Mischa T. Rijnierse

Relative Flow Reserve Derived From Quantitative Perfusion Imaging May Not Outperform Stress Myocardial Blood Flow for Identification of Hemodynamically Significant Coronary Artery Disease

Background—Quantitative myocardial perfusion imaging is increasingly used for the diagnosis of coronary artery disease. Quantitative perfusion imaging allows to noninvasively calculate fractional flow reserve (FFR). This so-called relative flow reserve (RFR) is defined as the ratio of hyperemic myocardial blood flow (MBF) in a stenotic area to hyperemic MBF in a normal perfused area. The aim of this study was to assess the value of RFR in the detection of significant coronary artery disease. Methods and Results—From a clinical population of patients with suspected coronary artery disease who underwent oxygen-15–labeled water cardiac positron emission tomography and invasive coronary angiography, 92 patients with single- or 2-vessel disease were included. Intermediate lesions (diameter stenosis, 30%–90%; n=75) were interrogated by FFR. Thirty-eight (41%) vessels were deemed hemodynamically significant (>90% stenosis or FFR ⩽0.80). Hyperemic MBF, coronary flow reserve, and RFR were lower for vessels with a hemodynamically significant lesion (2.01±0.78 versus 2.90±1.16 mL·min−1·g−1; P<0.001, 2.27±1.03 versus 3.10±1.29; P<0.001, and 0.67±0.23 versus 0.93±0.15; P<0.001, respectively). The correlation between RFR and FFR was moderate (r=0.54; P<0.01). Receiver operator characteristic curve analysis showed an area under the curve of 0.82 for RFR, which was not significantly higher compared with that for hyperemic MBF and coronary flow reserve (0.76; P=0.32 and 0.72; P=0.08, respectively). Conclusions—Noninvasive estimation of FFR by quantitative perfusion positron emission tomography by calculating RFR is feasible, yet only a trend toward a slight improvement of diagnostic accuracy compared with hyperemic MBF assessment was determined.

Impaired Hyperemic Myocardial Blood Flow Is Associated With Inducibility of Ventricular Arrhythmia in Ischemic Cardiomyopathy

Background—Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy. Methods and Results—Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65±8 years old; left ventricular ejection fraction, 29±6%). [15O]H2O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25±0.30 versus 1.66±0.38 mL·min−1·g−1; P<0.01) and coronary flow reserve (1.59±0.49 versus 2.12±0.48; P<0.01) compared with electrophysiological study negative patients (n=18). In electrophysiological study positive patients, the number of scar segments >75% transmurality was higher (P<0.05), although scar size and border zone did not differ. Receiver-operating characteristic curve analysis indicated that impaired hyperemic MBF (area under the curve, 0.84; 95% confidence intervals [0.69–0.99]) and coronary flow reserve (area under the curve, 0.77; 95% confidence intervals [0.57–0.96]) were associated with VA inducibility. Conclusions—In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs.

Quantification of [ 11 C]- meta -hydroxyephedrine uptake in human myocardium

BackgroundThe aims of this study were to determine the optimal tracer kinetic model for [11C]-meta- hydroxyephedrine ([11C]HED) and to evaluate the performance of several simplified methods.MethodsThirty patients underwent dynamic 60-min [11C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (VT) data.ResultsThe reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, VT derived using the single-tissue model correlated highly with that of the two-tissue model (r2 = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in VT. RI and SUV can provide misleading results because of non-linear relationships with VT.ConclusionsAlthough the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with VT, and therefore, care has to be taken when using RI as a quantitative measure.

Prevalence of ischaemia in patients with a chronic total occlusion and preserved left ventricular ejection fraction.

Aims Previous studies on invasive assessment of collateral function in patients with a chronic total occlusion (CTO) have displayed only a limited increase in collateral flow and high occurrence of coronary steal during pharmacological stress. This could question the necessity for ischaemia testing prior to revascularization of CTOs in the presence of myocardial viability. The purpose of the present study was to determine the prevalence of perfusion impairments in patients with a CTO as assessed by [15O]H2O positron emission tomography (PET). Methods and results Seventy-six consecutive patients (60 men, 62 ± 10 years) with a documented CTO and preserved left ventricular ejection fraction (LVEF) were included. All patients underwent PET to assess (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR). Collateral connection score was 0 in 7 (9%), 1 in 13 (17%), and 2 in 56 (74%) of the cases, with predominantly a high Rentrop grade (96% ≥2). MBF of the target area during hyperaemia was significantly lower when compared with the remote area (1.37 ± 0.37 vs. 2.63 ± 0.71 mL min-1 g-1, P < 0.001). Target to remote ratio during hyperaemia was on average 0.54 ± 0.13, and 73 (96%) patients demonstrated a significantly impaired target to remote ratio (≤0.75). Only 7 (9%) patients displayed a preserved CFR of ≥2.50, whereas coronary steal (CFR <1.0) was observed in 10 (13%) patients. Conclusions Even in the presence of angiographically well-developed collateral arteries, the vast majority of CTO patients with a preserved LVEF showed significantly impaired perfusion. These results suggest that collateral function during increased blood flow demand in viable myocardium is predominantly insufficient.

Principles and techniques of imaging in identifying the substrate of ventricular arrhythmia

Life-threatening ventricular arrhythmias (VA) are a major cause of death in patients with cardiomyopathy. To date, impaired left ventricular ejection fraction remains the primary criterion for implantable cardioverter-defibrillator therapy to prevent sudden cardiac death. In recent years, however, advanced imaging techniques such as nuclear imaging, cardiac magnetic resonance imaging, and computed tomography have allowed for a more detailed evaluation of the underlying substrate of VA. These imaging modalities have emerged as a promising approach to assess the risk of sudden cardiac death. In addition, non-invasive identification of the critical sites of arrhythmias may guide ablation therapy. Typical anatomical substrates that can be evaluated by multiple advanced imaging techniques include perfusion abnormalities, scar and its border zone, and sympathetic denervation. Understanding the principles and techniques of different imaging modalities is essential to gain more insight in their role in identifying the arrhythmic substrate. The current review describes the principles of currently available imaging techniques to identify the substrate of VA.

Non-invasive imaging to identify susceptibility for ventricular arrhythmias in ischaemic left ventricular dysfunction

Objective Non-invasive imaging of myocardial perfusion, sympathetic denervation and scar size contribute to enhanced risk prediction of ventricular arrhythmias (VA). Some of these imaging parameters, however, may be intertwined as they are based on similar pathophysiology. The aim of this study was to assess the predictive role of myocardial perfusion, sympathetic denervation and scar size on the inducibility of VA in patients with ischaemic cardiomyopathy in a head-to-head fashion. Methods 52 patients with ischaemic heart disease and left ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention implantable cardioverter-defibrillator (ICD) implantation, were included. Late gadolinium-enhanced cardiovascular MRI was performed to assess LV volumes, function and scar size. Using [15O]H2O and [11C]hydroxyephedrine positron emission tomography, both resting and hyperaemic myocardial blood flow (MBF), and sympathetic innervation were assessed. After ICD implantation, an electrophysiological study (EPS) was performed and was considered positive in case of sustained VA. Results Patients with a positive EPS (n=25) showed more severely impaired global hyperaemic MBF (p=0.003), larger sympathetic denervation size (p=0.048) and tended to have larger scar size (p=0.07) and perfusion defect size (p=0.06) compared with EPS-negative patients (n=27). No differences were observed in LV volumes, LVEF and innervation-perfusion mismatch size. Multivariable analysis revealed that impaired hyperaemic MBF was the single best independent predictor for VA inducibility (OR 0.78, 95% CI 0.65 to 0.94, p=0.007). A combination of risk markers did not yield incremental predictive value over hyperaemic MBF alone. Conclusions Of all previously validated approaches to evaluate the arrhythmic substrate, global impaired hyperaemic MBF was the only independent predictor of VA inducibility. Moreover, a combined approach of different imaging variables did not have incremental value.

Noninvasive Quantification of Myocardial 11C-Meta-Hydroxyephedrine Kinetics

11C-meta-hydroxyephedrine (11C-HED) kinetics in the myocardium can be quantified using a single-tissue-compartment model together with a metabolite-corrected arterial blood sampler input function (BSIF). The need for arterial blood sampling, however, limits clinical applicability. The purpose of this study was to investigate the feasibility of replacing arterial sampling with imaging-derived input function (IDIF) and venous blood samples. Methods: Twenty patients underwent 60-min dynamic 11C-HED PET/CT scans with online arterial blood sampling. Thirteen of these patients also underwent venous blood sampling. Data were reconstructed using both 3-dimensional row-action maximum-likelihood algorithm (3DR) and a time-of-flight (TF) list-mode reconstruction algorithm. For each reconstruction, IDIF results were compared with BSIF results. In addition, IDIF results obtained with venous blood samples and with a transformed venous-to-arterial metabolite correction were compared with results obtained with arterial metabolite corrections. Results: Correlations between IDIF- and BSIF-derived K1 and VT were high (r2 > =0.89 for 3DR and TF). Slopes of the linear fits were significantly different from 1 for K1, for both 3DR (slope = 0.94) and TF (slope = 1.06). For VT, the slope of the linear fit was different from 1 for TF (slope = 0.93) but not for 3DR (slope = 0.98). Use of venous blood data introduced a large bias in VT (r2 = 0.96, slope = 0.84) and a small bias in K1 (r2 = 0.99, slope = 0.98). Use of a second-order polynomial venous-to-arterial transformation was robust and greatly reduced bias in VT (r2 = 0.97, slope = 0.99) with no effect on K1. Conclusion: IDIF yielded precise results for both 3DR and TF. Venous blood samples can be used for absolute quantification of 11C-HED studies, provided a venous-to-arterial transformation is applied. A venous-to-arterial transformation enables noninvasive, absolute quantification of 11C-HED studies.

Measurement of LV Volumes and Function Using Oxygen-15 Water-Gated PET and Comparison With CMR Imaging

Myocardial perfusion imaging using positron emission tomography (PET) is a valuable tool in the diagnosis of coronary artery disease. And although PET using [15O]H2O has a high diagnostic accuracy for predicting coronary artery disease in routine clinical practices [(1)][1], left ventricular (LV)

PREVALENCE OF ISCHEMIA IN PATIENTS WITH A CHRONIC TOTAL OCCLUSION AND PRESERVED LEFT VENTRICULAR EJECTION FRACTION

Chronic total occlusions (CTO) with well functioning collaterals are frequently assumed to provide sufficient blood flow to prevent myocardial ischemia. Previous studies on invasive assessment of collateral function during pharmalogical stress, however, have displayed only a limited increase in

SYMPATHETIC DENERVATION IS ASSOCIATED WITH MICROVASCULAR DYSFUNCTION IN NON-INFARCTED MYOCARDIUM IN PATIENTS WITH CARDIOMYOPATHY

Sympathetic denervation typically occurs in the infarcted myocardium and is associated with sudden cardiac death. Impaired innervation was also demonstrated in non-infarcted myocardium in ischaemic and dilated cardiomyopathy (ICMPandDCMP). Factors affecting sympatheticnerveintegrity inremotemyocardium areunknown. Perfusionabnor- malities,evenintheabsenceofepicardialcoronaryarterydisease,mayrelatetosympatheticdysfunction.Thisstudywas aimed to assess the interrelations of myocardial blood flow (MBF), contractile function, and sympathetic innervation in non-infarcted remote myocardium. Seventy patients with ICMP or DCMP and LVEF ≤35% were included. ( 15 O)H2O- and ( 11 C)hydroxyephedrine (HED)PETwasperformedtoquantify restingMBF,hyperaemicMBF,andsympatheticinnervation.Cardiovascularmag- neticresonance(CMR)imagingwasperformedtoassessleftventricularfunction,mass,wallthickening,andscarsize.Wall thickening, ( 11 C)HED retention index (RI), and MBF wereassessed in remote segments without scar, selected on CMR. ( 11 C)HEDRIwascorrelatedwithrestingMBF(r ¼ 0.41,P , 0.001)andhyperaemicMBF(r ¼ 0.55,P , 0.001)inremote myocardiuminbothICMPandDCMP.Inaddition,LVvolumes(r ¼ 20.40,P ¼ 0.001),LVmass(r ¼ 20.31,P ¼ 0.008), andwallthickening(r ¼ 0.45,P , 0.001)correlatedwithremote( 11 C)HEDRI.Multivariableanalysisrevealedthathyper- aemic MBF (B ¼ 0.79, P , 0.001), wall thickening (B ¼ 0.01, P ¼ 0.03), and LVEDV (B ¼ 20.03, P ¼ 0.02) were inde- pendent predictors for remote ( 11 C)HED RI. Conclusion Hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted remote myocardium in patients with ICMP and DCMP. This suggests that microvascular dysfunction might be an important factor related to sympathetic nerve integrity. Whether impaired hyperaemic MBF is the primary cause of this relation remains unclear.