Serum neurofilament light chain in functionally relevant coronary artery disease and adverse cardiovascular outcomes.

Background: Functionally relevant coronary artery disease (fCAD), causing symptoms of myocardial ischemia, can currently only be reliably detected with advanced cardiac imaging. Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury known to be elevated by cardiovascular (CV) risk factors and cerebrovascular small-vessel diseases. Due to their pathophysiological similarities with fCAD and the link to CV risk factors, we hypothesised that sNfL may have diagnostic and prognostic value for fCAD and adverse cardiovascular outcomes.Methods: Of the large prospective Basel VIII study (NCT01838148), 4'016 consecutive patients undergoing cardiac work-up for suspected fCAD were included (median age 68 years, 32.5% women, 46.9% with history of CAD). The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography (MPI-SPECT) and coronary angiography. sNfL was measured using a high-sensitive single-molecule array assay. All-cause and cardiovascular death, myocardial infarction (MI), and stroke/transient ischaemic attack (TIA) during 5-year follow-up were the prognostic endpoints.Results: The diagnostic accuracy of sNfL for fCAD as quantified by the area under the curve (AUC) was low (0.58, 95%CI 0.56-0.60). sNfL was strongly associated with age, renal dysfunction, and body mass index and was a strong and independent predictor of all-cause death, cardiovascular death, and stroke/TIA but not MI. Time-dependent AUC for cardiovascular-death at 1-year was 0.85, 95%CI 0.80-0.89, and 0.81, 95%CI 0.77-0.86 at 2-years.Conclusion: While sNfL concentrations did not show a diagnostic role for fCAD, in contrast, sNfL was a strong and independent predictor of cardiovascular outcomes, including all-cause death, cardiovascular death and stroke/TIA.

Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker associated with anatomical CAD burden and cardiovascular outcomes including myocardial infarction (MI) and death. We aimed to validate previous findings of the prognostic value of suPAR and to evaluate its diagnostic potential for functional relevant CAD (fCAD). METHODS: Consecutive patients with suspected fCAD were enrolled. Adjudication of fCAD was performed blinded to suPAR concentrations by myocardial perfusion single-photon emission tomography (MPI-SPECT) and coronary angiography. Prognostic outcome measures included all-cause death, cardiovascular death, and incident MI during 2-year follow-up. RESULTS: Among consecutive 968 patients, suPAR concentrations were higher in patients with fCAD compared to those without (3.45 vs. 3.20 ng/mL, p = 0.007), but did not provide acceptable diagnostic accuracy (area under the curve [AUC]: 0.56, 95%CI 0.52-0.60). SuPAR correlated with high-sensitivity cardiac-troponin T (Spearman's rho (ρ) 0.393, p < 0.001), NT-proBNP (ρ = 0.327, p < 0.001), age (ρ = 0.364, p < 0.001) and very weakly with coronary atherosclerosis (ρ = 0.123, p < 0.001). Prognostic discrimination of suPAR was moderate for cardiovascular death (AUC = 0.72, 95%CI 0.62-0.81) and all-cause death (AUC = 0.72, 95%CI 0.65-0.79) at 2-years. SuPAR remained a significant predictor for all-cause death in multivariable Cox regression (HR = 1.96, p = 0.001). CONCLUSIONS: SuPAR was an independent predictor of all-cause death, without diagnostic utility for fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Diagnostic and prognostic value of mannan-binding lectin associated protein (MAp19) for functionally relevant coronary artery disease.

BACKGROUND: This study aimed to evaluate the diagnostic and prognostic potential of MAp19, a regulating component of the lectin pathway of the complement system, in patients with suspected functionally relevant coronary artery disease (fCAD) as well as the determinants of MAp19 levels. METHODS: The presence of fCAD was adjudicated using myocardial perfusion imaging with single-photon emission tomography and, where available, coronary angiography. MAp19 levels were measured in participants at rest, at peak stress tests, and two hours after the stress. The study also tracked major cardiovascular events, including non-fatal myocardial infarction and cardiovascular death, over a five-year follow-up period. RESULTS: Among the 1,571 patients analyzed (32.3 % women), fCAD was identified in 462 individuals (29.4 %). MAp19 demonstrated no diagnostic significance, yielding an area under the curve (AUC) of 0.51 (0.47-0.55). Throughout the five-year follow-up, 107 patients (6.8 %) experienced non-fatal myocardial infarctions, 99 (6.3 %) had cardiovascular death, 194 (12.3 %) experienced all cause death and 50 (3.1 %) suffered a stroke. Cox and Kaplan-Meier analysis confirmed prognostic value of MAp19 for myocardial infarction, but not for cardiovascular death. Significant increases in the concentration of MAp19 were observed during bicycle (p = 0.001) and combined stress tests (p = 0.001). CONCLUSION: MAp19 demonstrated an association with the risk of myocardial infarction. Increases in MAp19 concentration were observed during bicycle and combined stress-tests.

Diagnostic and prognostic value of H-ficolin for functionally relevant coronary artery disease.

BACKGROUND: We aimed to test the diagnostic and prognostic ability of H-ficolin, an initiator of the lectin pathway of the complement system, for functionally relevant coronary artery disease (fCAD), and explore its determinants. METHODS: The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography and coronary angiography. H-ficolin levels were measured by a sandwich-type immunoassay at rest, peak stress-test, and 2 h after stress-test. Cardiovascular death and non-fatal myocardial infarction were assessed during 5-year follow-up. RESULTS: Among 1,571 patients (32.3 % women), fCAD was detected in 462 patients (29.4 %). H-ficolin concentration at rest was 18.6 (15.3-21.8) µg/ml in patients with fCAD versus 17.8 (15.4-21.5) µg/ml, p = 0.33, in patients without fCAD, resulting in an AUC of 0.53 (95 %CI 0.48-0.56). During follow-up, 107 patients (6.8 %) had non-fatal myocardial infarction and 99 patients (6.3 %) experienced cardiovascular death. In Cox regression analysis, H-ficolin was not a predictor of events in the overall cohort. Subgroup analysis suggested a potential link between H-ficolin and non-fatal myocardial infarction in patients without fCAD (adjusted HR 1.03, 95 % CI 1.02-1.15, p = 0.005). H-ficolin concentration showed a weak positive correlation with systolic (r = 0.069, p < 0.001) and diastolic blood pressure (r = 0.111, p < 0.001). CONCLUSION: H-ficolin concentration did not have diagnostic and/or prognostic value in patients referred for fCAD work-up.

Artificial intelligence to improve ischemia prediction in Rubidium Positron Emission Tomography-a validation study.

Background: Patients are referred to functional coronary artery disease (CAD) testing based on their pre-test probability (PTP) to search for myocardial ischemia. The recommended prediction tools incorporate three variables (symptoms, age, sex) and are easy to use, but have a limited diagnostic accuracy. Hence, a substantial proportion of non-invasive functional tests reveal no myocardial ischemia, leading to unnecessary radiation exposure and costs. Therefore, preselection of patients before ischemia testing needs to be improved using a more predictive and personalised approach. Aims: Using multiple variables (symptoms, vitals, ECG, biomarkers), artificial intelligence-based tools can provide a detailed and individualised profile of each patient. This could improve PTP assessment and provide a more personalised diagnostic approach in the framework of predictive, preventive and personalised medicine (PPPM). Methods: Consecutive patients (n = 2417) referred for Rubidium-82 positron emission tomography were evaluated. PTP was calculated using the ESC 2013/2019 and ACC 2012/2021 guidelines, and a memetic pattern-based algorithm (MPA) was applied incorporating symptoms, vitals, ECG and biomarkers. Five PTP categories from very low to very high PTP were defined (i.e., < 5%, 5-15%, 15-50%, 50-85%, > 85%). Ischemia was defined as summed difference score (SDS) ≥ 2. Results: Ischemia was present in 37.1%. The MPA model was most accurate to predict ischemia (AUC: 0.758, p < 0.001 compared to ESC 2013, 0.661; ESC 2019, 0.673; ACC 2012, 0.585; ACC 2021, 0.667). Using the < 5% threshold, the MPA's sensitivity and negative predictive value to rule out ischemia were 99.1% and 96.4%, respectively. The model allocated patients more evenly across PTP categories, reduced the proportion of patients in the intermediate (15-85%) range by 29% (ACC 2012)-51% (ESC 2019), and was the only tool to correctly predict ischemia prevalence in the very low PTP category. Conclusion: The MPA model enhanced ischemia testing according to the PPPM framework:The MPA model improved individual prediction of ischemia significantly and could safely exclude ischemia based on readily available variables without advanced testing ("predictive").It reduced the proportion of patients in the intermediate PTP range. Therefore, it could be used as a gatekeeper to prevent patients from further unnecessary downstream testing, radiation exposure and costs ("preventive").Consequently, the MPA model could transform ischemia testing towards a more personalised diagnostic algorithm ("personalised"). Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00341-5.

Prognostic Value of Self-Reported Subjective Exercise Capacity in Patients With Acute Dyspnea.

Background: Self-reported exercise capacity is a well-established prognostic measure in stable ambulatory patients with cardiac and pulmonary disease. Objectives: The authors aimed to directly compare the prognostic accuracy of quantified self-reported exercise capacity using the Duke Activity Status Index (DASI) with the established objective disease-severity marker B-type natriuretic peptide (BNP) in patients presenting with acute dyspnea to the emergency department. Methods: The DASI was obtained in a prospective multicenter diagnostic study recruiting unselected patients presenting with acute dyspnea to the emergency department. The prognostic accuracy of DASI and BNP for 90-day and 720-day all-cause mortality was evaluated using C-index. Results: Among 1,019 patients eligible for this analysis, 75 (7%) and 297 (29%) patients died within 90 and 720 days after presentation, respectively. Unadjusted hazard ratios (HRs) and multivariable adjusted hazard ratios (aHRs) for 90- and 720-day mortality increased continuously from the fourth (best self-reported exercise capacity) to the first DASI quartile (worst self-reported exercise capacity). For 720-day mortality the HR of the first quartile vs the fourth was 9.1 (95% CI, 5.5-14.9) vs (aHR: 6.1, 95% CI: 3.7-10.1), of the second quartile 6.4 (95% CI: 3.9-10.6) vs (aHR: 4.4, 95% CI: 2.6-7.3), while of the third quartile the HR was 3.2 (95% CI: 1.9-5.5) vs (aHR: 2.4, 95% CI: 1.4-4.0). The prognostic accuracy of the DASI score was high, and higher than that of BNP concentrations (720-day mortality C-index: 0.67 vs 0.62; P = 0.024). Conclusions: Quantification of self-reported subjective exercise capacity using the DASI provides high prognostic accuracy and may aid physicians in risk stratification. (Basics in Acute Shortness of Breath EvaLuation [BASEL V] Study [BASEL V]; NCT01831115).

Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD).

BACKGROUND: Trimethylamine N-oxide (TMAO) has been associated with cardiovascular outcomes. However, the diagnostic value of TMAO and its precursors have not been assessed for functionally relevant coronary artery disease (fCAD) and its prognostic potential in this setting needs to be evaluated. METHODS: Among 1726 patients with suspected fCAD serum TMAO, and its precursors betaine, choline and carnitine, were quantified using liquid chromatography tandem mass spectrometry. Diagnosis of fCAD was performed by myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography blinded to marker concentrations. Incident all-cause death, cardiovascular death (CVD) and myocardial infarction (MI) were assessed during 5-years follow-up. RESULTS: Concentrations of TMAO, betaine, choline and carnitine were significantly higher in patients with fCAD versus those without (TMAO 5.33 µM vs 4.66 µM, p < 0.001); however, diagnostic accuracy was low (TMAO area under the receiver operating curve [AUC]: 0.56, 95% CI [0.53-0.59], p < 0.001). In prognostic analyses, TMAO, choline and carnitine above the median were associated with significantly (p < 0.001 for all) higher cumulative events for death and CVD during 5-years follow-up. TMAO remained a significant predictor for death and CVD even in full models adjusted for renal function (HR = 1.58 (1.16, 2.14), p = 0.003; HR = 1.66 [1.07, 2.59], p = 0.025). Prognostic discriminative accuracy for TMAO was good and robust for death and CVD (2-years AUC for CVD 0.73, 95% CI [0.65-0.80]). CONCLUSION: TMAO and its precursors, betaine, choline and carnitine were significantly associated with fCAD, but with limited diagnostic value. TMAO was a strong predictor for incident death and CVD in patients with suspected fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

P2X4 deficiency reduces atherosclerosis and plaque inflammation in mice.

Extracellular adenosine-5'-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X4 and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X4-axis in atherosclerosis. Expression of P2X4 was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X4 in atherosclerosis, P2X4-deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X4-deficient mice developed smaller atherosclerotic lesions compared to P2X4-competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X4-deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X4-deficient mice. Moreover, bone marrow derived macrophages isolated from P2X4-deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1ß (IL-1ß) and IL-6. Additionally, P2X4-deficient mice shared a lower proportion of pro-inflammatory Ly6Chigh monocytes and a higher proportion of anti-inflammatory Ly6Clow monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X4 expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study's findings for human atherosclerosis. Collectively, P2X4 deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X4 as a potential therapeutic target in the fight against atherosclerosis.

Residual inflammatory risk in coronary heart disease: incidence of elevated high-sensitive CRP in a real-world cohort.

BACKGROUND: Inflammation drives atherosclerosis and its complications. Anti-inflammatory therapy with interleukin 1 beta (IL-1ß) antibody reduces cardiovascular events in patients with elevated high-sensitive C-reactive protein (hsCRP). This study aims to identify the share of patients with coronary heart disease (CHD) and residual inflammation who may benefit from anti-inflammatory therapy. METHODS: hsCRP and low-density lipoprotein (LDL) levels were determined in 2741 all-comers admitted to the cardiological ward of our tertiary referral hospital between June 2016 and June 2018. Patients without CHD, with acute coronary syndrome, chronic or recurrent systemic infection, use of immunosuppressant or anti-inflammatory agents, chronic inflammatory diseases, chemotherapy, terminal organ failure, traumatic injury and pregnancy were excluded. RESULTS: 856 patients with stable CHD were included. 42.7% of those had elevated hsCRP ≥ 2 mg/l. Within the group of patients with LDL-cholesterol < 70 mg/dl, 30.9% shared increased hsCRP indicating residual inflammation. After multivariate adjusted backward selection elevated Lipoprotein (a) (OR 1.61, p = 0.048), elevated proBNP (OR 2.57, p < 0.0001), smoking (OR 1.70, p = 0.022), and obesity (OR 2.28, p = 0.007) were associated with elevated hsCRP. In contrast, the use of ezetimibe was associated with normal hsCRP (OR 0.51, p = 0.014). In the subgroup of patients with on-target LDL-cholesterol < 70 mg/dl, backward selection identified elevated proBNP (OR 3.49, p = 0.007) as independent predictor of elevated hsCRP in patients with LDL-cholesterol < 70 mg/dl. CONCLUSION: One-third of all-comers patients with CHD showed increased levels of hsCRP despite a LDL-cholesterol < 70 mg/dl potentially qualifying for an anti-inflammatory therapy. Elevated proBNP is an independent risk factor for hsCRP elevation.