Search Results (1,464)

Background and Objectives: Classical cardiovascular risk factors account for only a fraction of acute coronary syndromes (ACSs), and chronic Chlamydia pneumoniae infection has been proposed as a contributor to atherogenesis through persistent inflammation and endothelial dysfunction. We tested whether C. pneumoniae infection is independently associated with ACS by quantifying seroprevalence, inflammatory markers, and their relationship with conventional cardiovascular risk factors. Materials and Methods: In a prospective case–control design, we enrolled 47 patients with ACSs (29 with acute myocardial infarction and 18 with unstable angina) and 53 age- and locality-matched controls at Alexandria University Hospital. The clinical evaluation comprised electrocardiography, echocardiography, lipid profile, and high-sensitivity C-reactive protein (CRP). C. pneumoniae-specific IgG and IgM were measured by ELISA, with positive samples confirmed by microimmunofluorescence. Logistic regression models were adjusted for age, sex, hypertension, diabetes, dyslipidemia, and smoking. Results: IgM was undetectable in all 100 participants, excluding acute infection. IgG seropositivity was higher in cases than in controls (83.0% vs. 60.4%; OR: 3.20; 95% CI: 1.23–8.30; p = 0.017) and remained suggestive after multivariable adjustment (adjusted OR: 4.59; 95% CI: 1.33–18.28; p = 0.021), although the estimate is imprecise and does not meet our prespecified multivariate threshold of p < 0.01. Within the ACS cohort, IgG seropositivity was not significantly associated with CRP elevation (Fisher’s exact p = 1.000). CRP elevation was near-universal in cases (93.6%) and absent in controls (0%; p < 0.001). Conclusions: Chronic C. pneumoniae infection was associated with ACS in unadjusted analysis, with a suggestive but underpowered signal after multivariable adjustment, although the observational design precludes causal inference, and reverse causality cannot be excluded. Prospective studies using direct pathogen detection are required to determine whether the association reflects a contributory mechanism or shared susceptibility. Full article

Background: Inflammation plays a central role in the pathophysiology of acute coronary syndrome (ACS). Raftlin, a lipid raft-associated inflammatory protein involved in immune signaling, has emerged as a potential biomarker in cardiovascular disease. This study aimed to evaluate circulating raftlin levels and RFTN1 rs690037 polymorphism in patients with ACS. Methods: This prospective observational study included 100 participants comprising 50 patients diagnosed with ACS and 50 control subjects with angiographically normal coronary arteries. Serum raftlin concentrations were measured using enzyme-linked immunosorbent assay, and RFTN1 rs690037 polymorphisms were analyzed by real-time polymerase chain reaction. Correlation, receiver operating characteristic (ROC), multivariable logistic regression, and net reclassification improvement (NRI) analyses were performed. Results: Serum raftlin levels were significantly higher in the ACS group compared with controls (4.28 [3.48–5.78] vs. 3.38 [2.66–4.23] ng/dL, p = 0.003). Raftlin levels demonstrated significant positive correlations with LDL cholesterol and HbA1c levels in ACS patients (p < 0.05 for both). ROC analysis showed that raftlin had moderate discriminative ability for ACS detection (AUC: 0.672, 95% CI: 0.570–0.762, p = 0.002). Although raftlin was not independently associated with ACS after multivariable adjustment, incorporation of raftlin into the baseline clinical model improved overall risk classification (NRI: 0.213, p = 0.041). No significant association was observed between RFTN1 rs690037 polymorphism and ACS or circulating raftlin levels. Conclusions: Circulating raftlin levels are elevated in patients with ACS and appear to reflect the inflammatory and metabolic dysregulation accompanying acute coronary events. Although raftlin alone demonstrated limited diagnostic performance, its incremental contribution to multimarker risk assessment models suggests potential utility as a complementary inflammatory biomarker in ACS. Larger multicenter studies are warranted to clarify its prognostic and translational significance. Full article

Background: Hematological parameters derived from complete blood count (CBC) are inexpensive and widely available markers with potential utility in risk stratification of acute coronary syndrome (ACS). However, their incremental prognostic value when used alongside contemporary risk stratification tools such as the Troponin-only Manchester Acute Coronary Syndrome (T-MACS) score remains unclear. Methods: In this prospective, single-center cohort study, 521 patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina were enrolled. Admission CBC parameters (white blood cell count, neutrophils, monocytes, red cell distribution width, mean platelet volume) and derived inflammatory indices (neutrophil-to-lymphocyte ratio, white blood cell-to-mean platelet volume ratio, lymphocyte-to-monocyte ratio, mean platelet volume-to-platelet ratio, and red cell distribution width-to-platelet ratio) were recorded. T-MACS risk scores were calculated, and patients were followed for 30-day major adverse cardiac events (MACE), mortality, and coronary interventions. Associations were assessed using univariate and multivariate logistic regression analyses. Results: Patients experiencing 30-day MACE or mortality had significantly higher white blood cell counts, neutrophil counts, and WMR values (all p < 0.05). Several hematological indices showed significant associations with T-MACS risk categories. In multivariate analysis, intermediate- and high-risk T-MACS classifications independently predicted 30-day MACE (OR 4.49, 95% CI:1.46–13.77, p = 0.009; OR 9.34, 95% CI:3.00–29.03, p < 0.001, respectively), whereas white blood cell count, neutrophil count, and WMR did not demonstrate independent prognostic value beyond T-MACS classification. Conclusions: Admission white blood cell count, neutrophil count, and WMR are associated with short-term adverse outcomes and T-MACS risk severity in patients with NSTE-ACS. However, these markers do not provide additional prognostic value beyond T-MACS classification. These findings suggest that CBC-derived inflammatory markers primarily reflect disease severity rather than incremental prognostic information in the contemporary high-sensitivity troponin era. Full article

Background: Obesity is increasing worldwide and remains a major contributor to cardiovascular morbidity and mortality. It is strongly associated with hypertension, dyslipidemia, diabetes mellitus, endothelial dysfunction, and chronic inflammation, all of which promote coronary artery disease and acute coronary syndrome (ACS). Despite this well-established risk profile, multiple studies have described an “obesity paradox,” suggesting that obese patients may experience better outcomes after percutaneous coronary intervention (PCI) for ACS than normal-weight individuals. Objective: This narrative review aims to discuss the pathophysiological basis of the obesity paradox and to synthesize contemporary evidence regarding the relationship between body mass index (BMI), major adverse cardiovascular events (MACE), and mortality after PCI in patients presenting with ACS. Results: Contemporary observational cohorts consistently suggest a non-linear relationship between BMI and MACE outcomes after PCI. Overweight and mildly obese patients often demonstrate lower crude mortality and fewer MACE, whereas underweight patients consistently show the poorest prognosis. However, after adjustment for age, left ventricular ejection fraction (LVEF), renal function, frailty, and nutritional status, obesity is less consistently associated with improved outcomes. Overweight status appears to be more reproducibly associated with better prognosis than obesity itself. Conclusions: The obesity paradox is likely driven less by a true protective effect of excess adiposity and more by younger age at presentation, preserved physiological reserve, lower frailty burden, and the limitations of BMI as a marker of cardiovascular risk. Underweight status emerges as the strongest predictor of adverse outcomes. Nutritional assessment and body composition should complement BMI in risk stratification after ACS. Full article

The right ventricle (RV) is a primary determinant of outcomes in cardiac critical care. RV dysfunction independently predicts morbidity and mortality in conditions such as acute coronary syndromes, pulmonary embolism, and cardiogenic shock. This review synthesizes RV evaluation and management by integrating physiologic principles with bedside diagnostic and therapeutic strategies. The RV is exceptionally sensitive to acute afterload increases due to its adaptation to low-pressure pulmonary circulation. Evaluation utilizes a multimodal approach combining echocardiography, invasive hemodynamics, and specifically the pulmonary artery pulsatility index and central venous pressure/pulmonary capillary wedge pressure (CVP/PCWP) ratio and biomarkers. Management focuses on three pillars: individualized preload optimization, afterload reduction via selective pulmonary vasodilators, and contractility augmentation with inotropes. For refractory cases, mechanical circulatory support options like Impella RP, ProtekDuo, and VA-ECMO provide critical bridges to recovery or transplantation. Full article

Antithrombotic therapy is central to the management of coronary artery disease (CAD), yet its optimal use requires a continuous balance between ischemic protection and bleeding risk. While aspirin has historically been the cornerstone of treatment, contemporary evidence supports a transition toward increasingly individualized strategies across the spectrum of disease. In primary prevention, the role of aspirin remains marginal and is limited to carefully selected high-risk individuals. Following percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) remains the standard of care; however, both its duration and composition are progressively tailored according to patient-specific ischemic and bleeding risk profiles. In chronic coronary syndromes, shorter DAPT followed by single antiplatelet therapy—particularly P2Y₁₂ inhibitor monotherapy—has emerged as an effective bleeding-avoidance strategy without compromising ischemic outcomes. In acute coronary syndromes, 12 months of DAPT remains the recommended approach, although de-escalation strategies may be considered in selected patients at lower ischemic risk. For long-term secondary prevention, emerging evidence suggests a potential advantage of clopidogrel over aspirin, while in patients with persistently high ischemic risk, intensified antithrombotic regimens may provide additional benefit. Special populations require tailored treatment strategies. Overall, contemporary evidence supports a paradigm shift toward a precision medicine approach in CAD, in which antithrombotic therapy is dynamically adapted to the individual balance between ischemic and bleeding risk to optimize long-term clinical outcomes. Full article

Background: Cardiovascular disease remains the leading global cause of morbidity and mortality. Mental health disorders are common comorbidities that significantly influence how patients access and navigate specialist care. Increasingly, mental illness is recognized not merely as a comorbidity but as a potential driver of inequities in cardiovascular care, affecting diagnosis, referral, procedural management, and long-term secondary prevention. These concerns are particularly relevant in cardiac surgery, where care pathways are complex and resource-intensive. Aims and Objectives: This narrative review examines recent evidence on inequalities in access to cardiac surgery and postoperative outcomes among patients with mental health disorders. Particular emphasis is placed on severe mental illness, mood disorders, anxiety-related conditions, and mixed psychiatric cohorts. Materials and Methods: A structured narrative review approach was employed. PubMed and ScienceDirect were systematically searched for peer-reviewed studies published between 2020 and 2025, including cohort studies, registry analyses, systematic reviews, and meta-analyses. The evidence was synthesized thematically, focusing on access to care, perioperative management, clinical outcomes, underlying mechanisms, ethical considerations, policy implications, and future research directions. Results: Evidence suggests that patients with mental health disorders are more likely to undergo cardiac surgery via emergency pathways, experience longer hospital stays, and have higher rates of readmission. Individuals with severe mental illness are less likely to receive invasive coronary procedures compared to the general population and exhibit higher short- and long-term mortality following acute coronary syndromes. Among psychiatric subgroups, psychosis-spectrum disorders appear to be associated with the greatest excess risk of morbidity, mortality, and adverse long-term surgical outcomes. Conclusions: Patients with mental health disorders face inequities across the entire surgical pathway, including preoperative, perioperative, and postoperative phases. Key contributing factors include stigma, diagnostic overshadowing, fragmented healthcare systems, socioeconomic disadvantage, and insufficiently developed models of integrated care. Addressing these disparities requires redesigned referral pathways, strengthened multidisciplinary collaboration (including cardiology, cardiac surgery, psychiatry, and primary care), and a shift toward interventional research aimed at reducing inequities rather than solely documenting them. Full article

Background: Despite significant progress in management of acute coronary syndromes (ACSs), they continue to be a major cause of death worldwide due to residual inflammatory risk (RIR). Aim: This study reviews existing clinical evidence for anti-inflammatory therapies in coronary heart disease (CHD) and assesses precision medicine in classifying patients from clinical, immunological, and genetic perspectives. Results: Large clinical trials confirm the inflammatory hypothesis of atherosclerosis. Therapies targeted at the specific NLRP3 inflammasome/interleukin-1β (IL-1β)/interleukin-6 (IL-6) pathway reduce major adverse cardiovascular events (MACEs), while broad immunosuppression fails. This highlights the need for molecular specificity. Precision cardiology aims to identify high-risk inflammatory phenotypes through clonal hematopoiesis of indeterminate potential (CHIP). Mutations in genes such as TET2 and ASXL1 lead to macrophage hyperreactivity and increased plaque vulnerability. Available data suggest that the effectiveness of immunomodulatory treatment strongly depends on timing. Starting therapy early with SGLT2 inhibitors (SGLT2is) or agents that target temporarily activated receptors like P2Y11 seems to be essential for managing harmful inflammation while supporting myocardial repair. Conclusions: Precision cardiology aims to integrate targeted anti-inflammatory therapies with established clinical markers, while future pathways may incorporate advanced immunophenotyping and genetic risk assessment as they undergo clinical validation. Full article

Multisystem inflammatory syndrome in children (MIS-C) is a severe systemic inflammatory complication triggered by prior SARS-CoV-2 infection. It predominantly affects the cardiovascular system, and coronary artery injury, myocardial dysfunction, and myocardial ischemia are closely associated with disease severity and clinical outcomes. This article reviews the immunopathological characteristics and clinical manifestations of MIS-C-related coronary artery lesions, including coronary artery dilation and aneurysm formation, as well as the key pathophysiological mechanisms leading to myocardial ischemia. Based on recent clinical and translational research, we summarize current approaches to diagnosis, risk stratification, acute medical management, and long-term follow-up strategies. By synthesizing updated evidence, this review aims to provide theoretical support and practical clinical guidance for the early identification, timely intervention, and optimized management of affected children, ultimately improving their long-term cardiovascular prognosis. Full article

Acute Coronary Syndrome (ACS) is a severe manifestation of Coronary Artery Disease (CAD) caused by the rupture of unstable atherosclerotic plaques, resulting in reduced myocardial blood flow. Smoking is a major risk factor for ACS and has been associated with increased matrix metalloproteinase (MMP) activity, which contributes to the degradation of the plaque fibrous cap. However, the molecular alterations associated with smoking in ACS remain incompletely understood. This study aimed to investigate the expression of α1nAChR, ERK1/2, and c-FOS genes, together with MMP protein levels in atherosclerotic plaque tissues and peripheral blood mononuclear cells (PBMCs) of CAD patients. A total of 41 atherosclerotic plaque samples (26 smokers, 15 non-smokers) and 180 clinical subjects [n = 30 per group: ACS, chronic coronary syndrome (CCS), and controls; smokers and non-smokers] were included. Gene expression of ⍺1nAChR, ERK 1/2, and c-FOS was analyzed by RT-qPCR, while protein levels of MMP-2, MMP-9, and TIMP 3 were measured using ELISA. The expression of ERK 1/2 and c-FOS were significantly higher in plaque tissues of smokers compared with non-smokers (1.671- and 1.327-fold; p < 0.05). In PBMCs, α1nAChR expression was higher in CCS smokers (1.383-fold), while ERK 1/2 expression was higher in ACS smokers (1.355-fold). MMP-9 levels were significantly elevated in ACS and CCS compared with controls (p < 0.001). In conclusion, smoking CAD patients demonstrated increased expression of α1nAChR, ERK and MMP-9, indicating smoking-associated alterations in ⍺1nAChR-ERK signaling-related biomarkers in ACS. Full article

Focused Cardiac Ultrasound (FoCUS) is a targeted bedside imaging modality with an established role in the management of critically ill patients. Acute Coronary Syndrome (ACS) is a common cause of presentation to the Emergency Department (ED), and although electrocardiography (ECG) and cardiac biomarkers are the cornerstones for its diagnosis, FoCUS may facilitate diagnostic evaluation and disposition of patients in different levels of care. Initially, FoCUS plays a crucial diagnostic role through the identification of Regional Wall Motion Abnormalities (RWMAs), enabling direct visualization of the ischemic region and corroboration of ECG findings. Moreover, in patients with ACS complicated by cardiogenic shock, FoCUS is indispensable for determining the extent of ischemia and detecting mechanical complications, including ventricular septal or free wall rupture, or papillary muscle rupture. Likewise, FoCUS aids in the differential diagnosis of patients with ECG abnormalities mimicking ACS. This comprehensive review synthesizes the most recent evidence on the role of FoCUS in accelerating the management of patients with ACS presenting to the ED. Full article

Objective: Self-expanding (SE) transcatheter aortic prostheses (THV) have been associated with an increased risk of new permanent pacemaker implantation (PPMI), particularly with deeper implantations in the left ventricular outflow tract (LVOT) that result in more atrioventricular conduction system damage, leading to higher rates of post-procedural conduction disturbances (CDs) and subsequently more PPMIs. The cusp-overlap technique (COT) is designed to provide better visualisation of the LVOT during implantation, aiming to achieve a shallower implantation depth (ID) and potentially reduce both post-procedural CDs and PPMIs. This study seeks to compare the traditional three-cusp coplanar view technique (3CT) with the newer COT in patients undergoing transcatheter aortic valve replacement (TAVR). Methods: From March 2018 to April 2020, a total of 586 patients underwent TAVR at the university clinic in Kiel. Among them, 226 patients who received SE prostheses were included in the study. After applying exclusion criteria, a final cohort of 203 patients was analysed. Of these, 106 patients underwent TAVR using the COT, while 97 patients underwent TAVR using the 3CT. The primary endpoints of the study were the occurrence of new CD and PPMI within 30 days post-procedure. Secondary endpoints included various post-TAVR events as defined by the Valve Academic Research Consortium 3 (VARC-3) safety criteria. A specific focus was placed on assessing the risk of high valve implantation according to VARC-3 criteria, specifically paravalvular insufficiency, valve embolisation, and coronary occlusion. Statistical analysis was conducted to compare outcomes between the COT and 3CT groups. Results: Implantation depths were significantly lower in the COT group compared to the 3CT group, with ID values from the NCC and LCC being 2.7 mm (±1.5) and 2.8 mm (±1.5) for the COT, and 5.4 mm (±3) and 6.6 mm (±2.6) for the 3CT (p < 0.001 for both). The incidence of high-grade CD, particularly Atrioventricular Block (AVB) II and III, was significantly higher in the 3CT group (26.8%) compared to the COT group (13.2%) (p = 0.023). The overall 30-day PPMI rate was 18.2% (n = 37), with a significant difference between the COT and 3CT groups (12.2% vs. 24.7%, p = 0.021). The primary indication for PPMI was permanent high-grade AVB occurring during or after TAVR, accounting for 95% of cases. No cases of TAVR embolisation, acute coronary occlusion or related syndromes were observed within the first 30 days post-procedure. There were no significant differences in 30-day mortality or post-procedural paravalvular insufficiency between the groups. In multivariable logistic regression analysis, the COT remained independently associated with lower odds of new post-procedural CD after adjustment for prior right bundle branch block (RBBB), prior first-degree AVB, predilatation, valve size and coronary artery disease (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.24–0.82, p = 0.009). For 30-day PPMI, the cusp-overlap technique demonstrated a borderline association with lower adjusted odds (OR 0.46, 95% CI 0.20–1.02, p = 0.057), while prior RBBB was independently associated with increased PPMI risk (OR 3.54, 95% CI 1.22–10.28, p = 0.020). Conclusions: The COT was associated with shallower implantation depth and lower rates of new post-procedural CD after multivariable adjustment. The association with reduced 30-day PPMI remained directionally consistent but was borderline after adjustment. These findings support the potential value of COT as a procedural strategy to reduce conduction-related complications after TAVR with self-expanding prostheses. Full article

Background/Objectives: Early identification of ST-segment elevation myocardial infarction (STEMI) at first medical contact remains challenging, as high-sensitivity troponin T may be insufficiently sensitive during the initial phase of myocardial injury. Readily available complete blood count (CBC)-derived inflammatory indices may provide complementary early diagnostic signals. This study aimed to evaluate whether baseline CBC-derived inflammatory indices differ between STEMI and NSTEMI and whether they provide adjunctive discriminatory information at presentation (0 h) in patients with acute coronary syndrome (ACS). Methods: A 12-lead electrocardiogram (ECG), high-sensitivity troponin T, and CBC were obtained at presentation from 252 patients with ACS (195 STEMI and 57 NSTEMI). Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis and 2 × 2 contingency tables to determine the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios. Results: High-sensitivity troponin T demonstrated the highest specificity (84.44%) and PPV (92.93%), supporting its role as a confirmatory biomarker; however, its low sensitivity (50.83%) and NPV (29.92%) may reduce its utility during early assessment. In contrast, WBC and neutrophil counts demonstrated relatively favorable discriminatory performance at presentation (AUC > 0.72; Youden’s index > 0.40). Among composite indices, NLPR demonstrated the highest sensitivity (88.66%) and NPV (53.19%), along with the lowest negative likelihood ratio (0.25), suggesting potential adjunctive value during early assessment. NLR, SII, SIRI, and adjusted NLR showed moderate performance, with aNLR providing a balanced sensitivity (67.01%) and specificity (74.55%). Conclusions: CBC-derived inflammatory indices, particularly neutrophil-based markers such as NLPR, may provide adjunctive discriminatory information during the early assessment of patients with ACS, particularly at first medical contact when baseline hs-Troponin T sensitivity may still be limited. Full article

Cardiovascular disease is traditionally interpreted through macrocirculatory parameters such as cardiac output, vascular resistance, and epicardial coronary anatomy. However, clinical outcomes frequently diverge from predictions based solely on these indices, particularly in syndromes such as heart failure with preserved ejection fraction (HFpEF), cardiogenic shock, and sepsis-associated myocardial dysfunction. Increasing evidence suggests that the integrity of the microvascular–immune interface plays a central role in determining tissue perfusion and cardiovascular resilience. This review proposes a staged framework of cardiovascular decompensation centered on progressive failure of this interface. In Stage 1, chronic cardiometabolic and inflammatory stress produces a primed but compensated microvascular state characterized by endothelial activation, glycocalyx vulnerability, pericyte remodeling, platelet sensitization, and reduced lymphatic reserve. Perfusion is preserved at rest, but vasodilatory reserve and microvascular stability are reduced, narrowing the effective perfusion window under physiologic stress. In Stage 2, acute insults such as infection, ischemia, or neurohumoral activation precipitate threshold instability within the microcirculation. Perfusion becomes governed by the arterial pressure–critical closing pressure (Pa − Pcrit) relationship rather than traditional arterial–venous gradients. As this window narrows, segmental capillary derecruitment and heterogeneous flow emerge, producing loss of hemodynamic coherence in which systemic blood pressure and cardiac output may appear preserved despite impaired tissue perfusion. In Stage 3, inflammatory amplification and immunothrombotic processes consolidate microvascular dysfunction. Pericyte contraction, endothelial injury, cytokine escalation, and neutrophil extracellular trap formation promote platelet–fibrin deposition and capillary obstruction, transforming reversible conductance failure into structural microvascular impairment. This framework provides a unifying physiologic lens for diverse cardiovascular syndromes, including Type 2 myocardial infarction, HFpEF decompensation, and cardiogenic shock. It also suggests that therapeutic efficacy may depend less on macrocirculatory normalization alone and more on preserving microvascular integrity before immunothrombotic consolidation occurs. Although this model remains hypothesis-generating, it highlights the microvascular–immune interface as a central determinant of cardiovascular stability and a potential target for future precision hemodynamic and immunomodulatory strategies. Full article

Background: Low-density lipoprotein cholesterol (LDL-C) is a central modifiable driver of atherosclerotic cardiovascular disease, yet cardiovascular risk in type 2 diabetes mellitus (T2DM) may be better captured by longitudinal LDL-C exposure than by a single LDL-C measurement. We examined the association of current LDL-C, cumulative LDL-C burden, and prior time below LDL-C targets with incident acute coronary syndrome (ACS) in patients with T2DM. Methods: We conducted a retrospective longitudinal cohort study using routinely collected electronic health-record data. Patients with T2DM and at least one valid LDL-C measurement between 1 January 2018 and 31 December 2023 were followed from the first eligible LDL-C measurement until incident ACS or administrative censoring on 31 March 2024. LDL-C was modeled using time-updated start–stop Cox regression. The primary exposure was current LDL-C category: <1.4, 1.4 to <1.8, 1.8 to <2.6, 2.6 to <3.4, 3.4 to <4.9, and ≥4.9 mmol/L. Secondary exposure metrics were cumulative LDL-C burden above prespecified thresholds and prior percentage of follow-up time below LDL-C targets. Models were adjusted for age, sex, hypertension, chronic kidney disease, HbA1c, T2DM duration, and calendar year of baseline LDL-C measurement; HbA1c and T2DM duration were multiply imputed. Results: The analytic cohort included 106,185 patients, 426,965 LDL-C intervals, and 5416 incident ACS events over 419,251.0 person-years. Compared with current LDL-C <1.4 mmol/L, adjusted ACS risk was higher for current LDL-C 3.4 to <4.9 mmol/L (HR 1.35, 95% CI 1.21–1.50) and ≥4.9 mmol/L (HR 1.94, 95% CI 1.63–2.32), whereas lower LDL-C categories were not clearly different from the reference category after adjustment. Each 1 mmol/L-year higher cumulative LDL-C burden was associated with higher ACS risk across evaluated thresholds, with HRs ranging from 1.04 to 1.13. Greater prior time below LDL-C targets was associated with lower ACS risk, with HRs of 0.97–0.98 per 10% higher time below target. Findings were consistent in sensitivity analyses restricted to patients with at least three LDL-C measurements, landmark analyses, and complete-case analysis. Conclusions: In patients with T2DM, incident ACS risk was associated with very high current LDL-C and with longitudinal LDL-C exposure captured by cumulative burden and time below target. These findings support sustained, target-oriented LDL-C control and suggest that longitudinal LDL-C metrics may complement single LDL-C values in cardiovascular risk assessment. Full article