Addition of FFRct in the diagnostic pathway of patients with stable chest pain to reduce unnecessary invasive coronary angiography (FUSION) : Rationale and design for the multicentre, randomised, controlled FUSION trial.

BACKGROUND: Coronary computed tomography angiography (CCTA) is widely used in the diagnostic work-up of patients with stable chest pain. CCTA has an excellent negative predictive value, but a moderate positive predictive value for detecting coronary stenosis. Computed tomography-derived fractional flow reserve (FFRct) is a non-invasive, well-validated technique that provides functional assessment of coronary stenosis, improving the positive predictive value of CCTA. However, to determine the value of FFRct in routine clinical practice, a pragmatic randomised, controlled trial (RCT) is required. We will conduct an RCT to investigate the impact of adding FFRct analysis in the diagnostic pathway of patients with a coronary stenosis on CCTA on the rate of unnecessary invasive coronary angiography, cost-effectiveness, quality of life and clinical outcome. METHODS: The FUSION trial is a prospective, multicentre RCT that will randomise 528 patients with stable chest pain and anatomical stenosis of ≥ 50% but < 90% in at least one coronary artery of ≥ 2 mm on CCTA, to FFRct-guided care or usual care in a 1:1 ratio. Follow-up will be 1 year. The primary endpoint is the rate of unnecessary invasive coronary angiography within 90 days. CONCLUSION: The FUSION trial will evaluate the use of FFRct in stable chest pain patients from the Dutch perspective. The trial is funded by the Dutch National Health Care Institute as part of the research programme 'Potentially Promising Care' and the results will be used to assess if FFRct reimbursement should be included in the standard health care package.

Feasibility and potential benefit of pre-procedural CMR imaging in patients with ischaemic cardiomyopathy undergoing cardiac resynchronisation therapy.

AIM: To determine the feasibility and potential benefit of a full cardiac magnetic resonance (CMR) work-up for assessing the location of scarred myocardium and the region of latest contraction (LCR) in patients with ischaemic cardiomyopathy (ICM) undergoing cardiac resynchronisation therapy (CRT). METHODS: In 30 patients, scar identification and contraction timing analysis was retrospectively performed on CMR images. Fluoroscopic left ventricular (LV) lead positions were scored with respect to scar location, and when placed outside scar, with respect to the LCR. The association between the lead position with respect to scar, the LCR and echocardiographic LV end-systolic volume (LVESV) reduction was subsequently evaluated. RESULTS: The CMR work-up was feasible in all but one patient, in whom image quality was poor. Scar and contraction timing data were succesfully displayed on 36-segment cardiac bullseye plots. Patients with leads placed outside scar had larger LVESV reduction (-21 ± 21%, n = 19) compared to patients with leads within scar (1 ± 25%, n = 11), yet total scar burden was higher in the latter group. There was a trend towards larger LVESV reduction in patients with leads in the scar-free LCR, compared to leads situated in scar-free segments but not in the LCR (-34 ± 14% vs -15 ± 21%, p = 0.06). CONCLUSIONS: The degree of reverse remodelling was larger in patients with leads situated in a scar-free LCR. In patients with leads situated within scar there was a neutral effect on reverse remodelling, which can be caused both by higher scar burden or lead position. These findings demonstrate the feasibility of a CMR work-up and potential benefit in ICM patients undergoing CRT.

Survival analysis of patients with rheumatic MS after PBMV compared with MVS in a low-to-middle-income country.

INTRODUCTION: Rheumatic mitral stenosis continues to be prevalent in developing countries, notably in endemic areas. Over the last few decades, percutaneous balloon mitral valvuloplasty (PBMV) has been established as a lower-cost alternative treatment for mitral stenosis (MS) in low-to-middle-income countries. PBMV has also been suggested to be an effective and safe alternative treatment modality. This study aims to analyse the survival of rheumatic MS patients treated with PBMV compared with those treated with mitral valve surgery (MVS). METHODS: This study was a national, single-centre, longitudinal study using a survival analysis method in 329 consecutive patients suffering from rheumatic heart disease with severe MS who underwent PBMV compared with 142 consecutive patients with similar characteristics who underwent MVS between January 2011 and December 2016. Survival analysis and event-free duration were determined over a median follow-up of 24 months in the PBMV group and 27 months in the MVS group. RESULTS: The results showed that of the 329 consecutive patients in the PBMV group, 61 patients (18.5) had an event (6 patients died and 55 patients were hospitalised), and of the 142 consecutive patients in the MVS group, 19 patients (13.4%) had an event (5 patients died, and 14 patients were hospitalised). The hazard ratio was 0.631 (95% confidence interval, 0.376-1.058; P = 0.081). Longer short-term survival was found in the MVS group but was not statistically significant. Event-free survival was significantly longer in the MVS group (P = 0.002), by 5 months. CONCLUSIONS: In this study, the efficacy and safety of PBMV was reconfirmed, as PBMV proved to be non-inferior to MVS in survival prognosis, but sustained event-free duration was significantly better in the MVS group than in the PBMV group.

Delays in the treatment of patients with acute coronary syndrome: Focus on pre-hospital delays and non-ST-elevated myocardial infarction.

Delays in patients suspected of acute coronary syndrome (ACS) should be kept as short as possible to reduce complications and mortality. In this review we discuss the substantial pre-hospital delays of ST-elevated myocardial infarction (STEMI) patients as well as non-STEMI patients. The pre-hospital delays include patient, doctor and emergency medical transport (EMT) delay. Patient delay is among the longest in the pre-hospital chain of ACS patients. Interventions as mass media campaigns or individual education programs have not yet shown much improvement. Patients with chest pain most often contact the general practitioner (GP) instead of the recommended EMT, increasing delays as well. To decrease the delays by referring all patients promptly and without restriction to the emergency department (ED) is not feasible. Up to 80% of the patients with chest pain do not have a cardiac diagnosis and thus referral of all these patients would result in overcrowding of the ED. Triage is therefore crucial. Triage of patients with chest pain is therefore imperative and there is a great need of (validated) triage tools.

Autologous Mesenchymal Stem Cells Show More Benefit on Systolic Function Compared to Bone Marrow Mononuclear Cells in a Porcine Model of Chronic Myocardial Infarction.

Cardiac cell therapy is a strategy to treat patients with chronic myocardial infarction (MI). No consensus exists regarding the optimal cell type. First, a comparison between autologous bone marrow-derived mononuclear cells (BMMNC) and mesenchymal stem cells (MSC) on therapeutic efficacy after MI was performed. Next, the effect of repetitive, NOGA-guided transendocardial injection was determined via a crossover design. Nineteen pigs were allocated in three groups: (1) placebo (at 4 and 8 weeks), (2) MSC (followed by placebo at 8 weeks), or (3) BMMNC (followed by MSC at 8 weeks) delivery including a priming strategy to enhance MSC effect. At 4 weeks, ejection fraction (EF) was significantly improved after MSC injection and not by BMMNC injection. After 8 weeks, no difference was observed in EF between cell-treated groups demonstrating the positive systolic effect of MSC. This study showed that MSC rather than BMMNC injection improves systolic function in chronic MI.

Assessment of LV ejection fraction using real-time 3D echocardiography in daily practice: direct comparison of the volumetric and speckle tracking methodologies to CMR.

AIMS: This study is the first to directly compare two widely used real-time 3D echocardiography (RT3DE) methods of cardiac magnetic resonance imaging (CMR) and assess their reproducibility in experienced and less experienced observers. METHODS: Consecutive patients planned for CMR underwent RT3DE within 8 h of CMR with Philips (volumetric method) and Toshiba Artida (speckle tracking method). Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were measured using RT3DE, by four trained observers, and compared with CMR values. RESULTS: Thirty-five patients were included (49.7 ± 15.7 years; 55 % male), 30 (85.7 %) volumetric and 27 (77.1 %) speckle tracking datasets could be analysed. CMR derived LVEDV, LVESV and LVEF were 198 ± 58 ml, 106 ± 53 ml and 49 ± 15 %, respectively. LVEF derived from speckle tracking was accurate and reproducible in all observers (all intra-class correlation coefficients (ICC) > 0.86). LVEF derived from the volumetric method correlated well to CMR in experienced observers (ICC 0.85 and 0.86) but only moderately in less experienced observers (ICC 0.58 and 0.77) and was less reproducible in these observers (ICC = 0.55). Volumes were significantly underestimated compared with CMR (p < 0.001). CONCLUSION: This study demonstrates that both RT3DE methodologies are sufficiently accurate and reproducible for use in daily practice. However, experience importantly influences the accuracy and reproducibility of the volumetric method, which should be considered when introducing this technique into clinical practice.

A prospective validation of the HEART score for chest pain patients at the emergency department.

BACKGROUND: The focus of the diagnostic process in chest pain patients at the emergency department is to identify both low and high risk patients for an acute coronary syndrome (ACS). The HEART score was designed to facilitate this process. This study is a prospective validation of the HEART score. METHODS: A total of 2440 unselected patients presented with chest pain at the cardiac emergency department of ten participating hospitals in The Netherlands. The HEART score was assessed as soon as the first lab results and ECG were obtained. Primary endpoint was the occurrence of major adverse cardiac events (MACE) within 6 weeks. Secondary endpoints were (i) the occurrence of AMI and death, (ii) ACS and (iii) the performance of a coronary angiogram. The performance of the HEART score was compared with the TIMI and GRACE scores. RESULTS: Low HEART scores (values 0-3) were calculated in 36.4% of the patients. MACE occurred in 1.7%. In patients with HEART scores 4-6, MACE was diagnosed in 16.6%. In patients with high HEART scores (values 7-10), MACE occurred in 50.1%. The c-statistic of the HEART score (0.83) is significantly higher than the c-statistic of TIMI (0.75)and GRACE (0.70) respectively (p<0.0001). CONCLUSION: The HEART score provides the clinician with a quick and reliable predictor of outcome, without computer-required calculating. Low HEART scores (0-3), exclude short-term MACE with >98% certainty. In these patients one might consider reserved policies. In patients with high HEART scores (7-10) the high risk of MACE may indicate more aggressive policies.

High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the prevalence of (unknown) heart failure and left ventricular dysfunction in older patients with type 2 diabetes. METHODS: In total, 605 patients aged 60 years or over with type 2 diabetes in the south west of the Netherlands participated in this cross-sectional study (response rate 48.7%), including 24 with a cardiologist-confirmed diagnosis of heart failure. Between February 2009 and March 2010, the patients without known heart failure underwent a standardised diagnostic work-up, including medical history, physical examination, ECG and echocardiography. An expert panel used the criteria of the European Society of Cardiology to diagnose heart failure. RESULTS: Of the 581 patients studied, 161 (27.7%; 95% CI 24.1%, 31.4%) were found to have previously unknown heart failure: 28 (4.8%; 95% CI 3.1%, 6.6%) with reduced ejection fraction, and 133 (22.9%; 95% CI 19.5%, 26.3%) with preserved ejection fraction. The prevalence of heart failure increased steeply with age. Heart failure with preserved ejection fraction was more common in women. Left ventricular dysfunction was diagnosed in 150 patients (25.8%; 95% CI 22.3%, 29.4%); 146 (25.1%; 95% CI 21.6%, 28.7%) had diastolic dysfunction. CONCLUSIONS/INTERPRETATION: This is the first epidemiological study that provides exact prevalence estimates of (previously unknown) heart failure and left ventricular dysfunction in a representative sample of patients with type 2 diabetes. Previously unknown heart failure and left ventricular dysfunction are highly prevalent. Physicians should pay special attention to 'unmasking' these patients.

Image quality assessment of the right ventricle with three different delayed enhancement sequences in patients suspected of ARVC/D.

Histopathologic findings in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) are replacement of the normal myocardium with fatty and fibrous elements with preferential involvement of the right ventricle. The right ventricular fibrosis can be visualised by post-gadolinium delayed enhancement inversion recovery imaging (DE imaging). We compared the image quality of three different gradient echo MRI sequences for short axis DE imaging of the right ventricle (RV). We retrospectively analysed MRI scans performed between February 2005 and December 2008 in 97 patients (mean age: 41.2 years, 67% men) suspected of ARVC/D. For DE imaging either a 2D Phase Sensitive (PSIR), a 2D (2D) or a 3D (3D) inversion recovery sequence was used in respectively 38, 32 and 27 MRI-examinations. The RV, divided in 10 segments, was assessed for image quality by two radiologists in random sequence. A consensus reading was performed if results differed between the two readings. Image quality was good in 24% of all segments in the 3D group, 66% in the 2D group and 79% in the PSIR group. Poor image quality was observed in 51% (3D), 10% (2D), and 2% (PSIR) of all segments. Exams were considered suitable for clinical use in 7% of exams in the 3D group, 75% of exams in the 2D group and 90% of exams of the PSIR group. Breathing-artifacts occurred in 22% (3D), 59% (2D) and 53% (PSIR). Motion-artifacts occurred in 56% (3D), 28% (2D) and 29% (PSIR). Post-gadolinium imaging using the PSIR sequence results in better and more consistent image quality of the RV compared to the 2D and 3D sequences.

Prognostic value of the Rose questionnaire: a validation with future coronary events in the SMART study.

AIM: The Rose questionnaire was developed in epidemiological studies to obtain a reproducible diagnosis of angina pectoris. We studied the prognostic value of this questionnaire with respect to the occurrence of future coronary events. METHODS AND RESULTS: We studied 7916 consecutive patients (mean age 56 years; 67% men) with clinically manifest vascular disease or cardiovascular risk factors, enrolled in the Second Manifestations of ARTerial disease (SMART) study from 1996 to 2009. At inclusion, all patients completed the Rose questionnaire. We investigated the prognostic value of four definitions of angina pectoris that were based on the following elements of the questionnaire (1) the full questionnaire; (2) three key questions concerning chest pain; (3) one question about discomfort or pain in the chest; (4) two questions about complaints when slowing down or stopping activities (the definition that is used in the SMART study). All patients were followed for new coronary events and interventions for an average of 4.6 years. Analyses were with multivariable Cox regression models. Discriminatory ability of the four definitions as assessed with areas under the receiver-operator characteristics curves was similar (range 0.708-0.726) for coronary events in isolation as well as in combination with coronary interventions. The models were assessed for their ability to improve risk stratification compared with each other; differences between definitions are small. CONCLUSION: Our data implicate that the use of a subset of questions of the Rose questionnaire performs equally well compared with the full Rose questionnaire regarding the prediction of coronary events.

The time window of MRI of murine atherosclerotic plaques after administration of CB2 receptor targeted micelles: inter-scan variability and relation between plaque signal intensity increase and gadolinium content of inversion recovery prepared versus non-prepared fast spin echo.

Single fast spin echo scans covering limited time frames are mostly used for contrast-enhanced MRI of atherosclerotic plaque biomarkers. Knowledge on inter-scan variability of the normalized enhancement ratio of plaque (NER(plaque)) and relation between NER(plaque) and gadolinium content for inversion-recovery fast spin echo is limited. Study aims were: evaluation of (1) timing of MRI after intravenous injection of cannabinoid-2 receptor (CB2-R) (expressed by human and mouse plaque macrophages) targeted micelles; (2) inter-scan variability of inversion-recovery fast spin echo and fast spin echo; (3) relation between NER(plaque) and gadolinium content for inversion-recovery fast spin echo and fast spin echo. Inversion-recovery fast spin echo/fast spin echo imaging was performed before and every 15 min up to 48 h after injection of CB2-R targeted or control micelles using several groups of mice measured in an interleaved fashion. NER(plaque) (determined on inversion-recovery fast spin echo images) remained high (∼2) until 48 h after injection of CB2-R targeted micelles, whereas NER(plaque) decreased after 36 h in the control group. The inter-scan variability and relation between NER(plaque) and gadolinium (assessed with inductively coupled plasma- mass spectrometry) were compared between inversion-recovery fast spin echo and fast spin echo. Inter-scan variability was higher for inversion-recovery fast spin echo than for fast spin echo. Although gadolinium and NER(plaque) correlated well for both techniques, the NER of plaque was higher for inversion-recovery fast spin echo than for fast spin echo. In mice injected with CB2-R targeted micelles, NER(plaque) can be best evaluated at 36-48 h post-injection. Because NER(plaque) was higher for inversion-recovery fast spin echo than for fast spin echo, but with high inter-scan variability, repeated inversion-recovery fast spin echo imaging and averaging of the obtained NER(plaque) values is recommended.

Simultaneous aortic and coronary assessment in abdominal aortic aneurysm patients by thoraco-abdominal 64-detector-row CT angiography: estimate of the impact on preoperative management: a pilot study.

OBJECTIVES: To estimate the influence of information on the coronary arteries obtained from routine thoraco-abdominal CT angiography (CTA) on pre-operative clinical management in abdominal aortic aneurysm (AAA) patients. METHODS: Twenty-eight AAA patients underwent pre-operative thoraco-abdominal electrocardiography (ECG)-gated 64-detector-row CTA to evaluate aortic pulsatility for prosthesis size matching. Retrospectively, the coronaries were reconstructed from the same data set and scored on a per segment basis for stenosis (0%, 50%) and grading confidence (poor, adequate or high). An experienced cardiologist was presented information on patient characteristics obtained from patient records and CTA findings. Suggested changes in European Society of Cardiology guidelines based patient management based on CTA information were scored. RESULTS: On CTA, 17 patients (61%) had significant coronary disease (>50% stenosis) including left main (n=4), single (n=7) and multiple (n=6) vessel disease. Grading confidence was adequate or high in 86% of proximal and middle segments. Based on CTA findings, patient management would have been changed in 4 out of the 28 patients (14%; 95% CI 1-27%) by adding coronary angiography (n=4). In five patients who underwent coronary artery bypass grafting previously, CT did not change management but confirmed graft patency. CONCLUSIONS: Information on coronary pathology and coronary bypass graft patency can be readily obtained from thoraco-abdominal CTA and may alter pre-operative patient management, as shown in 14% of AAA patients in our study.

Air pollution as noxious environmental factor in the development of cardiovascular disease.

A strong epidemiological association has been revealed between air pollution and the occurrence of cardiovascular disease (CVD). Deleterious consequences of such pollution, including myocardial infarction and coronary ischaemia, have occurred after both acute as well as chronic exposure to air pollution. The causal pathophysiological mechanisms through which these effects occur have not been identified but potential pathways include endothelial dysfunction and systemic reactions such as inflammation and oxidative stress. Because of increasing urbanisation and associated anthropogenic activities, air pollution is considered an important topic in public health and it remains challenging to translate these epidemiological observations into clinical consequences and guidelines. Nevertheless, for the high cardiovascular risk population, air pollution might have direct clinical relevance. In the future, more knowledge is required about the absolute risk of air pollution in specific high-risk populations and the pathophysiological mechanisms behind this relationship.

Unrecognised myocardial infarction in subjects at high vascular risk: prevalence and determinants.

OBJECTIVE: To investigate the prevalence and determinants of unrecognised myocardial infarction (UMI). DESIGN, SETTING, PATIENTS: In this cross-sectional study in a tertiary centre, a delayed enhancement cardiac MRI (DE-CMR), which identifies both Q-wave and non-Q wave MIs, was performed in 502 subjects with manifest extracardiac atherosclerotic disease or marked risk factors for atherosclerosis without symptomatic coronary artery disease. MAIN OUTCOME MEASURES: UMI was defined as the presence of delayed enhancement without corresponding clinical history. RESULTS: DE-CMR was of sufficient image quality in 480 (95.6%) subjects. A UMI was present in 45 (9.4%) of all subjects; in 13.1% of men and in 3.7% of women. The risk of UMI increased from 6.0% (95% CI 2.2 to 9.8%) in those with two vascular risk factors up to 26.2% (95% CI 15.2 to 37.3%) in those with four or five risk factors. In a multivariable analysis, the risk of UMI was related to male gender (OR 2.3 (95% CI 1.0 to 5.6)), age (OR 1.04 (95% CI 1.00 to 1.07) per year), ever smoking (OR 3.1 (95% CI 1.0 to 9.1), history of stroke (OR 1.9 (95% CI 0.8 to 4.3)) and history of aneurysm of the abdominal aorta (OR 2.6 (95% CI 1.0 to 6.9)). CONCLUSIONS: In cardiac asymptomatic subjects at high vascular risk, UMI is common. The risk of UMI increases with increasing presence of risk factors.