We investigated the associations of ten previously identified high risk molecular lipid species and three ceramide ratios with the occurrence of major adverse cardiac events (MACEs) during a median ...follow-up of 4.7 years in patients with coronary artery disease (CAD). Between 2008 and 2011, 581 patients underwent diagnostic coronary angiography or percutaneous coronary intervention for stable angina pectoris (SAP) or acute coronary syndrome (ACS). Blood was drawn prior to the index procedure and lipid species were determined. The primary endpoint was the occurrence of a MACE, comprising all-cause mortality, nonfatal ACS, or unplanned coronary revascularization. The secondary endpoint comprised all-cause mortality or nonfatal ACS. During a median follow-up of 4.7 IQR: 4.2–5.6 years, 155 patients (27%) had MACEs. In multivariable analyses, Cer(d18:1/16:0) concentration was associated with MACEs {hazard ratio 2.32; 95% CI 1.09–4.96 per natural logarithm (ln) (pmol/ml) P = 0.030} after adjustment for cardiac risk factors, clinical presentation, statin use at baseline, and admission nonHDL cholesterol level. Furthermore, after multivariable adjustment, concentrations of Cer(d18:1/16:0), Cer(d18:1/20:0), Cer(d18:1/24:1), and their ratios to Cer(d18:1/24:0) were associated with the composite endpoint death or nonfatal ACS. The data together show the circulating ceramide lipids we investigated here are associated with adverse cardiac outcome during long-term follow-up independent of clinical risk factors.
Renin-angiotensin-aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is ...uncertain. Our objective was to analyse the effects of RAAS inhibitors as a class of drugs, as well as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality.
We performed a pooled analysis of 20 cardiovascular morbidity-mortality trials. In each trial at least two-thirds of the patients had to be diagnosed with hypertension, according to the trial-specific definition, and randomized to treatment with an RAAS inhibitor or control treatment. The cohort included 158 998 patients (71 401 RAAS inhibitor; 87 597 control). The incidence of all-cause death was 20.9 and 23.3 per 1000 patient-years in patients randomized to RAAS inhibition and controls, respectively. Overall, RAAS inhibition was associated with a 5% reduction in all-cause mortality (HR: 0.95, 95% CI: 0.91-1.00, P= 0.032), and a 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: 0.88-0.99, P= 0.018). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR: 0.90, 95% CI: 0.84-0.97, P= 0.004), whereas no mortality reduction could be demonstrated with ARB treatment (HR: 0.99, 95% CI: 0.94-1.04, P= 0.683). This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (P-value for heterogeneity 0.036).
In patients with hypertension, treatment with an ACE inhibitor results in a significant further reduction in all-cause mortality. Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved.
Abstract Background and aims Experimental studies have suggested that proprotein convertase substilisin/kexin type 9 (PCSK9) might directly promote inflammatory processes contributing to ...atherosclerosis by mechanisms independent of low-density lipoprotein (LDL) cholesterol levels. This study aims to investigate the association between serum PCSK9 levels and the fraction and amount of necrotic core tissue in coronary atherosclerotic plaque, as assessed by intravascular ultrasound virtual histology (IVUS-VH) imaging. Methods Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable angina. PCSK9 concentrations were measured in serum samples that were drawn prior to coronary angiography. None of the patients received PCSK9 inhibitors. Results After adjustment for established cardiac risk factors, statin use and serum LDL cholesterol, serum PCSK9 levels were linearly associated with the fraction of plaque consisting of necrotic core tissue (β = 1.24% increase per 100 μg/L increase in PCKS9, 95%CI 0.55–1.94, p = 0.001) and with the absolute volume of necrotic core tissue (β = 0.09, 95%CI 0.01–0.18, p = 0.033), but were not significantly associated with plaque burden (p = 0.11), plaque volume (p = 0.22) or the presence of IVUS-VH-derived thin-cap fibroatheroma lesions (p = 1.0). Conclusion Serum PCSK9 levels were linearly associated with the fraction and amount of necrotic core tissue in coronary atherosclerosis, independently of serum LDL cholesterol levels and statin use. Therefore, PCSK9 may be an interesting therapeutic target for the treatment of atherosclerotic disease beyond LDL cholesterol regulation.
Acute coronary syndromes (ACS) are mostly caused by plaque rupture. This study aims to investigate the prognostic value of in vivo detection of high-risk coronary plaques by intravascular ultrasound ...(IVUS) in patients undergoing coronary angiography.
Between November 2008 and January 2011, IVUS of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for ACS (n = 318) or stable angina (n = 263). Primary endpoint was major adverse cardiac events (MACEs) defined as mortality, ACS, or unplanned coronary revascularization. Culprit lesion-related events were not counted. Cumulative Kaplan-Meier incidence of 1-year MACE was 7.8%. The presence of IVUS virtual histology-derived thin-cap fibroatheroma (TCFA) lesions (present 10.8% vs. absent 5.6%; adjusted HR: 1.98, 95% CI: 1.09-3.60; P = 0.026) and lesions with a plaque burden of ≥70% (present 16.2% vs. absent 5.5%; adjusted HR: 2.90, 95% CI: 1.60-5.25; P < 0.001) were independently associated with a higher MACE rate. Thin-cap fibroatheroma lesions were also independently associated with the composite of death or ACS only (present 7.5% vs. absent 3.0%; adjusted HR: 2.51, 95% CI: 1.15-5.49; P = 0.021). Thin-cap fibroatheroma lesions with a plaque burden of ≥70% were associated with a higher MACE rate within (P = 0.011) and after (P < 0.001) 6 months of follow-up, while smaller TCFA lesions were only associated with a higher MACE rate after 6 months (P = 0.033).
In patients undergoing coronary angiography, the presence of IVUS virtual histology-derived TCFA lesions in a non-culprit coronary artery is strongly and independently predictive for the occurrence of MACE within 1 year, particularly of death and ACS. Thin-cap fibroatheroma lesions with a large plaque burden carry higher risk than small TCFA lesions, especially on the short term.
Renal dysfunction and anaemia are common in patients with acute heart failure (HF). It is not known whether their combined presence has additive prognostic value. We investigated their prognostic ...value separately and in combination, on prognosis in acute HF patients. Furthermore, we examined whether the improvement in prognosis was comparable between patients with and without renal dysfunction.
This prospective registry includes 1783 patients admitted to the (Intensive) Coronary Care Unit for acute HF in the period of 1985-2008. The outcome measure was the composite of all-cause mortality, heart transplantation and left ventricular assist device implantation. In patients without renal dysfunction, anemia was associated with worse 30-day outcome (HR 2.91; 95% CI 1.69-5.00), but not with 10-year outcome (HR 1.13 95% CI 0.93-1.37). On the contrary, anemia was found to influence prognosis in patients with renal dysfunction, both at 30 days (HR 1.93 95% CI 1.33-2.80) and at 10 years (HR 1.27 95% CI 1.10-1.47). Over time, the 10-year survival rate improved in patients with preserved renal function (HR 0.73 95% CI 0.55-0.97), but not in patients with renal dysfunction.
The long-term prognosis of acute HF patients with a preserved renal function was found to have improved significantly. However, the prognosis of patients with renal dysfunction did not change. Anemia was a strong prognosticator for short-term outcome in all patients. In patients with renal dysfunction, anemia was also associated with impaired long-term prognosis.
The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be ...used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .
Our aim was to explore potential use of temporal profiles of seven emerging cardio-renal and two pulmonary candidate biomarkers for predicting future adverse clinical outcome in stable patients with ...chronic heart failure (CHF).
In 263 CHF patients, we determined the risk of a composite endpoint of HF-hospitalization, cardiac death, LVAD-placement and heart transplantation in relation to repeatedly assessed (567 samples in total) blood biomarker levels, and slopes of their temporal trajectories (i.e., rate of biomarker change per year). In each patient, we estimated biomarker trajectories using repeatedly measured osteopontin (OPN), osteoprotegerin (OPG), epidermal growth factor receptor (EGFR), heparin-binding protein (HBP), trefoil factor-3 (TFF3), kallikrein-6 (KLK-6), matrix extracellular phosphoglycoprotein (MEPE), pulmonary surfactant-associated protein-D (PSP-D), and secretoglobulin family 3A-member-2 (SCGB3A2).
During 2.2 years of follow-up, OPN, OPG, and HBP levels predicted the composite endpoint (univariable hazard ratio 95% confidence interval per 1SD increase: 2.31 1.76–3.15, 2.23 1.69–3.00, and 1.361.09–1.70). Independently of the biomarkers' levels, the slopes of OPG, TFF-3, PSP-D trajectories were also strong clinical predictors (per 0.1SD increase: 1.24 1.14–1.38, 1.31 1.17–1.49, and 1.32 1.21–1.47). All associations persisted after multivariable adjustment for baseline characteristics, and repeatedly assessed CHF pharmacological treatment and cardiac biomarkers NT-proBNP and troponin T.
Repeatedly-measured levels of OPN, OPG, and HBP, and slopes of OPG, TFF-3, and PSP-D strongly predict clinical outcome. These candidate biomarkers may be clinically relevant as they could further define a patient's risk and provide additional pathophysiological insights into CHF.
•Repeatedly measured OPN, OPG, and HBP levels predict clinical outcome in CHF.•Slopes (marker change/year) of OPG, TFF-3, PSP-D predict clinical outcome in CHF.
Abstract Background and Aims Previous lipidomics analyses have demonstrated that several lipid molecules in plasma are associated with fatal outcome in patients with coronary artery disease (CAD). ...This study aims to investigate the associations of previously identified high risk lipid molecules in plasma with coronary plaque characteristics derived from intravascular ultrasound virtual histology (IVUS-VH) imaging, with coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS), and with one year cardiovascular outcome in patients with CAD. Methods Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable CAD. NIRS imaging was additionally performed in 191 patients. Plasma concentrations of molecular lipids were measured with mass spectrometry. Results Several cholesteryl ester, ceramide and lactosylceramide species and ceramide ratios were associated with vulnerable plaque characteristics on IVUS-VH and NIRS imaging and with 1-year major adverse cardiac events (MACE, defined as all-cause mortality, ACS and unplanned coronary revascularization). In particular, ceramide d18:1/16:0 was consistently associated with higher necrotic core fraction on IVUS-VH (p = 0.001), higher LCBI (p = 0.024) on NIRS and higher MACE rate (adjusted HR 1.79 per standard deviation increase in log-transformed lipid concentration, 95%CI 1.24–2.59, p = 0.002). Conclusion Several molecular lipid species, and particularly ceramide(d18:1/16:0), are associated with the fraction of necrotic core tissue and lipid core burden in coronary atherosclerosis, and are predictive for 1-year clinical outcome after coronary angiography. These molecular lipids may improve risk stratification in CAD and may also be interesting therapeutic targets for the treatment of atherosclerotic disease.
To study temporal trends in short- and long-term outcome after myocardial infarction (MI) according to diabetes status.
We included all 14,434 consecutive patients admitted for ST-segment elevation ...MI or non-ST-segment elevation MI at our center between 1985 and 2008. The study patients were compared according to prevalent diabetes. Temporal trend analyses were performed by comparing decades of admission (1985-1989 vs. 1990-1999 vs. 2000-2008).
A total of 2,015 (14%) of the patients had prevalent diabetes. The risk of presenting with diabetes increased from 8 to 17% from 1985 to 2008. Diabetic patients presented with a higher prevalence of cardiovascular risk factors. With time, the use of evidence-based therapies increased in both patients with and without diabetes. Diabetes is associated with a 1.5-fold increased risk of mortality at the 20-year follow-up. Ten-year mortality decreased over time in patients with diabetes, from 53% in 1985-1989 to 39% in 2000-2008 (adjusted hazard ratio 0.56 95% CI 0.43-0.73), and in those without diabetes, from 38% in 1985-1989 to 29% in 2000-2008 (0.66 0.60-0.73; P interaction = 0.83). Patients with diabetes benefitted from a higher 30-day and 10-year absolute survival increase.
Temporal mortality reductions after MI between 1985 and 2008 were at least as high in patients with diabetes compared with those without diabetes. However, long-term mortality remained higher in diabetic patients. Awareness of the high-risk profile of diabetic patients is warranted and might stimulate optimal medical care and outcome.
Abstract Background Near-infrared spectroscopy (NIRS) is capable of identifying lipid core-containing plaques, which can subsequently be quantified as a lipid core burden index (LCBI). Currently, no ...data are available on the long-term prognostic value of NIRS in patients with coronary artery disease (CAD). Objectives This study sought to determine the long-term prognostic value of intracoronary NIRS as assessed in a nonculprit vessel in patients with CAD. Methods In this prospective, observational study, NIRS imaging was performed in a nonculprit coronary artery in 203 patients referred for angiography due to stable angina pectoris (SAP) or acute coronary syndrome (ACS). The primary endpoint was the composite of all-cause mortality, nonfatal ACS, stroke, and unplanned coronary revascularization. Results The 1-year cumulative incidence of the primary endpoint was 10.4%. Cumulative 1-year rates in patients with an LCBI equal to and above the median (43.0) versus those with LCBI values below the median were 16.7% versus 4.0% (adjusted hazard ratio: 4.04; 95% confidence interval: 1.33 to 12.29; p = 0.01). The relation between LCBI and the primary endpoint was similar in SAP and ACS patients (p value for heterogeneity = 0.14). Similar differences between high and low LCBI were observed in pre-specified secondary endpoints. Conclusion CAD patients with an LCBI equal to or above the median of 43.0, as assessed by NIRS in a nonculprit coronary artery, had a 4-fold risk of adverse cardiovascular events during 1-year follow-up. This observation warrants confirmation by larger studies with extended follow-up. (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound Study AtheroRemoIVUS; NCT01789411 )
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