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3.  Left ventricular remodeling after acute myocardial infarction: the influence of viability and revascularization - an echocardiographic substudy of the VIAMI-trial 
Trials  2014;15(1):329.
Background
Viability seems to be important in preventing ventricular remodeling after acute myocardial infarction (AMI). We investigated the influence of viability, as demonstrated with low-dose dobutamine echocardiography, and the role of early revascularization on the process of left ventricular (LV) remodeling after AMI.
Methods
We retrospectively investigated 224 patients who were initially included in the viability-guided angioplasty after acute myocardial infarction-trial (VIAMI-trial). Patients in the VIAMI-trial did not undergo a primary or rescue percutaneous coronary intervention and were stable in the early in-hospital phase. Patients underwent viability testing within 72 hours after AMI. Patients with viability were randomized to an invasive strategy or an ischemia-guided strategy. Follow-up echocardiography was performed at a mean of 205 days. In this echocardiographic substudy, patients were divided into three new groups: group 1, viable and revascularized before follow-up echocardiogram; group 2, viable, but medically treated; and group 3, non-viable patients.
Results
Group 1 showed preservation of LV volume indices. The ejection fraction (EF) increased significantly from 54.0% to 57.5% (P = 0.047). Group 2 showed a significant increase in LV volume indices with no improvement in EF (53.3% versus 53.0%, P = 0.86). Group 3 showed a significant increase in LV volume indices, with a decrease in EF from 53.5% to 49.1% (P = 0.043). Multivariate logistic regression analysis indicated the number of viable segments and revascularization during follow-up as independent predictors for EF improvement, especially in patients with lower EF at baseline.
Conclusion
Viability early after AMI is associated with improvement in LV function after revascularization. When viable myocardium is not revascularized, the LV tends to remodel with increased LV volumes, without improvement of EF. Absence of viability results in ventricular dilatation and deterioration of EF, irrespective of revascularization status.
Trial registration
NCT00149591 (assigned: 6 September 2005).
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-329) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-329
PMCID: PMC4141086  PMID: 25135364
Myocardial infarction; Viability; Echocardiography; Percutaneous coronary intervention; Remodeling
4.  In-vivo T1 cardiovascular magnetic resonance study of diffuse myocardial fibrosis in hypertrophic cardiomyopathy 
Background
In hypertrophic cardiomyopathy (HCM), autopsy studies revealed both increased focal and diffuse deposition of collagen fibers. Late gadolinium enhancement imaging (LGE) detects focal fibrosis, but is unable to depict interstitial fibrosis. We hypothesized that with T1 mapping, which is employed to determine the myocardial extracellular volume fraction (ECV), can detect diffuse interstitial fibrosis in HCM patients.
Methods
T1 mapping with a modified Look-Locker Inversion Recovery (MOLLI) pulse sequence was used to calculate ECV in manifest HCM (n = 16) patients and in healthy controls (n = 14). ECV was determined in areas where focal fibrosis was excluded with LGE.
Results
The total group of HCM patients showed no significant changes in mean ECV values with respect to controls (0.26 ± 0.03 vs 0.26 ± 0.02, p = 0.83). Besides, ECV in LGE positive HCM patients was comparable with LGE negative HCM patients (0.27 ± 0.03 vs 0.25 ± 0.03, p = 0.12).
Conclusions
This study showed that HCM patients have a similar ECV (e.g. interstitial fibrosis) in myocardium without LGE as healthy controls. Therefore, the additional clinical value of T1 mapping in HCM seems limited, but future larger studies are needed to establish the clinical and prognostic potential of this new technique within HCM.
doi:10.1186/1532-429X-16-28
PMCID: PMC4026831  PMID: 24766828
T1 mapping; CMR; Diffuse fibrosis; HCM; Extracellular volume fraction
5.  Coronary artery disease in patients with atypical chest pain with and without diabetes mellitus assessed with coronary CT angiography 
Introduction
Coronary artery disease (CAD) in diabetes mellitus (DM) is often widespread when diagnosed. Non-invasive coronary calcium scoring and coronary CT angiography (CAC-score/CCTA) are accurate in the detection of CAD. This study compared CAD characteristics as identified by CCTA between patients with and without DM with atypical chest pain.
Methods
CAD was defined as CAC-score >0 and/or presence of coronary plaque. Several CAD characteristics (number of affected segments, obstructive (>50% stenosis) CAD and CAD distribution) were compared on a per patient and segment basis. Subanalysis of duration of DM (<5 or >5 years) and gender was performed.
Results
A total of 1148 patients (63.3% men, mean age 57.7±10.7), of whom 99 (8.6%) suffered from DM, were referred for CCTA. There was no difference in the prevalence of CAD between patients with and without DM (53.5% vs 50.9%, p=0.674). However patients with DM showed more affected coronary segments compared with patients without DM (2.5±3.4 vs 1.7±2.4, p=0.003). Multivariate analysis indicated that DM was an independent predictor of obstructive CAD (OR 2.16, 95% CI 1.23 to 3.78), as were age, women, and Diamond-Forrester score. In our study, obstructive CAD was more prevalent in women than in men (DM 40.0% vs 14.1%, p=0.003; non-DM 16.8% vs 8.4%, p<0.001). Patients suffering from DM >5 years showed more distal plaques (11.2% vs 7.7%, p=0.030).
Conclusions
Patients with atypical chest pain and DM showed more extensive CAD, as well as more obstructive CAD, particularly in women. Diabetes duration (>5 years) was not associated with more obstructive coronary disease or different plaque morphology, although more distal disease was present.
doi:10.1136/bmjdrc-2013-000004
PMCID: PMC4212558  PMID: 25452855
Coronary Artery; Coronary Artery Disease
6.  Feature tracking compared with tissue tagging measurements of segmental strain by cardiovascular magnetic resonance 
Background
Left ventricular segmental wall motion analysis is important for clinical decision making in cardiac diseases. Strain analysis with myocardial tissue tagging is the non-invasive gold standard for quantitative assessment, however, it is time-consuming. Cardiovascular magnetic resonance myocardial feature-tracking (CMR-FT) can rapidly perform strain analysis, because it can be employed with standard CMR cine-imaging. The aim is to validate segmental peak systolic circumferential strain (peak SCS) and time to peak systolic circumferential strain (T2P-SCS) analysed by CMR-FT against tissue tagging, and determine its intra and inter-observer variability.
Methods
Patients in whom both cine CMR and tissue tagging has been performed were selected. CMR-FT analysis was done using endocardial (CMR-FTendo) and mid-wall contours (CMR-FTmid). The Intra Class Correlation Coefficient (ICC) and Pearson correlation were calculated.
Results
10 healthy volunteers, 10 left bundle branch block (LBBB) and 10 hypertrophic cardiomyopathy patients were selected. With CMR-FT all 480 segments were analyzable and with tissue tagging 464 segments.
Significant differences in mean peak SCS values of the total study group were present between CMR-FTendo and tissue tagging (-23.8 ± 9.9% vs -13.4 ± 3.3%, p < 0.001). Differences were smaller between CMR-FTmid and tissue tagging (-16.4 ± 6.1% vs -13.4 ± 3.3%, p = 0.001). The ICC of the mean peak SCS of the total study group between CMR-FTendo and tissue tagging was low (0.19 (95%-CI-0.10-0.49), p = 0.02). Comparable results were seen between CMR-FTmid and tissue tagging. In LBBB patients, mean T2P-SCS values measured with CMR-FTendo and CMR-FTmid were 418 ± 66 ms, 454 ± 60 ms, which were longer than with tissue tagging, 376 ± 55 ms, both p < 0.05. ICC of the mean T2P-SCS between CMR-FTendo and tissue tagging was 0.64 (95%-CI-0.36-0.81), p < 0.001, this was better in the healthy volunteers and LBBB group, whereas the ICC between CMR-FTmid and tissue tagging was lower.
The intra and inter-observer agreement of segmental peak SCS with CMR-FTmid was lower compared with tissue tagging; similar results were seen for segmental T2P-SCS.
Conclusions
The intra and inter-observer agreement of segmental peak SCS and T2P-SCS is substantially lower with CMR-FTmid compared with tissue tagging. Therefore, current segmental CMR-FTmid techniques are not yet applicable for clinical and research purposes.
doi:10.1186/1532-429X-16-10
PMCID: PMC3926943  PMID: 24450803
Cardiovascular magnetic resonance; Myocardial wall motion; Tissue tagging; Myocardial feature-tracking
8.  Quality assessment of cardiovascular magnetic resonance in the setting of the European CMR registry: description and validation of standardized criteria 
Background
Cardiovascular magnetic resonance (CMR) has become an important diagnostic imaging modality in cardiovascular medicine. However, insufficient image quality may compromise its diagnostic accuracy. We aimed to describe and validate standardized criteria to evaluate a) cine steady-state free precession (SSFP), b) late gadolinium enhancement (LGE), and c) stress first-pass perfusion images. These criteria will serve for quality assessment in the setting of the Euro-CMR registry.
Methods
Thirty-five qualitative criteria were defined (scores 0–3) with lower scores indicating better image quality. In addition, quantitative parameters were measured yielding 2 additional quality criteria, i.e. signal-to-noise ratio (SNR) of non-infarcted myocardium (as a measure of correct signal nulling of healthy myocardium) for LGE and % signal increase during contrast medium first-pass for perfusion images. These qualitative and quantitative criteria were assessed in a total of 90 patients (60 patients scanned at our own institution at 1.5T (n=30) and 3T (n=30) and in 30 patients randomly chosen from the Euro-CMR registry examined at 1.5T). Analyses were performed by 2 SCMR level-3 experts, 1 trained study nurse, and 1 trained medical student.
Results
The global quality score was 6.7±4.6 (n=90, mean of 4 observers, maximum possible score 64), range 6.4-6.9 (p=0.76 between observers). It ranged from 4.0-4.3 for 1.5T (p=0.96 between observers), from 5.9-6.9 for 3T (p=0.33 between observers), and from 8.6-10.3 for the Euro-CMR cases (p=0.40 between observers). The inter- (n=4) and intra-observer (n=2) agreement for the global quality score, i.e. the percentage of assignments to the same quality tertile ranged from 80% to 88% and from 90% to 98%, respectively. The agreement for the quantitative assessment for LGE images (scores 0–2 for SNR <2, 2–5, >5, respectively) ranged from 78-84% for the entire population, and 70-93% at 1.5T, 64-88% at 3T, and 72-90% for the Euro-CMR cases. The agreement for perfusion images (scores 0–2 for %SI increase >200%, 100%-200%,<100%, respectively) ranged from 81-91% for the entire population, and 76-100% at 1.5T, 67-96% at 3T, and 62-90% for the Euro-CMR registry cases. The intra-class correlation coefficient for the global quality score was 0.83.
Conclusions
The described criteria for the assessment of CMR image quality are robust with a good inter- and intra-observer agreement. Further research is needed to define the impact of image quality on the diagnostic and prognostic yield of CMR studies.
doi:10.1186/1532-429X-15-55
PMCID: PMC3707748  PMID: 23787094
Cardiac Magnetic Resonance; Image Quality; Quality Score; Late Gadolinium Enhancement Images; Cine Images; Stress First Pass Myocardial Perfusion
10.  Metformin in non-Diabetic Patients Presenting with ST Elevation Myocardial Infarction: Rationale and Design of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction (GIPS)-III Trial 
Cardiovascular Drugs and Therapy  2012;26(5):417-426.
Background
Left ventricular dysfunction and the development of heart failure is a frequent and serious complication of myocardial infarction. Recent animal experimental studies suggested that metformin treatment reduces myocardial injury and preserves cardiac function in non-diabetic rats after experimental myocardial infarction. We will study the efficacy of metformin with the aim to preserve left ventricular ejection fraction in non-diabetic patients presenting with ST elevation myocardial infarction (STEMI).
Methods
The Glycometabolic Intervention as adjunct to Primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial is a prospective, single center, double blind, randomized, placebo-controlled trial. Three-hundred-and-fifty patients, without diabetes, requiring primary percutaneous coronary intervention (PCI) for STEMI will be randomized to metformin 500 mg twice daily or placebo treatment and will undergo magnetic resonance imaging (MRI) after 4 months. Major exclusion criteria were prior myocardial infarction and severe renal dysfunction. The primary efficacy parameter is left ventricular ejection fraction 4 months after randomization. Secondary and tertiary efficacy parameters include major adverse cardiac events, new onset diabetes and glycometabolic parameters, and echocardiographic diastolic function. Safety parameters include renal function deterioration and lactic acidosis.
Conclusions
The GIPS-III trial will evaluate the efficacy of metformin treatment to preserve left ventricular ejection fraction in STEMI patients without diabetes.
doi:10.1007/s10557-012-6413-1
PMCID: PMC3464381  PMID: 22968678
ST-elevation myocardial infarction; Metformin; Left ventricular ejection fraction; Heart failure; Cardiac remodeling
11.  The effect of a comprehensive lifestyle intervention on cardiovascular risk factors in pharmacologically treated patients with stable cardiovascular disease compared to usual care: a randomised controlled trial 
Background
The additional benefit of lifestyle interventions in patients receiving cardioprotective drug treatment to improve cardiovascular risk profile is not fully established.
The objective was to evaluate the effectiveness of a target-driven multidisciplinary structured lifestyle intervention programme of 6 months duration aimed at maximum reduction of cardiovascular risk factors in patients with cardiovascular disease (CVD) compared with usual care.
Methods
A single centre, two arm, parallel group randomised controlled trial was performed. Patients with stable established CVD and at least one lifestyle-related risk factor were recruited from the vascular and cardiology outpatient departments of the university hospital. Blocked randomisation was used to allocate patients to the intervention (n = 71) or control group (n = 75) using an on-site computer system combined with allocations in computer-generated tables of random numbers kept in a locked computer file. The intervention group received the comprehensive lifestyle intervention offered in a specialised outpatient clinic in addition to usual care. The control group continued to receive usual care. Outcome measures were the lifestyle-related cardiovascular risk factors: smoking, physical activity, physical fitness, diet, blood pressure, plasma total/HDL/LDL cholesterol concentrations, BMI, waist circumference, and changes in medication.
Results
The intervention led to increased physical activity/fitness levels and an improved cardiovascular risk factor profile (reduced BMI and waist circumference). In this setting, cardiovascular risk management for blood pressure and lipid levels by prophylactic treatment for CVD in usual care was already close to optimal as reflected in baseline levels. There was no significant improvement in any other risk factor.
Conclusions
Even in CVD patients receiving good clinical care and using cardioprotective drug treatment, a comprehensive lifestyle intervention had a beneficial effect on some cardiovascular risk factors. In the present era of cardiovascular therapy and with the increasing numbers of overweight and physically inactive patients, this study confirms the importance of risk factor control through lifestyle modification as a supplement to more intensified drug treatment in patients with CVD.
Trial registration
ISRCTN69776211 at http://www.controlled-trials.com
doi:10.1186/1471-2261-12-71
PMCID: PMC3479017  PMID: 22962863
Cardiovascular diseases; Lifestyle intervention; Smoking; Physical activity; Diet; Health behaviour; Randomised controlled trial; Cardiology; Therapy; Cardiovascular risk management
12.  SCN5A Mutations in Brugada Syndrome Are Associated with Increased Cardiac Dimensions and Reduced Contractility 
PLoS ONE  2012;7(8):e42037.
Background
The cardiac sodium channel (Nav1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Nav1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Nav1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Nav1.5 is involved in maintaining cardiac structural integrity.
Methods
Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers.
Results
SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers.
Conclusions
Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis.
doi:10.1371/journal.pone.0042037
PMCID: PMC3410911  PMID: 22876298
13.  Parametric imaging of myocardial viability using 15O-labelled water and PET/CT: comparison with late gadolinium-enhanced CMR 
Purpose
The perfusable tissue index (PTI) is a marker of myocardial viability. Recent technological advances have made it possible to generate parametric PTI images from a single [15O]H2O PET/CT scan. The purpose of this study was to validate these parametric PTI images.
Methods
The study population comprised 46 patients with documented or suspected coronary artery disease who were studied with [15O]H2O PET and late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR).
Results
Of the 736 myocardial segments included, 364 showed some degree of LGE. PTI and perfusable tissue fraction (PTF) diminished with increasing LGE. The areas under the curve of the PTI and PTF, used to predict (near) transmural LGE on CMR, were 0.86 and 0.87, respectively. Optimal sensitivity and specificity were 91 % and 73 % for PTI and 69 % and 87 % for PTF, respectively.
Conclusion
PTI and PTF assessed with a single [15O]H2O scan can be utilized as markers of myocardial viability in patients with coronary artery disease.
doi:10.1007/s00259-012-2134-8
PMCID: PMC3388258  PMID: 22576999
PET/CT; CMR; Perfusable tissue index; Late gadolinium enhancement
14.  Improved clinical outcome after invasive management of patients with recent myocardial infarction and proven myocardial viability: primary results of a randomized controlled trial (VIAMI-trial) 
Trials  2012;13:1.
Background
Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia, especially when viability in the infarct-area is present. Therefore, an invasive strategy with PCI of the infarct-related coronary artery in patients with viability would reduce the occurrence of a composite end point of death, reinfarction, or unstable angina (UA).
Methods
Patients admitted with an (sub)acute myocardial infarction, who were not treated by primary or rescue PCI, and who were stable during the first 48 hours after the acute event, were screened for the study. Eventually, we randomly assigned 216 patients with viability (demonstrated with low-dose dobutamine echocardiography) to an invasive or a conservative strategy. In the invasive strategy stenting of the infarct-related coronary artery was intended with abciximab as adjunct treatment. Seventy-five (75) patients without viability served as registry group. The primary endpoint was the composite of death from any cause, recurrent myocardial infarction (MI) and unstable angina at one year. As secondary endpoint the need for (repeat) revascularization procedures and anginal status were recorded.
Results
The primary combined endpoint of death, recurrent MI and unstable angina was 7.5% (8/106) in the invasive group and 17.3% (19/110) in the conservative group (Hazard ratio 0.42; 95% confidence interval [CI] 0.18-0.96; p = 0.032). During follow up revascularization-procedures were performed in 6.6% (7/106) in the invasive group and 31.8% (35/110) in the conservative group (Hazard ratio 0.18; 95% CI 0.13-0.43; p < 0.0001). A low rate of recurrent ischemia was found in the non-viable group (5.4%) in comparison to the viable-conservative group (14.5%). (Hazard-ratio 0.35; 95% CI 0.17-1.00; p = 0.051).
Conclusion
We demonstrated that after acute MI (treated with thrombolysis or without reperfusion therapy) patients with viability in the infarct-area benefit from a strategy of early in-hospital stenting of the infarct-related coronary artery. This treatment results in a long-term uneventful clinical course. The study confirmed the low risk of recurrent ischemia in patients without viability.
Trial registration
ClinicalTrials.gov: NCT00149591.
doi:10.1186/1745-6215-13-1
PMCID: PMC3261086  PMID: 22214287
15.  Quantitative relationship between coronary artery calcium score and hyperemic myocardial blood flow as assessed by hybrid 15O-water PET/CT imaging in patients evaluated for coronary artery disease 
Journal of Nuclear Cardiology  2011;19(2):256-264.
Background
The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.
Methods
We evaluated 173 (mean age 56 ± 10, 78 men) patients with a low to intermediate likelihood for coronary artery disease (CAD), without a documented history of CAD, undergoing vasodilator stress 15O-water PET/CT and CAC scoring. Obstructive coronary artery disease was excluded by means of invasive (n = 44) or CT-based coronary angiography (n = 129).
Results
91 of 173 patients (52%) had a CAC score of zero. Of those with CAC, the CAC score was 0.1-99.9, 100-399.9, and ≥400 in 31%, 12%, and 5% of patients, respectively. Global CAC score showed significant inverse correlation with hyperemic MBF (r = −0.32, P < .001). With increasing CAC score, there was a decline in hyperemic MBF on a per-patient basis [3.70, 3.30, 2.68, and 2.53 mL · min−1 · g−1, with total CAC score of 0, 0.1-99.9, 100-399.9, and ≥400, respectively (P < .001)]. CFR showed a stepwise decline with increasing levels of CAC (3.70, 3.32, 2.94, and 2.93, P < .05). Multivariate analysis, including age, BMI, and CAD risk factors, revealed that only age, male gender, BMI, and hypercholesterolemia were associated with reduced stress perfusion. Furthermore, only diabetes and age were independently associated with CFR.
Conclusion
In patients without significant obstructive CAD, a greater CAC burden is associated with a decreased hyperemic MBF and CFR. However, this association disappeared after adjustment for traditional CAD risk factors. These results suggest that CAC does not add incremental value regarding hyperemic MBF and CFR over established CAD risk factors in patients without obstructive CAD.
doi:10.1007/s12350-011-9476-7
PMCID: PMC3313028  PMID: 22076826
Coronary artery calcium; hyperemic myocardial blood flow; coronary risk factors
16.  Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction (EXAMI): study protocol for a randomized controlled trial 
Trials  2011;12:240.
Background
Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.
Methods
The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).
Discussion
If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.
Trial registration
ClinicalTrials.gov: NCT01254123
doi:10.1186/1745-6215-12-240
PMCID: PMC3235971  PMID: 22067476
exenatide; glucagon-like peptide 1; myocardial infarction; reperfusion injury
17.  Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease: a quantitative [15O]H2O PET/CT study 
Background
There has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.
Methods
A total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.
Results
Global average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30  ml·min−1·g−1 (range 0.54–2.35  and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.
Conclusion
Gender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
doi:10.1007/s00259-011-1956-0
PMCID: PMC3227802  PMID: 22005845
Myocardial blood flow; Positron emission tomography; Non-obstructive CAD; CAD risk factors; Gender
18.  Feasibility of subendocardial and subepicardial myocardial perfusion measurements in healthy normals with 15O-labeled water and positron emission tomography 
Journal of Nuclear Cardiology  2011;18(4):650-656.
Background
Positron emission tomography (PET) enables robust and reproducible measurements of myocardial blood flow (MBF). However, the relatively limited resolution of PET till recently prohibited distinction between the subendocardial and the subepicardial layers in non-hypertrophied myocardium. Recent developments in hard- and software, however, have enabled to identify a transmural gradient difference in animal experiments. The aim of this study is to determine the feasibility of subendocardial and subepicardial MBF in normal human hearts assessed with 15O-labeled water PET.
Methods
Twenty-seven healthy subjects (mean age 41 ± 13 years; 11 men) were studied with 15O-labeled water PET to quantify resting and hyperaemic (adenosine) MBF at a subendocardial and subepicardial level. In addition, cardiac magnetic resonance imaging was performed to determine left ventricular (LV) volumes and function.
Results
Mean rest MBF was 1.46 ± 0.49 in the subendocardium, and 1.14 ± 0.342 mL · min−1 · g−1 in the subepicardium (P < .001). MBF during vasodilation was augmented to a greater extent at the subepicardial level (subendocardium vs subepicardium: 3.88 ± 0.86 vs 4.14 ± 0.88 mL · min−1 · g−1, P = .013). The endocardial-to-epicardial MBF ratio decreased significantly during hyperaemia (1.35 ± 0.23 to 1.12 ± 0.20, P < .001). Hyperaemic transmural MBF was inversely correlated with left ventricular end-diastolic volume index (LVEDVI) (r2 = 0.41, P = .0003), with greater impact however at the subendocardial level.
Conclusions
15O-labeled water PET enables MBF measurements with distinction of the subendocardial and subepicardial layers in the normal human heart and correlates with LVEDVI. This PET technique may prove useful in evaluating patients with signs of ischaemia due to coronary artery disease or microvascular dysfunction.
doi:10.1007/s12350-011-9375-y
PMCID: PMC3143328  PMID: 21519976
Positron emission tomography; imaging; coronary microcirculation; myocardial blood flow; subendocardial
19.  Sequence optimization to reduce velocity offsets in cardiovascular magnetic resonance volume flow quantification - A multi-vendor study 
Purpose
Eddy current induced velocity offsets are of concern for accuracy in cardiovascular magnetic resonance (CMR) volume flow quantification. However, currently known theoretical aspects of eddy current behavior have not led to effective guidelines for the optimization of flow quantification sequences. This study is aimed at identifying correlations between protocol parameters and the resulting velocity error in clinical CMR flow measurements in a multi-vendor study.
Methods
Nine 1.5T scanners of three different types/vendors were studied. Measurements were performed on a large stationary phantom. Starting from a clinical breath-hold flow protocol, several protocol parameters were varied. Acquisitions were made in three clinically relevant orientations. Additionally, a time delay between the bipolar gradient and read-out, asymmetric versus symmetric velocity encoding, and gradient amplitude and slew rate were studied in adapted sequences as exploratory measurements beyond the protocol. Image analysis determined the worst-case offset for a typical great-vessel flow measurement.
Results
The results showed a great variation in offset behavior among scanners (standard deviation among samples of 0.3, 0.4, and 0.9 cm/s for the three different scanner types), even for small changes in the protocol. Considering the absolute values, none of the tested protocol settings consistently reduced the velocity offsets below the critical level of 0.6 cm/s neither for all three orientations nor for all three scanner types. Using multilevel linear model analysis, oblique aortic and pulmonary slices showed systematic higher offsets than the transverse aortic slices (oblique aortic 0.6 cm/s, and pulmonary 1.8 cm/s higher than transverse aortic). The exploratory measurements beyond the protocol yielded some new leads for further sequence development towards reduction of velocity offsets; however those protocols were not always compatible with the time-constraints of breath-hold imaging and flow-related artefacts.
Conclusions
This study showed that with current systems there was no generic protocol which resulted into acceptable flow offset values. Protocol optimization would have to be performed on a per scanner and per protocol basis. Proper optimization might make accurate (transverse) aortic flow quantification possible for most scanners. Pulmonary flow quantification would still need further (offline) correction.
doi:10.1186/1532-429X-13-18
PMCID: PMC3065419  PMID: 21388521
24.  Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness 
Background
Increased left ventricular (LV) torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM), and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness.
Methods
Seventeen carriers with an LV wall thickness <10 mm, and seventeen age and gender matched controls had cardiovascular magnetic resonance (CMR) cine imaging and tissue tagging. LV volumes and mass were calculated from the cine images. LV torsion, torsion rate, endocardial circumferential strain and torsion-to-endocardial-circumferential-shortening (TECS) ratio, which reflects the transmural distribution in contractile function, were determined using tissue tagging.
Results
LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively).
Conclusions
Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.
doi:10.1186/1532-429X-13-3
PMCID: PMC3025877  PMID: 21219655
25.  How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance 
Background
Clinical data on myocardial function in HCM mutation carriers (carriers) is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormalities using cardiovascular magnetic resonance (CMR), and to investigate if sensitive functional assessment could be employed to identify carriers.
Results
28 carriers and 28 controls were studied. Global left atrial (LA) and left ventricular (LV) dimensions, segmental peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR), as well as the presence of late Gadolinium enhancement (LGE) were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. lv mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio) was larger in carriers than in controls (1.3 ± 0.2 versus 1.1 ± 0.1, p < 0.001). Also, LA volumes were larger in carriers compared to controls (p < 0.05). Both peak SCS (p < 0.05) and peak DCSR (p < 0.01) were lower in carriers compared to controls, particularly in the basal lateral wall. Focal LGE was present in 2 carriers and not in controls. The combination of a SL ratio >1.2 and a peak DCSR <105%.s-1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio < 1.2 and peak DCSR >105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR.
Conclusions
HCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.
doi:10.1186/1532-429X-12-13
PMCID: PMC2842263  PMID: 20230637

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