Individualized Angiotensin-Converting Enzyme (ACE)-Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model.

BACKGROUND: Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model. METHODS AND RESULTS: Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective. CONCLUSIONS: Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit.

[LDL cholesterol lowering therapy: no target value but personalised treatment]. / LDL-cholesterolverlagende therapie: geen streefwaarde maar behandeling op maat.

We previously recommended that LDL cholesterol lowering therapy be based on the risk for (recurrent) coronary events, rather than on arbitrary targets for serum LDL cholesterol concentration. We also recommended refraining from therapy with ezetimibe until its efficacy in preventing cardiovascular events had been documented. At the American Heart Association scientific sessions 2014 the results of the IMPROVE-IT study were reported. In this large, randomised trial, a modest benefit of the combination of simvastatin plus ezetimibe over simvastatin alone was reported after 7 years of treatment. The efficacy of such combination therapy was similar to the efficacy of high-dose statin therapy, while the combination therapy is much more expensive. Comparing the efficacy and costs of different preventive therapies, we recommend first prescribing aspirin and a moderate dose of statin, secondly an ACE inhibitor. A high-dose statin should be considered in high-risk patients. The combination of simvastatin and ezetimibe should be prescribed only in high-risk patients (e.g. diabetics after myocardial infarction) who do not tolerate high-dose statins.

Development and validation of a cardiovascular risk assessment model in patients with established coronary artery disease.

Appropriate risk stratification of patients with established, stable coronary artery disease could contribute to the prevention of recurrent cardiovascular events. The purpose of the present study was to develop and validate risk prediction models for various cardiovascular end points in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) database, consisting of 12,218 patients with established coronary artery disease, with a median follow-up of 4.1 years. Cox proportional hazards models were used for model development. The end points examined were cardiovascular mortality, noncardiovascular mortality, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, resuscitated cardiac arrest, and combinations of these end points. The performance measures included Nagelkerke's R², time-dependent area under the receiver operating characteristic curves, and calibration plots. Backward selection resulted in a prediction model for cardiovascular mortality (464 events) containing age, current smoking, diabetes mellitus, total cholesterol, body mass index, previous myocardial infarction, history of congestive heart failure, peripheral vessel disease, previous revascularization, and previous stroke. The model performance was adequate for this end point, with a Nagelkerke R² of 12%, and an area under the receiver operating characteristic curve of 0.73. However, the performance of models constructed for nonfatal and combined end points was considerably worse, with an area under the receiver operating characteristic curve of about 0.6. In conclusion, in patients with established coronary artery disease, the risk of cardiovascular mortality during longer term follow-up can be adequately predicted using the clinical characteristics available at baseline. However, the prediction of nonfatal outcomes, both separately and combined with fatal outcomes, poses major challenges for clinicians and model developers.

Intra-operative assessment of human pulmonary alveoli in vivo using Sidestream Dark Field imaging: a feasibility study.

BACKGROUND: In vivo videomicroscopy has been used for years to visualize subpleural alveoli in animal studies. This has led to a better understanding of alveolar physiology. We tested the hypothesis whether a novel handheld videomicroscope could be used for intraoperative detection of alveoli in surgical patients during mechanical ventilation. MATERIAL/METHODS: Using Sidestream Dark Field imaging, we observed 6 patients (3 adults and 3 children) who underwent elective cardiac surgery. In each patient, the tip of the microscope was placed on the visceral pleural surface of the left upper pulmonary lobe after weaning from cardiopulmonary bypass. The acquired images were converted into digital signals and captured on a computer. RESULTS: Although cardiac motion artifacts were present, visceral pleural microvascular blood flow could be observed in adults and infants. In infants, sub-pleural cavities (alveoli) were observed. These alveoli were remarkably similar in dimension and structure to those identified previously as true alveoli in animal studies. Quantification of these alveoli demonstrated that mean alveolar diameter, perimeter and area increased with age among the investigated infants (all parameters p<0.001). CONCLUSIONS: High-quality images of visceral pleural microvessels as well as subpleural cavities, reflecting superficial alveoli, could be obtained in infants. These findings create the opportunity to begin human intervention studies, which should investigate alveolar dynamics during mechanical ventilation in cardio-thoracic surgery in more detail.

Reliable assessment of sedation level in routine clinical practice by adding an instruction to the Ramsay Scale.

OBJECTIVE: The level of sedation in mechanically ventilated patients is most often assessed with the Ramsay Scale. Its reliability, however, has never been evaluated in a large group of professionals using the Ramsay Scale in daily clinical practice, while differences in interpretations among professionals have been indicated. We developed a written stepwise instruction to optimize the inter-observer reliability of the Ramsay Scale within a large group of Intensive Care (IC) nurses. DESIGN: Reliability study. SETTING: The Intensive Care Cardiology (ICC) and the Intensive Care Thoracic surgery (ICT) units of a university hospital. PATIENTS AND PARTICIPANTS: The study population comprises randomly selected mechanically ventilated patients and IC nurses with a bachelor's degree in Nursing and an IC certification. In total 2x105 Ramsay measures were performed in 45 patients by 24 nurses. MEASUREMENT AND RESULTS: Analysis of 105 paired Ramsay scores showed an almost perfect agreement between observers (weighted K (Kw)=0.90). In both ICC patients and ICT patients, agreement between Ramsay scores was high (Kw=0.95 and Kw=0.86, respectively). CONCLUSION: By using a written stepwise instruction with the Ramsay Scale, the inter-observer reliability of the level of sedation measurements, performed in daily clinical practice within a large team of IC nurses, proved to be almost perfect.

Guidelines for cardiac management in noncardiac surgery are poorly implemented in clinical practice: results from a peripheral vascular survey in the Netherlands.

BACKGROUND: The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery recommend an algorithm for a stepwise approach to preoperative cardiac assessment in vascular surgery patients. The authors' main objective was to determine adherence to the ACC/AHA guidelines on perioperative care in daily clinical practice. METHODS: Between May and December 2004, data on 711 consecutive peripheral vascular surgery patients were collected from 11 hospitals in The Netherlands. This survey was conducted within the infrastructure of the Euro Heart Survey Programme. The authors retrospectively applied the ACC/AHA guideline algorithm to each patient in their data set and subsequently compared observed clinical practice data with these recommendations. RESULTS: Although 185 of the total 711 patients (26%) fulfilled the ACC/AHA guideline criteria to recommend preoperative noninvasive cardiac testing, clinicians had performed testing in only 38 of those cases (21%). Conversely, of the 526 patients for whom noninvasive testing was not recommended, guidelines were followed in 467 patients (89%). Overall, patients who had not been tested, irrespective of guideline recommendation, received less cardioprotective medications, whereas patients who underwent noninvasive testing were significantly more often treated with cardiovascular drugs (beta-blockers 43% vs. 77%, statins 52% vs. 83%, platelet inhibitors 80% vs. 85%, respectively; all P < 0.05). Moreover, the authors did not observe significant differences in cardiovascular medical therapy between patients with a normal test result and patients with an abnormal test result. CONCLUSION: This survey showed poor agreement between ACC/AHA guideline recommendations and daily clinical practice. Only one of each five patients underwent noninvasive testing when recommended. Furthermore, patients who had not undergone testing despite recommendations received as little cardiac management as the low-risk population.

The additional value of patient-reported health status in predicting 1-year mortality after invasive coronary procedures: a report from the Euro Heart Survey on Coronary Revascularisation.

OBJECTIVE: Self-perceived health status may be helpful in identifying patients at high risk for adverse outcomes. The Euro Heart Survey on Coronary Revascularization (EHS-CR) provided an opportunity to explore whether impaired health status was a predictor of 1-year mortality in patients with coronary artery disease (CAD) undergoing angiographic procedures. METHODS: Data from the EHS-CR that included 5619 patients from 31 member countries of the European Society of Cardiology were used. Inclusion criteria for the current study were completion of a self-report measure of health status, the EuroQol Questionnaire (EQ-5D) at discharge and information on 1-year follow-up, resulting in a study population of 3786 patients. RESULTS: The 1-year mortality was 3.2% (n = 120). Survivors reported fewer problems on the five dimensions of the EQ-5D as compared with non-survivors. A broad range of potential confounders were adjusted for, which reached a p<0.10 in the unadjusted analyses. In the adjusted analyses, problems with self-care (OR 3.45; 95% CI 2.14 to 5.59) and a low rating (< or =60) on health status (OR 2.41; 95% CI 1.47 to 3.94) were the most powerful independent predictors of mortality, among the 22 clinical variables included in the analysis. Furthermore, patients who reported no problems on all five dimensions had significantly lower 1-year mortality rates (OR 0.47; 95% CI 0.28 to 0.81). CONCLUSIONS: This analysis shows that impaired health status is associated with a 2-3-fold increased risk of all-cause mortality in patients with CAD, independent of other conventional risk factors. These results highlight the importance of including patients' subjective experience of their own health status in the evaluation strategy to optimise risk stratification and management in clinical practice.

Real-time transthoracic three-dimensional echocardiographic assessment of left ventricular volume and ejection fraction in congenital heart disease.

OBJECTIVE: The purpose of this study was to assess the (1) feasibility of real-time three-dimensional echocardiography (RT-3DE) data acquisition and (2) volumes and function of the abnormal left ventricle (LV) in adult patients with congenital heart disease (CHD), compared with magnetic resonance imaging (MRI) data. METHODS: Thirty-two patients (59% were male) with CHD were evaluated on the same day by MRI and RT-3DE. Acquisition of RT-3DE data sets was feasible in 29 of the 32 patients (91%). The time of 3D data acquisition was 4 +/- 2 minutes, and LV analysis was 17 +/- 5 minutes per patient for manual border tracing. RESULTS: A good correlation was observed between RT-3DE with manual border detection and MRI for LV end-diastolic volume (r = 0.97), LV end-systolic volume (r = 0.98), and LV ejection fraction (r = 0.94). CONCLUSION: RT-3DE is feasible for volumetric analysis of the abnormal LV allowing accurate determination of LV volume and ejection fraction compared with MRI in adult patients with CHD.

Feasibility and accuracy of real-time 3-dimensional echocardiographic assessment of ventricular septal defects.

The aim of this study was to evaluate feasibility, accuracy, and clinical applicability of real-time (RT) transthoracic 3-dimensional (3D) echocardiography (3DE) in the determination of the position, size, and shape of a ventricular septal defect (VSD). In all, 34 patients (age: 2 months-46 years), who were scheduled for surgical closure of a VSD, were enrolled in the study. VSD localization, shape, and dimensions were assessed and compared with measurements performed by the surgeon. Acquisition of RT-3DE datasets was feasible in 30 of 34 (88%) patients. Duration of 3D data acquisition was 6 +/- 2 minutes. Reconstruction time was 23 +/- 16 minutes. Localization and number of VSD were determined correctly by RT-3DE in all patients. There was a good correlation for VSD measurements between RT-3DE and operation (r = 0.95). RT-3DE allows accurate determination of VSD size, shape, and location. The short acquisition time and acceptable reconstruction time make this technique clinically applicable.

Surgical validation of real-time transthoracic 3D echocardiographic assessment of atrioventricular septal defects.

BACKGROUND: The purpose of this study was to evaluate the accuracy of AV valve morphology assessed by real-time transthoracic 3D echocardiography (RT-3DE) compared to surgical findings and to assess whether RT-3DE is applicable in clinical practice. METHODS: Between June 2004 to May 2005, 19 patients with an atrioventricular septal defect (AVSD) undergoing surgical treatment at our institution were enrolled in the study. RT-3DE was performed with Philips Sonos 7500 echo-system and off-line analysis with TomTec Echoview software. The AVSD was assessed for the morphology of AV valve, with particular interest to the superior and inferior bridging leaflets. 3D data were compared with measurements and descriptions acquired during the surgical procedure. RESULTS: Acquisition of RT-3DE datasets was feasible in all patients. Of the 19 patients, there were 11 infants (age <1 year). The duration of 3D data acquisition was 12+/-3 min for patients above 1 year and 4+/-2 for infants. Reconstruction time was 22+/-8 min. In all patients the AV valve orifice and RT-3DE observations of the superior and inferior bridging leaflets were all correctly identified by RT-3DE compared with the surgical findings. CONCLUSION: Real-time transthoracic 3D echocardiography provides accurate assessment of AVSDs and correctly depicts the AV valve morphology. After a short learning curve, RT-3DE is easily applicable during daily clinical practice.

Assessment of derived 12-lead electrocardiograms using general and patient-specific reconstruction strategies at rest and during transient myocardial ischemia.

Twelve-lead ST-segment monitoring is a widely used tool for capturing focal ischemia and transient intermittent episodes. However, continuous registration of all 10 electrodes is impractical in clinical settings. This study investigated the accuracy of 2 derived 12-lead strategies that required 6 electrodes, including all limb leads, and 2 precordial leads by using population-based (generalized) and individualized (patient-specific) reconstruction coefficients to derive the additional 4 chest leads. A total of 26,880 simultaneous digital conventional 12-lead generalized and patient-specific electrocardiograms were monitored over 112 hours in 39 patients during percutaneous coronary intervention, including 159 balloon occlusions in 63 arteries, to test accuracy at rest and during ischemia. Occlusion duration was 78 seconds (range 42 to 96) in the left main coronary in 2 patients, the left anterior descending artery in 15, the right coronary artery in 10, the circumflex artery in 2, and graft segments in 5 patients. Average summated 12-lead ST deviation over the study population at baseline was 377 microV (range 104 to 1,718), which increased at peak ischemia to an average of 1,086 microV (range 282 to 4,099). Median absolute differences at peak ischemic ST deviation were 25 microV in lead V(1), 0 microV in lead V(2), 35 microV in lead V(3), 34 microV in lead V(4), 0 microV in lead V(5), 11 microV in lead V(6), and 114 microV for summated 12-lead ST deviation with the generalized method and 7 microV in lead V(1), 4 microV in lead V(2), 1 muV in lead V(3), 5 microV in lead V(4), 4 microV in lead V(5), 9 microV in lead V(6), and 83 microV for the summated 12-lead ST deviation with the patient-specific method. Limb leads (I, II, III, aVR, aVL, and aVF) were identical in all patients. Thus, generalized and patient-specific methods derived from 12-lead electrocardiography using actual limb and 2 precordial electrodes accurately derived the additional chest leads at rest and during ischemia. These approaches appear to be more practical than conventional 10-electrode monitoring but preserve high accuracy.