infarction; and VO₂, oxygen uptake (peak oxygen consumption).

Interestingly, although innate immune modulation has long been the focus of many anti‐inflammatory cardiovascular trials, there has been growing interest in developing therapies targeting the adaptive immune system, partially triggered by the increased use of immune checkpoint inhibitors (ICIs) that harness the adaptive immune system to treat cancer. Although ICIs have revolutionized the treatment of melanoma and lung cancer, treatment with ICIs has been associated with adverse cardiotoxicities, ranging from arrhythmia ⁹ to heart failure ¹⁰ and myocarditis, ¹¹ highlighting how an uncontrolled adaptive immune system can contribute to cardiovascular pathology. One of the most well‐studied agents that modulates the adaptive immune system agents is rituximab, a monoclonal antibody that binds to CD20 protein on B cells. Two clinical trials to date (Rituximab in Patients With Acute ST‐Elevation Myocardial Infarction Study [RITA‐MI], NCT03072199; RITA‐MI2, NCT05211401) evaluating rituximab in patients with acute ST‐segment–elevation myocardial infarction have demonstrated treatment is safe and effective at depleting up to 96% of circulating B‐cell subsets. Rituximab was also shown to reduce high‐sensitivity CRP (C‐reactive protein), but whether treatment improves cardiovascular outcomes remains unclear. ¹² This paucity of trials underscores the requirement for furthering our knowledge of epitope‐specific mechanisms, before targeting of the adaptive immune system to modulate cardiovascular disease can be realized.

This Journal of the American Heart Association (JAHA) Spotlight features a compilation of studies dedicated to detailing and unraveling the intricate connection between systemic inflammation and cardiovascular disease. Its diverse collection of publications highlights the depth and interconnectivity of the cardiovascular and innate and adaptive immune systems and the way in which cardiovascular health is shaped through immune regulatory processes. These articles review the critical importance of basic and translational science in understanding the mechanisms behind systemic inflammation, resulting in the development of diverse pathologies such as atherosclerosis, valvular heart disease, hypertension, aneurysm formation, myocardial infarction, and rheumatic heart disease.

IMMUNE CHECKPOINT INHIBITORS AND CARDIOVASCULAR OUTCOMES

ICIs marked a paradigm shift in the therapeutic landscape of solid tumor management since Food and Drug Administration approval in 2011, emerging as standard modalities alongside a combination of cytotoxic chemotherapy and radiotherapy in the adjuvant, neoadjuvant, and metastatic settings. ¹³ A growing number of studies have reported an increase in atherosclerosis, acute coronary syndrome, and myocarditis in subsets of these patients, thus underscoring the necessity for further mechanistic insight to fully understand the associated cardiovascular risks in these therapeutic strategies. Within this special issue of JAHA, Saganty et al. give a thorough overview of the mechanisms and management of ICIs in acute coronary syndrome, simultaneously highlighting it as a pivotal treatment modality while also outlining the acute and chronic cardiovascular implications. ¹⁴ Suero‐Abreu et al. further this narrative with a single‐center retrospective study, investigating the factors associated with atherosclerotic disease in female patients following ICI therapy for a variety of oncology indications. ¹⁵ Of the 1188 treated patients, 5% (54) of female patients experienced atherosclerotic cardiovascular disease, with a 2.5‐fold prevalence for those with previous cardiovascular events. Interestingly, the overall plaque progression, defined by the volume change, did not differ when stratified by sex. Moreover, Pereyra et al. ¹⁶ investigate troponin T as a diagnostic criterion for cardiovascular events following ICI therapy, showing that a single elevated troponin T measurement post ICI in patients with ICI‐related cardiomyopathy is linked to poor prognosis, which was more common in male patients. ¹⁶ Lastly, by identifying novel drivers of cardiovascular disease from a population approach, Michaud et al. show the potential of monoclonal gammopathy, a noncancerous condition associated with blood cancer, in predicting atherosclerotic cardiovascular disease, specifically within the male sex. ¹⁷ Taken together, these studies demonstrate the need to better understand how biological sex and sex‐specific factors affect the underlying mechanisms driving ICI‐induced cardiotoxicity.

INFLAMMATORY MECHANISMS DRIVING HYPERTENSION AND STROKE

Hypertension, notably one of the main risk factors for heart disease, contributes to ∼11 million deaths per year. ¹⁸ Chronic arterial hypertension, often driven by high sodium intake, is associated with endothelial dysfunction, oxidative stress, and microvascular dysfunction, which trigger proinflammatory cascades that expose patients to a plethora of age‐related pathologies, ¹⁹ such as dementia, kidney failure, and stroke. Within this special issue, Goettert, ²⁰ Pan, ²¹ Buffolo, ²² and Arndt et al. ²³ use unbiased sequencing‐based approaches to delineate inflammatory pathways that drive hypertension. Here, Arndt et al. used a hypertensive rat model to demonstrate stage‐specific cerebral microvascular dysfunction, characterized by early hypertensive stress markers, rapid microglial activation, and immune cell infiltration, followed by a breakdown of the blood–brain barrier and later stage vascular remodeling. Critically, the authors link neuroinflammatory pathological changes with cognitive deficits in the rats, providing novel pathophysiology insights into vascular driven cognitive impairment. Pan et al. take this one step further and investigate the changing epigenetic immune cell profiles in patients, demonstrating that hypertensive patients exhibit unique methylation patterns across 13 immune cell populations, predominantly within the CD8 T cells. In contrast, Buffolo et al. investigate the effect of dietary sodium modulation on renal pathophysiology by investigating the micro‐RNA present within urinary extracellular vesicles. Here, the authors demonstrate that within 5 to 7 days of a high‐sodium diet, urinary extracellular vesicles shed from the nephron lumen and urinary tract contain increased levels of proinflammatory micro‐RNAs associated with interleukin and interferon signaling. This may, in turn, promote further infiltration of inflammatory cells and leukocyte adhesion by increasing ICAM‐1 (intercellular adhesion molecule 1, i) expression within the renal vascular endothelium. Although identifying low‐grade renal dysfunction attributed hypertension in patients is challenging clinically, the authors postulate that the noninvasive measurement of urine extracellular vesicle microRNAs may allow us to routinely monitor at‐risk patients, thereby providing an avenue for future therapeutic investigations focused on reducing hypertensive nephropathy in this cohort. Sustained hypertension, which affects almost half of adults in the United States, can result in hemorrhagic or ischemic stroke if left untreated, leading to life‐altering injury for the patient. In a secondary analysis of the OPENS (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke, NCT03620370) trial, Niu et al. identify the direct benefit of normobaric hyperoxia in reducing the inflammatory profile of patients following acute ischemic stroke, which may offer a low‐cost adjunct therapy to improve outcomes. ²⁴ Although these articles demonstrate active and exciting research within the field, we need a clearer stratification of risk factors for hypertension and stroke if we are to provide better management for this growing patient population.

PLAQUES, LIPIDS, AND INFLAMMATION

Atherosclerosis is associated with the development of aortic aneurysms, ²⁵ aortic stenosis, ²⁶ and ischemic stroke. ²⁷ In this issue of JAHA, we present a diverse spectrum of studies that underscore the knowledge gap in management and shed mechanistic insight into the role of immune cells in pathogenic progression. First, Nie et al. demonstrate that intracellular osteopontin within macrophages increases atherosclerotic plaque formation and promotes disease progression, through the induction of foam cell formation and the release of TNFα (tumor necrosis factor alpha), IL‐6 (interleukin‐6), and CCL2 (C‐C motif chemokine ligand 2). ²⁸ In line with previous work demonstrating histological ²⁹ and proteomic ³⁰ snapshots of osteopontin’s role within a procalcific signature, the authors then delve further and highlight a novel distinct subpopulation of osteopontin^hi macrophages that directly affect the development of atherosclerotic carotid plaques. Switching from the innate to the adaptive immune system, Krisnada et al. investigate CCR4 (C‐C chemokine receptor 4) expression on the development of abdominal aortic aneurysms, identifying a protective effect, which was associated with a shift in the T helper cell balance. ³¹ The authors show that a reduction of CCR4 in mice dramatically decreases the incidence of abdominal aortic aneurysms on an Apoe ^−/− background, diminishing inflammatory cell recruitment and preserving the elastic lamellae in the aorta. When deeply phenotyped, the protective effect was associated with an increase in the frequency of T helper (type 1) cells, promoting interferon‐γ production and suppressing pathogenic transforming group factor‐β signaling. Notably, the authors also detail that a lack of suppressor function of T regulatory cells in CCR4 deficient mice reduces both absolute number and capacity of T regulatory cells to suppress pro‐inflammatory mediators within the model, suggesting further investigation into Treg therapy for management of abdominal aortic aneurysms should be a potential avenue for future studies.

Finally, Mas‐Peiro et al. consider the relevance of inflammation and immune cell clonal hematopoiesis of indeterminate potential (CHIP) mutations in degenerative aortic valve stenosis, ³² specifically DNMT3A and TET2 mutations that are present in a third of all patients, which have been identified as a potential driver of pathogenesis. Associated with worse prognosis even after valve replacement, ‐ CHIP ‐, once thought to be associated with increasing age, may serve as a prognostic marker for recovery from surgery and long‐term outcomes. Although there is no medical therapy currently available for stenosis, Mas‐Peiro et al. summarize the current known mechanisms of CHIP within aortic valve stenosis, identifying potential prospects for novel therapeutics.

AUTOIMMUNITY AND CARDIAC PATHOGENESIS

Rheumatic heart disease is a significant global health concern, often overlooked as a critical area of cardiovascular research due to its prevalence in predominantly low‐ and middle‐income countries. Rheumatic heart disease is caused by an autoimmune reaction, whereby the immune system mistakenly attacks proteins in the heart (most commonly the heart valves) that resemble those belonging to a bacterial organism (eg, Group A Streptococcus). Within this issue of JAHA, Karhunen et al. detail the methods by which Streptococci evades immune detection, contributing to the proinflammatory environment. ³³ On the other end of the spectrum of autoimmune mediated cardiac disease, Lima et al. review the utility for cardiac imaging as a noninvasive methodology to identify cardiac graft rejection in heart transplantation. ³⁴ The authors elegantly relay the strengths, limitations, and practical roles of echocardiography, nuclear imaging, cardiac magnetic resonance, and coronary computed tomographic angiography across adult and pediatric populations, underscoring areas where quantitative methods add incremental value and provide a pragmatic, stage‐specific surveillance framework to reduce the requirement for invasive procedures. Taken together, these articles thoroughly consider the way in which inflammatory processes must be monitored and curtailed to improve the standard of care across inflammatory cardiovascular disease.

CONCLUSIONS

The articles featured in this JAHA Spotlight exemplify the current synergistic advancements at the intersection of cardiovascular disease and immunology, emphasizing the strengths of bringing together the interdisciplinary teams required to unpack and delineate these complex multiorgan pathologies. Further research to develop immune‐modulating therapies for both the management and mitigation of primary and secondary cardiovascular diseases is needed and will have a marked global impact.

Disclosures

None.