Prognostic value of syntax score, intravascular ultrasound and near-infrared spectroscopy to identify low-risk patients with coronary artery disease 5-year results from the ATHEROREMO and IBIS-3 cohorts.

The prognostic value of SYNTAX score (SS), intravascular ultrasound (IVUS)-derived plaque burden (PB) and near-infrared spectroscopy (NIRS)-derived lipid core burden index(LCBI) for identification of high-risk patients for major adverse cardiovascular events (MACE) has been proven in previous studies. The majority of patients presenting in the cathlab however do not endure MACE over time, and identification of low-risk groups has remained underexposed. This study evaluates the combined prognostic value of SS, PB and LCBI in identifying patients with low MACE risk. This post-hoc analysis combines the ATHEROREMO and IBIS-3 studies and included 798 patients undergoing coronary angiography. Anatomical SS was calculated (N = 617) and ≥40mm non-stenotic segment of a non-target vessel was investigated with IVUS (N = 645) and NIRS (N = 273) to determine PB and maximum 4mm LCBI (LCBI4mm). During five-year follow-up, 191 MACE were observed. Patients with PB ≤70%, LCBI4mm ≤227 (median), or SS ≤8 (median) had lower MACE incidence than their counterparts with higher values. Combined into one model, LCBI4mm ≤227 (adjusted hazard ratio [aHR] 0.49, 95% confidence interval [CI] 0.30-0.78; p-value = 0.003) and SS ≤8 (aHR 0.67, 95%CI 0.48-0.96, p-value = 0.027) were independently associated with (lower) MACE rate, but PB was not. Additionally, negative predictive value (NPV) of this model was high (SS<8: 0.80, PB<70%: 0.77, LCBI4mm<227: 0.79). In this cohort, SS and LCBI4mm proved to be independent predictors of MACE-free survival during five-year follow-up. Combination of SS and LCBI4mm is useful to identify a low-risk population. Furthermore, NPV of SS, PB and LCBI4mm for prediction of MACE is high.

Personalized screening intervals for kidney function in patients with chronic heart failure: a modeling study.

BACKGROUND: High mortality and rehospitalization rates demonstrate that improving risk assessment in heart failure patients remains challenging. Individual temporal evolution of kidney biomarkers is associated with poor clinical outcome in these patients and hence may carry the potential to move towards a personalized screening approach. METHODS: In 263 chronic heart failure patients included in the prospective Bio-SHiFT cohort study, glomerular and tubular biomarker measurements were serially obtained according to a pre-scheduled, fixed trimonthly scheme. The primary endpoint (PE) comprised cardiac death, cardiac transplantation, left ventricular assist device implantation or heart failure hospitalization. Personalized scheduling of glomerular and tubular biomarker measurements was compared to fixed scheduling in individual patients by means of a simulation study, based on clinical characteristics of the Bio-SHiFT study. For this purpose, repeated biomarker measurements and the PE were jointly modeled. For personalized scheduling, using this fitted joint model, we determined the optimal time point of the next measurement based on the patient's individual risk profile as estimated by the joint model and the maximum information gain on the patient's prognosis. We compared the schedule's capability of enabling timely intervention before the occurrence of the PE and number of measurements needed. RESULTS: As compared to a pre-defined trimonthly scheduling approach, personalized scheduling of glomerular and tubular biomarker measurements showed similar performance with regard to prognostication, but required a median of 0.4-2.7 fewer measurements per year. CONCLUSION: Personalized scheduling is expected to reduce the number of patient visits and healthcare costs. Thus, it may contribute to efficient monitoring of chronic heart failure patients and could provide novel opportunities for timely adaptation of treatment.

Associations of serially measured PCSK9, LDLR and MPO with clinical outcomes in heart failure.

Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology & results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4-2.5) years in 263 CHF patients. Seventy patients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23-2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04-2.06]) and LDLR (HR: 0.66 [0.49-0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12-1.76] per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61-0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538. https://clinicaltrials.gov/ct2/show/NCT01851538.

Serially Measured Cytokines and Cytokine Receptors in Relation to Clinical Outcome in Patients With Stable Heart Failure.

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment.

Temporal patterns of macrophage- and neutrophil-related markers are associated with clinical outcome in heart failure patients.

AIMS: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). METHODS AND RESULTS: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47-2.98), P < 0.001], TRAP [0.62 (0.43-0.90), P = 0.009], GRN [2.46 (1.64-3.84), P < 0.001], SPON1 [3.94 (2.50-6.50), P < 0.001], and PGLYRP1 [1.62 (1.14-2.31), P = 0.006]. CONCLUSIONS: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF.

Two decades after coronary radiation therapy: A single center longitudinal clinical study.

OBJECTIVES: The aim of this study was to evaluate the very long-term clinical outcome after radioactive stent (RS) implantation and intracoronary ß radiation brachytherapy (IRBT). BACKGROUND: Radioactive stents (RS) and intracoronary ß radiation brachytherapy (IRBT) were introduced to prevent restenosis after percutaneous coronary intervention (PCI). Both techniques were associated with a higher incidence of major adverse cardiac events (MACE) in the short and intermediate-term follow up as compared to conventional PCI. METHODS: One hundred and thirty-three patients received radioactive stents (32 P) and 301 patients were treated with IRBT adjunctive to PCI. These groups were propensity matched to respectively 266 and 602 control patients who were treated with routine PCI during the same inclusion period. Endpoints were all-cause mortality and MACE, defined as all-cause death, any myocardial infarction or any revascularization. RESULTS: Median follow-up duration was 17 years. All-cause mortality rates were similar in all groups. Adjusted hazard ratios for MACE and mortality in the RS cohort were 1.55 (95% CI 1.20-2.00) and 0.92 (95% CI 0.63-1.34), respectively. Adjusted hazard ratios for MACE and all-cause mortality in the IRBT cohort were 1.41 (95% CI 1.18-1.67) and 0.95 (95% CI 0.74-1.21), respectively. The difference in MACE rates was predominantly driven by coronary revascularizations in both groups, with a higher MI rate in the IRBT group as well. CONCLUSIONS: Coronary radiation therapy was associated with early increased MACE rates, but the difference in MACE rates decreased beyond 2 years, resulting in a comparable long-term clinical outcome. Importantly, no excess in mortality was observed.

SYNTAX score in relation to intravascular ultrasound and near-infrared spectroscopy for the assessment of atherosclerotic burden in patients with coronary artery disease.

AIMS: The aim of this study was to examine the relationship between the anatomical SYNTAX score (SXscore), derived from all three coronary arteries, and coronary wall pathology measured by radiofrequency intravascular ultrasound (RF-IVUS) and near-infrared spectroscopy (NIRS) in a single non-culprit segment. METHODS AND RESULTS: In patients referred for coronary angiography (N=88) or PCI (N=592) for stable angina or acute coronary syndrome, the SYNTAX score calculator (www.syntaxscore.com) was used to determine the SXscore before PCI, if applicable. RF-IVUS and/or NIRS were performed in a non-stenotic 40 mm study segment following the clinically indicated angiography/PCI. After adjustment for multiple confounders, a higher SXscore was associated with higher segmental plaque volume in the study segment (2.21 mm3 per SXscore point, 95% CI: 0.92-3.50, p-value 0.001), as well as with higher volume of fibrous (0.93 mm3 per point) and fibro-fatty tissue (0.29 mm3 per point). A higher SXscore was also associated with a higher NIRS-derived lipid core burden index (LCBI) in the full study segment (1.35 units per SXscore point, 95% CI: 0.22-2.47, p-value 0.019). Importantly, SXscore correlated with the fatty/fibro-fatty and LCBI signals despite adjusting for plaque burden. CONCLUSIONS: In patients with CAD, higher SXscores are associated with higher atherosclerotic burden as assessed by RF-IVUS and NIRS in a single non-stenotic coronary artery segment.

Prognostic Value of Intravascular Ultrasound in Patients With Coronary Artery Disease.

BACKGROUND: It has been shown that intravascular ultrasound (IVUS) and radiofrequency (RF-)IVUS can detect high-risk coronary plaque characteristics. OBJECTIVES: The authors studied the long-term prognostic value of (RF-)IVUS-derived plaque characteristics in patients with coronary artery disease (CAD) undergoing coronary angiography. METHODS: From 2008 to 2011, (RF-)IVUS was performed in 1 nonstenotic segment of a nonculprit coronary artery in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina. The pre-defined primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause death, nonfatal ACS, or unplanned revascularization. Hazard ratios (HRs) were adjusted for age, sex, and clinical risk factors. RESULTS: During a median follow-up of 4.7 years, 152 patients (26.2%) had MACE. The presence of a lesion with a minimal luminal area ≤4.0 mm2 was independently associated with MACE (HR: 1.49; 95% CI: 1.07 to 2.08; p = 0.020), whereas the presence of a thin-cap fibroatheroma lesion or a lesion with a plaque burden ≥70% on its own were not. Results were comparable when the composite endpoint included cardiac death instead of all-cause death. The presence of a lesion with a plaque burden of ≥70% was independently associated with the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization after exclusion of culprit lesion-related events (HR: 1.66; 95% CI: 1.06 to 2.58; p = 0.026). Likewise, each 10-U increase in segmental plaque burden was independently associated with a 26% increase in risk of this composite endpoint (HR: 1.26 per 10-U increase; 95% CI: 1.03 to 1.52; p = 0.022). CONCLUSIONS: IVUS-derived small luminal area and large plaque burden, and not RF-IVUS-derived compositional plaque features on their own, predict adverse cardiovascular outcome during long-term follow-up in patients with CAD. (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis-Intravascular Ultrasound Study [AtheroRemoIVUS]; NCT01789411).

SYNTAX score II predicts long-term mortality in patients with one- or two-vessel disease.

OBJECTIVE: SYNTAX score II (SSII) is a long-term mortality prediction model to guide the decision making of the heart-team between coronary artery bypass grafting or percutaneous coronary intervention (PCI) in patients with left main or three-vessel coronary artery disease. This study aims to investigate the long-term predictive value of SSII for all-cause mortality in patients with one- or two-vessel disease undergoing PCI. METHODS: A total of 628 patients (76% men, mean age: 61±10 years) undergoing PCI due to stable angina pectoris (43%) or acute coronary syndrome (57%), included between January 2008 and June 2013, were eligible for the current study. SSII was calculated using the original SYNTAX score website (www.syntaxscore.com). Cox regression analysis was used to assess the association between continuous SSII and long-term all-cause mortality. The area under the receiver-operating characteristic curve was used to assess the performance of SSII. RESULTS: SSII ranged from 6.6 to 58.2 (median: 20.4, interquartile range: 16.1-26.8). In multivariable analysis, SSII proved to be an independent significant predictor for 4.5-year mortality (hazard ratio per point increase: 1.10; 95% confidence interval: 1.07-1.13; p<0.001). In terms of discrimination, SSII had a concordance index of 0.77. CONCLUSION: In addition to its established value in patients with left main and three-vessel disease, SSII may also predict long-term mortality in PCI-treated patients with one- or two-vessel disease.

Near-infrared spectroscopy-derived lipid core burden index predicts adverse cardiovascular outcome in patients with coronary artery disease during long-term follow-up.

Aims: Near-infrared spectroscopy (NIRS) is able to quantify cholesterol within coronary arteries by the lipid core burden index (LCBI). We studied the prognostic value of NIRS-derived LCBI in patients with coronary artery disease (CAD) for adverse cardiac outcome during long-term follow-up. Methods and results: During 2009-2013, NIRS was performed in a non-culprit artery of 275 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina. LCBI was quantified by an independent corelab for the region of interest (LCBIROI) and the 4 and 10 mm long segment with the maximum LCBI (MaxLCBI4mm and MaxLCBI10mm). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, non-fatal ACS, or unplanned revascularization. Hazard ratios (HR) were adjusted for age, gender, clinical risk factors, and segment plaque burden based on intravascular ultrasound. During a median follow-up of 4.1 years, 79 patients (28.7%) had MACE. There was a statistically significant and independent continuous relationship between higher MaxLCBI4mm values and a higher risk of MACE. Each 100 units increase of MaxLCBI4mm was associated with a 19% increase in MACE [hazard ratios (HR) 1.19, 95% confidence intervals (95% CI): 1.07-1.32, P = 0.001]. Continuous MaxLCBI4mm remained independently associated with MACE after exclusion of target lesion-related events (HR 1.21, 95% CI: 1.08-1.35), as well as after exclusion of adverse events related to the NIRS-imaged coronary segment (HR 1.19, 95% CI: 1.06-1.34). Results for MaxLCBI10mm were comparable. Conclusion: NIRS-derived LCBI is associated with adverse cardiac outcome in CAD patients during long-term follow-up independent of clinical risk factors and plaque burden.