BACKGROUND:Complete revascularisation has been associated with improved short-term outcomes in patients with coronary artery disease, but whether these benefits persist long-term and can be defined non-invasively remains uncertain. We investigated the long-term prognostic impact of complete versus incomplete revascularisation determined by coronary CT angiography-derived fractional flow reserve (FFRCT). METHODS:In this prospective multicentre study, 900 patients with new-onset stable angina and at least one coronary stenosis of 30% or greater on coronary CT angiography were followed for a median of 7 years. FFRCT values were obtained for each vessel, and patients were categorised as completely revascularised (all vessels with FFRCT ≤0.80 revascularised), incompletely revascularised (one or more vessels with FFRCT ≤0.80 not revascularised), or with normal physiology (all vessels with FFRCT >0.80). Early revascularisation was defined as treatment within 90 days of the index scan. Quantitative coronary plaque burden was assessed using artificial intelligence-enabled plaque analysis. The primary endpoint was a composite of cardiovascular death or spontaneous myocardial infarction. RESULTS:Of 900 patients, 210 (23%) were classified as incompletely revascularised, 167 (19%) as completely revascularised and 523 (58%) as having normal physiology. The primary endpoint occurred in 34 of 210 (16.2%) incompletely revascularised patients, 13 of 167 (7.8%) completely revascularised patients and 30 of 523 (5.7%) with normal physiology. Incomplete revascularisation was associated with higher risk compared with complete revascularisation (HR 2.33, 95% CI 1.23 to 4.42; p=0.01) and normal physiology (HR 3.54, 95% CI 2.16 to 5.81; p<0.001). These associations remained significant after adjustment for total plaque burden, and the risk difference persisted beyond 3 years of follow-up. CONCLUSION:Complete revascularisation defined by CT-derived fractional flow reserve was associated with a sustained reduction in cardiovascular death and spontaneous myocardial infarction over 7 years, supporting its potential role as a non-invasive tool to guide revascularisation strategies in stable coronary artery disease.

BACKGROUND:There is increasing recognition that trauma exposure and related psychiatric consequences predict cardiovascular disease risk. However, most research has specifically examined post-traumatic stress disorder-despite evidence that a range of psychiatric disorders may follow trauma. We applied machine learning to identify key post-traumatic psychiatric predictors of incident major adverse cardiac and cerebrovascular events (MACCE) in a population-based cohort. METHODS:We conducted a case-control study of adults aged ≥18 years, nested within a trauma-exposed cohort of all Denmark residents from 1995 to 2018. Cases (n=43 994) experienced MACCE (non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, cardiovascular death) between 1995 and 2019. Controls (n=175 872) were matched 4:1 on MACCE date, sex, year of trauma, and age at trauma. Machine learning model predictors included a range of psychiatric disorders diagnosed ≤3 years following trauma. Sex-stratified machine learning models were trained using extreme gradient boosting (men: n=91 111; women: n=84 781) and tested in hold-out datasets (men: n=22 777; women: n=21 197). We identified the 15 most important psychiatric disorder predictors of MACCE using Shapley Additive Explanations values. RESULTS:For men and women, the most important psychiatric predictor of MACCE was alcohol use disorders. Other important psychiatric predictors included depressive disorders, post-traumatic stress disorder/stress-related disorders, brain-related/physiological conditions, and non-substance-induced delirium. Some sex-specific findings also emerged (eg, depressive episodes more important for women than men). Overall, odds ratios in training and testing sets indicated that odds of MACCE were greater among those with (versus without) psychiatric disorders. CONCLUSIONS:Results emphasize the importance of considering a range of psychiatric disorders when assessing cardiovascular risk following trauma.

BACKGROUND:Heart failure with reduced ejection fraction (HFrEF) affects millions worldwide and is characterized by chronic cardiac dysfunction, impaired perfusion, altered skeletal muscle energetics, and, thus, exercise intolerance. Efficient therapeutic strategies reducing the burden of the impaired muscle metabolism in HFrEF are currently lacking. Hence, in the present study, we sought to determine whether myosin dynamics and its important role in ATP consumption can constitute a potent biochemical target to optimize skeletal muscle energy usage in HFrEF. METHODS:We used skeletal muscle tissue from 11 human patients with HFrEF and 10 controls with comparable age, sex, and body mass index. We isolated individual myofibres and incubated them ex vivo with varying concentrations of a myosin inhibitor, mavacamten. We then performed 2'-(or-3')-O-(N-Methylanthraniloyl) adenosine 5'-triphosphate chase experiments, together with LC/MS-based proteomics profiling. RESULTS:We observed a distinct regulation of acetyl-lysine sites and higher myosin energy consumption in resting muscle fibers from patients with HFrEF than in controls. When exposed to mavacamten, we found a dose-dependent reduction in myosin ATP consumption in myofibres of patients with HFrEF, reversing the pathological over-consumption. CONCLUSIONS:Skeletal muscle myosin becomes inefficient in HFrEF. Pharmacological inhibition of myosin ATPase activity offers an inventive strategy to lower muscle energy demand and potentially address metabolic disturbances in HFrEF.

BACKGROUND:Mitochondrial dysfunction contributes to cardiac pathology and may influence myocardial recovery after heart transplantation (HTX). However, posttransplant mitochondrial function in human myocardial tissue remains poorly characterized. We hypothesized that myocardial mitochondrial function would recover in the early posttransplant period and that improvements would correlate with cardiac recovery and metabolic status. METHODS:In this prospective single-center study, 45 adult HTX recipients underwent serial endomyocardial biopsies from 1 week to 6 mo post-HTX. Mitochondrial function was assessed using high-resolution respirometry, evaluating complex I-mediated respiration, maximal oxidative phosphorylation, respiratory control ratio, and coupling control ratio. Correlations with echocardiographic, hemodynamic, and biochemical variables were evaluated. RESULTS:Mitochondrial function remained stable throughout follow-up, with no significant changes in complex I respiration, maximal oxidative phosphorylation, respiratory control ratio, or coupling control ratio. Echocardiography showed significant improvement in biventricular function, including a 15% increase in global longitudinal strain ( P  = 0.0003) and a 20% increase in tricuspid annular plane systolic excursion ( P  = 0.0004). At 6 mo, global longitudinal strain correlated with maximal oxidative phosphorylation ( r = -0.552; P  = 0.0005) and respiratory control ratio ( r = -0.479; P  = 0.0031). No associations were found with cardiac output, cardiac index, troponin I, or N-terminal pro-brain natriuretic peptide. Pretransplant glycated hemoglobin correlated inversely with maximal oxidative phosphorylation at 6 mo ( r = -0.351; P  = 0.0026). CONCLUSIONS:Myocardial mitochondrial function remained stable during early posttransplant recovery. Its association with echocardiographic improvement and pretransplant glycemic state suggests a link between left ventricular contractility and mitochondrial function, and a potential influence of metabolism on myocardial energetics.

Background and Aims:Rheumatoid arthritis (RA) is increasingly being recognized as cardiovascular risk factor. We examined temporal trends in the risks of myocardial infarction (MI) and all-cause mortality in patients with newly diagnosed RA without a history of cardiovascular disease (CVD) compared with a matched general population. Methods and Results:Patients with a first diagnosis of RA without prior CVD (N=20,937) were identified through national health registries between 1996 and 2017. On the index date, each patient was matched by age and sex to five individuals from the general population with neither RA nor CVD (N=104,685) and followed for 5 years. Among patients with RA, the 5-year cumulative incidence proportions for MI declined from 2.6% in 1996-2000 to 1.5% in 2011-2017 (hazard ratio (HR) 0.59; 95% CI 0.45-0.78), whereas all-cause mortality decreased from 9.3% to 7.7% (HR 0.83; 95% CI 0.72-0.95). The reduced risk of MI in patients with RA mirrored the decline observed in a matched general population while the mortality gap between RA and general population individuals was reduced between 1996 and 2010. Statin prescription fillings at 1-year follow-up, a proxy for prophylactic medical intervention, was highest in 2011-2017, reaching 19% among RA patients as well as general population individuals. Conclusion:Despite a gradual decline in the risk of MI and all-cause mortality from 1996 to 2017, patients with RA remain at higher risk of both MI and death than their matched general population individuals. This increased risk was not reflected by improved primary prophylactic medical interventions.

Medical advances have markedly improved survival among patients with cardiovascular disease (CVD). Psychosocial and behavioral factors, including stress and physical activity, are increasingly recognized as key determinants of outcomes in this population. We investigated the association between existing CVD and perceived stress and examined how this association was modulated by physical activity levels in a Danish cohort, accounting for physiological and psychosocial conditions. We analyzed data on 102,650 Danish residents aged 50-65 yr by linking self-reported questionnaire data from the Better Health in Late Life cohort with national health registry data. CVD was identified using hospital discharge diagnoses. Stress was measured with the 10-item Perceived Stress Scale. Physical activity was assessed with a pilot-tested questionnaire. Seven percent of participants had CVD. Compared with those without CVD, they had a higher prevalence of moderate-to-high perceived stress (42% vs. 33%) and a slightly lower prevalence of meeting guideline-recommended physical activity (42% vs. 45%). High stress was associated with physical activity not meeting the recommended level in both groups; however, this association was stronger among those with versus without CVD {prevalence ratio 2.01 [95% confidence interval (CI): 1.89-2.14] vs. 1.52 (95% CI: 1.48-1.56)}. We observed similar associations between stress and cardiovascular risk factors, comorbidity, psychosocial factors, and socioeconomic status. The association between stress and low physical activity persisted after stratification by these conditions. In conclusion, high stress was most strongly associated with low physical activity among adults with CVD. The underlying mechanisms seem to extend beyond physiological pathways and need further investigation.NEW & NOTEWORTHY In this population-based study of over 100,000 Danish adults, participants with cardiovascular disease reported higher perceived stress than those without. Elevated stress was associated with low physical activity across all participants, particularly among those with cardiovascular disease, but also with medical, psychosocial, and behavioral factors. These findings highlight the complex interplay between physiological and nonphysiological determinants of stress, underscoring the importance of integrating stress management and physical activity promotion into cardiovascular prevention and management strategies.

Aims Benefits of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) for patients with stable coronary artery disease (CAD) may be determined by total plaque burden alongside number of stenoses. We aimed to determine whether coronary artery calcification (CAC), reflecting overall plaque burden, predicts CABG versus PCI benefits. Methods Among 85,512 symptomatic patients undergoing computed tomography angiography, we conducted propensity-matched analyses. CABG-treated patients (n = 1,479) were 1:1:1 matched with PCI-treated patients and non-obstructive CAD patients. Cox proportional hazard models assessed risk for the primary endpoint (death, myocardial infarction, stroke), stratified by CAC<300, CAC 300-1000, and CAC>1000. Results Over 5.3 years, 710 primary endpoints occurred. CABG patients had higher prevalence of three-vessel obstructive CAD compared to PCI-treated patients (30 %vs.18 %). Event rates rose with increasing CAC scores; CAC<300 indicated low risk, CAC>1000 indicated very-high risk. Patients with non-obstructive CAD had similar risk to PCI-revascularized patients across CAC groups. Compared to PCI, risk for the primary endpoint were lower at higher plaque burden in CABG-treated patients with hazard ratios of 1.12 (95 %CI 0.70-1.80), 0.82 (95 %CI 0.55-1.20), and 0.75 (95 %CI 0.58-0.94) for CAC<300, CAC 300-1000, and CAC>1000, respectively. The lower CABG-associated risk was driven by reduced myocardial infarction risk (HR 0.44 (95 %CI 0.26-0.73)). Conclusions Among patients with high, but not low, coronary plaque burden, CABG yielded lower long-term risk than PCI, despite more multivessel obstructive CAD. This suggest that the benefit of CABG over PCI for patients with extensive CAD can, at least partly, be attributed to the bypassing of a larger plaque burden.

Chronic heart failure (CHF) involves skeletal muscle abnormalities, including atrophy, inflammation, mitochondrial dysfunction, and fibrosis, which impair contractile function. This study examines whether muscle deterioration correlates with CHF disease severity by assessing the relationship between circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, left ventricular ejection fraction (LVEF), and muscle characteristics in patients with CHF. In 36 patients with CHF (LVEF ≤ 45%, New York Heart Association class I-III), we measured circulating NT-proBNP concentrations, LVEF, muscle strength and functional measures, and myocellular features, including fiber type-specific cross-sectional area (CSA), muscle stem cell (MuSC) and myonuclei content, and capillary density. Also, muscle mitochondrial function was evaluated. The concentration of NT-proBNP inversely correlated with muscle strength (R2 = 0.25, P < 0.01), mean fiber CSA (R2 = 0.15, P = 0.04), and MuSC content (R2 = 0.37, P < 0.01). Moreover, a nonsignificant inverse correlation was observed for capillary density (R2 = 0.12, P = 0.06). The strength of associations between NT-proBNP, fiber CSA, and capillary density was primarily driven by fiber type-specific correlations. Associations with MuSC content were equally strong across fiber types. No correlation was observed for measures of mitochondrial function. For LVEF, a nonsignificant correlation was observed only for overall MuSC content (R2 = 0.11, P = 0.07). Skeletal muscle deterioration in patients with CHF correlates with NT-proBNP, but not LVEF, suggesting that NT-proBNP concentration constitutes a stronger indicator of the link between CHF severity and skeletal muscle decline than LVEF as function parameter. Our findings highlight circulating NT-proBNP concentrations as a potential biomarker for the identification of patients at risk of experiencing skeletal muscle deterioration.NEW & NOTEWORTHY In this study, the authors reveal that elevated NT-proBNP levels are inversely associated with muscle function and cellular features in patients with chronic heart failure (CHF), including muscle fiber cross-sectional area, muscle stem cell content, and capillarization. NT-proBNP appears to be a more reliable marker than left ventricular ejection fraction (LVEF) for identifying skeletal muscle abnormalities and predicting muscle loss in CHF, offering potential for early intervention and personalized care.

Patients face an increased risk of cardiovascular disease shortly after a cancer diagnosis, but evidence on long-term risk among cancer survivors remains limited. In this study the authors sought to estimate the risk of cardiovascular disease in cancer survivors previously treated with systemic cancer therapy. Using Danish population-based registries, we identified individuals who had received systemic cancer treatment and were free of both cancer and treatment 3 years after diagnosis (index date). For each cancer survivor, 5 cancer-free individuals from the general population were randomly selected, matched by birth year, sex, and calendar year. Participants were followed from the index date for up to 5 years. HRs were estimated using Cox regression, adjusted for potential confounders. Compared with 457,035 matched individuals, the 91,407 cancer survivors had an increased risk of heart failure or cardiomyopathy (HR: 1.08; 95% CI: 1.02-1.15), venous thromboembolism (HR: 1.50; 95% CI: 1.41-1.61), pericarditis, endocarditis, or myocarditis (HR: 1.30; 95% CI: 1.11-1.52), and kidney failure (HR: 1.17; 95% CI: 1.10-1.25), but not of ischemic heart disease, stroke, or atrial fibrillation. Estimates varied substantially by cancer type and treatment agent. For example, venous thromboembolism risk was consistently increased across nearly all cancer types, whereas hypertension risk was elevated for none. Ischemic heart disease risk was increased only among lung cancer survivors. Stroke was associated with platinum compounds but not with other systemic treatments. Several cardiovascular disease risks were elevated among cancer survivors, with substantial variation by cancer type and treatment.

Background.Strategies to minimize ischemic damage during heart transplantation (HTX) by donation after circulatory death (DCD) are warranted because the inevitable ischemic injury linked to DCD HTX deteriorates mitochondrial respiratory capacity and ultimately graft quality. This study aimed to examine the myocardial mitochondrial function during DCD HTX with hypothermic oxygenated machine perfusion (HOPE) and compare the effect of normothermic regional perfusion (NRP) with that of direct procurement and perfusion (DPP).Methods.A porcine DCD HTX model was used with hearts subjected to either DPP (n = 6) or NRP (n = 7) followed by HOPE and orthotopic HTX. Mitochondrial respiratory function was analyzed by high-resolution respirometry in left ventricle biopsies at baseline, after 180 min of HOPE, and after 60 min of reperfusion post-HTX.Results.Mitochondrial oxidative phosphorylation (P = 0.0008), respiratory control ratio (P = 0.04), and coupling efficiency (P = 0.04) declined during DCD HTX. Fatty acid oxidation was preserved after 3 h of HOPE with a modest, statistically nonsignificant decline after reperfusion (P = 0.2). Oxidative phosphorylation was inversely correlated with troponin-T levels (r = -0.70, P = 0.0004). No statistically significant difference in mitochondrial respiratory capacity was observed between participants exposed to NRP and DPP.Conclusions.Mitochondrial respiratory capacity declined gradually throughout the course of DCD HTX and correlated with the degree of myocardial damage. Following HOPE, the extent of mitochondrial deterioration was comparable between NRP and DPP.

BACKGROUND: Animal studies suggest that paroxetine, unlike other selective serotonin reuptake inhibitors (SSRIs), may attenuate post-myocardial infarction (MI) heart failure. We examine the effectiveness of paroxetine versus non-paroxetine SSRIs on the risk of post-MI mortality and heart failure in a clinical setting. METHOD: We conducted a nationwide population-based cohort study based on Danish medical registries. Using an active comparator design, we compared the effectiveness of paroxetine with non-paroxetine SSRI drugs on post-MI outcomes. This included all patients hospitalized for MI in Denmark during 1995-2020 who had redeemed an SSRI prescription within 90 days prior to admission and measured outcome variables after a 180-day follow-up period. We calculated cumulative incidences as a measure of risk and used Cox regression to compute hazard ratios (HRs) for all outcomes, adjusting for sex, age group, individual comorbidities, and comedications. RESULTS: We identified 13 053 patients receiving treatment with an SSRI at the time of hospital admission for MI. Cumulative incidences were lower for paroxetine SSRI users compared with non-paroxetine SSRI users for all-cause mortality (24.7% versus 33.8% (difference: -9.1% [95% CI: -12.4; -5.8])) and cardiovascular death (15.9% versus 22.7% (-6.8% [95% CI: -9.6; -4.0])), but not for heart failure (11.0% versus 11.8% (-0.7% [95% CI: -3.13; 1.65])). Adjusted hazard ratios (aHRs) showed no substantial differences for all-cause mortality (aHR 0.9 [95% CI: 0.8-1.1]), cardiovascular death (aHR 0.9 [95% CI: 0.8-1.1]), or heart failure (aHR 1.0 [95% CI: 0.8-1.3]). CONCLUSION: Paroxetine was not associated with clinically significant improvement in post-MI outcomes compared with non-paroxetine SSRI drugs.

Heart failure (HF) is not confined to contractile failure of cardiomyocytes or myocardial fibrosis. Coronary and systemic vascular dysfunction contributes to the initiation and progression of HF with or without reduced ejection fraction. Furthermore, HF compromises vascular function, creating and sustaining a vicious cycle with deranging effects on coronary blood flow, cardiac metabolism and cardiac function. In HF, systemic arterial dysfunction, characterized by increased arterial stiffness and resistance, raises cardiac afterload and impedes myocardial contractile function. Reduced coronary blood flow impairs myocardial oxygen delivery and consequently cardiomyocyte metabolism and function. Coronary microvascular dysfunction is heterogeneous in its pathogenesis and manifestations, complicating the diagnosis and management across different HF phenotypes. Understanding the alterations in function in different segments of the vasculature, from the aorta to the capillary level, offers mechanistic insights into disease drivers and therapeutic interventions. Interventional approaches can improve vascular haemodynamics, whereas established and emerging pharmacotherapies target the neurohumoral axis and reduce extravascular compression, inflammation, and oxidative stress, thereby improving vascular function and HF-related outcomes. In this Review, we provide a mechanistic framework of vascular dysfunction in the pathogenesis of HF with or without reduced ejection fraction, pointing towards integrated therapies that consider the vascular implications of contemporary HF management across HF phenotypes. Coronary and systemic vascular dysfunction contributes to the initiation and progression of heart failure (HF) with or without reduced ejection fraction and, vice versa, HF compromises vascular function. In this Review, Liberale and colleagues discuss vascular dysfunction in the pathogenesis of HF and how pharmacological, interventional and surgical management of HF can improve vascular function.

BACKGROUND:Butyrate, a short-chain fatty acid, has shown potential to improve left ventricular (LV) function and induce vasorelaxation in rodents. Butyrate may either be produced by the microbiome in the colon, be ingested or administered intravenously. This study aimed to evaluate effects of butyrate on cardiac output (CO) and associated hemodynamic variables in a porcine model. METHODS:In a randomized, blinded crossover study, ten healthy 60-kg pigs were given three hour infusions of 600 mM butyrate and equimolar sodium chloride (control). CO was measured by thermodilution via a pulmonary artery catheter. LV contractility was assessed using pressure-volume admittance catheterization. Additionally, isolated porcine coronary arteries were exposed to butyrate in a wire myograph to evaluate vasorelaxation. RESULTS:Butyrate infusion increased plasma butyrate concentration to 0.53 mM (95 % confidence interval (CI): 0.49 to 0.58 mM, P < 0.58 mM, P < 0.001) and CO by 1.6 L/min (95 % CI: 1.0 to 2.1 L/min, P < 0.001) compared with the control. Heart rate, LV ejection fraction, cardiac efficiency and dP/dtmax rose, while systemic vascular resistance, arterial elastance, mean arterial pressure and LV end-systolic volume decreased. Load-independent LV contractility and stroke volume did not significantly differ. In the myograph, porcine coronary arteries relaxed in response to butyrate in a concentration-dependent manner. CONCLUSION:Butyrate increases cardiac output and lowers vascular resistance in a large animal model, through increased HR and systemic vasorelaxation. Load-independent LV contractility was not significantly altered. We observed indices of increased end-organ perfusion. These potentially beneficial cardiovascular properties of butyrate should be further studied.

BACKGROUND Hemodynamically obstructive coronary plaques may contain more vulnerable plaque characteristics than nonobstructive lesions. OBJECTIVES The authors aimed to assess whether pressure-wire-based physiologic indices in nonculprit lesions are associated with vulnerable plaque characteristics. METHODS In the PROSPECT II study, patients with recent myocardial infarction underwent coronary angiography and culprit lesion percutaneous coronary intervention plus combined near-infrared spectroscopy and intravascular ultrasound assessment of all 3 coronary arteries. Instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements were performed in intermediate lesions with angiographic stenosis >40%. RESULTS Among 898 patients, 319 angiographically intermediate lesions in 275 patients had matched intravascular ultrasound/near-infrared spectroscopy and FFR/iFR measurements; 96 (30.1%) lesions were physiologically significant (FFR <= 0.80 or iFR <= 0.89) and 223 (69.9%) were not. Physiologically significant lesions, compared with those that were not, more likely had a minimal lumen area <= 4.0 mm(2) (96.9% vs 83.9%), plaque burden >= 70% (92.7% vs 71.3%) and maximum lipid core burden index in any 4 mm segment of the lesion >= 324.7 (57.0% vs 45.4%). By multivariable analysis, lesion location in the left anterior descending artery, small minimal lumen area, and larger plaque burden were independently associated with physiologic significance, whereas maximum lipid core burden index in any 4 mm segment of the lesion was not. CONCLUSIONS In patients with recent myocardial infarction, angiographically intermediate but physiologically significant coronary lesions were more likely to have high-risk vulnerable plaque features compared with nonphysiologically significant stenoses. However, coronary lesions without physiological significance also had a moderate-to-high prevalence of high-risk plaque characteristics, which may explain the residual risk associated with conservative noninterventional management of these lesions.

BACKGROUND Although lipoprotein(a) (Lp[a]) has been associated with acute myocardial infarction (MI), the relationship between Lp(a) and the presence of high-risk "vulnerable" coronary plaques has not been studied. OBJECTIVES The aim of this study was to investigate whether specific lipoproteins are associated with pancoronary plaque volume and lipid deposition vs the development of non-flow-limiting high-risk vulnerable plaques. METHODS In PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) II, 3-vessel coronary artery imaging was performed with a combined near-infrared spectroscopy and intravascular ultrasound catheter after treatment of all flow-limiting lesions in patients with recent MI. The relationships of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), HDL-C, Lp(a), and triglycerides to pancoronary plaque volume, pancoronary lipid core burden index (LCBI), and the presence of focal vulnerable plaques (plaque burden >= 70% and maximum LCBI over any 4-mm segment >= 324.7) were assessed in 865 patients. RESULTS By multivariable analysis, TC, LDL-C, and non-HDL-C (but not Lp[a]) were associated with pancoronary plaque volume and pancoronary LCBI (P < 0.01 for all), but not with the presence of vulnerable plaque. Conversely, Lp(a) (but not TC, LDL-C, or non-HDL-C) was associated with the presence of focal vulnerable plaques (P 1/4 0.01). CONCLUSIONS In PROSPECT II, elevated TC, LDL-C, and non-HDL-C were strongly associated with pancoronary atherosclerosis and lipid deposition, whereas elevated Lp(a) was strongly associated with the presence of focal vulnerable plaques. These findings may explain the association between high Lp(a) levels and future MI and suggest a unique role for Lp(a) role in atherosclerosis progression and plaque vulnerability. (PROSPECT II & PROSPECT ABSORB-An Integrated Natural History Study and Randomized Trial; NCT02171065) (JACC. 2025;85:2011-2024) (c) 2025 by the American College of Cardiology Foundation.

BACKGROUND:Inflammation is a driver of atherosclerosis and susceptibility to cardiovascular events. OBJECTIVES:The authors sought to evaluate whether high-sensitivity C-reactive protein (hsCRP) levels are associated with the prevalence of high-risk coronary plaques in patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS:PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) II was a multicenter, prospective study enrolling patients with recent myocardial infarction. Following treatment of all flow-limiting lesions, 3-vessel imaging with near-infrared spectroscopy and intravascular ultrasound was used to characterize untreated nonculprit lesions. We investigated the association between baseline hsCRP and plaque morphology (lipid content, plaque burden, lumen area) in 501 NSTEMI patients. hsCRP levels were categorized as low (<1 mg/L), intermediate (1-3 mg/L), or high (>3 mg/L). RESULTS:The percentages of patients with at least 1 highly lipidic plaque (maximum lipid core burden index for any 4-mm pullback length ≥324.7) increased from 39.4% to 57.2% to 59.3% in the low, intermediate, and high hsCRP groups, respectively (P = 0.01). The proportion of patients with at least 1 highly lipidic plaque with ≥70% burden increased with hsCRP levels from 22.7% to 27.2% to 36.7%, respectively (P = 0.01). Multivariable analyses showed that increasing hsCRP was associated with higher total coronary artery lipid core burden index and plaque volume. Higher hsCRP increased the odds of having any highly lipidic plaque and those with ≥70% plaque burden. CONCLUSIONS:Among patients with recent NSTEMI, a high baseline hsCRP level was associated with the presence of pan-coronary atherosclerosis and focal high-risk plaques. (PROSPECT II & PROSPECT ABSORB - an Integrated Natural History Study and Randomized Trial; NCT02171065).