The 2026 American College of Cardiology/American Heart Association (ACC/AHA) dyslipidemia guideline represents a major shift in secondary prevention of atherosclerotic cardiovascular disease (ASCVD), moving beyond a predominantly low-density lipoprotein cholesterol (LDL-C)-centered model toward earlier, lower, longer, and more individualized lipid-lowering strategies. This review summarizes 10 practice-changing concepts from the guideline with direct relevance to patients with clinical ASCVD. Despite high-intensity statin therapy, substantial residual cardiovascular risk may persist because of delayed treatment intensification, persistent apolipoprotein B (apoB)-containing lipoprotein burden, elevated lipoprotein(a) [Lp(a)], triglyceride-rich remnants, and high-risk cardiovascular-kidney-metabolic (CKM) comorbidities. Major updates include reintroduction of goal-directed therapy, lower LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) targets, and broader use of non-statin therapies, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bempedoic acid, and inclisiran. In patients with clinical ASCVD at very high risk, LDL-C and non-HDL-C targets of < 55 mg/dL and < 85 mg/dL, respectively, are recommended. The guideline also emphasizes structured lipid monitoring and a systematic approach to statin-attributed muscle symptoms to reduce therapeutic inertia, preserve effective lipid-lowering therapy, and support sustained goal attainment. Collectively, these updates mark a transition toward precision lipidology, emphasizing individualized risk assessment, earlier treatment escalation, structured follow-up, preservation of effective therapy despite treatment-related symptoms, and more comprehensive reduction of residual cardiovascular risk in secondary prevention.
Subclinical atherosclerosis represents an important stage in the continuum of cardiovascular disease, characterized by structural or functional vascular abnormalities in the absence of overt clinical events. This review examines the biological mechanisms and clinical evidence supporting exercise as both a preventive and potential disease-modifying intervention in individuals with imaging-detected subclinical atherosclerosis, with particular emphasis on endothelial function, vascular remodeling, inflammation, plaque composition, and cardiovascular risk. Increasing evidence indicates that exercise exerts vascular effects that extend beyond conventional risk-factor modification. Exercise improves endothelial function, vascular compliance, and nitric oxide bioavailability through shear stress-mediated activation of endothelial nitric oxide synthase (eNOS), while also modulating oxidative stress, myokine signaling, vascular inflammation, and macrophage phenotype. These effects may promote plaque stabilization and influence atherosclerotic lesion composition. Importantly, exercise-associated increases in coronary artery calcium observed in highly active individuals may reflect a shift toward more densely calcified and potentially more stable plaque rather than an accumulation of high-risk lipid-rich lesions. Clinical and meta-analytic evidence further suggests modality-specific effects, with interval training showing favorable effects on arterial stiffness and combined aerobic-resistance training improving endothelial function. Exercise may therefore complement pharmacological risk-factor modification by targeting vascular pathways that are not fully addressed by conventional therapies. Exercise should be considered an integral component of cardiovascular risk management in individuals with subclinical atherosclerosis rather than solely a primary-prevention strategy. Its potential benefits extend from improving vascular function and reducing inflammation to modifying plaque characteristics and promoting plaque stability. Future studies should determine whether exercise prescriptions can be individualized according to atherosclerotic burden, plaque phenotype, imaging characteristics, and circulating biomarkers to establish the optimal exercise modality, intensity, and dose across different patient populations.
This paper aims to review the current development of oral incretin-based therapies for treatment of overweight and obesity, and outline the efficacy of upcoming therapeutic candidates as well as their safety profiles. Clinical recommendations are provided regarding the role of oral incretin-based therapies for treatment of overweight and obesity. Until recently, almost all incretin-based therapies have been injectable formulations due to limitations in absorption and bioavailability. Recently, novel techniques have emerged to overcome these barriers, with two agents (oral semaglutide and orforglipron) having obtained FDA approval; multiple other candidates are currently in development. Semaglutide is a peptide GLP-1 receptor agonist and orforglipron is a small-molecule biased GLP-1 receptor agonist approved for treatment of obesity; oral semaglutide is additionally approved for secondary cardiovascular risk reduction. In phase 3 trials, oral semaglutide and orforglipron have demonstrated clinically significant weight loss efficacy of > 10
This narrative review aims to synthesize global literature on existing food policies relevant to cardiovascular disease (CVD) prevention and assess their alignment with global CVD burden. Mandatory food reformulation policies, particularly industrial trans-fat elimination and sodium reduction targets, demonstrate the strongest and most consistent impacts on population dietary risk factors and cardiovascular outcomes. Fiscal measures, notably sugar-sweetened beverage taxes, are associated with reduced purchases, product reformulation, and potential cardiometabolic benefits, though implementation remains uneven. Marketing restrictions—largely focused on children—and front-of-pack labelling can reduce exposure to unhealthy foods and improve nutritional visibility, but their effectiveness varies by regulatory strength, enforcement, and context. Across all policy domains, adoption and evaluation remain limited in low-and middle-income countries (LMICs). Despite strong evidence supporting food policies as effective tools for CVD prevention, substantial gaps persist in coverage, enforcement, and alignment with global disease burden. Regions with rapidly rising CVD rates continue to lack comprehensive, mandatory policies. Integrated policy packages combining reformulation, fiscal measures, marketing regulation, and labelling are likely required to achieve equitable and sustained reductions in cardiovascular risk.
This review highlights the barriers and facilitators that implementation science studies face in the institutional review board (IRB) approval pathway and provides recommendations on how to potentially streamline this process. Significant gaps persist between evidence-based recommendations and real-world clinical practice. Implementation science projects investigate how to promote uptake of evidence-based and guideline-recommended practices. Regulatory ambiguity may arise because implementation science involves aspects of traditional research and quality improvement. Currently, there is a lack of well-delineated processes to determine the optimal review pathway for implementation science projects. Current research review pathways do not facilitate efficient approval for implementation science projects due to ambiguous IRB submission guidelines, limited exposure to implementation science, and recent integration of digital tools. In this review, we suggest further development of expedited review pathways for low-risk projects, creation of tools for researchers to determine IRB application category, and further investment in digital health-focused implementation science projects and approval pathways to prepare for the emerging wave of implementation science and maximize the positive impact on patient health outcomes.
Structured exercise is a cornerstone of secondary prevention after percutaneous coronary intervention (PCI), yet its specific relationship with in-stent restenosis (ISR) is less well characterized. This narrative review summarizes the biological rationale, clinical evidence, safety, and practical prescription of exercise training in patients with coronary stents, with a focus on its potential impact on ISR. Exercise training improves endothelial nitric oxide bioavailability, reduces systemic inflammation, and favorably modulates neointimal proliferation in experimental and clinical studies. Pooled clinical data suggest that exercise-based cardiac rehabilitation after PCI is associated with a reduction in angiographically defined restenosis, although individual trials, largely from the bare-metal and early drug-eluting stent (DES) eras, have shown inconsistent results on binary restenosis endpoints. Available contemporary data do not suggest an excess risk of stent thrombosis, clinically relevant arrhythmias, or adverse ventricular remodeling when exercise is initiated in clinically stable patients using an individualized and supervised approach. The direct anti-restenotic effect of exercise remains biologically plausible and clinically suggestive but is not yet firmly established, particularly in the contemporary thin-strut DES era. Nevertheless, the well-documented benefits of exercise on functional capacity, endothelial health, and cardiovascular prognosis justify its role as an essential, time-sensitive component of post-PCI care. Larger, contemporary trials with standardized intracoronary imaging endpoints are needed to clarify whether, and in which patient subsets, exercise meaningfully affects the biology of ISR.
Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Plasma Lp(a) levels are 70–90
Post-COVID syndrome (PASC) has emerged as a multisystem condition associated with persistent cardiovascular abnormalities, including endothelial dysfunction, arterial stiffness, chronic inflammation, metabolic disturbances, autonomic imbalance, and increased atherosclerotic risk. This review summarizes the current evidence regarding the pathophysiological mechanisms linking PASC to cardiovascular disease and discusses the potential role of exercise training as a strategy to mitigate vascular dysfunction and cardiovascular risk. Recent studies demonstrate that individuals with PASC exhibit persistent low-grade inflammation, impaired endothelial function, accelerated vascular aging, platelet hyperreactivity, insulin resistance, sarcopenia, and autonomic dysfunction. These alterations contribute to a pro-atherogenic phenotype that may persist months to years after SARS-CoV-2 infection. Emerging evidence indicates that exercise training improves inflammatory status, endothelial function, arterial stiffness, metabolic health, autonomic regulation, and functional capacity in post-COVID patients, potentially attenuating mechanisms involved in atherosclerotic progression. Post-COVID syndrome is associated with multiple interconnected biological pathways that increase long-term cardiovascular risk. Exercise training appears to be a promising non-pharmacological intervention capable of targeting several of these mechanisms simultaneously. Although further randomized controlled trials are needed, current evidence supports the integration of individualized exercise-based rehabilitation into the management of patients with PASC to promote vascular recovery and reduce cardiovascular risk.
To evaluate the role of finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), in heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Finerenone has demonstrated cardiovascular and renal benefits in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), including reductions in hospitalizations for heart failure (HF). The FINEARTS-HF trial showed a reduced rate of worsening HF events in patients with left ventricular ejection fraction (LVEF) ≥40
This review summarizes the pathophysiology of hypertriglyceridemia (HTG) and describes the evidence for dietary interventions in the management of HTG. HTG is most often caused by multiple triglyceride (TG)-raising gene variants. Rare monogenic disorders cause extreme HTG. Recommendations from dyslipidemia management guidelines emphasize that dietary interventions for HTG management should be tailored to the underlying causes and degree of TG elevation. Evidence-based cardioprotective dietary patterns can effectively reduce TG concentrations. The severity of TG elevation influences the level of restriction for intakes of foods/beverages with added sugars, alcoholic beverages, and total fat. Individual macronutrients impact TGs differently, with evidence supporting partial replacement of carbohydrates with unsaturated fatty acids, protein, or a combination for lowering the TG level. Physical activity is also a cornerstone of lifestyle intervention for HTG management. Weight loss for persons with overweight or obesity reduces TGs and can be achieved with dietary interventions, pharmacotherapy, and/or metabolic bariatric surgery, each of which may have a TG-lowering effect independent of weight loss.
We integrate evidences from human and mouse model studies which emphasize sphingolipid metabolism-mediated endothelium–lipoprotein–atherogenic plaque framework. The review may provide a new angel for understanding the development of atherosclerosis and its prevention and treatment. Sphingolipids, such as ceramide, sphingomyelin, glucosylceramide, sphingosine-1-phosphate, are one of the major players in atherogenesis. Atherosclerosis begins when ApoB-containing lipoproteins accumulate and undergo modification in the subendothelial space and then progresses through endothelial dysfunction, leukocyte recruitment, foam-cell formation, and plaque formation. Sphingolipids participate in each of these stages both as structural membrane components and as signaling molecules. In this review, we highlight recent advances in sphingolipid biomarkers and discuss their clinical promise and limitations.
To examine the role of exercise training (ET), cardiorespiratory fitness (CRF), and heart rate variability (HRV)-guided training in reducing cardiometabolic risk associated with type 2 diabetes (T2DM), obesity, and metabolic syndrome (MetS), and to discuss the emerging clinical utility of wearable HRV-monitoring devices. Low CRF is one of the strongest predictors of all-cause and cardiovascular disease (CVD) mortality, often surpassing traditional CVD risk factors such as obesity, hypertension, dyslipidemia, and T2DM. Increasing evidence supports CRF as a clinical vital sign, with each 1-metabolic equivalent increase associated with significant reductions in mortality risk. Both aerobic ET (aET) and resistance ET (rET) improve CRF and metabolic health through mechanisms involving enhanced glucose regulation, mitochondrial biogenesis, endothelial function, lipoprotein remodeling, autonomic balance, and reduced systemic inflammation. High-intensity interval training consistently produces greater maximal oxygen consumption (VO₂max) improvements than moderate-intensity continuous training, although excessive high-intensity ET without adequate recovery may impair adaptation. HRV-guided ET has emerged as a practical strategy to individualize ET intensity based on autonomic readiness, improving training efficiency while reducing excessive physiological strain and overtraining risk. Contemporary consumer wearable devices (CWDs), including WHOOP, Oura Ring, Apple Watch, Garmin, and Polar systems, increasingly allow real-time HRV monitoring outside clinical settings. ET remains a foundational therapy for cardiometabolic disease prevention and management. Current evidence supports prioritizing CRF optimization over weight-centric approaches alone, as higher CRF levels substantially attenuate mortality risk independent of adiposity. HRV-guided ET further enhances individualized ET prescription by aligning exercise intensity with physiologic recovery status. As wearable technology continues to evolve, HRV-monitoring CWDs may provide scalable tools to improve ET personalization, recovery monitoring, and long-term cardiometabolic health outcomes.
This review summarizes current evidence linking triglyceride-rich lipoproteins (TRLs) to atherosclerotic cardiovascular disease (ASCVD) with emphasis on challenges in translating the epidemiological- and genetic epidemiological findings into therapeutic risk reduction. Elevated triglycerides and TRL-cholesterol are consistently associated with ASCVD risk in both primary- and secondary-prevention populations. Human genetic studies of pathways involving LPL, APOC3, ANGPTL3, and ANGPTL4 strongly support a causal role for TRL metabolism in atherosclerosis. The pathogenic effects of TRLs may differ from those of low-density lipoproteins (LDLs), with TRLs potentially contributing through both cholesterol deposition and activation of inflammatory pathways. However, therapeutic translation has been less straightforward than for LDL. Fibrates have produced inconsistent cardiovascular outcome results, icosapent ethyl reduces cardiovascular events but probably through mechanisms beyond triglyceride lowering alone, and potent APOC3 inhibition has failed to show short-term coronary plaque regression. Together, these findings suggest that TRLs are causal contributors to ASCVD, but that their therapeutic relevance may depend on disease stage, background LDL-C/apoB burden, and residual metabolic risk. TRLs are biologically and genetically linked to ASCVD, but whether lowering TRLs translates into cardiovascular risk reduction may depend on background therapy and cardiovascular risk context. Future trials must determine whether TRL-targeted therapies reduce ASCVD events beyond contemporary prevention, and in which patients this residual risk remains modifiable.
To evaluate the evidence supporting combined sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 2 diabetes, focusing on cardiometabolic outcomes and practical treatment approaches. Cardiovascular outcomes trials and real-world studies indicate that SGLT2is and GLP-1RAs confer complementary, non-redundant cardiovascular, kidney, and metabolic benefits. SGLT2is primarily reduce hospitalization for heart failure and slow kidney disease progression, while GLP-1RAs more effectively reduce atherosclerotic events, particularly stroke; dedicated kidney-outcome and heart-failure trials of GLP-1RAs in chronic kidney disease and obesity-related heart failure with preserved ejection fraction have further broadened their role. Randomized data show that each class retains its benefit irrespective of background use of the other, supporting independent mechanisms; whether this translates into reductions in hard outcomes is being tested prospectively. Emerging evidence supports a phenotype-guided approach that aligns therapy with dominant comorbidities such as atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, and obesity. Despite advances in pharmacotherapy, substantial cardiometabolic risk remains in type 2 diabetes. Combined SGLT2i and GLP-1RA therapy addresses multiple risk domains through complementary mechanisms and may be most effective within a phenotype-guided framework. This framework prioritizes therapy according to predominant comorbidity and reserves combination treatment for individuals with overlapping high-risk phenotypes.
Social isolation and loneliness have emerged as important cardiovascular risk factors, yet the biological mechanisms linking adverse social experiences to cardiovascular disease remain incompletely understood. This review examines current evidence relating social isolation and loneliness to subclinical atherosclerosis and explores the underlying neuroendocrine, autonomic, inflammatory, and vascular mechanisms. Recent epidemiological studies have associated social isolation and loneliness with endothelial dysfunction, arterial stiffness, carotid plaque, carotid intima-media thickness, and coronary artery calcium. Advances in transcriptomic and proteomic research have identified molecular signatures characterized by increased inflammatory signaling and altered immune regulation in socially isolated individuals. Experimental animal studies further support a causal relationship between adverse social environments and accelerated atherosclerosis. Accumulating evidence suggests that social isolation and loneliness contribute to subclinical vascular disease through interconnected pathways involving hypothalamic-pituitary-adrenal axis activation, autonomic dysregulation, chronic inflammation, oxidative stress, and endothelial dysfunction. Although available studies are limited and predominantly cross-sectional, findings support a biologically plausible link between social disconnection and early atherogenesis. Future longitudinal studies and intervention trials are needed to determine whether improving social connectedness can slow atherosclerosis progression and reduce cardiovascular risk.
An aneurysm is a frequently occurring and potentially life-threatening cardiovascular disease. However, limited clinical therapeutic drugs are available. Here, we aimed to provide a framework for aneurysm treatment by targeting Furin. Our recent study reported, for the first time, that several Furin variants are found in patients with aneurysm, indicating the important role of Furin in aneurysm. Given that Furin is an important endoproteolytic enzyme that modulates the biochemical activity of proproteins involved in aneurysm formation and progression, interfering with Furin could be a promising strategy for aneurysm treatment. Since several Furin substrates like TGF-β1, NOTCH, IGF1R/IR and MMPs/ADAMs are closely associated with the hallmarks of aneurysm, Furin is a potential target for aneurysm treatment. However, significant gaps remain in our understanding of Furin in the different biological the hallmarks of aneurysms, due to the different role of Furin substrates in regulating the hallmarks of aneurysm. Further research is needed to clarify how the summarized interfering strategies targeting Furin impact on the aneurysm formation and progression in vivo.
The natural fate of chronic kidney disease (CKD) is the progression to dialysis; however, most patients face fatal and nonfatal cardiovascular events throughout their lifetime. We here address the role of low-density lipoprotein cholesterol (LDL-C) in the excess cardiovascular risk and the impact of traditional and innovative LDL-lowering therapies across the whole spectrum of CKD. Current guidelines on the prevention of atherosclerotic cardiovascular disease (ASCVD) from European and US cardiology societies recommend the assessment of total cardiovascular disease risk to modulate the intensity of preventive strategies in relation to the cardiovascular risk of patients: the higher the cardiovascular risk, the more intense should be the intervention. New drugs have demonstrated efficacy in achieving the lower LDL-C goals not attained by traditional therapy. The detection of vulnerable coronary plaque, rather than merely be the presence of luminal narrowing, provides an attractive imaging target to guide intensified preventive strategies in high-risk population including patients with CKD. In the context of CKD, the patient journey represents a dynamic, longitudinal care pathway in which cardiovascular risk progressively increases in parallel with declining renal function. Despite clear recommendations from nephrology and non-nephrology guidelines, treatment initiation, maintenance and intensification as well as LDL-C target are frequently overlooked in CKD population. Since novel LDL-lowering therapies provide additional therapeutic options for the patients with CKD, it is today mandatory to raise awareness on cardiovascular risk and to integrate lipid management into the broader, longitudinal care of patients with CKD across all stages of disease.
This paper reviews the genetic spectrum underlying the Familial Hypercholesterolemia (FH) phenotype, aiming to improve diagnosis, awareness and understanding of these inherited lipid disorders. Although genetic testing for FH has traditionally targeted LDLR, APOB, and PCSK9, the adoption of an expanded eight-gene sequencing panel is now recommended. This broader approach improves diagnostic accuracy by identifying additional lipid disorders that mimic the FH phenotype. Among these, sitosterolemia and the APOE variant p.(Leu167del) appear to be more prevalent than previously recognized. LDLR variants remain the predominant cause of FH, yet the functional significance of approximately half of the reported variants remains undetermined. Recent research efforts are increasing and aimed at resolving these uncertainties through functional characterization studies. Penetrance varies markedly among FH genes, with LDLR variants showing highest penetrance (> 90
While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class. Unique mechanisms for obesity treatment include peripherally restricted cannabinoid-1 receptor antagonism, myostatin/activin inhibitors, selective androgen receptor modulators, melanocortin-4 receptor agonism, mitochondrial modulation, thyroid receptor agonists, and fibroblast growth factor analogues. By targeting fat distribution, muscle preservation, inflammatory/oxidative stress pathways, lipid metabolism, and energy expenditure, these agents may improve both the magnitude and quality of weight loss. Early evidence suggests complementary roles alongside NuSH-based therapies for induction, augmentation, and maintenance strategies. Several non-NuSH agents have demonstrated potential in preclinical and early clinical studies to optimize body composition, but additional studies are required to prove large-scale, long-term safety and efficacy.
In this narrative review complemented by a novel meta-analysis, we critically analyzed current scientific evidence from RCTs and cohort studies regarding the impact of non-nutritive sweeteners (NNS) on cardiometabolic health, and assessed the interplay with the gut microbiome as a potential mechanistic pathway. We focused on the question of direct physiological effects of NNS, rather than the additional effects of energy displacement by NNS, to inform future research and the development of dietary and clinical guidelines. Cohort studies assessing NNS from all dietary sources suggest that total NNS and each commonly used NNS are associated with higher risk of type 2 diabetes, and that total intake and specific agents are associated with certain cardiovascular disease outcomes. These findings are consistent with prior evidence from cohorts focusing on NNS in beverages. Such observational evidence may be confounded by reverse causation: people at higher cardiometabolic risk choosing to use NNS. However, our new meta-analysis of RCTs with non-caloric comparators and a recent RCT on glycemia outcomes with human-to-mice microbiota transplant suggest that NNS have harmful effects on glucose-insulin homeostasis including fasting insulin, HbA1c, and glucose area under the curve during oral glucose tolerance test (OGTT), potentially mediated by effects on the composition and functional potential of the gut microbiome. The summed evidence supports potential long-term risk of cardiometabolic diseases associated with NNS intake and short-term harmful effects of NNS on glycemia. Future clinical trials of physiologic effects and molecular mechanisms will strengthen interpretations and causal inference. Given potential for harm, caution is warranted for the use of NNS.
