Current evidence supports a transition toward comprehensive cardiometabolic prevention integrating lipid management, lifestyle modification, metabolic optimization, and targeted anti-inflammatory therapy and future precision medicine strategies incorporating inflammatory biomarkers and individualized risk assessment may further improve cardiovascular outcomes and reduce the global burden of atherosclerotic disease.
Abstract
Cardiovascular disease remains the leading cause of mortality worldwide despite substantial advances in lipid-lowering therapies. Although achieving recommended low-density lipoprotein cholesterol (LDL-C) targets significantly reduces cardiovascular risk, many patients continue to experience recurrent cardiovascular events, a phenomenon known as residual cardiovascular risk. Increasing evidence indicates that chronic low-grade inflammation is a major contributor to this persistent risk. This review analyzes current scientific evidence regarding the biological mechanisms, inflammatory biomarkers, and emerging therapeutic strategies associated with residual inflammatory risk beyond LDL cholesterol. The literature demonstrates that activation of the NLRP3 inflammasome and the interleukin-1β/interleukin-6 pathway plays a central role in endothelial dysfunction, plaque progression, and atherosclerotic instability. High-sensitivity C-reactive protein (hs-CRP) remains the most widely validated biomarker for identifying persistent inflammatory activity in clinical practice. Landmark clinical trials, including CANTOS, COLCOT, and LoDoCo2, have demonstrated that selective anti-inflammatory therapies reduce recurrent cardiovascular events independently of additional LDL-C lowering, whereas nonspecific anti-inflammatory approaches have shown limited benefit. Furthermore, obesity, type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease substantially amplify residual inflammatory risk through shared pathophysiological mechanisms. Current evidence supports a transition toward comprehensive cardiometabolic prevention integrating lipid management, lifestyle modification, metabolic optimization, and targeted anti-inflammatory therapy. Future precision medicine strategies incorporating inflammatory biomarkers and individualized risk assessment may further improve cardiovascular outcomes and reduce the global burden of atherosclerotic disease.
A large body of evidence has helped reframe atherosclerotic cardiovascular disease from a mere lipid storage disorder to a chronic inflammatory disease. Both innate and adaptive immune pathways contribute to atherogenesis, plaque progression, and plaque destabilization. Macrophages, T cells, and cytokines—among them IL‐1β, IL‐6, and IL‐18—have emerged as key immune cells and mediators implicated in atherosclerosis progression. Residual inflammatory risk—as measured by highly sensitive C‐reactive protein (hsCRP) – has gained broad clinical acceptance as an important biomarker of cardiovascular risk prediction independent of cholesterol burden. Finding strategies that target residual inflammatory risk has proven an elusive goal in preventative cardiology. Specific approaches—such as IL‐1β inhibition or low‐dose colchicine—have shown benefit in reducing cardiovascular events, while other strategies have failed, underscoring the importance of targeting disease‐relevant immune pathways and selecting patients that will benefit. Newer approaches—including IL‐6 inhibitors, NLRP3 inflammasome inhibitors, and low‐dose IL‐2—offer promise for further risk reduction. Efforts to use inflammatory biomarkers to more precisely identify patients who may benefit may further improve the benefit‐to‐risk profile of emerging therapies.
M. Spindler, P. Libby, P. M. Ridker· Immunological Reviews· 1 citation
Cardiovascular disease has emerged as a leading cause of morbidity and mortality among patients with cancer, yet conventional lipid-based risk assessment remains poorly suited to this population. Growing evidence supports a cancer-associated lipid paradox, in which atherosclerotic events occur frequently despite low or well-controlled low-density lipoprotein cholesterol (LDL-C) levels. This paradox reflects the convergence of systemic inflammation, immune activation, hypercoagulability, tumor-driven metabolic reprogramming, and therapy-related vascular injury. Collectively, these processes decouple circulating lipid concentrations from cardiovascular risk. Cancer therapies including anthracyclines, immune checkpoint inhibitors, human epidermal growth factor receptor 2-targeted agents androgen-deprivation therapy, and thoracic radiation promote endothelial dysfunction, atherosclerotic plaque inflammation, and instability through mechanisms largely independent of LDL-C burden. Concurrent reductions in circulating cholesterol related to cancer metabolism, cachexia, and treatment effects may further obscure the residual cardiovascular risk in cancer patients. Lipoprotein(a) has also emerged as a potential mediator of inflammation and thrombosis-driven risk that is not captured by standard lipid metrics. This review synthesizes mechanistic, angiographic, and clinical evidence underpinning the lipid paradox in cancer, evaluates contemporary lipid-lowering strategies, and proposes a precision cardio-oncology framework that moves beyond LDL-centric paradigms toward a dynamic longitudinal risk-based prevention. Such an approach is essential to reduce cardiovascular events and to ultimately improve long-term outcomes in cancer survivors.
Nicole Prescott, Victoria Eichten, Vishal Ahuja et al.· American Journal of Cardiolo...· 0 citations
Cardiovascular disease remains the leading cause of death among women, yet female cardiovascular risk continues to be underrecognized, and women remain underrepresented in many cardiovascular trials. Sex-related differences in hormonal exposure, immune regulation, vascular function, pregnancy-related conditions, and clinical presentation contribute to heterogeneity in cardiovascular disease across the life course. Statins reduce atherosclerotic cardiovascular events in women and men, with no consistent evidence of treatment-effect heterogeneity by sex. In addition to lowering low-density lipoprotein cholesterol, statins influence inflammatory signaling, endothelial nitric oxide bioavailability, oxidative stress, thrombosis, and plaque biology. These effects are biologically relevant to atherosclerosis; however, current clinical evidence does not establish that LDL-independent statin effects confer a uniquely greater benefit in women. Historical pathological studies suggested that plaque erosion may contribute relatively more often to acute coronary thrombosis in selected younger women, whereas contemporary optical coherence tomography studies show similar overall frequencies of plaque rupture and erosion between sexes and important age-related variation. Evidence for a female-specific effect of statins on post-myocardial infarction remodeling, cognition, or pharmacogenomic susceptibility is also insufficient. This narrative review distinguishes established clinical evidence from mechanistic plausibility and unresolved sex-specific hypotheses. It emphasizes equitable implementation of guideline-directed lipid-lowering therapy, careful evaluation of statin-associated symptoms, and the need for adequately powered studies reporting sex-stratified estimates and formal treatment-by-sex interactions.
Rogerio Castellan de Moraes, P. Dourado, V. Z. Rocha et al.· Journal of Cardiovascular De...· 0 citations
Atherosclerosis remains the leading cause of global mortality, most commonly manifesting as ischemic heart disease, stroke, and peripheral arterial disease. Although age-adjusted cardiovascular mortality has declined in many developed nations, the global burden of atherosclerotic disease continues to rise due to population aging and growth. This narrative review examines the evolving understanding of atherosclerosis, which has shifted from a predominantly lipid-centric model to a chronic inflammatory disease. Atherosclerosis is initiated by the retention and modification of apolipoprotein B-containing lipoproteins within the arterial wall and propagated by innate and adaptive immune responses, alongside the development of new treatment strategies. Central to this process is activation of the NLRP3 inflammasome and downstream IL-1β–IL-6 signaling and pyroptotic cell death, which amplify vascular inflammation and promote plaque progression and instability. Clinical evidence demonstrates that targeting inflammation, independent of lipid lowering, reduces cardiovascular events, as exemplified by agents such as canakinumab and colchicine. Consequently, the therapeutic landscape is rapidly evolving, with ongoing efforts to refine cytokine-targeted approaches (e.g., IL-6 inhibition), develop selective NLRP3 inhibitors, and advance innovative modalities including cell-based interventions. These strategies aim to provide more durable, precise, and potentially disease-modifying or even curative approaches. However, challenges related to safety, the high cost of biologic agents, and optimal patient selection have limited widespread implementation. A major barrier remains the lack of sensitive and specific biomarkers to identify patients with active vascular inflammation, complicating trial design and therapeutic targeting. In addition to circulating markers such as high-sensitivity C-reactive protein (hsCRP) and IL-6, emerging insights highlight the liver as a central hub linking inflammation and thrombosis through complement and coagulation pathways, offering potential avenues for developing novel biomarkers. Despite promising advances, clinical translation faces persistent challenges, including increased infection risk, inadequate biomarkers for patient selection, cost constraints, and regulatory and payer requirements for hard clinical endpoints. Precision medicine approaches, drug repurposing, and innovative delivery systems may help accelerate development. Ultimately, the management of atherosclerosis is shifting toward a multifaceted approach that integrates lipid-lowering, inflammation resolution, and genetic correction to achieve durable cardiovascular protection.
L. Mandinov, Chris A. Learn· Reviews in cardiovascular me...· 0 citations
Cardiovascular disease (CVD) remains the leading cause of mortality and disability worldwide, characterized by high incidence, morbidity, and mortality. Although guideline-directed medical therapy has improved clinical outcomes and slowed disease progression to some extent, a substantial residual risk persists, and the progression of CVD has not been fundamentally halted. Beyond traditional risk factors such as hypertension, diabetes mellitus, and dyslipidemia, dysregulated inflammatory responses are now recognized as a central driver of CVD initiation, progression, and adverse outcomes. Neutrophil extracellular traps (NETs), as key effectors of innate immunity, contribute to inflammatory cascades through mechanisms including inflammasome activation, modulation of immune responses, and promotion of thrombosis. Accumulating evidence indicates that NETs play a critical role in a spectrum of cardiovascular conditions, including atherosclerosis, myocardial infarction, and heart failure, and are closely associated with poor prognosis. This review systematically summarizes the mechanisms by which NETs mediate inflammatory responses in CVD and discusses their roles across different disease contexts. It further explores the potential of NETs as inflammation-related biomarkers and therapeutic targets, with the aim of providing new insights into inflammation-based strategies for the prevention and treatment of CVD.
Aolong Wang, Jing-Jing Wei, Rui Yu et al.· Frontiers in Immunology· 0 citations
Lp(a) may soon shift from a “silent threat” to a precise, actionable target in cardiovascular prevention, according to a review of the current evidence, which highlights gaps in knowledge, and discusses emerging therapeutic strategies.
Michał Miszczak, P. Piwowarczyk, G. Sobieszek et al.· Biomedicines· 0 citations
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