Axel Cosmus Pyndt Diederichsen

Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells

The purpose of this study was to clarify whether HLA-DR expression of colorectal tumour cells or the CD4+/CD8+ ratio of the tumour infiltrating lymphocytes is significantly associated with the prognosis of colorectal cancer. Using flow cytometry, we studied the tumour cell expression of the HLA class II in 70 enzymatically dissociated colorectal cancers and the phenotype of tumour infiltrating lymphocytes (TILs) in 41 cases. There was no trend in 5-year survival between three levels (low, medium, high) of HLA-DR expression on the tumour cells. Patients with low CD4+/CD8+ ratios had a better clinical course, with significantly higher 5-year survival, p=0.046, independent of the Dukes stage and age. Our results have implications for tumour immunology; colorectal cancer cells might be a target for cytotoxic T-lymphocytes, however the tumour cells are not able to initiate an immune response. Stimulation of the immune system could possible be obtained using dendritic cells cultured in vitro and loaded with tumour antigens.

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Classification of Myocardial Infarction: Frequency and Features of Type 2 Myocardial Infarction

BACKGROUND The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture-related type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established. METHODS We prospectively studied unselected hospital patients who had cardiac troponin I measured on clinical indication. The diagnosis and classification of myocardial infarction were established, and the frequency and features of type 2 myocardial infarction were investigated by use of novel developed criteria. RESULTS From January 2010 to January 2011, a total of 7230 consecutive patients who had cardiac troponin I measured were evaluated, and 4499 patients qualified for inclusion. The diagnosis of myocardial infarction was established in 553 patients, of whom 386 (72%) had a type 1 myocardial infarction and 144 (26%) had a type 2 myocardial infarction. Patients in the group with type 2 myocardial infarction were older and more likely to be female, and had more comorbidities. The proportion of patients without significant coronary artery disease was higher in those with type 2 myocardial infarction (45%) than in those with type 1 myocardial infarction (12%) (P < .001). Tachyarrhythmias, anemia, and respiratory failure were the most prevalent mechanisms causing type 2 myocardial infarction. CONCLUSIONS In a cohort of patients with myocardial infarction who were admitted consecutively through 1 year, the category of type 2 myocardial infarction comprised one fourth when diagnosed by the use of newly developed criteria. Approximately half of patients with type 2 myocardial infarction had no significant coronary artery disease.

Mortality rate in type 2 myocardial infarction: Observations from an unselected hospital cohort

BACKGROUND The classification of myocardial infarction into 5 types was introduced in 2007. The prognostic impact of this universal definition, with particular focus on type 2 myocardial infarction, has not been studied prospectively in unselected hospital patients. METHODS During a 1-year period, all hospitalized patients having cardiac troponin I measured were considered. The diagnosis of a myocardial infarction was according to the universal definition, and specified criteria were used in the classification of type 2 myocardial infarction. Follow-up was at least 1 year, with mortality as the end point. RESULTS A total of 3762 consecutive patients were studied, of whom 488 (13%) had a myocardial infarction. In 119 patients a type 2 myocardial infarction was diagnosed. After a median of 2.1 years (interquartile range, 1.6-2.5 years), 150 patients had died, with a mortality rate of 49% (58/119) in those with type 2 myocardial infarction and 26% (92/360) in those with type 1 myocardial infarction (P < .0001). In a multivariable Cox regression analysis the following variables were independently associated with mortality: current or prior smoker, high age, prior myocardial infarction, type 2 myocardial infarction, hypercholesterolemia, high p-creatinine, and diabetes mellitus. The multivariable-adjusted hazard ratio for type 2 myocardial infarction was 2.0 (95% confidence interval, 1.3-3.0). With shock as the only exception, mortality was independent of the triggering conditions leading to type 2 myocardial infarction. CONCLUSIONS Mortality in patients with type 2 myocardial infarction is high, reaching approximately 50% after 2 years. Further descriptive and survival studies are needed to improve the scientific evidence on which treatment of type 2 myocardial infarction is based.

Discrepancy between coronary artery calcium score and HeartScore in middle-aged Danes: the DanRisk study

Background: Coronary artery calcification (CAC) is an independent and incremental risk marker. This marker has previously not been compared to the HeartScore risk model. Design: A random sample of 1825 citizens (men and women, 50 or 60 years of age) was invited for screening. Methods: Using the HeartScore model, the 10-year risk of fatal cardiovascular events based on gender, age, smoking, systolic blood pressure, and total cholesterol was estimated. A low risk was defined as <5%. The CAC score was calculated from a non-contrast enhanced cardiac-CT scan and given in Agatston U. Results: A total of 1257 (69%) of the invited subjects were interested in the screening. Due to previous cardiovascular disease or diabetes mellitus, 101 were excluded. Of the remaining 1156, 47% were men and 53% women; one half were 50 years old and the other half 60 years old. A low HeartScore was found in 901 of which 334 (37%) had CAC. A high HeartScore was recorded in 251 of which 80 (32%) did not have any CAC. High HeartScores and CAC were significantly more common in males than females. Conclusions: CAC is common in healthy middle-aged Danes with a low HeartScore, and, on the contrary, high-risk subjects very frequently do not have CAC. The therapeutic and prognostic implications of these observations remain to be clarified.

Effect of repeated intracoronary injection of bone marrow cells in patients with ischaemic heart failure the Danish stem cell study--congestive heart failure trial (DanCell-CHF)

It has been suggested that myocardial regeneration may be achieved by a single intracoronary bone marrow derived stem cell infusion in selected patients with ischaemic heart disease. The effect is uncertain in patients with chronic ischaemic heart failure and it is not known whether repeated infusions would have additional positive effects.

Clinical Characteristics and Outcomes of Patients with Myocardial Infarction, Myocardial Injury, and Nonelevated Troponins

BACKGROUND Cardiac troponins have emerged as the preferred biomarkers for detecting myocardial necrosis and diagnosing myocardial infarction. However, current cardiac troponin assays do not discriminate between ischemic and nonischemic causes of myocardial cell death. Thus, when an increased troponin value is encountered in the absence of obvious myocardial ischemia, a careful search for other clinical conditions is crucial. METHODS In 2010 to 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. An acute myocardial infarction was diagnosed in cases of a cardiac troponin I increase or decrease pattern with at least 1 value >30 ng/L (99th percentile) together with myocardial ischemia. Myocardial injury was defined as cardiac troponin I values >30 ng/L, but without signs or symptoms indicating overt cardiac ischemia. Patients with peak values ≤30 ng/L were classified as nonelevated cardiac troponin I. Follow-up was at least 3 years with all-cause mortality as the sole clinical end point. RESULTS A total of 3762 patients were included. Of these, 488 (13%) had acute myocardial infarction, 1089 (29%) had myocardial injury, and 2185 (58%) had nonelevated cardiac troponin I values. Patients with myocardial injury frequently presented with dyspnea, were older, and had more comorbidity than patients in the 2 other groups. During a median follow-up of 3.2 years, 1342 patients died. Mortality differed significantly between groups: 39% in those with myocardial infarction, 59% in those with myocardial injury, and 23% in those with nonelevated cardiac troponin I (log-rank test; P < .0001). No significant difference in mortality between patients with type 2 myocardial infarction and patients with myocardial injury was observed (63% and 59%, respectively). CONCLUSIONS Patients with myocardial injury are older and have more comorbidity than those with acute myocardial infarction. Both groups exhibit a poorer prognosis than patients with nonelevated cardiac troponin I values. Of note, a very high long-term mortality is observed in patients with type 2 myocardial infarction and patients with myocardial injury.

Clinical impact of 18F-FDG-PET/CT in the extra cardiac work-up of patients with infective endocarditis

OBJECTIVE The purpose of this study was to assess the clinical importance of 18F-FDG-PET/CT used in the extra cardiac work-up of patients with infective endocarditis (IE). BACKGROUND IE is a serious condition with a significant mortality. Besides the degree of valvular involvement, the prognosis relies crucially on the presence of systemic infectious embolism. METHODS Seventy-two patients (71% males and mean age 63 ± 17 years) with IE were evaluated with 18F-FDG-PET/CT in addition to standard work-up including patient history, physical examination, conventional imaging modalities, and weekly interdisciplinary conferences. When previous unknown lesions detected by 18F-FDG-PET/CT were confirmed by succeeding examinations, they were considered true positive new findings and were further assessed for their clinical importance. Number needed to investigate was calculated as the number of patients who needed to undergo 18F-FDG-PET/CT to find at least one clinical important true positive new finding, not identified by standard work-up prior to 18F-FDG-PET/CT. RESULTS 18F-FDG-PET/CT detected 114 lesions and 64 were true positive, of which 25 were new findings and detected in 17 patients. In 11 patients, the lesions were considered to have a clinical importance; osteomyelitis (n = 7), iliopsoas abscess (n = 1), gastrointestinal lesions (n = 2), and vascular prosthetic graft (n = 1). Number needed to investigate was 7 (11 of 72 patients). CONCLUSIONS 18F-FDG-PET/CT detected lesions of clinical importance in one of seven IE patients and may be a substantial imaging technique for tracing peripheral infectious embolism due to IE. Thus, 18F-FDG-PET/CT may help to guide adequate therapy and thereby improve the prognosis of patients with IE.

Localization of Microfibrillar-Associated Protein 4 (MFAP4) in Human Tissues: Clinical Evaluation of Serum MFAP4 and Its Association with Various Cardiovascular Conditions

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.

Diagnostic value of cardiac 64-slice computed tomography: Importance of coronary calcium

Objectives. Coronary computed tomography angiography (CTA) has proven clinically useful for non-invasive assessment of coronary pathology. However, coronary calcium can reduce its diagnostic value. The objective of this study was to define a calcium score above which CTA appears less reliable. Design. We prospectively investigated 109 patients referred for elective coronary angiography (CA). With a 64-slice CT-scanner, coronary calcium was determined and expressed in Agatston unit (AU). A significant coronary stenosis was defined as ≥50% luminal diameter reduction. Following blinded interpretation, diagnostic values of CTA at different levels of AU were calculated using quantitative CA as reference. Results. A strong association with stent and the severity of coronary calcium was observed. In patients without stents (n = 91) sensitivity, specificity and positive and negative predictive value for presence of significant stenosis were: 100%, 91%, 74%, and 100% in patients with a calcium score ≤400 AU versus 100%, 17%, 75%, and 100% in patients with a score >400 AU. Conclusions. The diagnostic accuracy of CTA in patients with no or little coronary calcium is excellent. However, in patients with an Agatston score >400 specificity declines and therefore, these patients should not go on to CTA, but be referred to CA instead.