Extracellular Vesicle cystatin c is associated with unstable angina in troponin negative patients with acute chest pain.

BACKGROUND: Despite the use of high-sensitive cardiac troponin there remains a group of high-sensitive cardiac troponin negative patients with unstable angina with a non-neglectable risk for future adverse cardiovascular events, emphasising the need for additional risk stratification. Plasma extracellular vesicles are small bilayer membrane vesicles known for their potential role as biomarker source. Their role in unstable angina remains unexplored. We investigate if extracellular vesicle proteins are associated with unstable angina in patients with chest pain and low high-sensitive cardiac troponin. METHODS: The MINERVA study included patients presenting with acute chest pain but no acute coronary syndrome. We performed an exploratory retrospective case-control analysis among 269 patients. Cases were defined as patients with low high-sensitive cardiac troponin and proven ischemia. Patients without ischemia were selected as controls. Blood samples were fractionated to analyse the EV proteins in three plasma-subfractions: TEX, HDL and LDL. Protein levels were quantified using electrochemiluminescence immunoassay. RESULTS: Lower levels of (adjusted) EV cystatin c in the TEX subfraction were associated with having unstable angina (OR 0.93 95% CI 0.88-0.99). CONCLUSION: In patients with acute chest pain but low high-sensitive cardiac troponin, lower levels of plasma extracellular vesicle cystatin c are associated with having unstable angina. This finding is hypothesis generating only considering the small sample size and needs to be confirmed in larger cohort studies, but still identifies extracellular vesicle proteins as source for additional risk stratification.

Plasma extracellular vesicle proteins are associated with stress-induced myocardial ischemia in women presenting with chest pain.

Diagnosing stable ischemic heart disease (IHD) is challenging, especially in females. Currently, no blood test is available. Plasma extracellular vesicles (EV) are emerging as potential biomarker source. We therefore aimed to identify stress induced ischemia due to stable IHD with plasma extracellular vesicle protein levels in chest pain patients. We analyzed 450 patients suspected for stable IHD who were referred for 82Rb PET/CT in the outpatient clinic. Blood samples were collected before PET/CT and plasma EVs were isolated in 3 plasma subfractions named: TEX, HDL, LDL. In total 6 proteins were quantified in each of these subfractions using immuno-bead assays. CD14 and CystatinC protein levels were independent significant predictors of stress-induced ischemia in the LDL and the HDL subfraction and SerpinC1 and SerpinG1 protein levels in the HDL fraction. Subgroup-analysis on sex revealed that these associations were completely attributed to the associations in women. None of the significant EV proteins remained significant in men. Plasma EV proteins levels are associated with the presence of stable IHD in females presenting with chest pain. This finding, if confirmed in larger cohort studies could be a crucial step in improving diagnostic assessment of women with suspected IHD.

The role of the tubular biomarkers NAG, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in patients with chest pain before contrast media exposition.

Aim: We evaluated the role of the tubular biomarkers N-acetyl-ß-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in patients with chest pain. Methods: Serum and urine samples were collected of 223 patients and 47 healthy controls. None of them was exposed to contrast media. Results: NAG showed among others significant correlation with N-terminal pro brain natriuretic peptide (NTproBNP), troponin I and creatinine. KIM-1 and NGAL showed weaker correlations. NAG was significantly elevated in all subgroups of acute coronary syndrome (ACS) compared with chest wall syndrome and controls. NAG was an independent predictor for the diagnosis of myocardial infarction. Conclusion: NAG may demonstrate the presence of acute tubular injury due to cardiac impairment already in the emergency department. NAG should be evaluated as marker of acute cardiorenal syndrome in patients with chest pain.

Effect of a HEART Care Pathway on Chest Pain Management Within an Integrated Health System.

STUDY OBJECTIVE: We describe the association of implementing a History, ECG, Age, Risk Factors, and Troponin (HEART) care pathway on use of hospital care and noninvasive stress testing, as well as 30-day patient outcomes in community emergency departments (EDs). METHODS: We performed a prospective interrupted-time-series study of adult encounters for patients evaluated for suspected acute coronary syndrome. The primary outcome was hospitalization or observation, noninvasive stress testing, or both within 30 days. The secondary outcome was 30-day all-cause mortality or acute myocardial infarction. A generalized estimating equation segmented logistic regression model was used to compare the odds of the primary outcome before and after HEART implementation. All models were adjusted for patient and facility characteristics and fit with physicians as a clustering variable. RESULTS: A total of 65,393 ED encounters (before, 30,522; after, 34,871) were included in the study. Overall, 33.5% (before, 35.5%; after, 31.8%) of ED chest pain encounters resulted in hospitalization or observation, noninvasive stress testing, or both. Primary adjusted results found a significant decrease in the primary outcome postimplementation (odds ratio 0.984; 95% confidence interval [CI] 0.974 to 0.995). This resulted in an absolute adjusted month-to-month decrease of 4.39% (95% CI 3.72% to 5.07%) after 12 months' follow-up, with a continued trend downward. There was no difference in 30-day mortality or myocardial infarction (0.6% [before] versus 0.6% [after]; odds ratio 1.02; 95% CI 0.97 to 1.08). CONCLUSION: Implementation of a HEART pathway in the ED evaluation of patients with chest pain resulted in less inpatient care and noninvasive cardiac testing and was safe. Using HEART to risk stratify chest pain patients can improve the efficiency and quality of care.

Copeptin as a Prognostic Marker in Acute Chest Pain and Suspected Acute Coronary Syndrome.

BACKGROUND: In patients admitted with chest pain and suspected acute coronary syndrome (ACS), it is crucial to early identify those who are at higher risk of adverse events. The study aim was to assess the predictive value of copeptin in patients admitted to the emergency department with chest pain and nonconclusive ECG. METHODS: Consecutive patients suspected for an ACS were enrolled prospectively. Copeptin and high-sensitive troponin T (hs-TnT) were measured at admission. Patients were followed up at six and 12 months for the occurrence of death and major adverse cardiac and cerebrovascular events (MACCE). RESULTS: Among 154 patients, 11 patients died and 26 experienced MACCE. Mortality was higher in copeptin-positive than copeptin-negative patients with no difference in the rate of MACCE. Copeptin reached the AUC 0.86 (0.75-0.97) for prognosis of mortality at six and 0.77 (0.65-0.88) at 12 months. It was higher than for hs-TnT and their combination at both time points. Copeptin was a strong predictor of mortality in the Cox analysis (HR14.1 at six and HR4.3 at 12 months). CONCLUSIONS: Copeptin appears to be an independent predictor of long-term mortality in a selected population of patients suspected for an ACS. The study registration number is ISRCTN14112941.

Chest pain in patients with COPD: the fascia's subtle silence.

COPD is a progressive condition that leads to a pathological degeneration of the respiratory system. It represents one of the most important causes of mortality and morbidity in the world, and it is characterized by the presence of many associated comorbidities. Recent studies emphasize the thoracic area as one of the areas of the body concerned by the presence of pain with percentages between 22% and 54% in patients with COPD. This article analyzes the possible causes of mediastinal pain, including those less frequently taken into consideration, which concern the role of the fascial system of the mediastinum. The latter can be a source of pain especially when a chronic pathology is altering the structure of the connective tissue. We conclude that to consider the fascia in daily clinical activity may improve the therapeutic approach toward the patient.

Usefulness of delta troponin for diagnosis and prognosis assessment of non-ST-segment elevation acute chest pain.

BACKGROUND: The additional diagnostic and prognostic information provided by delta high-sensitivity troponin T (hs-cTnT) in patients with acute chest pain and hs-cTnT elevation remains unclear. METHODS: The study group consisted of 601 patients presenting at the emergency department with non-ST-segment elevation acute chest pain and hs-cTnT elevation after two determinations (admission and within the first six hours). Maximum hs-cTnT and delta hs-cTnT (absolute or percentage change between the two measurements) were considered. Cutoff values were optimized using the quartile distribution for the endpoints. The endpoints were diagnostic (significant stenosis in the coronary angiogram) and prognostic (death or recurrent myocardial infarction at one year). RESULTS: Regarding the diagnostic endpoint, 114 patients showed a normal angiogram. Both maximum hs-cTnT ⩾80 ng/ml (OR 2.5, 95% CI 1.3-4.8, P=0.005) and delta hs-cTnT ⩾20 ng/l (OR 2.1, 95% CI 1.1-4.0, P=0.02) median value cutoffs were related to significant coronary stenosis. Furthermore, the combination of hs-cTn <80 ng/l and delta hs-cTn <20 ng/l showed the lowest probability of significant coronary stenosis (OR 0.3, 95% CI 0.1-0.4, P=0.001). During follow-up, 86 patients experienced the prognostic endpoint. After full adjustment for clinical data, maximum hs-cTnT ⩾30 ng/l, first quartile cutoff, was related to the outcome (HR 1.8, 95% CI 1.0-3.4, P=0.05), while delta hs-cTnT, either absolute or percentage change, lacked prognostic value. CONCLUSIONS: Maximum hs-cTnT captures all the prognostic information provided by hs-cTnT in non-ST-segment elevation acute chest pain. Low maximum and low delta hs-cTnT are associated with a normal coronary angiogram, which could make the final diagnosis challenging in some cases.

A 4-week pilot study with the cannabinoid receptor agonist dronabinol and its effect on metabolic parameters in a randomized trial.

PURPOSE: Dronabinol (synthetic Δ(9)- tetrahydrocannabinol) is used in patients with nausea and vomiting from chemotherapy and in AIDS patients for appetite stimulation. Recently, dronabinol was used to successfully treat visceral hypersensitivity causing noncardiac chest pain. With widening uses of this medication, we aim to explore its effects on metabolic parameters in long-term dosing and hypothesize that it will not affect major metabolic parameters. METHODS: A double-blind, placebo-controlled, 28-day trial was performed with patients 18 to 75 years old without cardiac disease. Patients had at least 2 weekly episodes of chest pain for the last 3 months and evidence of esophageal hypersensitivity after balloon distention testing. Prior use of pain medication, psychiatric diagnosis, or significant medical comorbidities precluded inclusion in the study. Patients were randomized to receive 5 mg dronabinol or placebo twice daily with metabolic parameters examined before and after the use of medication. FINDINGS: Thirteen patients completed the study (7 with dronabinol [6 women and 1 man] and 6 with placebo [5 women and 1 man]). None of the measured values, including body mass index, HDL, triglycerides, calculated LDL, high-sensitivity C-reactive protein, glucose, insulin, leptin, aspartate aminotransferase, alanine aminotransferase, LDH, or non-HDL, differed significantly in either group before or after treatment. In general, treatment with dronabinol coincided with favorable trends in some parameters, although these trends were not statistically significant. IMPLICATIONS: Dronabinol administration does not significantly affect basic metabolic components after a period of 28 days. The implications of these findings are important because dronabinol may be able to be used in patients with metabolic disorders. The favorable trends observed here warrant further exploration into its long-term effects. ClinicalTrials.gov identifier: NCT01598207.

Detecting cardiac events - state-of-the-art.

Cardiac biomarker measurement currently addresses two key questions in patient management: the differential diagnosis of chest pain and the differential diagnosis of the patient with breathlessness. There are currently three major themes in the strategies for the differential diagnosis of chest pain. The first is to undertake troponin measurement in patients selected to be at lower risk, hence to have a low prior probability of disease. The second is the introduction of high-sensitivity cardiac troponin (hs cTn) assays into routine clinical use with measurement at 0 and 3 h from admission. Two other approaches that utilize the diagnostic characteristics of these assays have also been suggested. The first is to use the limit of detection or limit of blank of the assay as the diagnostic discriminant. The second approach is to use the low imprecision of the assay within the reference interval and combine a discriminant value with an absolute rate of change (delta value). The third is the use of additional biomarkers to allow early discharge from the emergency department. The concept is to measure high-sensitivity cardiac troponin plus the extra marker on admission. The role of measurement of B-type natriuretic peptide or its N-terminal prohormone, N-terminal pro-B-type natriuretic peptide, has been accepted and incorporated into guidelines for chronic heart failure for some time. More recently, guidelines for acute heart failure can also recommend a single measurement of B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide in people presenting with new suspected acute heart failure.

The HDL anti-inflammatory function is impaired in myocardial infarction and may predict new cardiac events independent of HDL cholesterol.

BACKGROUND: Intrinsic functional properties of high density lipoproteins (HDL) are considered to be physiologically important for atheroprotection. We compared the HDL anti-inflammatory capacity between patients with acute myocardial infarction (MI) and patients with non-cardiac chest pain, and prospectively determined the association of new major adverse cardiovascular events (MACE) with this metric of HDL function. METHODS: A prospective study was carried out in 93 patients referred for acute chest pain (65 patients with acute MI). The HDL anti-inflammatory capacity was determined as the ability to suppress tumor necrosis factor-α-induced vascular cell adhesion molecule-1 mRNA expression in endothelial cells in vitro. RESULTS: Acute MI at admission was associated with impaired HDL anti-inflammatory capacity (p=0.001), even after adjustment for HDL cholesterol and apolipoprotein A-I (p=0.003). Twenty nine MACE were ascertained during a median follow-up of 1210 (910-1679) days. New MACE was associated with impaired HDL anti-inflammatory capacity (hazard ratio: 1.80 (1.17-2.77) per SD change, p=0.007) in age, sex, HDL cholesterol and apolipoprotein-AI adjusted analysis. CONCLUSIONS: The ability of HDL to attenuate endothelial inflammation is impaired in acute MI, and this metric of HDL function may serve as a predictor of new MACE, even independent of HDL cholesterol and apolipoprotein A-I.

Elevated PAPP-A sets alarm bells ringing in patients with cardiac chest pain.

Novel biochemical markers may improve the estimation of overall risk in subjects at a high risk of adverse cardiac events. Measurement of some of these markers, including pregnancy-associated plasma protein A (PAPP-A), brings significant prognostic information independent of traditional risk factors. PAPP-A has been recently identified as a marker of plaque destabilization with growing interest in cardiovascular research. Our group has recently demonstrated that higher levels of serum PAPP-A were independently associated with an increased short-term risk of cardiovascular events in a large sample of 2568 consecutive patients presenting with cardiac chest pain. PAPP-A levels above 34.6 mIU/l in cardiac chest-pain patients sets alarm bells ringing as a warning for higher risk of short-term cardiovascular adverse events, including stent thrombosis, myocardial infarction, ischemic stroke or cardiovascular-related death within 90 days, the combined primary end point of this study. Cardiac chest pain patients with PAPP-A levels above 34.6 mIU/l may suffer from adverse cardiovascular events five times more frequently within 90 days than those with lower PAPP-A levels (hazard ratio: 5.28; 95% CI: 3.81-7.31). However, current data do not support the diagnostic role of PAPP-A for acute coronary syndrome in comparison to the gold standard biomarker troponin. Additionally, PAPP-A is known to interact with heparin, which may diminish its potential utility in every day clinical life. Future multicenter and large-volume studies are warranted to validate the use of PAPP-A in routine clinical practice.

Intravenous adenosine activates diffuse nociceptive inhibitory controls in humans.

Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 µg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.

Should computed tomography coronary angiography be aborted when the calcium score exceeds a certain threshold in patients with chest pain?

BACKGROUND: There is ongoing debate about whether a computed tomography coronary angiography (CTCA) should be aborted when the calcium score (CS) exceeds a certain threshold in patients with chest pain. The aim of this study was to discover whether specific "cutpoints" regarding coronary artery CS could be determined to predict severe coronary stenoses assessed by CTCA, thus identifying patients amenable to an invasive diagnostic approach. METHODS: 294 consecutive patients with chest pain of uncertain cause who were referred for non-invasive diagnostic CTCA were included. Subjects underwent Agatston CS and CTCA using current 64-slice technology. RESULTS: Severe coronary stenoses were noted in 75 of 294 (25.1%) patients on CTCA. A very high prevalence of severe coronary stenoses was found in patients with CS ≥ 400 (87.0%). The CS had area under the ROC curve 0.86 to predict severe coronary stenoses on CTCA. The best discriminant cut-off point was CS ≥ 400 (sensitivity of 55.3%, specificity of 93.5, positive predictive value of 85.8%, negative predictive value of 84.0%). Multivariable logistic regression analysis controlling for traditional risk factors showed CS ≥ 400 remained an independent predictor of severe coronary stenoses on CTCA (OR 14.553, 95% confidence interval 4.043 to 52.384, p<0.001). CONCLUSIONS: CS can be used as a "gatekeeper" to CTCA in patients with chest pain. Due to the very high prevalence of severe coronary stenoses in patients with CS ≥ 400, further evaluation with CTCA is not warranted as these patients should be referred to invasive coronary angiography, avoiding the repeated exposure to ionizing radiation and iodinated contrast.

Functional chest pain responds to biofeedback treatment but functional heartburn does not: what is the difference?

BACKGROUND: Patients with functional esophageal disorders represent a challenging treatment group. The purpose of this study was to evaluate the role of biofeedback in the treatment of patients with functional esophageal disorders. METHODS: In this prospective study, patients with typical/atypical symptoms of gastroesophageal reflux disease underwent upper endoscopy and 24-h pH monitoring. All patients filled out gastroesophageal Reflux Disease Symptom, Hospital Anxiety and Depression, and Symptom Stress Rating questionnaires. Patients with functional heartburn and those with functional chest pain were offered biofeedback treatment. A global assessment questionnaire was filled out at the end of treatment and then 2.8 (range 1-4) years later. RESULTS: From January 2006 to December 2009, 22 patients with functional esophageal diseases were included in the study. Thirteen had functional heartburn and nine had functional chest pain. Six patients from each group received biofeedback treatment. After treatment for 1-4 years, patients with functional chest pain showed significant improvements in symptoms compared with those who were not treated. Patients with functional heartburn showed no improvement. Patients with functional chest pain had a longer time of esophageal acid exposure than those with functional heartburn. CONCLUSION: Patients with functional chest pain have different central and intraesophageal factors associated with symptom generation in comparison with patients with functional heartburn. Biofeedback is a useful tool in the treatment of patients with functional chest pain, but not for those with functional heartburn.

Women, cardiac syndrome X, and microvascular heart disease.

New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists.

Degradation of troponin I in serum or plasma: mechanisms, and analytical and clinical implications.

A prolonged myocardial ischemia, which results from a total deprivation of blood supply to an area of cardiac muscle for an appreciable period of time, is the leading mechanism responsible for acute myocardial infarction (AMI). The irreversible injury of myocardiocytes and the subsequent release of a variety of intracellular components into blood is the cornerstone of the diagnosis of AMI. Cardiac troponins are advocated as the biochemical gold standards among the various biomarkers of plaque instability, plaque rupture, ischemia, reversible cellular injury, and early and late necrosis (i.e., irreversible injury). The assessment of cardiac troponins in the diagnostic approach of patients with chest pain presents, however, some specific challenges due to the complex mechanisms of release from the injured myocardium, as well as to the enzymatic degradation by cardiac and extracardiac proteases (i.e., calpains, caspases, cathepsin L, and gelatinase A) that might alter the immunoreactivity (and thus laboratory detection) of the molecules. These two aspects will be discussed in this article, with specific focus on cardiac troponin I, as a variety of immunoassays based on antibodies which recognize different epitopes on the molecule is available for the measurement of this important cardiac biomarker.