Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as biomarkers of acute kidney injury after ST-segment elevation myocardial infarction treated by percutaneous coronary intervention.

BACKGROUND: Two biomarkers of early acute kidney injury-plasmatic neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C-are not used in routine clinical practice in patients with ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) because of a lack of supporting data. AIMS: To evaluate the predictive value of NGAL and cystatin C regarding the incidence of contrast-induced acute kidney injury (CI-AKI) and clinical outcomes after STEMI in patients treated by primary PCI. METHODS: Plasmatic NGAL and cystatin C were measured on admission, before any contrast exposure, in 701 unselected patients with STEMI. Associations between biomarker concentrations and incidence of CI-AKI (assessed at 48h), haemodialysis requirement at 1 year and all-cause mortality at 1 year were assessed by logistic regression analyses and receiver operating characteristic area under the curve analysis (c-statistic). Discrimination performance comparison was performed using the DeLong test. RESULTS: NGAL and cystatin C had mild discrimination regarding CI-AKI, with c-statistics of 0.60 (P=0.001) and 0.60 (P=0.002), respectively. Combining NGAL and cystatin C did not improve their discrimination (c-statistic 0.61; P=0.001). There was no significant difference in discrimination between NGAL, cystatin C and baseline creatinine (P=0.57). Regression analyses showed no independent association between NGAL and CI-AKI, haemodialysis or 1-year mortality. Similarly, cystatin C was not associated with these clinical outcomes. CONCLUSIONS: In this cohort of patients with STEMI treated by primary PCI, plasmatic NGAL and cystatin C did not provide additional value regarding CI-AKI prediction compared with known risk factors such as baseline creatinine.

Vasospastic angina: A literature review of current evidence.

Vasospastic angina (VSA) is a variant form of angina pectoris, in which angina occurs at rest, with transient electrocardiogram modifications and preserved exercise capacity. VSA can be involved in many clinical scenarios, such as stable angina, sudden cardiac death, acute coronary syndrome, arrhythmia or syncope. Coronary vasospasm is a heterogeneous phenomenon that can occur in patients with or without coronary atherosclerosis, can be focal or diffuse, and can affect epicardial or microvasculature coronary arteries. This disease remains underdiagnosed, and provocative tests are rarely performed. VSA diagnosis involves three considerations: classical clinical manifestations of VSA; documentation of myocardial ischaemia during spontaneous episodes; and demonstration of coronary artery spasm. The gold standard diagnostic approach uses invasive coronary angiography to directly image coronary spasm using acetylcholine, ergonovine or methylergonovine as the provocative stimulus. Lifestyle changes, avoidance of vasospastic agents and pharmacotherapy, such as calcium channel blockers, nitrates, statins, aspirin, alpha1-adrenergic receptor antagonists, rho-kinase inhibitors or nicorandil, could be proposed to patients with VSA. This review discusses the pathophysiology, clinical spectrum and management of VSA for clinicians, as well as diagnostic criteria and the provocative tests available for use by interventional cardiologists.

Simplifying the assessment of coronary artery stenosis by enhancing instantaneous wave free ratio.

BACKGROUND: Instantaneous wave free ratio (iFR) does not require adenosine, but has a relatively wide intermediate range where functional assessment remains inconclusive. In this pilot study, we sought to enhance iFR through with the use of intracoronary (IC) saline (iFRs) and contrast media (iFRc) and determine whether these techniques correlated well with fractional flow reserve (FFR). METHODS: Patients with coronary artery stenosis (CAS) associated with an iFR in the intermediate zone (≥0.86 and ≤0.93) were prospectively assessed with resting distal coronary pressure/aorta pressure (Pd/Pa), iFR, iFRs, iFRc and FFR. RESULTS: A total of 40 coronary lesions were studied (40 patients). Pearson correlation coefficients for FFR and iFR, FFR and iFRs, FFR and iFRc were respectively: 0.57 (P=0.0002), 0.80 (P<0.0001) and 0.77 (P<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of iFRs and iFR [0.90 (95% CI: 0.76-1) vs. 0.89 (95% CI: 0.79-0.99), P=0.89]. Youden's index established cut-off values of ≤0.90 for iFR (sensitivity =91%, specificity =74%) and ≤0.78 for iFRs (sensitivity =73%, specificity =100%). In contrast, the AUC of iFRc was superior to the AUC of iFR [0.99 (95% CI: 0.98-1), P=0.049]. iFRc showed excellent accuracy and established cut-off values of ≤0.81 in predicting an FFR value of ≤0.80 (sensitivity =100%, specificity =93%). CONCLUSIONS: When iFR is in the intermediate zone, functional assessment of CAS by iFR is enhanced with the use of contrast media but not saline. This pilot study could be hypothesis generating for further study to enhance iFR specificity and sensibility.

Weather and risk of ST-elevation myocardial infarction revisited: Impact on young women.

BACKGROUND: During the last decade, the incidence and mortality rates of ST-elevation myocardial infarction (STEMI) has been steadily increasing in young women but not in men. Environmental variables that contribute to cardiovascular events in women remain ill-defined. METHODS AND RESULTS: A total of 2199 consecutive patients presenting with acute ST-elevation myocardial infarction (STEMI, 25.8% women, mean age 62.6±12.4 years) were admitted at the Montreal Heart Institute between June 2010 and December 2014. Snow fall exceeding 2cm/day was identified as a positive predictor for STEMI admission rates in the overall population (RR 1.28, 95% CI 1.07-1.48, p = 0.005), with a significant effect being seen in men (RR 1.30, 95% CI 1.06-1.53, p = 0.01) but not in women (p = NS). An age-specific analysis revealed a significant increase in hospital admission rates for STEMI in younger women ≤55 years, (n = 104) during days with higher outside temperature (p = 0.004 vs men ≤55 years) and longer daylight hours (p = 0.0009 vs men ≤55 years). Accordingly, summer season, increased outside temperature and sunshine hours were identified as strong positive predictors for STEMI occurrence in women ≤55 years (RR 1.66, 95% CI 1.1-2.5, p = 0.012, RR 1.70, 95% CI 1.2-2.5, p = 0.007, and RR 1.67, 95% CI 1.2-2.5, p = 0.011, respectively), while an opposite trend was observed in men ≤55 years (RR for outside temperature 0.8, 95% CI 0.73-0.95, p = 0.01). CONCLUSION: The impact of environmental variables on STEMI is age- and sex-dependent. Higher temperature may play an important role in triggering such acute events in young women.

Contrast-induced acute kidney injury and mortality in ST elevation myocardial infarction treated with primary percutaneous coronary intervention.

OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially severe complication in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). There is no consensus on the best definition of CI-AKI to identify patients at risk of haemodialysis or death. The objective of this study was to assess the association of CI-AKI, using four definitions, on inhospital mortality, mortality or haemodialysis requirement over 1-year follow-up, in patients with STEMI treated with pPCI. METHODS: In this prospective, observational study, all patients with STEMI referred for pPCI were included. We identified independent variables associated with CI-AKI and mortality. RESULTS: We included 1114 consecutive patients with STEMI treated by pPCI. CI-AKI occurred in 18.3%, 12.2%, 15.6% and 10.5% of patients according to the CIN, Acute Kidney Injury Network (AKIN), Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) Modification of Diet in Renal Disease (MDRD) and RIFLE Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) definitions, respectively. The RIFLE (CKD-EPI) definition was the most discriminant definition to identify patients at higher risk of inhospital mortality (27.1% vs 4.0%; adjusted OR 2.7 (95% CI 1.4 to 5.1), p=0.003), 1-year mortality (27.4% vs 6.6%; adjusted OR 2.8 (95% CI 1.5 to 5.3), p=0.002) and haemodialysis requirement at 1-year follow-up (15.6% vs 2.7%; adjusted OR 6.7 (95% CI 3.3 to 13.6), p=0.001). Haemodynamic instability, cardiac arrest, preexisting renal failure, elderly age and a high contrast media volume were independently associated with 1-year mortality. Of interest, contrast-media volume was not correlated to increase of creatininaemia (r=0.06) or decrease in estimated glomerular filtration rate (r=0.05) after percutaneous coronary intervention in our population. CONCLUSIONS: CI-AKI is a frequent and serious complication of STEMI treated by pPCI. The RIFLE definition is the most accurate definition to identify patients with CI-AKI at high risk of mortality or haemodialysis.

The Multi-center Evaluation of the Accuracy of the Contrast MEdium INduced Pd/Pa RaTiO in Predicting FFR (MEMENTO-FFR) Study.

AIMS: Adenosine administration is needed for the achievement of maximal hyperaemia fractional flow reserve (FFR) assessment. The objective was to test the accuracy of Pd/Pa ratio registered during submaximal hyperaemia induced by non-ionic contrast medium (contrast FFR [cFFR]) in predicting FFR and comparing it to the performance of resting Pd/Pa in a collaborative registry of 926 patients enrolled in 10 hospitals from four European countries (Italy, Spain, France and Portugal). METHODS AND RESULTS: Resting Pd/Pa, cFFR and FFR were measured in 1,026 coronary stenoses functionally evaluated using commercially available pressure wires. cFFR was obtained after intracoronary injection of contrast medium, while FFR was measured after administration of adenosine. Resting Pd/Pa and cFFR were significantly higher than FFR (0.93±0.05 vs. 0.87±0.08 vs. 0.84±0.08, p<0.001). A strong correlation and a close agreement at Bland-Altman analysis between cFFR and FFR were observed (r=0.90, p<0.001 and 95% CI of disagreement: from -0.042 to 0.11). ROC curve analysis showed an excellent accuracy (89%) of the cFFR cut-off of ≤0.85 in predicting an FFR value ≤0.80 (AUC 0.95 [95% CI: 0.94-0.96]), significantly better than that observed using resting Pd/Pa (AUC: 0.90, 95% CI: 0.88-0.91; p<0.001). A cFFR/FFR hybrid approach showed a significantly lower number of lesions requiring adenosine than a resting Pd/Pa/FFR hybrid approach (22% vs. 44%, p<0.0001). CONCLUSIONS: cFFR is accurate in predicting the functional significance of coronary stenosis. This could allow limiting the use of adenosine to obtain FFR to a minority of stenoses with considerable savings of time and costs.

High platelet reactivity on aspirin in patients with acute ST elevation myocardial infarction.

BACKGROUND: Despite dual antiplatelet treatment, major ischemic events are common following ST elevation myocardial infarction (STEMI). We aimed to assess high platelet reactivity on aspirin (HPR-aspirin) and its association with P2Y12i (HPR-P2Y12i) during the acute phase of STEMI. METHODS: We included all consecutive patients admitted for STEMI treated by primary angioplasty in our center for 1year. All patients received a loading dose followed by a maintenance dose of aspirin (75mg/day) and prasugrel (ticagrelor or clopidogrel if contraindicated). Platelet reactivity was assessed 4±1days and 75±15days after admission using light transmission aggregometry with arachidonic acid (LTA-AA-HPR-aspirin) and VASP (HPR-P2Y12i) to define HPR as well as serum Thromboxane-B2 and LTA-ADP. Major cardiac and cerebrovascular events were recorded for 1year. RESULTS: We included 106 patients - mean age was 61y.o., 76% were male and 20% had diabetes. STEMI was anterior in 52% and LV ejection fraction at discharge was 51±9%. 50% of patients were treated with prasugrel and 34% with ticagrelor. At day 4 after STEMI, HPR-aspirin was found in 26% patients and HPR-P2Y12i in 7%. HPR- both aspirin and P2Y12i was found in 4%. Diabetes and age were predictors of HPR-aspirin. HPR-aspirin was persistent 75days later in 36% patients. At 1year, 7.9% patients had experienced major adverse cardiovascular and cerebrovascular events (MACCE). HPR-aspirin and HPR on both aspirin and P2Y12i were significantly associated with MACCE. CONCLUSION: HPR-aspirin is frequent just after STEMI and associated with MACCE especially when associated with HPR-P2Y12i.

Myocardial Fractional Flow Reserve Measurement Using Contrast Media as a First-Line Assessment of Coronary Lesions in Current Practice.

BACKGROUND: Fractional flow reserve (FFR) measurement requires adenosine injection. However, adenosine can induce conductive and rhythmic complications, or be contraindicated in some patients. Contrast-induced hyperemia could provide a simple first-line method (contrast-enhanced FFR; cFFR) to assess coronary lesions. In this study we evaluated the accuracy of cFFR to predict lesion significance. METHODS: This prospective study included 104 patients with 138 coronary lesions. Each stenosis was evaluated using resting distal coronary pressure to aortic pressure ratio (Pd/Pa) measurements using intracoronary iodixanol (cFFR) and adenosine (FFR) injection. An FFR value ≤ 0.8 defined a significant lesion. RESULTS: Dose-ranging analysis (n = 12 lesions) showed that 10 mL iodixanol was required to obtain the lowest cFFR value. Intermeasurement reproducibility of cFFR (n = 18 lesions) showed limited variability and small mean estimated bias (0.001 ± 0.014). Values of cFFR and FFR were highly correlated in a first series of n = 36 lesions (r = 0.9; P < 0.001). Receiver-operating characteristic curve analysis showed an excellent accuracy of cFFR cutoff value of ≤ 0.85 in predicting FFR value ≤ 0.80 (area under the curve, 0.94; 95% confidence interval, 0.90-0.98; sensitivity, 95%; specificity, 73%). This threshold was then tested prospectively in an independent cohort of n = 72 lesions. A cFFR value ≤ 0.85 correctly identified hemodynamically significant lesions with a sensitivity of 100%, specificity of 78%, positive predictive value of 78%, and negative predictive value of 100%. CONCLUSIONS: cFFR is reproducible and can be achieved with usual volumes of contrast. A cFFR threshold value of 0.85 provides excellent sensitivity and negative predictive value in coronary artery stenosis.

Contrast-Induced Nephropathy: From Pathophysiology to Preventive Strategies.

Contrast-induced nephropathy (CIN) is a frequent cause of acute kidney injury in hospitalized patients. CIN is most commonly defined as either an absolute (≥ 0.5 mg/dL; ≥ 44 µmol/L) or relative (≥ 25%) increase in serum creatinine levels at 48-72 hours after exposure to iodinated contrast media (CM). Its occurrence is associated with worsened clinical outcomes. Patients undergoing cardiac catheterization and percutaneous coronary intervention are particularly vulnerable to CIN. The complex pathophysiology of CIN involves different mechanisms, such as vasoconstriction, oxidative stress, medullary ischemia, and the direct toxic effects of CM. In CIN pathophysiology, both patient-related and procedure-related risk factors have been identified. The risk for CIN can be reliably estimated with clinical scores such as that proposed by Mehran. Because no definitive treatment exists for CIN, the most effective strategy remains prevention. Several interventions have been investigated--from hydration to various pharmacologic agents and mechanical devices. In this state-of-the-art article, we review the pathophysiology, diagnosis, risk stratification, and preventive strategies for CIN.

Novel anti-inflammatory therapies for the treatment of atherosclerosis.

The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1ß (IL-1ß), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels.

Pentoxifylline in heart failure: a meta-analysis of clinical trials.

BACKGROUND: Pentoxifylline possess antiinflammatory and rheological properties and has been tested in heart failure (HF). METHODS: A comprehensive search was performed from 1980 until July 2013 in PubMed, to identify randomized controlled trials evaluating pentoxifylline versus placebo in HF, to determine impact on mortality. Search strategy is as follows: "Pentoxifylline" AND "heart" AND "trial". Study selection of six randomized controlled trials evaluating mortality as outcome. Then, we conducted a meta-analysis of randomized controlled trials versus placebo in HF. Determination of Mantel-Haenszel fixed effect and random-effect pooled odds ratios for all-cause mortality and corresponding 95% confidence intervals. RESULTS: Data from a total of 221 patients with LVEF ≤40% from six randomized controlled trials were included in this analysis. Pentoxifylline 1200 mg per day was administered during 6 months, except in one study (administered during 1 month for severe acute HF). The use of pentoxifylline was not significantly associated with a reduction in mortality in HF in individual studies. The pooled data including 221 patients showed a nearly fourfold reduction in mortality (5.4% vs. 18.3%; OR 0.29; CI 0.12-0.74; P < 0.01) with homogenous results (I² 0%). CONCLUSION: A meta-analysis evaluating pentoxifylline versus placebo in HF suggested a significant nearly fourfold decrease in all-cause mortality in the pentoxifylline group.