Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

AIMS: An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed. METHODS AND RESULTS: International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 'C' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]). CONCLUSION: The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.

Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.

BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. RESULTS: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.

Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension: Hemodynamic Phenotyping and Histomorphometric Assessment.

BACKGROUND: Pulmonary endarterectomy (PEA) is the gold standard treatment for patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension (PH) after PEA remains a major determinant of poor prognosis. A concomitant small-vessel arteriopathy in addition to major pulmonary artery obstruction has been suggested to play an important role in the development of persistent PH and survival after PEA. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence and severity of small-vessel arteriopathy. Using the pulmonary artery occlusion technique, we sought to assess the presence and degree of small-vessel disease in patients with chronic thromboembolic pulmonary hypertension undergoing PEA to predict postoperative outcome before surgery. METHODS: Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure, we partitioned pulmonary vascular resistance in larger arterial (upstream resistance [Rup]) and small arterial plus venous components (downstream resistance) in 90 patients before PEA. For validation, lung wedge biopsies were taken from nonobstructed and obstructed lung territories during PEA in 49 cases. Biopsy sites were chosen according to the pulmonary angiogram still frames that were mounted in the operating room. All vessels per specimen were measured in each patient. Percent media (%MT; arteries) and intima thickness (%IT; arteries, veins, and indeterminate vessels) were calculated relative to external vessel diameter. RESULTS: Decreased Rup was an independent predictor of persistent PH (odds ratio per 10%, 0.40 [95% CI, 0.23-0.69]; P=0.001) and survival (hazard ratio per 10%, 0.03 [95% CI, 0.00-0.33]; p=0.004). Arterial %MT and %IT of nonobstructed lung territories and venous %IT of obstructed lung territories were significantly increased in patients with persistent PH and nonsurvivors. Rup correlated inversely with %MT (r=-0.72, P<0.001) and %IT (r=-0.62, P<0.001) of arteries from nonobstructed lung territories and with %IT (r=-0.44, P=0.024) of veins from obstructed lung territories. Receiver operating characteristic analysis disclosed that Rup <66% predicted persistent PH after PEA, whereas Rup <60% identified patients with poor prognosis after PEA. CONCLUSIONS: Pulmonary artery occlusion waveform analysis with estimation of Rup seems to be a valuable technique for assessing the degree of small-vessel disease and postoperative outcome after PEA in chronic thromboembolic pulmonary hypertension.

The importance of right ventricular evaluation in risk assessment and therapeutic strategies: Raising the bar in pulmonary arterial hypertension.

Pulmonary arterial hypertension is an obstructive pulmonary vasculopathy that leads to increased pulmonary vascular resistance, right ventricular overload and failure, and death. Patients' clinical status and prognosis depend mostly on the capability of the right ventricle to adapt to the increased afterload, maintain function, and preserve cardiac output. As a result, reducing the hemodynamic burden of the right ventricle should be a key target of current treatments, along with improvement in WHO functional class, 6-minute walk distance, and rates of hospitalization. However, physicians still find it challenging to integrate the evaluation of right ventricular function into widely accepted clinical parameters in order to stratify patients more accurately. This limitation is very relevant, since higher-risk patients are more likely to benefit from a more aggressive therapeutic approach. We analyzed the hemodynamic burden in pulmonary arterial hypertension, the importance of echocardiographic evaluation of the right ventricle, the impact of current treatments on hemodynamic parameters, and the identification of patients who are more likely to benefit from a more aggressive therapeutic approach.

Visual assessment of right ventricular function by echocardiography: how good are we?

The complex anatomy and physiology of the right ventricle (RV) is a major limitation of visual echocardiographic gradation of RV systolic function (RVF). The aim of this study was to compare visual assessment ("eyeballing") of RVF with gold standard magnetic resonance imaging (MRI)-derived right ventricular ejection fraction (RVEF). Medical professionals from a range of clinical settings and with varying degrees of echocardiography experience were recruited via an online ultrasound teaching platform. In an anonymized web-based test, participants graded RVF in 10 patients with varying degrees of RVF via "eyeballing" of an RV-focused four-chamber view. Two skills were evaluated: (1) ability to differentiate between normal and reduced RVF; and (2) ability to determine the correct degree of RV systolic dysfunction. A total of 868 participants from 99 countries were included. For detection of reduced RVF (MRI-RVEF < 50%), sensitivity was 97.1%, 96,8%, 96.5%, and 95.8% and specificity was 55.7%, 52.8%, 54.6%, and 42.5% for the expert, advanced, intermediate, and beginner groups, respectively. For determination of the correct degree of RV dysfunction, even experienced examiners assigned a diagnosis that was discordant with MRI in > 40% of cases. In the present cohort, "eyeballing" was associated with excellent sensitivity but poor specificity in terms of differentiation between normal and abnormal RVF. Even among experts, classification of the degree of RV dysfunction was imprecise. In accordance with current guidelines, the present data suggest that "eyeballing" should be combined with evaluation of other echocardiographic parameters of RVF.

Echocardiographic assessment of right ventricular function: current clinical practice.

Echocardiographic evaluation of right ventricular (RV) function is a challenge due to the complex anatomy of the RV. Several transthoracic echocardiographic methods have been suggested for the quantification of RV function. However, many of the parameters are time consuming and need dedicated hardware and software. We suspected that the majority of the established markers are not used on a wide basis. In a multinational online survey, we evaluated the use of current clinical standards for the quantification of RV function in clinical practice. Through the network of an Ultrasound Online Teaching Platform, echocardiographers were invited to participate in an open online survey. The participants were asked about the parameters (eyeballing, TAPSE, S', fractional area change, RIMP, 3D-EF, dp/dt, longitudinal strain) they used in clinical practice. A total of 1150 participants from 109 countries completed the survey. Only eyeballing (72%), TAPSE (69%), and S' (31%) were commonly used in clinical routine. These methods were applied significantly less common in low-income economies when compared to high-income economies. Twenty-three percent of all participants stated to rely on eyeballing only, when evaluating RV function in clinical routine. New technologies, such as global longitudinal strain (3%) and 3D echocardiography (1%) were rarely applied independent of region and economic strength. Eyeballing and TAPSE are the most widely used methods in echocardiography for the assessment of RV function. Although advanced parameters such as longitudinal strain and 3D echocardiography were shown to be highly accurate, they are rarely used in clinical routine.

Normal values for Doppler echocardiographic assessment of prosthetic valve function after transcatheter aortic valve replacement: a systematic review and meta-analysis.

Transcatheter aortic valve replacement has emerged as valuable treatment modality for patients with severe aortic stenosis and an unacceptable risk/benefit ratio for open heart surgery, but particularities specific to TAVR and a rapidly growing number of available TAVR prosthesis make post-procedural assessment of valve function challenging. Aim of the present analysis was to collect and pool all available data currently in the literature regarding normal doppler values for transcatheter prosthetic heart valves and to provide a comprehensive overview. A PRISMA checklist-guided systematic review and meta-analysis of prospective observational studies or national and device specific registries or randomized clinical trials was conducted. Studies were identified by searching PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials and LILACs from January 2000 to March 2017. Out of 240 abstracts, 155 studies reporting echocardiographic parameter for twelve different valves prosthesis in a total of 27,159 patients were in included in this meta-analysis. The means and standard deviations of peak velocity, peak gradient, mean gradient and effective orifice were extracted and pooled from the included studies. The pooled means and standard deviations for all available TAVR prosthesis were classified according to implanted valve size and time since implantation. The present study firstly describes a pooled analysis of normal values for all available TAVR prosthesis in order to empower treating physicians with a reliable tool to perform follow-up echocardiographic assessment in TAVR patients and to safely identify patients with prostheses dysfunction.

Long-term outcome and risk assessment in premature acute myocardial infarction: A 10-year follow-up study.

BACKGROUND: Premature acute myocardial infarction (AMI) is a rare disease carrying significant morbidity and mortality. Existing data on outcome in these patients is based on retrospective analysis of angiographic reports or refer to time periods with incomparable treatment regimes, making them unusable for risk assessment in times of widespread use of reperfusion therapy. Aim of this study was to assess the outcome of premature AMI in a prospectively recruited study population enrolled in the times of modern reperfusion therapy. METHODS: We included 102 consecutive AMI survivors (≤40years) in this prospective multicentre study. Outcome was assessed via retrieval query of the Austrian Death Registry and the centralized patient management system of Vienna. RESULTS: During a median follow up time of 10.3years (IQR:8.9-11.1), 23% of all patients experienced MACE, of those 6% died, 17% experienced re-AMI and 5% patients an ischemic stroke. Furthermore, forty patients underwent cardiac re-catheterization and twenty-five needed recurrent revascularization. MACE were associated among the classic cardiovascular risk factors with elevated levels of HbA1c (adj. HR 1.32; 95%CI 1.06-1.64; P=0.012), total cholesterol (adj. HR 2.16; 95%CI 1.27-3.48; P=0.004), and c-reactive protein (adj. HR 1.67; 95%CI 1.29-2.17; P=0-003) for an increase of 1-standard deviation. CONCLUSION: Although myocardial re-infarction was the driving force of morbidity in premature myocardial infarction, we observed an excellent long-term survival opposed to previous reports. We found that persistence risk factors rather than the clinical risk profile at baseline influences the outcome in these patients, emphasizing the importance of secondary prevention in young patients after AMI.

Impaired High-Density Lipoprotein Anti-Oxidant Function Predicts Poor Outcome in Critically Ill Patients.

INTRODUCTION: Oxidative stress affects clinical outcome in critically ill patients. Although high-density lipoprotein (HDL) particles generally possess anti-oxidant capacities, deleterious properties of HDL have been described in acutely ill patients. The impact of anti-oxidant HDL capacities on clinical outcome in critically ill patients is unknown. We therefore analyzed the predictive value of anti-oxidant HDL function on mortality in an unselected cohort of critically ill patients. METHOD: We prospectively enrolled 270 consecutive patients admitted to a university-affiliated intensive care unit (ICU) and determined anti-oxidant HDL function using the HDL oxidant index (HOI). Based on their HOI, the study population was stratified into patients with impaired anti-oxidant HDL function and the residual study population. RESULTS: During a median follow-up time of 9.8 years (IQR: 9.2 to 10.0), 69% of patients died. Cox regression analysis revealed a significant and independent association between impaired anti-oxidant HDL function and short-term mortality with an adjusted HR of 1.65 (95% CI 1.22-2.24; p = 0.001) as well as 10-year mortality with an adj. HR of 1.19 (95% CI 1.02-1.40; p = 0.032) when compared to the residual study population. Anti-oxidant HDL function correlated with the amount of oxidative stress as determined by Cu/Zn superoxide dismutase (r = 0.38; p<0.001). CONCLUSION: Impaired anti-oxidant HDL function represents a strong and independent predictor of 30-day mortality as well as long-term mortality in critically ill patients.

Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents in patients with multivessel coronary artery disease compared to coronary artery bypass surgery five-years after intervention.

OBJECTIVES: Cost-effectiveness of percutaneous coronary intervention (PCI) using drug-eluting stents (DES), and coronary artery bypass surgery (CABG) was analyzed in patients with multivessel coronary artery disease over a 5-year follow-up. BACKGROUND: DES implantation reducing revascularization rate and associated costs might be attractive for health economics as compared to CABG. METHODS: Consecutive patients with multivessel DES-PCI (n = 114, 3.3 ± 1.2 DES/patient) or CABG (n = 85, 2.7 ± 0.9 grafts/patient) were included prospectively. Primary endpoint was cost-benefit of multivessel DES-PCI over CABG, and the incremental cost-effectiveness ratio (ICER) was calculated. Secondary endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE), including acute myocardial infarction (AMI), all-cause death, revascularization, and stroke. RESULTS: Despite multiple uses for DES, in-hospital costs were significantly less for PCI than CABG, with 4551 €/patient difference between the groups. At 5-years, the overall costs remained higher for CABG patients (mean difference 5400 € between groups). Cost-effectiveness planes including all patients or subgroups of elderly patients, diabetic patients, or Syntax score >32 indicated that CABG is a more effective, more costly treatment mode for multivessel disease. At the 5-year follow-up, a higher incidence of MACCE (37.7% vs. 25.8%; log rank P = 0.048) and a trend towards more AMI/death/stroke (25.4% vs. 21.2%, log rank P = 0.359) was observed in PCI as compared to CABG. ICER indicated 45615 € or 126683 € to prevent one MACCE or AMI/death/stroke if CABG is performed. CONCLUSIONS: Cost-effectiveness analysis of DES-PCI vs. CABG demonstrated that CABG is the most effective, but most costly, treatment for preventing MACCE in patients with multivessel disease.

Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.

The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term "non-PAH PH" summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.

Quantitative assessment of human serum high-abundance protein depletion.

The aim of this study is to quantify the effectivity of the depletion of human high-abundance serum and plasma proteins for improved protein identification and disease marker candidate discovery and to assess the risk of concomitant removal of relevant marker proteins. 2-DE and bottom-up shotgun MS combining 2-D capillary chromatography with MS/MS were applied in parallel for the analysis of fractions resulting from the depletion procedure. For many proteins the factors of enrichment by the depletion were obvious allowing their enhanced detection and identification upon high-abundance protein depletion. Nano-liquid chromatography linked MS allowed the efficient identification of several low-abundant proteins that were not identified on the 2-DE gels. Resolving the fractions that were eluted from the matrix upon depletion indicated unspecific binding of disease relevant proteins in plasma samples from acute myocardial infarction patients. The unspecific binding to the depletion matrix of inflammatory markers spiked into the serum was found to depend on the type of capturing agent used. Polyclonal avian antibodies (IgY) displayed the least unspecific binding due to the high immunogenicity of mammalian proteins in avian hosts.