Circulating chemokines in relation to coronary plaque characteristics on radiofrequency intravascular ultrasound and cardiovascular outcome.

OBJECTIVE: To investigate relations of several circulating chemokines with extent and phenotype of coronary atherosclerosis and with 1-year clinical outcome. METHODS: Intravascular ultrasound virtual histology (IVUS-VH) imaging of a coronary artery was performed in 581 patients. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-1ß and regulated upon activation normal T cell expressed and secreted (RANTES) were measured in plasma. RESULTS: Higher MCP-1, MIP-1α and lower RANTES were associated with coronary plaque burden. Higher MCP-1, MIP-1α and lower RANTES were associated with the presence of IVUS-VH-derived thin-cap fibroatheroma lesions. RANTES was associated with major adverse cardiac events. CONCLUSIONS: RANTES is a promising biomarker that is inversely associated with coronary plaque burden and vulnerability, as well as with death and acute coronary syndrome.

Microsimulation for clinical decision-making in individual patients with established coronary artery disease: a concept.

BACKGROUND: In cardiovascular disease, numerous evidence-based prognostic models have been created, usually based on regression analyses of isolated patient datasets. They tend to focus on one outcome event, based on just one baseline evaluation of the patient, and fail to take the disease process in its dynamic nature into account. We present so-called microsimulation as an attractive alternative for clinical decision-making in individual patients. We aim to further familiarize clinicians with the concept of microsimulation and to inform them about the modeling process. METHODS AND RESULTS: We describe the modeling process, advantages and disadvantages of microsimulation. We illustrate the concept using a hypothetical 60-year-old patient, with several cardiac risk factors, who is hospitalized for myocardial infarction. By using microsimulation, we calculate this patient's probability of death. In our example, this particular patient's estimated life expectancy turns out to be 8.9 years. While calculating this life expectancy, we were able to account for multiple outcome events and changing patient characteristics. CONCLUSIONS: Microsimulation takes into account the dynamic nature of coronary artery disease by estimating most likely outcomes regarding a broad range of clinical events. Moreover, microsimulation can be used to evaluate treatment effects by estimating the event-free life expectancy with and without treatment. Hence, microsimulation has several advantages compared to modeling techniques such as regression.

Four-year clinical outcome of sirolimus- and paclitaxel-eluting stents compared to bare-metal stents for the percutaneous treatment of stable coronary artery disease.

BACKGROUND: There are limited data on the long-term safety and efficacy profile of coronary stent implantation in patients with stable coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). OBJECTIVE: We aimed to assess the 4-year clinical outcome in patients who received a bare-metal stent (BMS), sirolimus-eluting stent (SES), or a paclitaxel-eluting stent (PES) for the percutaneous treatment of stable angina in our center during 2000-2005. METHODS: In the study period, a total of 2,449 consecutive patients (BMS = 1,005; SES = 373; and PES = 1071) underwent a PCI as part of three historical PCI-cohorts for stable angina and were routinely followed for the occurrence of major adverse cardiac events (MACE). RESULTS: At 4 years follow-up, 264 BMS patients (26.8%) had a MACE, compared to 75 SES patients (20.9%) and 199 PES patients (23.9%). Multivariate analysis showed that SES and PES were superior to BMS with respect to MACE [hazard ratio (HR) = 0.62, 95% confidence interval (CI): 0.47-0.81; HR = 0.67, 95% CI: 0.55-0.82, respectively]. The occurrence of MACE was significantly lower in the SES and PES population, primarily due to less target-vessel revascularization (TVR) procedures (HR = 0.53, 95% CI: 0.37-0.75; HR = 0.71, 95% CI: 0.62-0.81, respectively). The occurrence of early, late, and very late stent thrombosis was equally rare with each stent type. There were no significant differences between SES and PES on death, myocardial infarction, TVR, and MACE. CONCLUSION: These findings suggest that SES and PES result in decreased TVR procedures and MACE compared to BMS at 4 years follow-up. SES or PES implantation should be the preferred choice over BMS for patients with stable CAD undergoing PCI.

Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients with chronic heart failure: The Bio-SHiFT study.

BACKGROUND: Several studies have suggested circulating microRNAs (miRs) are associated with heart failure, but these studies were small, and limited to single miR measurements. We examined 7 miRs which were previously linked to heart failure, and tested whether their temporal expression level predicts prognosis in a prospective cohort of chronic heart failure (CHF) patients. METHODS AND RESULTS: In 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3months, we measured 7miRs. The primary endpoint (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation and LVAD implantation. Associations between temporal miR patterns and the PE were investigated by joint modelling, which combines mixed models with Cox regression. Mean age was 67±13years, 72% were men and 27% NYHA classes III-IV. We obtained 873 blood samples (median 3 [IQR 2-5] per patient). The PE was reached in 41 patients (16%) during a median follow-up of 0.9 [0.6-1.4] years. The temporal pattern of miR-22-3p was independently associated with the PE (HR [95% CI] per doubling of level: 0.64 [0.47-0.77]). The instantaneous change in level (slope of the temporal miR pattern) of miR-22-3p was also independently associated with the PE (HR [95% CI] per doubling of slope: 0.33 [0.20-0.51]). These associations remained statistically significant after adjustment for temporal patterns of NT-proBNP, Troponin T and CRP. CONCLUSIONS: The temporal pattern of circulating miR-22-3p contains important prognostic and independent information in CHF patients. This concept warrants further investigation in larger series with extended follow-up.

Repeated measurements of NT-pro-B-type natriuretic peptide, troponin T or C-reactive protein do not predict future allograft rejection in heart transplant recipients.

BACKGROUND: Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR. METHODS: From 2005 to 2010, 77 consecutive heart transplantation (HTx) recipients were included. The NT-proBNP, TropT, and CRP were measured at 16 ± 4 (mean ± standard deviation) consecutive routine endomyocardial biopsy surveillance visits during the first year of follow-up. Allograft rejection was defined as International Society for Heart and Lung Transplantation (ISHLT) grade 2R or higher at endomyocardial biopsy. Joint modeling was used to assess the association between repeated biomarker measurements and occurrence of future AR. Joint modeling accounts for dependence among repeated observations in individual patients. RESULTS: The mean age of the patients at HTx was 49 ± 9.2 years, and 68% were men. During the first year of follow-up, 1,136 biopsies and concurrent blood samples were obtained, and 56 patients (73%) experienced at least one episode of AR. All biomarkers were elevated directly after HTx and achieved steady-state after ∼ 12 weeks, both in patients with or without AR. No associations were present between the repeated measurements of NT-proBNP, TropT, or CRP and AR both early (weeks 0-12) and late (weeks 13-52) in the course after HTx (hazard ratios for weeks 13-52: 0.96 (95% confidence interval, 0.55-1.68), 0.67 (0.27-1.69), and 1.44 (0.90-2.30), respectively, per ln[unit]). Combining the three biomarkers in one model also rendered null results. CONCLUSION: The temporal evolution of NT-proBNP, TropT, and CRP before AR did not predict occurrence of acute AR both in the early and late course of the first year after HTx.

Smoking in Relation to Coronary Atherosclerotic Plaque Burden, Volume and Composition on Intravascular Ultrasound.

BACKGROUND: This study aimed to evaluate the relationship between cigarette smoking and coronary atherosclerotic burden, volume and composition as determined in-vivo by grayscale and virtual histology (VH) intravascular ultrasound (IVUS). METHODS AND RESULTS: Between 2008 and 2011, (VH-)IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. To account for differences in baseline characteristics, current smokers were matched to never smokers by age, gender and indication for catheterization, resulting in 280 patients available for further analysis. Coronary atherosclerotic plaque volume, burden, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and high-risk lesions (VH-IVUS derived thin-cap fibroatheroma (TCFA), plaque burden ≥70%, minimal luminal area ≤4.0 mm2) were assessed. Cigarette smoking showed a tendency towards higher coronary plaque burden (mean±SD, 38.6±12.5% in current versus 36.4±11.0% in never smokers, p = 0.080; and odds ratio (OR) of current smoking for plaque burden above versus below the median 1.69 (1.04-2.75), p = 0.033). This effect was driven by an association in patients presenting with an acute coronary syndrome (ACS) (current smokers, plaque burden 38.3±12.8% versus never smokers, plaque burden 35.0±11.2%, p = 0.049; OR 1.88 (1.02-3.44), p = 0.042). Fibrous tissue tended to be lower in current smokers (mean±SD, 57.7±10.5% versus 60.4±12.6%, p = 0.050) and fibro-fatty tissue was higher in current smokers (median[IQR], 9.6[6.0-13.7]% versus 8.6[5.8-12.2]%, p = 0.039). However, differences in percentage necrotic core and dense calcium could not be demonstrated. Also, no differences were found with regard to high-risk lesions. CONCLUSIONS: An association between smoking and degree of coronary atherosclerosis was present in patients undergoing coronary angiography who presented with ACS. Although smoking was associated with higher fibro-fatty percentage, no associations could be demonstrated with percentage necrotic core, nor with VH-IVUS derived TCFA lesions. Since the magnitude of the differences in both degree and composition of atherosclerosis was modest, clinical relevance of the findings may be questioned.

Circulating cytokines in relation to the extent and composition of coronary atherosclerosis: results from the ATHEROREMO-IVUS study.

OBJECTIVE: We investigated whether concentrations of TNF-α, TNF-ß, TNF-receptor 2, interferon-γ, IL-6, IL-8, IL-10 and IL-18 are associated with extent and composition of coronary atherosclerosis determined by grayscale and virtual histology (VH)- intravascular ultrasound (IVUS). METHODS: Between 2008 and 2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients (stable angina pectoris (SAP), n = 261; acute coronary syndrome (ACS), n = 309) undergoing coronary angiography from the ATHEROREMO-IVUS study. Plaque burden, presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, and presence of VH-TCFA lesions with plaque burden ≥70% were assessed. Blood samples for cytokine measurement were drawn from the arterial sheath prior to the angiography procedure. We applied linear and logistic regression. RESULTS: TNF-α levels were positively associated with plaque burden (beta (ß) [95%CI]: 4.45 [0.99-7.91], for highest vs lowest TNF-α tertile) and presence of VH-TCFA lesions (odds ratio (OR) [95%CI] 2.30 (1.17-4.52), highest vs lowest TNF-α tertile) in SAP patients. Overall, an inverse association was found between IL-10 concentration and plaque burden (ß [95%CI]: -1.52 [-2.49 to -0.55], per Ln (pg/mL) IL-10) as well as IL-10 and VH-TCFA lesions with plaque burden ≥70% (OR: 0.31 [0.12-0.80],highest vs lowest IL-10 tertile). These effects did not reach statistical significance in the separate SAP and ACS groups. CONCLUSION: Higher circulating TNF-α was associated with higher plaque burden and VH-TCFA lesions in SAP patients. Lower circulating IL-10 was associated with higher plaque burden and large VH-TCFA lesions. These in-vivo findings suggest a role for these cytokines in extent and vulnerability of atherosclerosis.

Circulating acute phase proteins in relation to extent and composition of coronary atherosclerosis and cardiovascular outcome: results from the ATHEROREMO-IVUS study.

INTRODUCTION: We examined whether the acute phase proteins (APPs): Alpha-1-Antitrypsin, Alpha-2-Macroglobulin, Complement C3, ferritin, haptoglobin, and Plasminogen Activator Inhibitor 1 (PAI-1) are associated with cardiovascular outcome, as well as with the extent and composition of coronary atherosclerosis as determined by intravascular ultrasound (IVUS) virtual histology (VH). METHODS: In 2008-2011, IVUS(-VH) imaging of a non-culprit coronary artery was performed in 581 patients from the ATHEROREMO-IVUS study undergoing coronary angiography for acute coronary syndrome (ACS) (n=318) or stable angina pectoris (SAP) (n=263). Coronary atherosclerotic plaque volume, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and vulnerability (VH-derived thin-cap fibroatheroma (TCFA) lesions) were assessed. Major adverse cardiac events (MACE; all-cause mortality, ACS or unplanned coronary revascularization) were assessed during 1-year follow-up. We applied linear, logistic and Cox regression. RESULTS: Mean age was 61.5 ± 11.4 years and 75.4% were men. Higher ferritin was associated with higher coronary plaque volume (beta [95% CI]: 0.19 [0.07-0.31] percent atheroma volume), for the highest vs the lowest tertile of ferritin; p for linear association=0.013. Higher PAI-1 was associated with higher rates of all-cause mortality or ACS (hazard ratio [95% CI]: 2.98 [1.10-8.06]), for the highest vs the lowest tertile of PAI-1. No clear-cut associations could be demonstrated between APPs and composition of atherosclerosis or plaque vulnerability. CONCLUSIONS: Higher circulating ferritin was associated with higher coronary plaque volume, and higher PAI-1 was associated with higher incidence of all-cause mortality or ACS. None of the APPs displayed consistent associations with composition of atherosclerosis or plaque vulnerability.

Biomarkers of heart failure with normal ejection fraction: a systematic review.

AIMS: Heart failure with normal ejection fraction (HFNEF) is a major and growing public health problem, currently representing half of the heart failure burden. Although many studies have investigated the diagnostic and prognostic value of new biomarkers in heart failure, limited data are available on biomarkers other than natriuretic peptides in HFNEF. We performed a systematic review of epidemiological studies on the associations of biomarkers with the occurrence of HFNEF and with the prognosis of HFNEF patients. METHODS AND RESULTS: Biomarkers examined most extensively in HFNEF include biomarkers of myocyte stress, inflammation, and extracellular matrix remodelling. Some biomarkers have been shown to be increased to a different extent in HFNEF compared with heart failure with reduced ejection fraction (HFREF). Several biomarkers, including biomarkers of myocyte stress, inflammation, extracellular matrix remodelling, growth differentiation factor 15 (GDF-15), cystatin C, resistin, and galectin-3, were associated with development of HFNEF and with clinical outcomes of HFNEF patients in terms of morbidity and mortality. CONCLUSION: Several biomarkers, including biomarkers of myocyte stress, inflammation, extracellular matrix remodelling, GDF-15, cystatin C, resistin, and galectin-3, appeared to be promising diagnostic and prognostic tools in patients with HFNEF. Investigation of the incremental diagnostic and prognostic value of these biomarkers, or a combination thereof, over established clinical covariates and imaging techniques in large, prospective studies is warranted.

Development and validation of a cardiovascular risk assessment model in patients with established coronary artery disease.

Appropriate risk stratification of patients with established, stable coronary artery disease could contribute to the prevention of recurrent cardiovascular events. The purpose of the present study was to develop and validate risk prediction models for various cardiovascular end points in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) database, consisting of 12,218 patients with established coronary artery disease, with a median follow-up of 4.1 years. Cox proportional hazards models were used for model development. The end points examined were cardiovascular mortality, noncardiovascular mortality, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, resuscitated cardiac arrest, and combinations of these end points. The performance measures included Nagelkerke's R², time-dependent area under the receiver operating characteristic curves, and calibration plots. Backward selection resulted in a prediction model for cardiovascular mortality (464 events) containing age, current smoking, diabetes mellitus, total cholesterol, body mass index, previous myocardial infarction, history of congestive heart failure, peripheral vessel disease, previous revascularization, and previous stroke. The model performance was adequate for this end point, with a Nagelkerke R² of 12%, and an area under the receiver operating characteristic curve of 0.73. However, the performance of models constructed for nonfatal and combined end points was considerably worse, with an area under the receiver operating characteristic curve of about 0.6. In conclusion, in patients with established coronary artery disease, the risk of cardiovascular mortality during longer term follow-up can be adequately predicted using the clinical characteristics available at baseline. However, the prediction of nonfatal outcomes, both separately and combined with fatal outcomes, poses major challenges for clinicians and model developers.

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

BACKGROUND: Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. METHODS: Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. RESULTS: Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. CONCLUSIONS: Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect.