Jason M. Tarkin

Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study.

OBJECTIVES The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity. BACKGROUND Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. METHODS A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine. RESULTS Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively. CONCLUSIONS Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).

PET imaging of inflammation in atherosclerosis

PET imaging of atherosclerosis can quantify several in vivo pathological processes occurring within the arterial system. 18F-fluorodeoxyglucose (FDG) is the most-commonly used PET tracer, with well-established roles in atherosclerosis imaging. In this context, the 18F-FDG signal largely reflects tracer uptake by plaque macrophages and, therefore, inflammation with smaller contributions from other resident cell types. As a marker of plaque vulnerability, the 18F-FDG PET signal can be used to help to identify patients at the highest risk of clinical events. 18F-FDG PET has also been used successfully as a surrogate end point in clinical trials of antiatherosclerotic therapies. Nonetheless, imaging atherosclerosis with 18F-FDG has several limitations. Most importantly, coronary artery imaging is problematic because 18F-FDG accumulates in all cells that metabolize glucose, and background myocardial uptake is generally greater than any signal originating from a plaque. To help to overcome these limitations, several novel PET tracers, which might be more-specifically targeted than 18F-FDG, have been tested in atherosclerosis imaging. These tracers are designed to track inflammation, hypoxia, neoangiogenesis, or active calcification, which are all precursors to plaque rupture and its clinical sequelae.

Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging

Background Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. Methods We confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis. Results Target SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients. Conclusions We validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques.

Management of Tako-tsubo Syndrome

IntroductionThis manuscript reviews the current evidence for proposed pathophysiological mechanisms of Tako-tsubo syndrome and its management.DiscussionThe Tako-tsubo syndrome is defined by the presence of transient left ventricular apical ballooning after an acute coronary syndrome in patients with angiographically normal coronary arteries. Intriguingly, only the apex is affected and compensatory basal hypercontractility is seen. Several mechanisms have been offered as explanations for the characteristic clinical presentation and echocardiographic appearance of this syndrome.ConclusionTako-tsubo syndrome encompasses heterogeneous patient populations and it is likely that different pathogenic mechanisms may operate in different patients. Treatment of the condition is at present empirical and aimed at preserving ventricular function.

Low Coronary Microcirculatory Resistance Associated With Profound Hypotension During Intravenous Adenosine Infusion Implications for the Functional Assessment of Coronary Stenoses

Background—Intravenous adenosine infusion produces coronary and systemic vasodilatation, generally leading to systemic hypotension. However, adenosine-induced hypotension during stable hyperemia is heterogeneous, and its relevance to coronary stenoses assessment with fractional flow reserve (FFR) remains largely unknown. Methods and Results—FFR, coronary flow reserve, and index of microcirculatory resistance were measured in 93 stenosed arteries (79 patients). Clinical and intracoronary measurements were analyzed among tertiles of the percentage degree of adenosine-induced hypotension, defined as follows: %&Dgr;Pa=–[100–(hyperemic aortic pressure×100/baseline aortic pressure)]. Overall, %&Dgr;Pa was –13.6±12.0%. Body mass index was associated with %&Dgr;Pa (r=0.258; P=0.025) and obesity, an independent predictor of profound adenosine-induced hypotension (tertile 3 of %&Dgr;Pa; odds ratio, 3.95 [95% confidence interval, 1.48–10.54]; P=0.006). %&Dgr;Pa was associated with index of microcirculatory resistance (&rgr;=0.311; P=0.002), coronary flow reserve (r=–0.246; P=0.017), and marginally with FFR (r=0.203; P=0.051). However, index of microcirculatory resistance (&bgr;=0.003; P<0.001) and not %&Dgr;Pa (&bgr;=–0.001; P=0.564) was a predictor of FFR. Compared with tertiles 1 and 2 of %&Dgr;Pa (n=62 [66.6%]), stenoses assessed during profound adenosine-induced hypotension (n=31 [33.3%]) had lower index of microcirculatory resistance (12.4 [8.6–22.7] versus 20 [15.8–35.5]; P=0.001) and FFR values (0.77±0.13 versus 0.83±0.12; P=0.021), as well as a nonsignificant increase in coronary flow reserve (2.5±1.1 versus 2.2±0.87; P=0.170). Conclusions—The modification of systemic blood pressure during intravenous adenosine infusion is related to hyperemic microcirculatory resistance in the heart. Profound adenosine-induced hypotension is associated with obesity, lower coronary microcirculatory resistance, and lower FFR values.

Fractional flow reserve and minimum Pd/Pa ratio during intravenous adenosine infusion: very similar but not always the same

AIMS Maximum and stable hyperaemia are critical prerequisites for the accurate measurement of fractional flow reserve (FFR). However, in some patients in whom hyperaemia is induced through a central vein (IV) the minimum distal coronary pressure to aortic pressure ratio (Pd/Pa ratio) develops before the stabilisation of hyperaemia. We sought to describe the prevalence, magnitude and clinical implications of this phenomenon. METHODS AND RESULTS The FFR tracing archive of a single institution was reviewed and a total of 104 high-quality IV-FFR recordings from 90 patients were identified. Whenever the minimum Pd/Pa ratio was found before the onset of stable hyperaemia, a search for the lowest Pd/Pa ratio within the steady-state hyperaemic plateau was performed and labelled as FFRstable. Whilst in most cases the minimum Pd/Pa ratio developed during stable hyperaemia, in 19 cases (prevalence of 18.3% [95% CI: 12.0% to 26.8%]) this value was found before the stabilisation of the hyperaemic state. In such cases, the minimum Pd/Pa ratio stabilised later at a higher level (0.77±0.09 vs. 0.81±0.08, p<0.001) (mean difference, 0.03±0.02, range, 0.01 to 0.10). In terms of dichotomous classification of stenosis severity and if FFRstable had been used to decide on revascularisation, reclassification would have occurred in three (2.9%) cases, all presenting a minimum Pd/Pa ratio ≤0.80 with FFRstable >0.80. CONCLUSIONS During IV adenosine infusion, the minimum Pd/Pa ratio occurs before the stabilisation of hyperaemia in a significant proportion of cases. While the overall difference between the minimum Pd/Pa ratio and its FFRstable counterpart is small, reclassification of stenosis severity might occur, if choosing between the minimum and stable values of FFR within the same trace.

PET Imaging of Atherosclerotic Disease: Advancing Plaque Assessment from Anatomy to Pathophysiology.

Atherosclerosis is a leading cause of morbidity and mortality. It is now widely recognized that the disease is more than simply a flow-limiting process and that the atheromatous plaque represents a nidus for inflammation with a consequent risk of plaque rupture and atherothrombosis, leading to myocardial infarction or stroke. However, widely used conventional clinical imaging techniques remain anatomically focused, assessing only the degree of arterial stenosis caused by plaques. Positron emission tomography (PET) has allowed the metabolic processes within the plaque to be detected and quantified directly. The increasing armory of radiotracers has facilitated the imaging of distinct metabolic aspects of atherogenesis and plaque destabilization, including macrophage-mediated inflammatory change, hypoxia, and microcalcification. This imaging modality has not only furthered our understanding of the disease process in vivo with new insights into mechanisms but has also been utilized as a non-invasive endpoint measure in the development of novel treatments for atherosclerotic disease. This review provides grounding in the principles of PET imaging of atherosclerosis, the radioligands in use and in development, its research and clinical applications, and future developments for the field.

Techniques for noninvasive molecular imaging of atherosclerotic plaque

We thank Federico Caobelli and Frank M. Bengel for their Correspondence (In vivo evaluation of atherosclerotic plaques and culprit lesions using noninvasive techniques. Nat. Rev. Cardiol. doi:10.1038/ nrcardio.2014.80-c1)1 on our Review (PET imaging of inflammation in atherosclerosis. Nat. Rev. Cardiol. 11, 443–457; 2014)2 and welcome their comments. We agree that advances in molecular imaging of plaques have the potential to change how we think about the management of athero sclerosis, and help to direct treatment towards patients at the highest risk of future clinical events. Several noninvasive molecular imaging platforms have been used to study atherosclerosis, each with varied success and limitations.3 Caobelli and Bengel highlight some exciting results from plaque imaging studies using SPECT, and the benefits of cadmium–zinc–telluride (CZT) SPECT over conventional SPECT with sodium iodide scintillation cameras. The remit of our Review was specific to PET imaging; other noninvasive molecular imaging modalities used in athero sclerosis research include MRI with ultrasmall super paramagnetic iron oxide, ultrasonography with microbubble antibody ligands, multidetector CT with iodine-based or gold-based nanoparticles, and SPECT with 99mTc-labellin g or 111In-labelling. Notably, in vivo leukocyte tracking using 99mTc-labelled autologous peripheral blood monocytes with serial SPECT imaging seems to correlate with vascular inflammation determined by 18F-FDG PET uptake, as well as disease severity assessed using MRI.4 99mTc-labelled folate is another potentially useful imaging marker for plaque, which has been examined using ex vivo microSPECT imaging of human carotid arteries.5 At present, these molecular imaging techniques are experimental and, therefore, none is widely accessible for use in patients with atherosclerosis. With any nuclear imaging method, whether SPECT or PET, inherent technical REPLY

PET imaging of atherosclerosis

Atherosclerosis is a chronic, progressive, multifocal disease of the arterial wall, which is mainly fuelled by local and systemic inflammation, often resulting in acute ischemic events following plaque rupture and vessel occlusion. When assessing the cardiovascular risk of an individual patient, we must consider both global measures of disease activity and local features of plaque vulnerability, in addition to anatomical distribution and degree of established atherosclerosis. These parameters cannot be measured with conventional anatomical imaging techniques alone, which are designed primarily to identify the presence of organic intraluminal obstruction in symptomatic patients. However, molecular imaging with PET, using specifically targeted radiolabeled probes to track active in vivo atherosclerotic mechanisms noninvasively, may potentially provide a method that is better suited for this purpose. Vascular PET imaging can help us to further understand aspects of plaque biology, and current evidence supports a future role as an emerging clinical tool for the quantification of cardiovascular risk in order to guide and monitor responses to antiatherosclerosis treatments and to distinguish high-risk plaques.