Paul Knaapen

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Left ventricular torsion: an expanding role in the analysis of myocardial dysfunction.

During left ventricular (LV) torsion, the base rotates in an overall clockwise direction and the apex rotates in a counterclockwise direction when viewed from apex to base. LV torsion is followed by rapid untwisting, which contributes to ventricular filling. Because LV torsion is directly related to fiber orientation, it might depict subclinical abnormalities in heart function. Recently, ultrasound speckle tracking was introduced for quantification of LV torsion. This fast, widely available technique may contribute to a more rapid introduction of LV torsion as a clinical tool for detection of myocardial dysfunction. However, knowledge of the exact function and structure of the heart is fundamental for understanding the value of LV torsion. LV torsion has been investigated with different measurement methods during the past 2 decades, using cardiac magnetic resonance as the gold standard. The results obtained over the years are helpful for developing a standardized method to quantify LV torsion and have facilitated the interpretation and value of LV torsion before it can be used as a clinical tool.

Myocardial Energetics and Efficiency Current Status of the Noninvasive Approach

The heart is an aerobic organ that relies almost exclusively on the aerobic oxidation of substrates for generation of energy. Consequently, there is close coupling between myocardial oxygen consumption (MVo2) and the main determinants of systolic function: heart rate, contractile state, and wall stress.1 As in any mechanical pump, only part of the energy invested is converted to external power. In the case of the heart, the ratio of useful energy produced (ie, stroke work [SW]) to oxygen consumed is defined as mechanical efficiency, as originally proposed by Bing et al.2 Under normal conditions this ratio is ≈25%, and the residual energy mainly dissipates as heat.3 In pathophysiological disease states, such as heart failure, mechanical efficiency is reduced, and it has been hypothesized that the increased energy expenditure relative to work contributes to progression of the disease.4,5 Moreover, therapeutic interventions that enhance mechanical efficiency have proven to be beneficial with respect to outcome.6 It is therefore desirable to quantify efficiency of the heart to study disease processes and monitor interventions. Both cardiac oxidative metabolism and mechanical work, and thus efficiency, can be quantified through invasive measurements. Although these measurements are accurate and currently considered the gold standard, in clinical practice they are limited because of the need for dual-sided heart catheterization and selective catheterization of the coronary sinus. Recent advances in imaging techniques, however, offer the possibility to noninvasively estimate MVo2 and mechanical work by positron emission tomography and echocardiography or by magnetic resonance imaging, respectively. This review discusses the principles of mechanical efficiency, together with its invasive and noninvasive assessment, as well as their strengths and pitfalls. Finally, results from clinical pathophysiological studies are discussed. To calculate the efficiency of the heart, input and output energy must be obtained. The …

Carbon-11 acetate as a tracer of myocardial oxygen consumption

Abstract. Estimation of myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) is important for the understanding of various (patho)physiological mechanisms and diseases. Clearance rates of carbon-11 labelled acetate, determined with positron emission tomography, allow estimation of MVO2 on a segmental level and non-invasively. In addition, MBF can be determined from uptake rates. In this review, the background to estimation of MVO2 and MBF is discussed, as well as the currently available literature that has used 11C-acetate to estimate MVO2 and MBF.

Hybrid Imaging Using Quantitative H215O PET and CT-Based Coronary Angiography for the Detection of Coronary Artery Disease

Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H215O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H215O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H215O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H215O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H215O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H215O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H215O PET/CTCA is superior to either H215O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.

Coronary microvascular resistance: methods for its quantification in humans

Coronary microvascular dysfunction is a topic that has recently gained considerable interest in the medical community owing to the growing awareness that microvascular dysfunction occurs in a number of myocardial disease states and has important prognostic implications. With this growing awareness, comes the desire to accurately assess the functional capacity of the coronary microcirculation for diagnostic purposes as well as to monitor the effects of therapeutic interventions that are targeted at reversing the extent of coronary microvascular dysfunction. Measurements of coronary microvascular resistance play a pivotal role in achieving that goal and several invasive and noninvasive methods have been developed for its quantification. This review is intended to provide an update pertaining to the methodology of these different imaging techniques, including the discussion of their strengths and weaknesses.

Diagnostic accuracy of quantitative H215O PET measurements of hyperemic myocardial blood flow versus coronary flow reserve for the detection of obstructive coronary artery disease

Triple-negative breast cancer, an aggressive subtype, represents 15% of invasive breast tumors. This prospective study investigated whether early changes in 18F-FDG tumor uptake during neoadjuvant chemotherapy (NAC) can predict outcomes. Methods: Twenty (M0) patients underwent 18F-FDG PET/CT at baseline and after the second cycle. NAC was continued irrespective of PET results. Results: At surgery, 6 patients had a pathologic complete response, whereas 14 had residual tumor. Four patients showed early relapse (in the 2 y after surgery). There were 11 metabolic responders and 9 nonresponders using a 42% decrease in maximum standardized uptake value as a cutoff. In nonresponding patients, the risk of residual tumor at surgery was 100% (vs. 45% in responders; P = 0.014), and the risk of early relapse was 44% (vs. 0%; P = 0.024). Conclusion: A less than 42% decrease in 18F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse.

Automatic generation of absolute myocardial blood flow images using [15O]H2O and a clinical PET/CT scanner

PurposeParametric imaging of absolute myocardial blood flow (MBF) using [15O]H2O enables determination of MBF with high spatial resolution. The aim of this study was to develop a method for generating reproducible, high-quality and quantitative parametric MBF images with minimal user intervention.MethodsNineteen patients referred for evaluation of MBF underwent rest and adenosine stress [15O]H2O positron emission tomography (PET) scans. Ascending aorta and right ventricular (RV) cavity volumes of interest (VOIs) were used as input functions. Implementation of a basis function method (BFM) of the single-tissue model with an additional correction for RV spillover was used to generate parametric images. The average segmental MBF derived from parametric images was compared with MBF obtained using nonlinear least-squares regression (NLR) of VOI data. Four segmentation algorithms were evaluated for automatic extraction of input functions. Segmental MBF obtained using these input functions was compared with MBF obtained using manually defined input functions.ResultsThe average parametric MBF showed a high agreement with NLR-derived MBF [intraclass correlation coefficient (ICC) = 0.984]. For each segmentation algorithm there was at least one implementation that yielded high agreement (ICC > 0.9) with manually obtained input functions, although MBF calculated using each algorithm was at least 10% higher. Cluster analysis with six clusters yielded the highest agreement (ICC = 0.977), together with good segmentation reproducibility (coefficient of variation of MBF <5%).ConclusionParametric MBF images of diagnostic quality can be generated automatically using cluster analysis and a implementation of a BFM of the single-tissue model with additional RV spillover correction.

Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis

Aims The aim of this study was to determine the diagnostic performance of single-photon emission computed tomography (SPECT), stress echocardiography (SE), invasive coronary angiography (ICA), coronary computed tomography angiography (CCTA), fractional flow reserve (FFR) derived from CCTA (FFRCT), and cardiac magnetic resonance (MRI) imaging when directly compared with an FFR reference standard. Method and results PubMed and Web of Knowledge were searched for investigations published between 1 January 2002 and 28 February 2015. Studies performing FFR in at least 75% of coronary vessels for the diagnosis of ischaemic coronary artery disease (CAD) were included. Twenty-three articles reporting on 3788 patients and 5323 vessels were identified. Meta-analysis was performed for pooled sensitivity, specificity, likelihood ratios (LR), diagnostic odds ratio, and summary receiver operating characteristic curves. In contrast to ICA, CCTA, and FFRCT reports, studies evaluating SPECT, SE, and MRI were largely retrospective, single-centre and with generally smaller study samples. On a per-patient basis, the sensitivity of CCTA (90%, 95% CI: 86–93), FFRCT (90%, 95% CI: 85–93), and MRI (90%, 95% CI: 75–97) were higher than for SPECT (70%, 95% CI: 59–80), SE (77%, 95% CI: 61–88), and ICA (69%, 95% CI: 65–75). The highest and lowest per-patient specificity was observed for MRI (94%, 95% CI: 79–99) and for CCTA (39%, 95% CI: 34–44), respectively. Similar specificities were noted for SPECT (78%, 95% CI: 68–87), SE (75%, 95% CI: 63–85), FFRCT (71%, 95% CI: 65–75%), and ICA (67%, 95% CI: 63–71). On a per-vessel basis, the highest sensitivity was for CCTA (pooled sensitivity, 91%: 88–93), MRI (91%: 84–95), and FFRCT (83%, 78–87), with lower sensitivities for ICA (71%, 69–74), and SPECT (57%: 49–64). Per-vessel specificity was highest for MRI (85%, 79–89), FFRCT (78%: 78–81), and SPECT (75%: 69–80), whereas ICA (66%: 64–68) and CCTA (58%: 55–61) yielded a lower specificity. Conclusions In this meta-analysis comparing cardiac imaging methods directly to FFR, MRI had the highest performance for diagnosis of ischaemia-causing CAD, with lower performance for SPECT and SE. Anatomic methods of CCTA and ICA yielded lower specificity, with functional assessment of coronary atherosclerosis by SE, SPECT, and FFRCT improving accuracy.

Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment: a report from the Iberian-Dutch-English (IDEAL) collaborators

Abstract Background Our understanding of human coronary physiological behaviour is derived from animal models. We sought to describe physiological behaviour across a large collection of invasive pressure and flow velocity measurements, to provide a better understanding of the relationships between these physiological parameters and to evaluate the rationale for resting stenosis assessment. Methods and results Five hundred and sixty-seven simultaneous intracoronary pressure and flow velocity assessments from 301 patients were analysed for coronary flow velocity, trans-stenotic pressure gradient (TG), and microvascular resistance (MVR). Measurements were made during baseline and hyperaemic conditions. The whole cardiac cycle and the diastolic wave-free period were assessed. Stenoses were assessed according to fractional flow reserve (FFR) and quantitative coronary angiography DS%. With progressive worsening of stenoses, from unobstructed angiographic normal vessels to those with FFR ≤ 0.50, hyperaemic flow falls significantly from 45 to 19 cm/s, Ptrend < 0.001 in a curvilinear pattern. Resting flow was unaffected by stenosis severity and was consistent across all strata of stenosis ( Ptrend > 0.05 for all). Trans-stenotic pressure gradient rose with stenosis severity for both rest and hyperaemic measures ( Ptrend < 0.001 for both). Microvascular resistance declines with stenosis severity under resting conditions ( Ptrend < 0.001), but was unchanged at hyperaemia (2.3 ± 1.1 mmHg/cm/s; Ptrend = 0.19). Conclusions With progressive stenosis severity, TG rises. However, while hyperaemic flow falls significantly, resting coronary flow is maintained by compensatory reduction of MVR, demonstrating coronary auto-regulation. These data support the translation of coronary physiological concepts derived from animals to patients with coronary artery disease and furthermore, suggest that resting pressure indices can be used to detect the haemodynamic significance of coronary artery stenoses.