Evaluation of Ischemic Heart Disease

Abstract

The use of PET/CT hybrid imaging in ischemic heart disease, integrating information from PET and CT, has grown in the last decade, particularly because of its capacity of quantifying myocardial perfusion, allowing the assessment of myocardial blood flow (MBF) and myocardial flow reserve (MFR). This feature makes PET/CT the technique best suited to detect multivessel coronary artery disease which might not be identified with SPECT due to its inherent limitation in cases of balanced ischemia. Additionally, the CT component of these hybrid imaging systems allows calculation of coronary artery calcium score (ChACS) and the visualization of the epicardial coronary arteries with coronary CT angiography (CCTA). PET/CT has therefore a great potential in the diagnosis and management of CAD. This chapter will cover several clinical cases, illustrating many different clinical applications in ischemic heart disease.

The use of PET/CT hybrid imaging in ischemic heart disease, integrating information from PET and CT, has grown in the last decade, particularly because of its capacity of quantifying myocardial perfusion, allowing the assessment of myocardial blood flow (MBF) and myocardial flow reserve (MFR). This feature makes PET/CT the technique best suited to detect multivessel coronary artery disease which might not be identified with SPECT due to its inherent limitation in cases of balanced ischemia. Additionally, the CT component of these hybrid imaging systems allows calculation of coronary artery calcium score (ChACS) and the visualization of the epicardial coronary arteries with coronary CT angiography (CCTA). PET/CT has therefore a great potential in the diagnosis and management of CAD. This chapter will cover several clinical cases, illustrating many different clinical applications in ischemic heart disease.

2.1 Multi-Parametric Evaluation of Ischemic Heart Disease

As discussed in Sect. 1.3, all modern PET tomographs are now combined with CT scanner into a hybrid PET/CT camera. Each component of the integrated system provides unique and comprehensive quantitative information for the evaluation of patients with known or suspected CAD (Fig. 2.1a–d).

The extent and severity of regional perfusion defects on the summed myocardial perfusion images allow delineation of the extent and severity of focal coronary artery disease (Fig. 2.1a). Regional myocardial perfusion is usually assessed by semi-quantitative visual analysis of the rest and stress images. The segmental scores are then summed into global scores that reflect the total burden of regional and global ischemia and/or scar. Objective quantitative image analysis is a helpful tool for a more accurate and reproducible estimation of total defect size and severity and is generally used in combination with the semi-quantitative visual analysis. The semi-quantitative (visual) and quantitative scores of ischemia and scar are linearly related to the risk of adverse CV events and are useful in guiding patient management, especially the need for revascularization, and for assessing response to medical therapy.

The acquisition of ECG-gated myocardial perfusion images allows quantification of regional and global systolic function, and LV volumes (Fig. 2.1b). ECG-gated images with PET are typically collected at rest and during peak stress. A drop in LVEF during stress testing is always an abnormal response and can be helpful to identify high-risk patients with multivessel CAD.

ECG-gated CT scanning for coronary artery calcium offers a reproducible, easy-to-perform method to reliably determine whether coronary calcification is present or absent, without the need of intravenous contrast administration (Fig. 2.1c). The extent and severity of coronary calcification can be quantified by validated scoring techniques (e.g., Agatston score). The non-gated CT transmission scan used for attenuation correction of the PET data may also be used to assess the extent of coronary calcifications using semi-quantitative visual analysis. Given the apparent clinical relevance of atherosclerotic burden assessment in guiding intensification of preventive therapies, a formal CAC score or at least a semiquantitative assessment of CAC should be assessed and reported in all patients without known CAD undergoing myocardial perfusion PET/CT imaging.

The quantification of myocardial blood flow (in mL/min/g of myocardium) and myocardial flow reserve (defined as the ratio between maximal stress and rest myocardial blood flow) are important physiologic parameters that reflect the extent and severity of diffuse atherosclerosis (obstructive and nonobstructive) and microvascular dysfunction, and can be measured by routine post-processing of myocardial perfusion PET images (Fig. 2.1d). As discussed in the section of Evaluation of Ischemic Heart Disease, these measurements of flow and flow reserve have important diagnostic and prognostic implications in the evaluation and management of the patients with known or suspected CAD.

Fig. 2.1

Comprehensive qualitative and quantitative information for the evaluation of patients with known or suspected CAD using PET/CT. (a) Focal disease. (b) LV function and volumes. (c) Atherosclerosis burden. (d) Diffuse disease + CMD

Further Reading

• Di Carli M, Hachamovitch R. New Technology for Noninvasive Evaluation of Coronary Artery Disease. Circulation. 2007;115:1464–1480.

• Murthy V, Bateman T, Beanlands R, Berman D, Borges-Neto S, Chareonthaitawee P, et al. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. Journal of Nuclear Cardiology. 2017;25:269–297.

• Patel K, Spertus J, Chan P, Sperry B, Al Badarin F, Kennedy K, et al. Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization. European Heart Journal. 2019;41:751–759.

• Einstein AJ, Johnson LL, Bokhari S, Son J, Thompson RC, Bateman TM et al. Agreement of visual estimation of coronary artery calcium from low-dose CT attenuation correction scans in hybrid PET/CT and SPECT/CT with standard Agatston score. J Am Coll Cardiol. 2010 Nov 30;56(23):1914–21. https://doi.org/10.1016/j.jacc.2010.05.057.

2.2 Asymptomatic Patient

2.2.1 Intermediate-High Clinical Risk: High CACS

Case 9

History

• 58-year-old male with history of dyslipidemia, hypertension, type 2 diabetes was admitted to emergency room with vertigo, nausea, excessive sweating

• Echocardiogram: mild LV hypertrophy, mild valvular fibrosis, normal LV function

• Exercise ECG negative for ischemia at 80% of maximal predicted HR

• Previous CTA showed an Agatston score = 956 and multiple stenotic lesions (Fig. 2.2)

• Referred for myocardial perfusion PET to assess for functionally significant CAD (Fig. 2.3)

Fig. 2.2

Coronary computed tomography angiography showing 30% occlusion of LM and proximal LAD and 50–70% stenosis after origin of D1

Fig. 2.3

Summed rest and Regadenoson-stress myocardial perfusion PET/CT images obtained with ¹³N-ammonia showing normal perfusion

Myocardial blood flow (MBF) and myocardial flow reserve (MFR) were also calculated (Table 2.1).

Table 2.1 Normal MBF and MFR after Regadenoson in all three coronary vascular territories

CCTA and PET studies were used, confirming the substantially normal perfusion in the LAD territory (Fig. 2.4).

Fig. 2.4

CCTA/MPI fusion image showing a very mild and limited in size tracer uptake reduction on the distal LAD

Findings

• Normal regional myocardial perfusion.

• Normal MBF and MFR after Regadenoson in all three coronary vascular territories.

• The CCTA/PET fusion confirms the substantially normal perfusion in the LAD territory.

Teaching Points

• CCTA/MPI fusion imaging helps to localize perfusion defects in specific coronary territories.

• Quantitative PET can help assess the hemodynamic significance of coronary lesions.

• Despite a normal PET study, the high CACS makes this patient at high risk.

Management

• High-risk patient with indication to OMT, no ICA was performed.

Further Reading

• Santana C, Garcia E, Faber T, Sirineni G, Esteves F, Sanyal R, et al. Diagnostic performance of fusion of myocardial perfusion imaging (MPI) and computed tomography coronary angiography. Journal of Nuclear Cardiology. 2009;16:201–211.

• Gaemperli O, Schepis T, Kalff V, Namdar M, Valenta I, Stefani L, et al. Validation of a new cardiac image fusion software for three-dimensional integration of myocardial perfusion SPECT and stand-alone 64-slice CT angiography. European Journal of Nuclear Medicine and Molecular Imaging. 2007;34:1097–1106.

• Piccinelli M, Santana C, Sirineni G, Folks R, Cooke C, Arepalli C, et al. Diagnostic performance of the quantification of myocardium at risk from MPI SPECT/CTA 2G fusion for detecting obstructive coronary disease: A multicenter trial. Journal of Nuclear Cardiology. 2018;25:1376–1386.

2.2.2 Intermediate-High Clinical Risk: Abnormal Prior Test

Case 10

History

• A 75-year-old asymptomatic male with hypertension after a prior abnormal myocardial perfusion SPECT (Fig. 2.5) was referred for a rest/stress myocardial perfusion PET/CT (Fig. 2.6) to evaluate before thoracic surgery.

SPECT Images

Fig. 2.5

Rest and adenosine-stress ^99mTc-Sestamibi myocardial perfusion SPECT images demonstrate a medium sized perfusion defect of moderate intensity involving the mid and basal inferior and basal inferoseptal walls (arrows), showing mild reversibility

PET/CT Images

Fig. 2.6

Summed rest and adenosine-stress myocardial perfusion PET images obtained with ⁸²Rubidium demonstrate normal myocardial perfusion

Findings

• At SPECT imaging, the stress images demonstrate a medium sized perfusion defect throughout the inferior and basal inferoseptal walls showing mild reversibility.

• The ECG-gated images were normal and the post-stress LVEF was 62%.

• PET/CT study was completely normal with no evidence of regional perfusion defects.

Differential Diagnosis

• Obstructive CAD with ischemia in the RCA territory

Correlative Imaging

• None

Management

• Reassurance and risk factor management

Teaching Points

• While females often show artifactual uptake reduction on the anterolateral wall due to breast tissue attenuation, males may show the same artifact in the inferior wall, due to the diaphragm.

• Soft tissue attenuation on myocardial perfusion SPECT can lead to equivocal and/or false positive studies.

• Although attenuation correction helps troubleshooting these artifacts, it is not commonly performed in practice. Recent meta-analyses (see further reading below) suggest that PET is more accurate even when compared to attenuation-corrected SPECT imaging.

• PET imaging has improved sensitivity and specificity for evaluating patients with equivocal and/or abnormal SPECT MPI results.

Further Reading

• Mc Ardle B, Dowsley T, deKemp R, Wells G, Beanlands R. Does Rubidium-82 PET Have Superior Accuracy to SPECT Perfusion Imaging for the Diagnosis of Obstructive Coronary Disease?. Journal of the American College of Cardiology. 2012;60:1828–1837.

• Parker M, Iskandar A, Limone B, Perugini A, Kim H, Jones C, et al. Diagnostic accuracy of cardiac positron emission tomography versus single photon emission computed tomography for coronary artery disease: a bivariate meta-analysis. Circulation Cardiovascular Imaging. 2020;5:700–707.

2.3 Patient with Ischemic Equivalent (Angina and/or Dyspnea)

2.3.1 Single Vessel MPI and Normal LVEF, with Single Vessel Abnormal MFR

Case 11

History

• v78-year-old male with typical angina

• Risk factors: dyslipidemia, hypertension

• RCA stenosis at previous coronary angiography (Fig. 2.7)

• Referred to PET/CT for assessment of ischemic burden (Fig. 2.8) and quantification of MFR (Table 2.2) and functionality (Table 2.3)

Fig. 2.7

Selective view of the right (a, b) and left (c, d) coronary arteries demonstrating an 80% RCA stenosis (yellow arrows), mild irregularities in the LAD without stenoses and LCX without stenoses

PET/CT Images

Fig. 2.8

Summed rest and adenosine-stress myocardial perfusion PET images obtained with ¹³N ammonia demonstrate severe perfusion defect involving the inferior wall with complete reversibility

Table 2.2 Summary of the quantitative blood flow data demonstrating reduced MFR in the RCA territory, but preserved in the LAD and LCX territories

Table 2.3 Left ventricular function

Findings

• MPI: reversible perfusion defect in the RCA territory (Fig. 2.8).

• The rest LVEF was 65% and it remained almost unchanged during stress at 66%.

• Stress MBF and MFR were reduced in the RCA territory.

Differential Diagnosis

• None

Teaching Points

• The presence of a regional perfusion defect with associated abnormality in quantitative MBF and MFR identify the presence of hemodynamically significant CAD.

• The normal rest LVEF with an increase during stress is also consistent with low risk ischemia in a single vascular territory.

• Preserved hyperemic MBF and MFR in the LAD and LCX territories help exclude flow-limiting CAD.

Correlative Imaging

• Coronary angiography

Management

• Single vessel disease with normal LV function.

• Revascularization may be performed to improve patient’s symptoms.

Further Reading

• Naya M, Murthy V, Blankstein R, Sitek A, Hainer J, Foster C, et al. Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion. Journal of the American College of Cardiology. 2011;58:1807–1816.

• Ziadi M, deKemp R, Williams K, Guo A, Renaud J, Chow B, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease?. Journal of Nuclear Cardiology. 2012;19:670–680.

Case 12

History

• A 64-year-old female former smoker was referred to PET/CT for evaluation of atypical chest pain (Fig. 2.9 and Table 2.4).

• She did not have any other coronary risk factors.

PET/CT Images

Fig. 2.9

Summed rest and vasodilator-stress myocardial perfusion PET images obtained Rubidium-82 show a medium sized perfusion defect of severe intensity involving the mid anteroseptal wall, the apical LV segments, and the LV apex with complete reversibility

Table 2.4 Summary of the quantitative blood flow data demonstrating high MBF at rest, with good augmentation during stress albeit lower in the LAD territory. The MFR is reduced in the LAD territory but preserved in the LCX and RCA territories

This patient also underwent CCTA fused with PET image (Fig. 2.10a, b)

Fig. 2.10

The fused myocardial perfusion PET/CCTA demonstrate severe stenosis of the mid LAD coronary artery (panels a and b) involving the proximal first diagonal branch (arrows). 3D rendering of PET study (b) shows hypoperfusion involving the antero-septal wall

Findings

• The PET images demonstrate normal LV size and a medium sized perfusion defect of severe intensity involving the mid anteroseptal wall, the apical LV segments, and the LV apex with complete reversibility.

• The quantitative blood flow data demonstrating high MBF at rest, with good augmentation during stress albeit lower in the LAD territory. The MFR is reduced in the LAD territory but preserved in the LCX and RCA territories.

• The coronary CTA shows subtotal occlusion of the mid LAD coronary artery which seems to also involve the take-off of a first diagonal branch.

Differential Diagnosis

• Obstructive CAD

Correlative Imaging

• Invasive coronary angiography (Fig. 2.11)

Fig. 2.11

Selective views from coronary angiography demonstrating a complex critical stenosis of the mid LAD and diagonal coronary arteries (red arrow)

Management

• The patient underwent successful PCI of the LAD/diagonal arteries.

Teaching Points

• This case example illustrates the complementary value of quantitative stress MBF and flow reserve information in diagnosis and management. In this example, the normal stress MBF and MFR in the LCX and RCA territories helped exclude the presence of multivessel CAD.

Further Reading

• Johnson N, Gould K, Di Carli M, Taqueti V. Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What is the Future?. Journal of the American College of Cardiology. 2016;67:2772–2788.

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72(21):2625–2641.

• Ziadi M, deKemp R, Williams K, Guo A, Renaud J, Chow B, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease?. Journal of Nuclear Cardiology. 2012;19:670–680.

2.3.2 Single Vessel MPI and Normal LVEF, with MultiVessel Abnormality on MFR

Case 13

History

• 78-year-old male with atypical angina

• Risk factors: dyslipidemia, hypertension, previous smoker

• Referred to PET/CT for assessment of possible myocardial ischemia (Fig. 2.12) and quantification of MBF (Table 2.5) and LV functionality (Table 2.6)

PET/CT Images

Fig. 2.12

Summed rest and Regadenoson-stress myocardial perfusion PET images obtained ¹³N ammonia demonstrate a perfusion defect involving the anterior wall and the apex with complete reversibility at rest.

Table 2.5 Stress MBF is diffusely abnormal in all coronary vascular territories with no gradient of flow from base to apex in the RCA territory. MFR is regionally reduced in the LAD and LCX territories

Table 2.6 LVEF and LV volumes at rest and at peak stress

Coronary angiography showed multivessel disease (Fig. 2.13).

Fig. 2.13

Selective views of the left coronary system (left panel) demonstrating a 70% LAD stenosis (red arrow), 90% LCX stenosis (yellow arrow) and diffuse atherosclerosis of the RCA (right panel)

Findings

• MPI: reversible perfusion defect in the LAD territory.

• Stress MBF is diffusely reduced in all 3 vascular territories. However, MFR is only reduced in the LAD and LCX territories.

• Gated study shows normal LV function at rest (68%) and during maximal vasodilation (72%).

Differential Diagnosis

• Multivessel obstructive CAD

Teaching Points

• Multivessel disease may be underestimated by semi-quantitative assessment of myocardial perfusion images due to balanced flow reduction.

• Quantitative MBF data helps overcome these limitations by providing absolute flow values that increase the sensitivity for delineating flow-limiting CAD.

• In this patient, the presence of reduced stress MBF without a base to apical gradient with preserved MFR in the RCA territory, without stenosis on coronary angiography, is consistent with the presence of nonobstructive diffuse atherosclerosis (which can be associated with normal coronary angiography) and/or microvascular dysfunction and identifies low clinical risk.

• Global hypoperfusion with reduction of both max MBF and MFR in all vascular territories due to severe stenoses (LAD and LCX) and microvascular dysfunction (RCA).

Correlative Imaging

• Coronary angiography

Management

• PCI of the LAD and LCX arteries

• Medical treatment and management of risk factors

Further Reading

• Schelbert H. Quantification of Myocardial Blood Flow: What is the Clinical Role?. Cardiology Clinics. 2009;27:277–289.

• Naya M, Murthy V, Blankstein R, Sitek A, Hainer J, Foster C, et al. Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion. Journal of the American College of Cardiology. 2011;58:1807–1816.

• Murthy V, Bateman T, Beanlands R, Berman D, Borges-Neto S, Chareonthaitawee P, et al. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. Journal of Nuclear Cardiology. 2017;25:269–297.

2.3.3 Single Vessel MPI and Normal LVEF, with MultiVessel Abnormal MFR

Case 14

History

• A 65-year-old male with a history of renal transplant and new onset LV dysfunction and heart failure, was referred for a Regadenoson myocardial perfusion PET study to evaluate for CAD (Fig. 2.14), MBF quantification (Table 2.7), and CCTA (Fig. 2.15).

PET/CT Images

Fig. 2.14

Rest and Regadenoson-stress ¹³N-ammonia myocardial perfusion PET/CT images demonstrate severely dilated LV, moderate lung uptake, and a small perfusion defect of severe intensity involving the mid and basal inferolateral wall, which is fixed (arrows)

Fig. 2.15

Cross-sectional ECG-gated non-contrast cardiac CT image demonstrating severe coronary calcifications in the proximal LAD (purple) and LCX (orange) coronary arteries. The Agatston score was 2905

Table 2.7 Summary of the quantitative blood flow data demonstrating severe reduction in stress myocardial blood flow in all coronary artery territories and globally (normal value >1.8 mL/min/g), resulting in moderate reduction in myocardial flow reserve (normal value >2.0)

Findings

• The images demonstrated a severely dilated LV with moderate lung uptake. They also demonstrated normal RV size with severely increased RV tracer uptake on the rest and stress images.

• There is a small perfusion defect of severe intensity involving the mid and basal inferolateral wall, which is fixed.

• There are severe coronary calcifications in the proximal LAD (purple) and LCX (orange) coronary arteries.

• The maximal stress myocardial blood flow and flow reserve are severely reduced both regionally and globally.

• The rest LV ejection fraction was 19% with severely dilated volumes and increased minimally to 23% during stress. There was severe global hypokinesis. The RV function appeared normal.

Differential Diagnosis

• Severe obstructive multivessel CAD.

• Coronary microvascular dysfunction

Correlative Imaging

• Invasive coronary angiography demonstrates: (1) minimal irregularities in the left anterior descending (LAD) artery, (2) diffuse disease in the first, second, and third diagonal branches, (3) minimal irregularities in the left circumflex (LCX) artery, and 30% stenosis in the proximal right coronary artery (RCA) (Fig. 2.16).

Fig. 2.16

Selected coronary angiographic views demonstrating minimal irregularities in the LAD artery; diffuse disease in the first, second, and third diagonal branches; minimal irregularities in the LCX artery, and 30% stenosis in the proximal RCA

Management

• Medical therapy for heart failure and myocardial ischemia and aggressive risk factor management

Teaching Points

• Patho-physiologically, stress myocardial blood flow and flow reserve values provide a measure of the integrated hemodynamic effects of focal epicardial coronary stenoses, diffuse atherosclerosis and vessel remodeling, and microvascular dysfunction on myocardial perfusion. While these quantitative indices of tissue perfusion are one of the most sensitive measures of myocardial ischemia, they have somewhat limited specificity to differentiate obstructive vs nonobstructive angiographic CAD as both can affect flow values similarly.

• Coronary angiography (invasive or noninvasive) is an important complementary assessment to the PET quantification to refine the risk assessment and guide management.

Further Reading

• Johnson N, Gould K, Di Carli M, Taqueti V. Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What is the Future?. Journal of the American College of Cardiology. 2016;67:2772–2788.

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72(21):2625–2641.

• Ziadi M, deKemp R, Williams K, Guo A, Renaud J, Chow B, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease?. Journal of Nuclear Cardiology. 2012;19:670–680.

Case 15

History

• A 52-year-old male with hypercholesterolemia, HIV, hepatitis B, previous Burkitt’s lymphoma, and typical angina was referred for myocardial perfusion PET (Fig. 2.17) with quantitation of MBF (Table 2.8).

PET Images

Fig. 2.17

Stress and rest ⁸²Rb myocardial perfusion PET demonstrate a medium sized perfusion defect of severe intensity throughout the inferior wall with complete reversibility

Table 2.8 Summary of the quantitative blood flow data demonstrating severe reduction in stress myocardial blood flow in all coronary artery territories and globally (normal value >1.8 mL/min/g). Myocardial flow reserve is only impaired in the RCA territory (normal value >2.0)

CCTA was also performed and fused with PET (Fig. 2.18).

Fig. 2.18

Fused myocardial perfusion PET/coronary CT angiography (PET/CCTA). The coronary CTA images demonstrate a total occlusion of the proximal dominant RCA (panels a and b). There is also evidence of diffuse coronary artery calcifications on the LAD and LCX arteries. 3D rendering of PET study (b) shows hypoperfusion involving the inferior wall

Findings

• The myocardial perfusion PET images demonstrate a medium sized perfusion defect of severe intensity throughout the inferior wall with complete reversibility.

• The quantitative flow data demonstrates severe diffuse reduction in stress MBF in all coronary territories with focal reduction in MFR only in the RCA distribution.

• The fused PET/CCTA data confirmed the presence of a total occlusion of the RCA, corresponding to the perfusion defect and the reduction in stress MBF and MFR.

• The reduction in stress MBF with preserved MFR in the LAD and LCX territories correlated with the presence of diffuse coronary calcifications in those vessels.

Differential Diagnosis

• Obstructive CAD

• Diffuse nonobstructive atherosclerosis

• Coronary microvascular dysfunction

Correlative Imaging

• Invasive coronary angiography confirmed the presence of a totally occluded RCA (Fig. 2.19).

Fig. 2.19

Selective angiographic views of the coronary arteries demonstrate obstructive CAD in the RCA and no lesions on the left system

Management

• The patient underwent recanalization of the total RCA occlusion.

Teaching Points

• The coronary CTA has complementary diagnostic and management implications. As illustrated in this patient example, it helped confirm the presence of obstructive CAD in the RCA while also helped exclude the presence of obstructive CAD in the LAD and LCX territories which was important considering the severely reduced stress MBF.

• The presence of diffuse coronary calcifications, implying diffuse atherosclerosis, especially in the LAD and LCX arteries explain in part the reduction in stress MBF.

Further Reading

• Teddy Weiss A, Berman D, Lew A, Nielsen J, Potkin B, Swan H, et al. Transient ischemic dilation of the left ventricle on stress thallium-201 scintigraphy: A marker of severe and extensive coronary artery disease. Journal of the American College of Cardiology. 1987;9:752–759.

• Di Carli M, Murthy V. Cardiac PET/CT for the Evaluation of Known or Suspected Coronary Artery Disease. RadioGraphics. 2011;31:1239–1254.

2.3.4 High-Risk Scan (Multivessel Defects, TID, Drop in EF, Abnormal MFR)

Case 16

History

• 84-year-old male

• No cardiovascular risk factors

• Referred to PET/CT for episodes of atypical angina and exertional dyspnea (Fig. 2.20 and Table 2.9)

PET/CT Images

Fig. 2.20

Rest and Regadenoson-stress ¹³N-ammonia myocardial perfusion PET/CT images demonstrate dilated LV and a large and severe perfusion defect throughout the mid and distal anterior and anteroseptal walls, LV apical segments, and the LV apex, showing complete reversibility

Table 2.9 Summary of the quantitative blood flow data demonstrating MBF and MFR impairment during Regadenoson in LAD and RCA territories and globally (normal value >1.8 mL/min/g). Myocardial flow reserve is impaired in the RCA and LAD territories (normal value >2.0)

Findings

• MPI: large, severe, and reversible perfusion defect in the LAD and RCA territories

• Reduced stress MBF and MFR in LAD and RCA territories

• Normal LV function at rest (55%) with a drop in LVEF during peak stress (48%)

Differential Diagnosis

• Single vessel vs. multivessel disease

Correlative Imaging

• Coronary angiography (Fig. 2.21)

Fig. 2.21

Selective angiographic views of the coronary arteries showed a severe stenosis of the proximal LAD with post-stenotic aneurysm and >90 stenosis of the first diagonal branch (a, b). A long LAD wraps around the apex and supplies the mid to distal inferior wall of the left ventricle (b, d). The LCX and RCA show luminal irregularities without focal stenosis (c, d)

Management

• The patient underwent by-pass grafting of the LAD.

Teaching Points

• The large, severe area of ischemia throughout the LAD territory with associated abnormalities in MBF and MFR, and a drop in LVEF during stress are consistent with a high-risk ischemic burden.

• Anatomical and functional information are both important to characterize the extent of functionally significant CAD. In this case, the large perfusion defect with associated reduction in stress MBF and MFR in multiple territories corresponded to a very large wrap-around LAD coronary artery.

Further Reading

• Kobayashi N, Maehara A, Brener S, Généreux P, Witzenbichler B, Guagliumi G, et al. Usefulness of the Left Anterior Descending Coronary Artery Wrapping Around the Left Ventricular Apex to Predict Adverse Clinical Outcomes in Patients With Anterior Wall ST-Segment Elevation Myocardial Infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial). The American Journal of Cardiology. 2015;116:1658–1665.

• Sapin P, Musselman D, Dehmer G, Cascio W. Implications of inferior ST-segment elevation accompanying anterior wall acute myocardial infarction for the angiographic morphology of the left anterior descending coronary artery morphology and site of occlusion. The American Journal of Cardiology. 1992;69:860–865.

• Peters S. Takotsubo cardiomyopathy and structural abnormalities of the left anterior descending coronary artery. International Journal of Cardiology. 2016;223:510–511.

Case 17

History

• A 78-year-old female with history of dyslipidemia, hypertension, diabetes mellitus type 2, and Chron’s disease was referred for vasodilator PET/CT with ⁸²Rb, after suffering a prolonged episode of chest pain (Fig. 2.22 and Table 2.10).

PET Images

Fig. 2.22

Stress and rest ⁸²Rb myocardial perfusion PET images. There is transient ischemic dilatation of the left ventricle during stress. Also, there is increased tracer uptake of the free wall of the right ventricle, more pronounced during stress. There is a large, severe, and reversible perfusion defect involving the mid anteroseptal wall, apical LV segments and LV apex, showing complete reversibility. In addition, there is a medium sized perfusion defect of moderate severity throughout the inferolateral wall, also showing complete reversibility

Table 2.10 Summary of the quantitative blood flow data demonstrating severe reduction in stress myocardial blood flow in all coronary artery territories and globally (normal value >1.8 mL/min/g). MFR is impaired in the RCA and LAD territories (normal value >2.0)

Findings

• Transient ischemic dilation of the left ventricle during stress.

• Transiently increased uptake of the free wall of the right ventricle during stress.

• Large, severe, and reversible perfusion defect involving the mid anteroseptal wall, apical LV segments and LV apex, showing complete reversibility.

• Medium sized perfusion defect of moderate severity throughout the inferolateral wall, also showing complete reversibility.

• Globally reduced myocardial blood flow reserve.

• LVEF at rest was 69% and it dropped to 57% during peak stress.

Differential Diagnosis

• Severe multivessel obstructive CAD

Correlative Imaging

• Invasive coronary angiography (Fig. 2.23)

Fig. 2.23

Selective angiographic views of the coronary arteries: RAO cranial projection showing a high-degree stenosis of the mid LAD (left panel: yellow circle) and proximal obtuse marginal coronary artery (red circle). Right panel: LAO view showing a high-degree stenosis of the proximal to mid RCA (red circle)

Management

• This patient was deemed at high risk and—in line with the best current evidence for treatment of multivessel disease in patients with diabetes mellitus—was referred for coronary artery by-pass surgery.

Teaching Points

• The presence of TID, RV tracer uptake, and large multivessel perfusion abnormalities along with the reduced MFR identify patients at very high risk of adverse cardiac events.

• In patients with multivessel perfusion abnormalities, the quantitative blood flow data has a marginal diagnostic contribution, as illustrated in this case.

Further Reading

• BARI 2D Study Group, Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. The New England Journal of Medicine. 2009;360:2503–2515.

• Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. The New England Journal of Medicine. 2012;367:2375–2384.

2.4 High-Risk Scan, with Reduced Stress MBF but Normal MFR

Case 18

History

• 74-year-old male with a history of dyslipidemia, hypertension, and former tobacco use

• Referred to PET/CT to assess post-prandial episodes of angina (Fig. 2.24 and Table 2.11)

PET/CT Images

Fig. 2.24

Stress-rest ¹³N-ammonia PET images demonstrate TID at peak stress and a large and severe defect, completely reversible at rest, involving the mid anterior and anteroseptal walls, the apical LV segments and the LV apex

Table 2.11 Summary of the quantitative blood flow data demonstrating severe reduction in stress myocardial blood flow in all coronary artery territories and globally (normal value >1.8 mL/min/g), with relatively normal myocardial flow reserve (normal value >2.0)

Findings

• The myocardial perfusion PET images demonstrate TID during stress (TID ratio: 1.42).

• There is a large perfusion defect of severe intensity throughout the mid anterior and anteroseptal walls, the apical LV segments and the LV apex, showing complete reversibility. In addition, there is a medium sized defect of moderate intensity throughout the inferior and basal inferolateral walls, also showing complete reversibility.

• The quantitative flow data shows severe and diffuse reduction in stress MBF and relatively preserved MFR due to a low rest flow.

• LV systolic function was severely reduced with an LVEF of 21% on both the rest and stress images with severe global hypokinesis and LV dilatation that worsened with stress.

Differential Diagnosis

• Severe multivessel obstructive CAD.

Correlative Imaging

• Coronary angiography (Fig. 2.25).

Fig. 2.25

Selective view of the left coronary system demonstrating a 70% left main stenosis and 70% ostial LAD stenosis and 70% stenosis of the mid RCA

Management

• The patient underwent high-risk CABG.

Teaching Points

• In patients with high-risk scan findings including TID, large multivessel perfusion abnormalities, and severe LV dysfunction, the contribution of the quantitative flow information to diagnosis is relatively limited.

• When examining the quantitative flow information, it is important to consider both the stress MBF and the MFR. While these measurements often agree, there are cases when the two are discrepant like in this patient. Stress MBF is a better marker of flow-limiting CAD, while MFR is a better discriminator of clinical risk.

Further Reading

• Johnson N, Gould K, Di Carli M, Taqueti V. Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What is the Future?. Journal of the American College of Cardiology. 2016;67:2772–2788.

• Ziadi M, deKemp R, Williams K, Guo A, Renaud J, Chow B, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease?. Journal of Nuclear Cardiology. 2012;19:670–680.

Case 19

History

• 67-year-old male on peritoneal dialysis due to chronic renal insufficiency

• He presented with inferior-posterior STEMI (TnI max 90.2 ng/ml, CK-MB 183.4 ng/ml), which was treated with primary PCI (Fig. 2.26a, b)

• The coronary angiogram demonstrated additional disease in the LCX and LAD coronary arteries (Fig. 2.26c, d). Two months after the index STEMI, he underwent PCI of the LCX artery (Fig. 2.26e).

Fig. 2.26

Coronary angiography showing occlusion of the RCA before primary PCI (a) and patent vessel (b) after PCI. Additional disease is present on LCX and LAD (c). LCX is treated with staged PCI (d, e)

• 9 months later the patient was readmitted to the emergency room due to recurrent chest pain.

• The cardiac enzymes were negative.

• He was referred for myocardial perfusion PET (Fig. 2.27 and Table 2.12).

Fig. 2.27

Stress-rest ¹³N-ammonia PET images demonstrate a reversible perfusion defect involving the apical LV segments and the LV apex

Table 2.12 Summary of the quantitative blood flow data demonstrating reduced MBF in all vascular territories with MFR reduction only in the LAD and LCX territories

Findings

• The stress PET images revealed at peak stress a severe perfusion defect involving the apical LV segments and the LV apex, with good reversibility at rest.

• The stress MBF was reduced in all vascular territories but MFR was reduced only in the LAD and LCX territories.

Management

• This patient was referred for ICA (Fig. 2.28).

Fig. 2.28

The new ICA documented a tight stenosis of the distal RCA (panel a—before, panel b after PCI) with a wrap-around distribution to the apical LV segments and LV apex, which explains the distribution of the perfusion abnormality and MFR data. ICA of left coronary system demonstrated a persistent good result of previous PCI (panel c)

Teaching Points

• The PET scan was able to confirm that the patient’s recurrent angina was due to an area of severe myocardial ischemia.

• Assignment of coronary vascular distribution when reporting myocardial perfusion imaging is based on a standard model of coronary artery distribution. In this case, the perfusion abnormality corresponded to an unusually large, wrap-around RCA artery rather than the LAD. This also explains the paradoxically normal MFR in the RCA territory, which was based on typical coronary vascular distribution.

Further Reading

• Shibutani H, Akita Y, Yutaka K, Yamamoto S, Matsui Y, Yoshinaga M, et al. Acute myocardial infarction with “wrap around” right coronary artery mimicking Takotsubo cardiomyopathy: a case report. BMC Cardiovascular Disorders. 2016;16:16–71.

• Naya M, Murthy V, Blankstein R, Sitek A, Hainer J, Foster C, et al. Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion. Journal of the American College of Cardiology. 2011;58:1807–1816.

• Gaemperli O, Schepis T, Valenta I, Husmann L, Scheffel H, Duerst V, et al. Cardiac Image Fusion from Stand-Alone SPECT and CT: Clinical Experience. Journal of Nuclear Medicine. 2007;48(5):696–703.

• Javadi M, Lautamaki R, Merrill J, Voicu C, Epley W, McBride G, et al. Definition of Vascular Territories on Myocardial Perfusion Images by Integration with True Coronary Anatomy: A Hybrid PET/CT Analysis. Journal of Nuclear Medicine. 2010;51:198–203.

2.4.1 Normal MPI, TID, and Globally Reduced MFR

Case 20

History

• A 79-year-old asymptomatic male with a history of dyslipidemia and hypertension referred to PET/CT (Fig. 2.29 and Table 2.13) for evaluation of new onset LV dysfunction by echocardiography (not shown).

PET/CT Images

Fig. 2.29

Stress-rest ¹³N-ammonia PET images showing a medium sized perfusion defect of severe intensity throughout the inferior and basal inferoseptal wall

Table 2.13 Summary of rest and stress MBF and myocardial flow reserve showing a global severe reduction in stress MBF and MFR.

Findings

• The myocardial perfusion PET images demonstrate mild TID during stress. There is a medium sized perfusion defect of severe intensity throughout the inferior and basal inferoseptal wall, showing complete reversibility. In addition, there is a medium sized perfusion defect of severe intensity involving the apical LV segments and the LV apex, also showing complete reversibility.

• The quantitative flow data demonstrated diffuse and severe reduction in stress MBF and MFR in all three coronary territories.

Correlative Imaging

• Invasive coronary angiography (Fig. 2.30):

Fig. 2.30

Selective coronary angiographic views demonstrate severe three vessel obstructive CAD including a long and severe stenosis in the mid LAD, a severe stenosis in the proximal LCX artery, and a total occlusion of a dominant RCA

Management

• The patient underwent CABG.

Teaching Points

• The quantitative flow information helps ascertain the extent and severity of obstructive CAD.

Further Reading

• Sambuceti G, Marzullo P, Giorgetti A, Neglia D, Marzilli M, Salvadori P, et al. Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease. Circulation. 1994;90:1696–1705.

• Naya M, Murthy V, Blankstein R, Sitek A, Hainer J, Foster C, et al. Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion. Journal of the American College of Cardiology. 2011;58:1807–1816.

Case 21

History

• 78-year-old male with atypical angina, chronic renal failure.

• Risk factors: dyslipidemia, hypertension, former smoker.

• Referred to PET/CT (Fig. 2.31 and Table 2.14) for angina assessment.

PET/CT Images

Fig. 2.31

Stress-rest ¹³N-ammonia PET images demonstrate transient mild LV dilatation during stress (TID ratio = 1.27) without evidence of regional perfusion defects

Table 2.14 Summary of rest and stress MBF and myocardial flow reserve showing diffuse reduction of stress MBF without base to apical gradients and of MFR

Findings

• At MPI evidence of transient LV dilatation during stress (TID ratio = 1.27) without evidence of regional perfusion defects.

• Diffuse reduction of stress MBF without base to apical gradients and MFR.

• LVEF mild reduction at stress (67%) vs rest (69%).

Differential Diagnosis

• Obstructive CAD vs microvascular disease.

Teaching Points

• The presence of TID without regional perfusion defects is typically related to diffuse subendocardial ischemia, commonly seen in patients with hypertensive heart disease and other forms of LVH.

• The diffuse reduction in stress MBF without the typical gradients from base to apex of obstructive CAD and the associated reduction in MFR is consistent with diffuse nonobstructive atherosclerosis and microvascular dysfunction.

Management

• Follow-up coronary angiography demonstrated no evidence of obstructive CAD.

• The patient underwent aggressive risk factor management.

Further Reading

• Fukushima K, Javadi M, Higuchi T, Bravo P, Chien D, Lautamaki R, et al. Impaired Global Myocardial Flow Dynamics Despite Normal Left Ventricular Function and Regional Perfusion in Chronic Kidney Disease: A Quantitative Analysis of Clinical 82Rb PET/CT Studies. Journal of Nuclear Medicine. 2012;53:887–893.

• Koivuviita N, Tertti R, Jarvisalo M, Pietila M, Hannukainen J, Sundell J, et al. Increased basal myocardial perfusion in patients with chronic kidney disease without symptomatic coronary artery disease. Nephrology Dialysis Transplantation. 2009;24:2773–2779.

Case 22

History

• A 68-year-old male with a history of hypertension. He underwent recent coronary CT angiography (Fig. 2.32), which demonstrated extensive coronary atherosclerosis.

• He was referred to PET/CT (Fig. 2.33 and Table 2.15) for evaluation of exertional dyspnea and chest pain.

Fig. 2.32

Coronary CT angiography showing extensive coronary atherosclerosis involving LAD and LCX (arrows)

PET/CT Images (Figs. 2.33 and 2.34)

Fig. 2.33

Stress-rest ¹³N-ammonia PET images demonstrate normal myocardial perfusion

Table 2.15 Summary of the quantitative blood flow data demonstrating a moderate reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) with preserved myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Fig. 2.34

Segmental MBF showing no gradients

Findings

• The images demonstrate normal LV size. There is a normal regional myocardial perfusion on both the stress and rest imaging.

• The ECG-gated images demonstrated a rest LV ejection fraction of 52% which increased to 60% post stress with normal LV volumes. There was normal regional wall motion and thickening.

• The maximal stress myocardial blood flow is moderately reduced in all coronary territories and globally without base to apical gradients, but his myocardial flow reserve is normal.

Differential Diagnosis

• None

Correlative Imaging

• None

Management

• Aggressive risk factor management

Teaching Points

• The presence of extensive atherosclerosis on the CCTA without regional perfusion abnormalities on the PET myocardial perfusion images, associated with moderate reduction in stress myocardial blood flow and preserved flow reserve is consistent with nonobstructive atherosclerosis.

• The presence of reduced stress myocardial blood flow with normal myocardial flow reserve by quantitative PET imaging associates with low clinical risk (<1% cardiac death rate/year). However, he has severe nonobstructive atherosclerosis that increases the risk for myocardial infarction and requires aggressive lipid lowering therapy and management of his hypertension.

Further Reading

• Gupta A, Taqueti VR, van de Hoef TP, Bajaj NS, Bravo PE, Murthy VL, et al. Integrated Non-invasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients with Stable Coronary Artery Disease. Circulation. 2017;136:2325–2336.

• Scot-Heart Investigators, Newby DE, Adamson PD, Berry C, Boon NA, Dweck MR, et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. The New England Journal of Nuclear Medicine. 2018;379:924–933.

Case 23

History

• A 52-year-old obese female (BMI: 35) with a history of hypertension referred for evaluation for atypical angina and dyspnea. She underwent a rest and Regadenoson-stress ¹³N-ammonia myocardial perfusion PET/CT study (Fig. 2.35 and Table 2.16) and CACS assessment (Fig. 2.36).

PET/CT Images

Fig. 2.35

Rest and Regadenoson-stress ¹³N-ammonia myocardial perfusion PET/CT images demonstrate normal myocardial perfusion both at rest and during stress

Table 2.16 Summary of the quantitative blood flow data demonstrating preserved stress myocardial blood flow (normal value >1.8 mL/min/g) but reduced myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Fig. 2.36

Cross-sectional transaxial chest CT image demonstrating no evidence of coronary artery calcifications

Findings

• The images demonstrate normal LV size. There is a normal regional myocardial perfusion on both the stress and rest imaging.

• The ECG-gated images demonstrated a rest LV ejection fraction of 63% which increased to 66% post stress with normal LV volumes. There was normal regional wall motion and thickening.

• The transmission CT scan demonstrated no evidence of coronary artery calcification.

• The maximal stress myocardial blood flow is relatively normal (>1.8 mL/min/g) in all coronary territories and globally, but the myocardial flow reserve is reduced due to an increase in her resting flows.

• The CT transmission scan demonstrates no evidence of coronary artery calcifications.

Differential Diagnosis

• Nonobstructive CAD

• Coronary microvascular dysfunction

Correlative Imaging

• None

Management

• Management of hypertension and weight reduction

Teaching Points

• The normal myocardial perfusion PET images associated with the absence of coronary calcifications and normal stress myocardial blood flow are consistent with a low likelihood of flow-limiting CAD or nonobstructive atherosclerosis.

• However, the presence of increased rest myocardial blood flow and mild reduction in myocardial flow reserve places her at an intermediate clinical risk (1–3% cardiac death rate/year). This phenotype is common among women who typically have a low prevalence of obstructive atherosclerosis and has been linked to microvascular disease, which may be the source of her symptoms.

Further Reading

• Gupta A, Taqueti VR, van de Hoef TP, Bajaj NS, Bravo PE, Murthy VL, et al. Integrated Non-invasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients with Stable Coronary Artery Disease. Circulation. 2017;136:2325–2336.

• Taqueti V, Shaw L, Cook N, Murthy V, Shah N, Foster C, et al. Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease. Circulation. 2017;135:566–577.

• Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, et al. Effects of Sex on Coronary Microvascular Dysfunction and Cardiac Outcomes. Circulation. 2014 Jun 17;129(24):2518–27. https://doi.org/10.1161/CIRCULATIONAHA.113.008507. Epub 2014 Apr 30.

2.4.2 Abnormal PET with Abnormal FFR

Case 24

History

• 62-year-old male with a history of hypertension, hypercholesterolemia and diabetes, and known CAD with prior PCI of the left anterior descending (LAD) and left circumflex (LCX) arteries, referred for evaluation of atypical chest pain. He underwent rest/stress myocardial perfusion PET imaging using ¹⁵O-water (Fig. 2.37).

PET/CT Images

Fig. 2.37

Rest/stress MPI shows severe defect involving the anterior wall, septum, and apex, with normal LV size. Complete reversibility at rest.

Findings

• The images demonstrate normal LV size. The stress images demonstrate a large and severe perfusion defect throughout the anterior, septal, apical LV segments and LV apex, showing complete reversibility consistent with severe ischemia in the LAD territory.

• Quantitative assessment revealed an abnormal hyperemic myocardial blood flow of 1.10 ml/min/g and MFR of 1.59 in the LAD territory.

Differential Diagnosis

• Obstructive CAD

Correlative Imaging

• Invasive coronary angiography (Fig. 2.38)

Fig. 2.38

Invasive coronary angiography showing an angiographic severe luminal stenosis in the proximal LAD (*) and diffuse distal atherosclerosis. The LCX and small right coronary artery (RCA) did not show any significant stenosis. Corresponding fractional flow reserve (FFR) measurement of the LAD stenosis was abnormal of 0.52 (normal value ≥0.80)

Management

• The LAD lesion was successfully treated with a PCI and 2 drug eluting stents.

Teaching Points

• The presence of a severe stress perfusion defect and reduced myocardial blood flow and flow reserve by PET, reflecting myocardial ischemia, have excellent correlation with invasive FFR measurements, reflecting lesion-specific ischemia.

• Randomized clinical trials have shown improved outcomes using physiologically as opposed to angiographically guided revascularization.

Further Reading

• Driessen R, Danad I, Stuijfzand W, Raijmakers P, Schumacher S, van Diemen P, et al. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. Journal of the American College of Cardiology. 2019;73:161–173.

• Pijls N, de Bruyne B, Peels K, van der Voort P, Bonnier H, Bartunek J, et al. Measurement of Fractional Flow Reserve to Assess the Functional Severity of Coronary-Artery Stenoses. New England Journal of Medicine. 1996;334:1703–1708.

• Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407–477.

Acknowledgement

PET and angiographic images are courtesy of Drs. Roel Driessen, Ibrahim Danad, and Paul Knaapen, VU University Medical Center, Amsterdam, the Netherlands.

2.5 Patient with Suspected Coronary Microvascular Dysfunction

2.5.1 Without Atherosclerosis

2.5.1.1 Hypertensive Heart Disease

Case 25

History

• 61-year-old female with a history of controlled hypertension for 20 years and an active smoker.

• She underwent PET/CT evaluation (Fig. 2.39 and Table 2.17) for atypical angina and dyspnea (3 months evolution).

PET/CT Images

Fig. 2.39

Rest and vasodilator-stress ¹³N-ammonia showing normal rest and stress myocardial perfusion images. The mild and fixed reduction in tracer uptake in the inferolateral wall represents a normal variant for ¹³N-ammonia

Table 2.17 Summary of the quantitative blood flow data demonstrating severe and diffuse abnormalities of MBF and MFR

Findings

• The rest and stress myocardial perfusion images demonstrated no evidence of regional perfusion defects.

• The ECG-gated study showed a drop in LVEF from 57% at rest to 48% during peak stress.

• Stress MBF and flow reserve are diffusely abnormal.

Differential Diagnosis

• Multivessel obstructive CAD with balanced ischemia vs microvascular dysfunction

Correlative Imaging

• CCTA (Fig. 2.40)

Fig. 2.40

Coronary CT angiography shows no evidence of coronary atherosclerosis

Teaching Points

• Coronary microvascular dysfunction is common in patients with hypertensive heart disease.

• The presence of diffuse and severe reduction in stress MBF and MFR requires correlation with coronary angiography to exclude the possibility of multivessel obstructive CAD. In this case, CCTA shows angiographically normal coronary arteries.

Management

• Optimized medical treatment

Further Reading

• Garcia M, Mulvagh S, Bairey Merz C, Buring J, Manson J. Cardiovascular Disease in Women. Circulation Research. 2016;118:1273–1293.

• Schindler T, Dilsizian V. Coronary Microvascular Dysfunction. JACC: Cardiovascular Imaging. 2020;13:140–155.

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72:2625–2641.

2.5.1.2 Nonischemic CM

Case 26

History

• A 78-year-old female with a history of hypertension and diabetes presenting with new onset heart failure, reduced LV systolic function, and ventricular arrhythmias was referred to PET/CT (Fig. 2.41 and Table 2.18). Her ECG shows a left bundle branch block (Fig. 2.42).

PET/CT Images

Fig. 2.41

Rest and adenosine-stress ¹³N-ammonia myocardial perfusion PET/CT images. There is severe LV dilatation and moderately increased RV tracer uptake on both the stress and rest images. There is mildly reduced tracer uptake in the septum on both stress and rest imaging, which is consistent with her LBBB. The fixed defect involving the LV apex is consistent with apical thinning and resulting partial volume effect

Table 2.18 Summary of the quantitative blood flow data demonstrating a moderate reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) and myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Fig. 2.42

Rest ECG demonstrating a LBBB

Findings

• The images demonstrate a severely dilated LV. There is also normal RV size with moderately increased RV tracer uptake on the rest and stress images. The myocardial perfusion images demonstrate no evidence of regional perfusion defects.

• The maximal stress myocardial blood flow and myocardial flow reserve are moderately reduced both regionally and globally.

• The ECG-gated images demonstrated a rest LVEF of 15% increasing to 20% post stress with severely dilated LV volumes. There was paradoxical septal motion consistent with a LBBB on her rest ECG.

Differential Diagnosis

• Severe obstructive multivessel CAD

• Coronary microvascular dysfunction

Correlative Imaging

• Rest ECG

Teaching Points

• Coronary microvascular dysfunction (CMD) is prevalent in several clinical conditions where atherosclerosis plays little or no role in its pathogenesis. These conditions include arterial hypertension, aortic stenosis, and nonischemic cardiomyopathies.

• The group of nonischemic cardiomyopathies in whom CMD has been documented to be prevalent and prognostically important include idiopathic, hypertrophic, infiltrative, and stress cardiomyopathies.

• Whether CMD in nonischemic cardiomyopathies is a cause or effect of the underlying myopathic process is unknown. However, in all of these conditions, severe CMD has been implicated in the pathophysiology of subendocardial ischemia and increased myocardial stress, subclinical myocardial injury and diffuse interstitial fibrosis, worsening systolic and diastolic function, heart failure, arrhythmias, and adverse cardiovascular events.

Management

• Invasive coronary angiography demonstrated normal coronary arteries.

• Medical therapy for heart failure and management of ventricular arrhythmias.

Further Reading

• Majmudar M, Murthy V, Shah R, Kolli S, Mousavi N, Foster C, et al. Quantification of coronary flow reserve in patients with ischaemic and non-ischaemic cardiomyopathy and its association with clinical outcomes. European Heart Journal – Cardiovascular Imaging. 2015;16:900–909.

• Neglia D, Michelassi C, Trivieri M, Sambuceti G, Giorgetti A, Pratali L, et al. Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction. Circulation. 2002;105(2):186–193.

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72(21):2625–2641.

2.5.1.3 Fabry’s Disease

Case 27

History

• 54-year-old female with diagnosis of Anderson-Fabry’s disease (molecular genetic analysis positive for GLA gene)

• Not yet on enzyme replacement therapy

• Referred to PET/CT (Fig. 2.43 and Table 2.19) for evaluation of myocardial perfusion and function

Fig. 2.43

Rest and Regadenoson-stress ¹³N-ammonia showing severe transient LV dilatation during stress with increased RV tracer uptake. There are no regional perfusion abnormalities. At rest, there is evidence of LV hypertrophy

Table 2.19 Summary of the quantitative blood flow data demonstrating diffuse reduction in stress MBF regionally and globally, as well as of MFR

Findings

• MPI: Severe transient LV dilatation during stress with increased RV tracer uptake, without regional perfusion defects. Evidence of LV hypertrophy.

• Diffuse reduction in stress MBF regionally and globally.

• Low normal EF at rest measured at 50% with a significant drop to 37% with severe enlargement of end systolic volume during vasodilator stress.

Differential Diagnosis

• Obstructive CAD vs microvascular dysfunction from Fabry’s disease.

Correlative Imaging

• Cardiac MR (Figs. 2.44 and 2.45)

Fig. 2.44

Cardiac MR images demonstrating severe LV hypertrophy

Fig. 2.45

Cardiac MR images with T1-mapping demonstrating abnormally short T1 velocity (<800 ms), consistent with glycosphingolipid accumulation, associated with edema on T2-weighted imaging

Management

• Coronary angiography demonstrated normal coronary arteries.

• The patient was placed on enzyme replacement therapy.

Teaching Points

• Infiltrative cardiomyopathies are characterized by the presence of LV hypertrophy.

• The PET scan shows the typical perfusion pattern of infiltrative disease including TID resulting from subendocardial ischemia and associated microvascular dysfunction, as shown in this case.

Further Reading

• El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A, Barreto F. Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies. PLOS ONE. 2017;12.

• Simonetta I, Tuttolomondo A, Di Chiara T, Miceli S, Vogiatzis D, Corpora F, et al. Genetics and Gene Therapy of Anderson-Fabry Disease. Current Gene Therapy. 2018;18:96–106.

Acknowledgement

Cardiac MR images courtesy of Prof Davide Farina and Dr. Emanuele Gavazzi, Institute of Radiology, University of Brescia.

Case 28

History

• 67-year-old female with a history of hypercholesterolemia and controlled hypertension. She is an active smoker. She was admitted to the hospital for dyspnea and atypical angina.

• She underwent coronary angiography which showed normal coronary arteries (Fig. 2.46).

• She was referred for PET myocardial perfusion imaging to assess for microvascular dysfunction (Fig. 2.47 and Table 2.20).

• ECG showed ischemic modifications during vasodilator stress (Fig. 2.48).

Coronary angiography

Fig. 2.46

Selective views of invasive coronary angiography showing normal coronary tree

Fig. 2.47

Rest and Regadenoson-stress ¹³N-ammonia showing mild LV dilatation at stress without regional perfusion abnormalities

Table 2.20 Summary of the quantitative blood flow data demonstrating severe and diffuse reduction in stress MBF and MFR impairment

Fig. 2.48

ECG at rest (panel on the left) and 2′ after Regadenoson infusion (panel on the right), showing ischemic modifications during vasodilator stress

Findings

• Mild LV dilatation at stress without regional perfusion abnormalities

• Severe and diffuse reduction in stress MBF and MFR impairment

• Normal LV function with an LVEF of 64% at rest and during peak stress

• Ischemic ECG modifications during vasodilator stress

Differential Diagnosis

• Hypertensive heart disease

• Hypertrophic cardiomyopathy and infiltrative cardiomyopathies

Correlative Imaging

• Cardiac MRI (Figs. 2.49 and 2.50)

Fig. 2.49

Cardiac MRI showing LV hypertrophy

Fig. 2.50

Cardiac MRI showing mild subepicardial late gadolinium enhancement in the inferior and lateral walls (arrows)

Management

• Based on PET and cardiac MRI results, the patient was evaluated for Fabry’s disease. She had a negative enzyme assay for alpha galactosidase.

• Molecular genetic analysis was positive for the galactosidase alpha (GLA) gene.

• She has started on enzyme replacement therapy.

Teaching Points

• Coronary microvascular dysfunction is common in Fabry’s disease and develops early in the natural history the disease.

Further Reading

• Tomberli B, Cecchi F, Sciagrà R, Berti V, Lisi F, Torricelli F, et al. Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. European Journal of Heart Failure. 2013;15:1363–1373.

Acknowledgement

Cardiac MR images courtesy of Prof Davide Farina and Dr. Emanuele Gavazzi, Institute of Radiology, University of Brescia.

2.5.1.4 Amyloidosis

Case 29

History

• A 61-year-old male with progressive dyspnea on exertion and atypical chest pain was referred for a myocardial perfusion PET study (Fig. 2.51 and Table 2.21).

• He had a strong family history of CAD.

• His cardiac risk factors include hypertension and dyslipidemia.

• He also had a report of thickened left ventricular walls and diastolic dysfunction at an echocardiogram (not shown).

PET/CT Imaging

Fig. 2.51

Rest and adenosine-stress ¹³N-ammonia myocardial perfusion PET/CT images. There is marked transient ischemic dilatation (TID ratio: 1.43, normal: 1.05) of the LV cavity during stress. The stress myocardial perfusion images demonstrate a large perfusion defect of severe intensity throughout the mid and basal LV segments, showing complete reversibility. The combined extent and severity of ischemia during stress involved 45% of the LV mass

Table 2.21 Summary of the quantitative blood flow data demonstrating a severe reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) and myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Findings

• There is marked transient ischemic dilatation (TID ratio: 1.43, normal: 1.05) of the LV cavity during stress.

• The stress myocardial perfusion images demonstrate a large perfusion defect of severe intensity throughout the mid and basal LV segments, showing complete reversibility. The combined extent and severity of ischemia during stress involved 45% of the LV mass.

• The stress myocardial blood flow and flow reserve are markedly reduced both regionally and globally.

• Gated Cardiac CT: The Agatston coronary calcium score was 0.

Differential Diagnosis

• Multivessel obstructive CAD vs coronary microvascular dysfunction

Correlative Imaging

• Coronary angiography demonstrates no evidence of coronary artery disease (Fig. 2.52).

• Cardiac MRI shows diffuse subendocardial late gadolinium enhancement in the base of the left ventricle in the short axis view (Fig. 2.53).

Fig. 2.52

Selective views of the coronary angiography demonstrate no evidence of coronary artery disease

Fig. 2.53

Short axis view of the cardiac MRI showing diffuse subendocardial late gadolinium enhancement in the base of the left ventricle

Management

• The patient underwent coronary angiography, which demonstrated minimal nonobstructive atherosclerosis of the epicardial coronary arteries.

• Cardiac MRI was performed to evaluate for causes of left ventricular hypertrophy with marked microvascular disease. This showed increased thickening of both ventricles, and diffuse late gadolinium enhancement of the left ventricle, features highly suggestive of cardiac amyloidosis. His subsequent investigations (serum free light chain levels, serum and urine immunofixation, and a fat pad biopsy) confirmed light chain amyloidosis with cardiac involvement.

• This patient underwent chemotherapy.

Teaching Points

• Perfusion defects in a non-vascular distribution with a pattern that involves the base with relative sparing of the LV apex, like in this patient, should raise the suspicion of microvascular dysfunction and nonischemic cardiomyopathy. However, coronary angiography should always be considered to exclude obstructive CAD.

• Left ventricular wall thickening and microvascular dysfunction can be seen in patients with hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, cardiac amyloidosis, and Fabry’s disease.

• This patient was diagnosed with light chain cardiac amyloidosis.

• The mechanism of microvascular dysfunction in cardiac amyloidosis is thought to be due to several factors including extravascular compressive forces due to a high left ventricular end diastolic pressure, autonomic dysfunction, vascular infiltration, or capillary rarefaction.

Further Reading

• Dorbala S, Vangala D, Bruyere J, Quarta C, Kruger J, Padera R, et al. Coronary Microvascular Dysfunction Is Related to Abnormalities in Myocardial Structure and Function in Cardiac Amyloidosis. JACC: Heart Failure. 2014;2:358–367.

• Bravo P, Di Carli M, Dorbala S. Role of PET to evaluate coronary microvascular dysfunction in non-ischemic cardiomyopathies. Heart Failure Reviews. 2017;22:455–464.

• Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici P. Coronary Microvascular Dysfunction and Prognosis in Hypertrophic Cardiomyopathy. New England Journal of Medicine. 2003;349:1027–1035.

2.5.1.5 Hypertrophic Cardiomyopathy

Case 30

History

• A 56-year-old female with HCM and heart failure but no known CAD was referred to for evaluating non-anginal chest pain.

• Her cardiac risk factors include hypertension, dyslipidemia, diabetes, and obesity.

• The patient underwent a Regadenoson-stress myocardial perfusion PET study (Fig. 2.54 and Table 2.22).

PET/CT Imaging

Fig. 2.54

Rest and adenosine-stress ¹³N-ammonia myocardial perfusion PET/CT images. There is moderate TID of the LV cavity during stress. The stress myocardial perfusion images demonstrate a medium sized perfusion defect of moderate intensity involving the apical LV segments and the LV apex, showing complete reversibility. The combined extent and severity of ischemia during stress involves 10% of the LV mass. There is evidence of asymmetric septal hypertrophy

Table 2.22 Summary of the quantitative blood flow data demonstrating a diffuse and severe reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) and myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Findings

• There is moderate transient ischemic dilatation (TID) of the LV cavity during stress.

• The stress myocardial perfusion images demonstrate a medium sized perfusion defect of moderate intensity involving the apical LV segments and the LV apex, showing complete reversibility. The combined extent and severity of ischemia during stress involves 10% of the LV mass.

• There is evidence of asymmetric septal hypertrophy.

• The stress myocardial blood flow and flow reserve are markedly reduced both regionally and globally.

• Her LV ejection fraction was 58% at rest and remained essentially unchanged during stress.

Differential Diagnosis

• Multivessel obstructive coronary artery disease vs microvascular disease.

Correlative Imaging

• Invasive coronary angiography demonstrates no evidence of obstructive coronary artery disease (Fig. 2.55).

• Cardiac MRI shows severe left ventricular hypertrophy, with more pronounced septal hypertrophy. There is a large amount of patchy mesocardial late gadolinium enhancement in multiple myocardial segments but is more pronounced in the severely hypertrophied segments. Overall, findings are consistent with asymmetric obstructive hypertrophic cardiomyopathy (Fig. 2.56).

Fig. 2.55

Invasive coronary angiography demonstrates no evidence of obstructive coronary artery disease

Fig. 2.56

Four and two chamber contrast-enhanced cardiac MRI images show severe left ventricular hypertrophy, with more pronounced septal hypertrophy. There is a large amount of patchy mesocardial late gadolinium enhancement in multiple myocardial segments but is more pronounced in the severely hypertrophied segments. Overall, findings are consistent with asymmetric obstructive hypertrophic cardiomyopathy

Management

• Coronary angiography is an important consideration in the context of the PET findings and anginal symptoms, which in this case helped exclude epicardial coronary artery disease.

Teaching Points

• The presence of transient ischemic dilatation and diffusely reduced myocardial blood flow and flow reserve is consistent with subendocardial ischemia. The presence of a regional perfusion defect involving the LV apex and apical LV segments in a patient with multiple risk factors including diabetes should raise concerns of multivessel obstructive CAD. However, these findings could still be related to coronary microvascular dysfunction (CMD). Coronary angiography is always necessary to exclude obstructive CAD.

• Coronary microvascular dysfunction is common in patients with HCM even in the absence of epicardial CAD.

• Like in other forms of cardiomyopathy, the severity of CMD in patients with HCM identifies those at higher risk of adverse cardiovascular events.

Further Reading

• Bravo P, Di Carli M, Dorbala S. Role of PET to evaluate coronary microvascular dysfunction in non-ischemic cardiomyopathies. Heart Failure Reviews. 2017;22:455–464.

• Camici P, Olivotto I, Rimoldi O. The coronary circulation and blood flow in left ventricular hypertrophy. Journal of Molecular and Cellular Cardiology. 2012;52:857–864.

• Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici P. Coronary Microvascular Dysfunction and Prognosis in Hypertrophic Cardiomyopathy. New England Journal of Medicine. 2003;349:1027–1035.

2.5.1.6 Stress Cardiomyopathy

Case 31

History

• 69-year-old female with a history of breast cancer and bioprosthetic aortic valve replacement in 2017, presented with out of hospital cardiac arrest. Her cardiac risk factors included hypertension, dyslipidemia, diabetes, and obesity.

• She was found to have a new left bundle branch block and a transthoracic echocardiogram revealed newly reduced LV ejection fraction of 35%. There was global hypokinesis with akinesis of the apex and septum.

• She was referred for a Regadenoson SPECT myocardial perfusion study to evaluate for CAD (Fig. 2.57).

SPECT Imaging

Fig. 2.57

Stress/rest ^99mTc-sestamibi SPECT myocardial perfusion images demonstrate aneurysmal dilatation of the LV associated with a large perfusion defect of severe intensity throughout the mid anteroseptal wall, apical LV segments and the LV apex, which was essentially fixed.

Findings

• The stress/rest SPECT myocardial perfusion images demonstrate aneurysmal dilatation of the LV associated with a large perfusion defect of severe intensity throughout the mid anteroseptal wall, apical LV segments and the LV apex, which is essentially fixed.

• The ECG-gated images demonstrated severe global LV systolic dysfunction with akinesis of the LV apex and apical LV segments.

• A follow-up PET with FDG was recommended to assess myocardial viability and paired with rest SPECT (Fig. 2.58). Results were consistent with the presence of combined nonviable and viable but hibernating myocardium throughout the mid LAD territory involving approximately 38% of the LV mass (perfusion-FDG mismatch).

FDG PET/CT Imaging

Fig. 2.58

Rest ^99mTc-sestamibi SPECT myocardial perfusion (rest perfusion rows) and ¹⁸F-FDG PET images (FDG rows) demonstrating significant FDG uptake throughout all hypoperfused LV segments (perfusion-FDG mismatch), consistent with the presence of combined nonviable and viable but hibernating myocardium throughout the mid LAD territory involving approximately 38% of the LV mass

Findings

• There is significant FDG uptake throughout all hypoperfused LV segments (perfusion-FDG mismatch), consistent with the presence of combined nonviable and viable but hibernating myocardium throughout the mid LAD territory involving approximately 38% of the LV mass.

Differential Diagnosis

• Subacute anterior myocardial infarction with significant residual viable but hibernating myocardium due to obstructive CAD

Correlative Imaging

• Invasive coronary angiography demonstrated minimal luminal irregularities without obstructive CAD (Fig. 2.59).

Fig. 2.59

Invasive coronary angiography demonstrates no evidence of obstructive coronary artery disease

Management

• The patient underwent a secondary prevention AICD placement.

• The patient was subsequently discharged home on optimal medical therapy for ischemic heart failure including beta blocker, ARB, loop diuretic, ASA, and statin therapy.

Teaching Points

• The presence of fixed perfusion defects in a patient with a subacute myocardial infarction should always prompt the consideration of assessing residual myocardial viability.

• Identification of significant viable but hibernating myocardium not only identifies patients who may benefit from revascularization but also a high-risk cohort for adverse cardiac events.

• The absence of obstructive CAD on coronary angiography suggests that severe coronary microvascular dysfunction is the underlying pathophysiology for the extensive area of hibernating myocardium in the LAD territory and, likely, for the acute presentation with cardiac arrest. The clinical presentation and imaging findings are consistent with stress cardiomyopathy.

• The absence of revascularizable disease poses a management challenge as there is residual ischemic myocardium.

Further Reading

• Pelliccia F, Kaski J, Crea F, Camici P. Pathophysiology of Takotsubo Syndrome. Circulation. 2017;135:2426–2441.

• Templin C, Ghadri J, Diekmann J, Napp L, Bataiosu D, Jaguszewski M, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. New England Journal of Medicine. 2015;373:929–938.

2.5.2 Nonobstructive Atherosclerosis

2.5.2.1 Diabetes

Case 32

History

• 86-year-old female with a history of hypertension, dyslipidemia, diabetes, and obesity but no known CAD underwent evaluation for dyspnea and palpitations.

• She was referred for PET/CT to assess myocardial perfusion (Figs. 2.60 and 2.61; Table 2.23).

PET/CT Images

Fig. 2.60

Adenosine-stress and rest ¹³N-ammonia myocardial perfusion PET/CT images demonstrate normal LV size. There is mild RV dilatation with moderate increase tracer uptake during stress. There are no regional perfusion defects on the stress and rest images

Table 2.23 Summary of the quantitative blood flow data demonstrating severe reduction in stress MBF (normal value >1.8 mL/min/g) and MFR (normal value >2.0) in all coronary artery territories and globally

Fig. 2.61

Segmental stress myocardial blood flow demonstrates no significant base to apical gradients

Findings

• The images demonstrate normal LV size. There is mild RV dilatation with moderate increase tracer uptake during stress. There are no regional perfusion defects on the stress and rest images.

• The ECG-gated images demonstrated a rest LV ejection fraction of 52% with minimal increase during stress to 54% with normal LV volumes. There was normal regional wall motion and thickening.

• The maximal stress myocardial blood flow is severely reduced (<1.8 mL/min/g) in all coronary territories and globally without significant base to apical gradient. The myocardial flow reserve is also severely reduced in all coronary territories.

• The CT transmission scan demonstrates no evidence of coronary artery calcifications.

Differential Diagnosis

• Multivessel obstructive CAD

• Coronary microvascular dysfunction

Correlative Imaging

• Invasive coronary angiography (Fig. 2.62)

Fig. 2.62

Selective coronary angiographic views demonstrate nonobstructive stenosis. The moderate stenosis in the proximal LAD (arrows) was associated with an FFR of 0.87

Management

• Management of ischemic heart disease, coronary risk factors, and glycemic control.

Teaching Points

• The normal myocardial perfusion PET images associated with the absence of coronary calcifications and normal stress myocardial blood flow are consistent with a low likelihood of flow-limiting CAD or nonobstructive atherosclerosis.

• However, the presence of increased rest myocardial blood flow and mild reduction in myocardial flow reserve places her at an intermediate clinical risk (1–3% cardiac death rate/year). This phenotype is common among women who typically have a low prevalence of obstructive atherosclerosis and has been linked to microvascular disease, which may be the source of her symptoms.

Further Reading

• Gupta A, Taqueti VR, van de Hoef TP, Bajaj NS, Bravo PE, Murthy VL, et al. Integrated Non-invasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients with Stable Coronary Artery Disease. Circulation. 2017;136:2325–2336.

• Taqueti V, Shaw L, Cook N, Murthy V, Shah N, Foster C, et al. Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease. Circulation. 2017;135:566–577.

• Murthy V, Naya M, Taqueti V, Foster C, Gaber M, Hainer J, et al. Effects of Sex on Coronary Microvascular Dysfunction and Cardiac Outcomes. Circulation. 2014;129:2518–2527.

2.5.2.2 Obese

Case 33

History

• 65-year-old male with morbid obesity was referred for a coronary CTA after an episode of atypical chest pain. The CCTA revealed only minimal coronary calcifications.

• Given his symptoms, he was then referred for a quantitative PET MPI to assess for microvascular dysfunction (Fig. 2.63 and Table 2.24).

PET/CT Images

Fig. 2.63

Stress/rest ¹³N-ammonia PET myocardial perfusion images. There is normal regional myocardial perfusion on both the stress and rest images

Table 2.24 Summary of the quantitative blood flow data demonstrating a diffuse and severe reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) with moderate reduction in myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Findings

• The stress/rest ¹³N-ammonia PET scan demonstrates normal regional myocardial perfusion on both the rest and stress images.

• The ECG-gated images demonstrated an LVEF of 59% at rest and 63% post stress with normal LV volumes.

• The stress myocardial blood flow is markedly reduced, and the myocardial flow reserve is moderately reduced both regionally and globally.

Differential Diagnosis

• None

Teaching Points

• The absence of regional perfusion defects with reduced stress myocardial flow and flow reserve in the absence of epicardial coronary stenosis is consistent with diffuse nonobstructive atherosclerosis and microvascular dysfunction.

• This imaging phenotype is quite prevalent in patients with cardiometabolic disease, including obesity.

• The presence of coronary microvascular dysfunction identifies patients at increased risk of adverse cardiovascular events including heart failure and death.

Correlative Imaging

• None

Management

• Counselling on lifestyle modifications and weight loss

Further Reading

• Schindler T, Cardenas J, Prior J, Facta A, Kreissl M, Zhang X, et al. Relationship Between Increasing Body Weight, Insulin Resistance, Inflammation, Adipocytokine Leptin, and Coronary Circulatory Function. Journal of the American College of Cardiology. 2006;47:1188–1195.

• Tona F, Serra R, Di Ascenzo L, Osto E, Scarda A, Fabris R, et al. Systemic inflammation is related to coronary microvascular dysfunction in obese patients without obstructive coronary disease. Nutrition, Metabolism and Cardiovascular Diseases. 2014;24:447–453.

• Bajaj N, Osborne M, Gupta A, Tavakkoli A, Bravo P, Vita T, et al. Coronary Microvascular Dysfunction and Cardiovascular Risk in Obese Patients. Journal of the American College of Cardiology. 2018;72:707–717.

2.5.2.3 Heart Failure with Preserved Ejection Fraction

Case 34

History

• 51-year-old male with known CAD and a prior STEMI with stenting of the proximal LAD 3 months prior to his current hospitalization, now presenting with chest pain, dyspnea, and heart failure. He has type 1 diabetes mellitus complicated by nephropathy status post renal transplant in 2008 and peripheral neuropathy. He also has hypertension and hyperlipidemia.

• The patient was referred for a myocardial perfusion PET scan to assess for obstructive CAD (Fig. 2.64 and Table 2.25).

PET/CT Imaging

Fig. 2.64

Stress/rest ¹³N-ammonia PET myocardial perfusion images. The images demonstrate transient ischemic dilatation (TID). There is a medium sized perfusion defect of moderate intensity involving the LV apex, apical LV segments, the mid and basal anterior wall, showing complete reversibility. In addition, there is medium sized perfusion defect of moderate severity throughout the inferoseptal wall, also showing complete reversibility

Table 2.25 Summary of the quantitative blood flow data demonstrating a diffuse and severe reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) with moderate reduction in myocardial flow reserve (normal value >2.0) in all coronary artery territories and globally

Findings

• The ¹³N-ammonia PET myocardial perfusion scan demonstrates transient ischemic dilatation (TID).

• There is a medium sized perfusion defect of moderate intensity involving the LV apex, apical LV segments, the mid and basal anterior wall, showing complete reversibility. In addition, there is medium sized perfusion defect of moderate severity throughout the inferoseptal wall, also showing complete reversibility.

• The ECG-gated images demonstrated an LVEF of 62% at rest that dropped to 45% with transient enlargement of the end systolic volume.

• The stress myocardial blood flow and flow reserve are markedly reduced both regionally and globally.

Differential Diagnosis

• Multivessel obstructive CAD

• Coronary microvascular dysfunction

Correlative Imaging

• Given the PET scan findings, the patient was referred to invasive coronary angiography, which showed a patent LAD stent with diffuse nonobstructive CAD and a long 70% stenosis in the mid RCA with an FFR of 0.78 (Fig. 2.65).

Fig. 2.65

Selective invasive coronary angiographic views demonstrating a patent LAD stent with diffuse nonobstructive CAD and a long 70% stenosis in the mid RCA (blue arrow) with an associated FFR of 0.78

Management

• Medical management of myocardial ischemia and heart failure

Teaching Points

• There is evidence of extensive multivessel myocardial ischemia by both visual and quantitative analysis, with associated TID and a transient drop in LVEF with stress with enlargement of the LV end systolic volume. These are all high-risk findings which did not associate with multivessel obstructive CAD on coronary angiography.

• In this context, the markedly reduced stress myocardial blood flow and flow reserve are consistent with diffuse nonobstructive atherosclerosis and severe coronary microvascular dysfunction (CMD).

• Recent evidence supports that CMD associated with cardiomyocyte injury (troponin elevation without obstructive CAD) and abnormal myocardial mechanics likely play an important role in the pathophysiology of HFpEF. In patients with stable CAD and preserved LV ejection fraction, chronic circulating levels of high-sensitivity troponins are common in patients with LV hypertrophy, diabetes, and chronic kidney disease and are associated with increased incidence of cardiovascular death and heart failure.

Further Reading

• Shah S, Lam C, Svedlund S, Saraste A, Hage C, Tan R, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. European Heart Journal. 2018;39:3439–3450.

• Taqueti V, Solomon S, Shah A, Desai A, Groarke J, Osborne M, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. European Heart Journal. 2017;39:840–849.

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72:2625–2641.

2.5.3 Obstructive CAD

2.5.3.1 Normal PI + Single Vessel Reduced MFR

Case 35

History

• 67-year-old male with a history of heart transplantation 17 years prior to the current visit.

• Referred for evaluation of cardiac allograft vasculopathy for a recent pre-syncopal episode. He has controlled hypertension.

• Underwent PET/CT (Fig. 2.66 and Table 2.26).

PET/CT Imaging

Fig. 2.66

Stress/rest ¹³N-ammonia PET myocardial perfusion images. There is evidence of apical thinning but overall the images demonstrate normal myocardial perfusion without definitive regional defects. The ECG-gated images demonstrated an LVEF of 64% at rest that increased to 67% at stress, with normal LV volumes

Table 2.26 Summary of the quantitative blood flow data demonstrating a severe reduction in stress myocardial blood flow (normal value >1.8 mL/min/g) in the LAD territory with normal stress flow in flow reserve in the LCX and RCA territories (normal value >2.0)

Findings

• The ¹³N-ammonia PET myocardial perfusion scan demonstrates normal regional myocardial perfusion without definitive defects.

• The ECG-gated images demonstrated an LVEF of 64% at rest that increased to 67% at stress, with normal LV volumes.

• The stress myocardial blood flow and flow reserve are markedly reduced in the LAD coronary artery territory and normal in the LCX and RCA territories.

Differential Diagnosis

• Obstructive CAD in the LAD coronary artery

Correlative Imaging

• Given the PET scan findings, the patient was referred to invasive coronary angiography, which showed an 85% stenosis in the proximal LAD with mild diffuse nonobstructive cardiac allograft vasculopathy in the LCX and RCA (Fig. 2.67).

Fig. 2.67

Selective invasive coronary angiographic views demonstrating a severe stenosis in the proximal LAD coronary artery (arrow). There is mild diffuse allograft vasculopathy in the LCX and RCA arteries

Management

• The patient was referred to invasive coronary angiography which confirmed a severe stenosis in the proximal LAD coronary artery, which was subsequently stented.

Teaching Points

• Quantitative myocardial blood flow and flow reserve increase the sensitivity of PET myocardial perfusion imaging to detect flow-limiting CAD.

• It is always important to examine both regional and global myocardial blood flow. In this case, stress myocardial blood flow and flow reserve are markedly reduced compared to the other vascular territories. This regional difference should raise the suspicion of obstructive CAD.

Further Reading

• Driessen R, Danad I, Stuijfzand W, Raijmakers P, Schumacher S, van Diemen P, et al. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. Journal of the American College of Cardiology. 2019;73:161–173.

• Ziadi M, deKemp R, Williams K, Guo A, Renaud J, Chow B, et al. Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease?. Journal of Nuclear Cardiology. 2012;19:670–680.

• Naya M, Murthy V, Taqueti V, Foster C, Klein J, Garber M, et al. Preserved Coronary Flow Reserve Effectively Excludes High-Risk Coronary Artery Disease on Angiography. Journal of Nuclear Medicine. 2014;55:248–255.

2.6 Patient with Known CAD

2.6.1 Prior PCI

Case 36

History

• 76-year-old male with a history of hypertension, smoking, and dyslipidemia, and known CAD with prior STEMI followed by PCI of the left circumflex coronary artery.

• The patient was referred for evaluation of recurrent atypical angina (Fig. 2.68 and Table 2.27).

PET/CT Images

Fig. 2.68

Stress-rest ¹³N ammonia PET MPI demonstrating a small and severe perfusion defect in the mid and basal inferolateral wall, which is fixed.

Table 2.27 There is mildly reduced stress MBF in the RCA territory. MFR is preserved in all coronary territories and globally

Findings

• A small area of prior myocardial infarction throughout the mid and basal inferolateral wall without residual stress-induced ischemia.

• The LVEF was 63% at rest and 61% during peak stress.

• LV with conserved ejection fraction, normal motion, and normal MBF.

Differential Diagnosis

• Non-cardiac chest pain

Correlative Imaging

• Coronary CT angiography (Fig. 2.69)

Fig. 2.69

Selective multiplanar reformatted CT angiographic images demonstrating scattered calcifications of all three coronary arteries without obstructive stenosis. Stent on LCX is patent

Management

• Optimized medical treatment

Teaching Points

• Myocardial perfusion PET imaging with quantitative flow information can help guide diagnosis and management of patients with known CAD and prior revascularization.

• The presence of relatively preserved stress MBF and MFR help exclude the presence of obstructive CAD and/or stent restenosis, and the possibility that chest pain may be related to microvascular dysfunction.

Further Reading

• Murthy V, Bateman T, Beanlands R, Berman D, Borges-Neto S, Chareonthaitawee P, et al. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. Journal of Nuclear Cardiology. 2017;25:269–297.

• Patel KK, Spertus JA, Chan PS, Sperry BW, Thompson RC, Al Badarin F et al. Extent of Myocardial Ischemia on Positron Emission Tomography and Survival Benefit With Early Revascularization. J Am Coll Cardiol. 2019 Oct 1;74(13):1645–1654. https://doi.org/10.1016/j.jacc.2019.07.055.

2.6.2 Prior CABG

Case 37

History

• 40-year-old female with known CAD and prior CABG (LIMA to LAD) and end-stage renal disease in the setting of lupus nephritis.

• She has a history of mechanical mitral valve replacement for severe calcific mitral stenosis and tricuspid repair for severe tricuspid insufficiency.

• She was referred for a Regadenoson myocardial perfusion PET study for pre-renal transplant evaluation (Fig. 2.70 and Table 2.28).

PET/CT Imaging

Fig. 2.70

Stress/rest ¹³N-ammonia PET myocardial perfusion images demonstrate a medium sized perfusion defect of severe intensity involving the mid and basal anterior and anteroseptal walls (arrows), showing complete reversibility. The apical LV segments and the LV apex have relatively preserved myocardial perfusion during stress. In addition, there is a small and severe perfusion defect involving the basal inferolateral wall (arrows), which is fixed.

Table 2.28 Summary of quantitative flow data demonstrating moderate diffuse reduction in stress myocardial blood flow in all territories, more severe in the proximal LAD territory. MFR regionally reduced in the area of the myocardial perfusion defect

Findings

• There is a medium sized perfusion defect of severe intensity involving the mid and basal anterior and anteroseptal walls, showing complete reversibility. The apical LV segments and the LV apex have relatively preserved myocardial perfusion during stress.

• In addition, there is a small and severe perfusion defect involving the basal inferolateral wall, which is fixed.

• The ECG-gated images demonstrated a normal LVEF calculated at 56% at rest with paradoxical septal motion, consistent with prior open heart surgery.

• The quantitative flow data demonstrated a moderate diffuse reduction in stress myocardial blood flow, more severe in the proximal LAD territory. The flow reserve is regionally reduced in the area of the myocardial perfusion defect.

Differential Diagnosis

• Obstructive CAD

Correlative Imaging

• Follow-up invasive coronary angiography demonstrated:

  • Proximal 100% LAD occlusion, with collateral flow from the RCA.

  • The LCX has a 95% mid lesion and is occluded distally.

  • The LIMA Graft to the mid LAD is patent.

  • The RCA is without significant disease.

Management

• The area of moderate ischemia in the proximal LAD territory with preservation of perfusion in the distal part of the territory is caused by progression of disease in the native LAD proximal to the touchdown of the LIMA graft. The small fixed defect in the LCX/obtuse marginal territory corresponds to a totally occluded LCX. She was continued on dual anti-platelet therapy and anti-anginal therapy was intensified. On a follow-up office visit, she remains angina free.

Teaching Points

• Quantitative PET MPI is helpful to localize the culprit vessel and assess the magnitude of myocardial ischemia post CABG.

• Stress myocardial blood flow after CABG tends to be reduced even in asymptomatic patients. This is likely related to the fact that the native coronary arteries typically developed diffuse atherosclerosis and calcifications.

• Reporting of myocardial perfusion images in patients post CABG should be ideally performed with knowledge of the operative report to better guide the localization of the culprit artery in cases with documented ischemia undergoing repeat angiography.

Further Reading

• Murthy V, Bateman T, Beanlands R, Berman D, Borges-Neto S, Chareonthaitawee P, et al. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. Journal of Nuclear Cardiology. 2017;25:269–297.

2.6.3 Prior MI (Single Territory MI + Globally Reduced MFR and Multi VD on Cath)

Case 38

History

• 59-year-old female with known CAD and prior inferior myocardial infarction (MI) was referred for a Regadenoson myocardial perfusion PET study to evaluate for atypical chest pain (Fig. 2.71 and Table 2.29).

• Her cardiac risk factors include hypertension, dyslipidemia, tobacco use, and obesity.

PET/CT Imaging

Fig. 2.71

Stress/rest ¹³N-ammonia PET myocardial perfusion images. There is mild transient ischemic dilation of the LV cavity during stress. There is a medium sized perfusion defect of severe intensity throughout the inferior wall, showing only mild reversibility (arrows). In addition, there is a small perfusion defect of severe intensity involving the LV apex, which shows complete reversibility (arrow)

Table 2.29 Summary of the quantitative blood flow data demonstrating marked reduction in stress myocardial blood flow and moderate reduction in flow reserve in all coronary artery territories

Findings

• There is mild transient ischemic dilation of the LV cavity during stress. There is a medium sized perfusion defect of severe intensity throughout the inferior wall, showing only mild reversibility. In addition, there is a small perfusion defect of severe intensity involving the LV apex, which shows complete reversibility.

• The ECG-gated images demonstrated a mild reduction in global LV systolic function with severe hypokinesis of the inferior wall and an LVEF at rest of 47%.

• The quantitative flow data demonstrates marked reduction in stress myocardial blood flow and moderate reduction in flow reserve in all coronary artery territories.

Differential Diagnosis

• Multivessel obstructive CAD

• Coronary microvascular dysfunction (CMD)

Correlative Imaging

• Follow-up invasive coronary angiography demonstrated a total occlusion of the mid RCA with moderate right-to-right collaterals. The left main and LAD arteries had mild irregularities. The LCX has a moderate stenosis (Fig. 2.72).

Fig. 2.72

Selective invasive coronary angiographic views demonstrating a total occlusion of the RCA (arrow) with right-to-tight collaterals and moderate diffuse nonobstructive atherosclerosis of the LCX and LAD coronary arteries (arrows)

Management

• The patient underwent PCI of the total mid RCA occlusion and intensification of medical therapy of myocardial ischemia.

Teaching Points

• The presence of mild TID with diffuse reduction in myocardial blood flow and flow reserve in the non-infarcted territories in the context of nonobstructive atherosclerosis illustrates the fact that diffuse atherosclerosis and CMD are prevalent in patients with known obstructive CAD. This affects the magnitude of myocardial ischemia and the quantitative imaging pattern can look like multivessel obstructive CAD.

• This high prevalence of CMD in patients with known CAD is not surprising because endothelial and coronary vasomotor dysfunction represent an early manifestation of atherosclerosis, which may long precede the development of obstructive stenosis. In patients with stable CAD, reductions in microcirculatory reserve exacerbate the functional significance of upstream coronary stenosis and may magnify the severity of inducible myocardial ischemia.

• From a clinical perspective, the presence of CMD in patients with stable obstructive CAD has several important diagnostic, prognostic, and management implications.

Further Reading

• Taqueti V, Di Carli M. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2018;72:2625–2641.

• Johnson N, Gould K, Di Carli M, Taqueti V. Invasive FFR and Noninvasive CFR in the Evaluation of Ischemia: What is the Future?. Journal of the American College of Cardiology. 2016;67:2772–2788.

2.6.3.1 Infarct with Peri-infarct Ischemia

Case 39

History

• 49-year-old male with history of smoking, hypertension, diabetes mellitus, dyslipidemia, and prior STEMI, treated with PCI on RCA

• Referred to PET/CT for investigation of typical angina (Fig. 2.73 and Table 2.30)

PET/CT Images

Fig. 2.73

Stress/rest ¹³N-ammonia PET myocardial perfusion images. There is no tracer uptake on the infero-basal segment and mild reduction on the remaining inferior wall. Gated study shows an LVEF of 50% at rest that decreased to 46% on stress

Table 2.30 Summary of the quantitative blood flow data demonstrating reduction in flow reserve in RCA and LCX artery territories

This patient also underwent CCTA (Fig. 2.74)

Fig. 2.74

CCTA shows a permeable RCA stent (without restenosis); LAD and LCX without significant occlusion. The reduced MFR may be explained due to microvascular dysfunction

Findings

• ¹³N ammonia PET MPI: Inferoseptal infarction on basal and medial segments with mild ischemia of the residual tissue

• LV ejection fraction of 50% at rest that decreased to 46% on stress, related to ischemia.

• Diminished MBF on RCA and LCX with reduced MFR

Differential Diagnosis

• Stent dysfunction or progression of coronary obstructive disease in non-treated coronaries

Teaching Points

• Myocardial perfusion imaging with PET is good to detect new areas of ischemia in patients treated previously with a stent.

• Revascularization guided by ischemia optimizes the treatment of the patients.

Management

• New cath to evaluate the presence of intrastent stenosis or new significant obstructive lesions

Further Reading

• Gewirtz H. Cardiac PET: A Versatile, Quantitative Measurement Tool for Heart Failure Management. JACC: Cardiovascular Imaging. 2011;4:292–302.

• Anavekar N, Chareonthaitawee P, Narula J, Gersh B. Revascularization in Patients with Severe Left Ventricular Dysfunction. Journal of the American College of Cardiology. 2016;67:2874–2887.

2.6.3.2 Evaluation of Patients with Total Coronary Occlusions

Case 40

History

• 33-year-old male with a history of premature CAD with prior MI and PCI of the LAD coronary artery.

• He has a history of controlled hypertension and hyperlipidemia. Due to his past history and recurrent symptoms, he underwent invasive coronary angiography (Fig. 2.75), which demonstrated a widely patent LAD stent and a total occlusion of the RCA, which is essentially unchanged since his first coronary angiogram.

• She was referred to PET/CT for evaluation of recurrent atypical angina to assess the extent and severity of myocardial ischemia (Fig. 2.76 and Table 2.31).

Fig. 2.75

Selective invasive coronary angiographic views demonstrating a total occlusion of the RCA (arrow) with right-to-tight collaterals and moderate diffuse nonobstructive atherosclerosis of the LCX and LAD coronary arteries (arrows)

PET/CT Imaging

Fig. 2.76

Stress/rest ¹³N-ammonia PET myocardial perfusion images. There is a large and severe perfusion defect throughout the inferior, inferoseptal, and inferolateral walls (arrows), showing moderate inferolateral reversibility

Table 2.31 Summary of the quantitative blood flow data demonstrates markedly reduced stress myocardial blood flow in the infarct-related territory of the RCA, which is expected. Stress myocardial blood flow and flow reserve are preserved in the LAD and LCX territories

Findings

• There is a large and severe perfusion defect throughout the inferior, inferoseptal, and inferolateral walls, showing significant reversibility.

• The ECG-gated images demonstrated a rest LV ejection fraction of 38% that increased to 44% post stress. The LV volumes appeared mildly dilated. There was akinesis of the inferior and inferoseptal walls.

• The quantitative flow data demonstrate markedly reduced stress myocardial blood flow in the infarct-related territory of the occluded RCA. Stress myocardial blood flow and flow reserve are preserved in the LAD and LCX territories.

Differential Diagnosis

• None

Correlative imaging

• None

Management

• He was managed medically by intensifying his anti-anginal regimen with good symptomatic response.

Teaching Point

• The combination of semi-quantitative and quantitative myocardial perfusion imaging makes PET an effective noninvasive modality to help manage symptomatic patients with complex CAD and known chronic total occlusions.

• The presence of reversibility in the territory supplied by the vessel with a chronic total occlusion indicates the presence of myocardial viability. When the defect is mostly fixed, additional FDG imaging may be helpful to better define the presence of viable myocardium.

• The quantitative flow data helps uncover extensive balanced ischemia in patients with multivessel CAD and exclude microvascular dysfunction as a potential source of recurrent symptoms.

Further Reading

• Murthy V, Bateman T, Beanlands R, Berman D, Borges-Neto S, Chareonthaitawee P, et al. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. Journal of Nuclear Cardiology. 2017;25:269–297.

• Galassi A, Brilakis E, Boukhris M, Tomasello S, Sianos G, Karmpaliotis D, et al. Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview. European Heart Journal. 2015;37:2692–2700.

2.6.3.3 Evaluation of Ischemia in Patients with Staged PCI

Case 41

History

• 63-year-old male with a history of type 2 diabetes mellitus, hypertension, a former tobacco user presenting with typical angina.

• He had previous PCI of the left main coronary artery.

• He was referred for assessing the physiologic significance of remaining angiographic stenosis for potential staged PCI (Fig. 2.77 and Table 2.32).

PET/CT Images

Fig. 2.77

Small perfusion defect of modetate intensity involving the LV apex and inferoapical segment showing complete reversibility

Table 2.32 Summary of the quantitative blood flow data demonstrates a reduction of stress MBF in all coronary territories with preserved MFR

Findings

• Small area of moderate ischemia involving the distal LAD territory

• Normal LV function at rest and during maximal vasodilation

• Diffuse reduction of stress MBF in all 3 vascular territories with normal MFR

Differential Diagnosis

• None

Correlative Imaging

• Coronary angiography (Fig. 2.78).

Fig. 2.78

Selective angiographic images demonstrating severe left main stenosis before and after stent placement (red arrows). Additionally, there is diffuse atherosclerosis of the RCA, distal LAD, and LCX coronary arteries

Management

• The patient was managed by optimization of anti-ischemic therapy.

Teaching Points

• Quantitative myocardial perfusion PET imaging is useful in the management of patients with complex CAD. In this case, the PET scan defined the presence of a small area of mild ischemia in the distal LAD territory. The diffusely reduced stress MBF with normal MFR is consistent with the angiographic demonstration of diffuse atherosclerosis.

• The relatively mild amount of ischemia and normal MFR supported the conservative management of this patient.

Further Reading

• DePuey E, Roubin G, Depasquale E, Nody A, Garcia E, King S, et al. Sequential multivessel coronary angioplasty assessed by thallium-201 tomography. Catheterization and Cardiovascular Diagnosis. 1989;18:213–221.

• Nikolsky E, Halabi M, Roguin A, Zdorovyak A, Gruberg L, Hir J, et al. Staged versus one-step approach for multivessel percutaneous coronary interventions. American Heart Journal. 2002;143:1017–1026.

• Patel K, Spertus J, Chan P, Sperry B, Al Badarin F, Kennedy K, et al. Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization. European Heart Journal. 2019;41:751–759.

2.7 Patient with Ischemic Cardiomyopathy

2.7.1 Patient Preparation for Viability Evaluation

The PET viability protocol includes an assessment of myocardial perfusion at rest and stress, when clinically appropriate, followed by a metabolic assessment with F-18 fluorodeoxyglucose (FDG). In the glucose-loaded state and in ischemia (regardless of glucose loading), glucose is the preferred substrate for myocardial energy metabolism. Under these circumstances, FDG uptake and retention reflects the rate of exogenous glucose utilization and is a marker of myocardial viability.

Patient Preparation for FDG Imaging

Because utilization of energy-producing substrates by the myocardium is largely a function of their concentration in plasma and hormone levels (especially plasma insulin, insulin/glucagon ratio, growth hormone, and catecholamines) and of oxygen availability for oxidative metabolism, careful patient preparation is necessary to obtain diagnostic FDG images. For a detailed step-by-step description of the available methods for patient preparation before FDG imaging, the reader should review the Guidelines for PET Imaging published by the American Society of Nuclear Cardiology and the Society of Nuclear Medicine. Briefly, the available approaches to patient preparation include:

Fasting: This is the simplest method because it does not require any substrate manipulation. With this approach, ischemic but viable tissue shows as a “hot spot” due to the preferential FFA utilization by normal (nonischemic) myocardium. While imaging interpretation would seem straightforward, the lack of tracer uptake in normal (reference) myocardium may occasionally lead to an overestimation of the amount of residual viability within a dysfunctional territory.

Oral or intravenous glucose loading: This is the recommended approach to FDG imaging. The goal of glucose loading is to stimulate the release of endogenous insulin in order to decrease the plasma levels of FFA and facilitate the transport of FDG into cardiomyocytes. Patients are usually fasted for at least 6 h and then receive an oral or intravenous glucose load. Most patients require the administration of IV insulin to maximize myocardial FDG uptake.

Hyperinsulinemic-euglycemic clamp: This approach is technically demanding and time-consuming. It consists of a constant infusion of insulin IV with adjustments in glucose infusion to avoid hypoglycemia until the body reaches steady state between glucose infusion and disposal. At this point, no further adjustments are necessary and FDG can be administered. Because it is technically demanding, most laboratories reserve this approach for challenging conditions (e.g., diabetes and severe congestive heart failure).

Free fatty acid inhibition: Acipimox (not available in the United States) and niacin are both nicotinic acid derivatives that inhibit peripheral lipolysis, thereby reducing plasma FFA levels and, indirectly, forcing a switch to preferential myocardial glucose utilization. These drugs are usually given 60 to 90 minutes prior to FDG administration.

2.7.2 Mismatch

Case 42

History

• 81-year-old woman with a history of ischemic cardiomyopathy and prior PCI of the LAD coronary artery.

• Follow-up coronary angiography demonstrated persistent good result of the LAD stent and a total occlusion of the proximal LCX (Fig. 2.79).

• She was referred to the nuclear cardiology lab for assessment of myocardial viability study for possible PCI of the LCX coronary artery.

• She underwent SPECT and PET/CT (Fig. 2.80).

Coronary angiography

Fig. 2.79

Selective angiographic views of the left coronary system demonstrating a chronic LCX occlusion before (yellow arrow in left panel) and after successful PCI (right panel)

SPECT and PET/CT Images

Fig. 2.80

Rest ^99mTc Tetrosfosmin myocardial perfusion SPECT and FDG PET study showing a dilated LV with a large and severe perfusion defect involving the mid and apical anterior and anteroseptal, and lateral walls, the apical LV segments and the LV apex with moderate FDG uptake especially in the lateral wall.

Findings

• Rest ^99mTc Tetrosfosmin myocardial perfusion SPECT and FDG PET study show a dilated LV with a large and severe perfusion defect involving the mid and apical anterior and anteroseptal, and lateral walls, the apical LV segments and the LV apex with moderate FDG uptake especially in the lateral wall. Mismatch of severe perfusion defect and residual FDG uptake shows persistent viability in chronically hypoperfused myocardial segments.

Differential Diagnosis

• Myocardial scar vs hibernating myocardium

Management

• The patient underwent revascularization of the LCX coronary artery.

Teaching Points

• FDG PET is a useful technique for evaluation of myocardial viability in patients with ischemic LV dysfunction.

• The standard protocol includes the assessment of both myocardial perfusion and FDG.

• The presence of a perfusion-FDG mismatched defect identifies viable but hibernating myocardium, while a perfusion-FDG matched defect implies nonviable myocardium.

• A perfusion-FDG mismatched defect predicts improvement in regional/global LV dysfunction after revascularization.

Further Reading

• Mc Ardle B, Shukla T, Nichol G, deKemp R, Bernick J, Guo A, et al. Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging–Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease. Circulation: Cardiovascular Imaging. 2016;9.

• Shukla T, Nichol G, Wells G, deKemp R, Davies R, Haddad H, et al. Does FDG PET-Assisted Management of Patients With Left Ventricular Dysfunction Improve Quality of Life? A Substudy of the PARR-2 Trial. Canadian Journal of Cardiology. 2012;28:54–61.

• Abraham A, Nichol G, Williams K, Guo A, deKemp R, Garrard L, et al. 18F-FDG PET Imaging of Myocardial Viability in an Experienced Center with Access to 18F-FDG and Integration with Clinical Management Teams: The Ottawa-FIVE Substudy of the PARR 2 Trial. Journal of Nuclear Medicine. 2010;51:567–574.

2.7.3 Match

Case 43

History

• 69-year-old male with ischemic cardiomyopathy and prior CABG was referred for a PET scan to assess for myocardial viability (Fig. 2.81). His cardiac risk factors include hypertension, dyslipidemia, and a family history of ischemic heart disease.

PET/CT Imaging

Fig. 2.81

Rest ¹³N-ammonia myocardial perfusion and 18F-deoxyglucose (FDG) PET images. The images demonstrate a severely dilated LV and normal tracer uptake in the lungs. They also demonstrate a mildly dilated RV with normal RV tracer uptake at rest. The rest perfusion images show a large and severe perfusion defect throughout the inferior and inferolateral walls with concordantly reduced FDG uptake (perfusion-FDG matched defect), consistent with nonviable myocardium in the LCX/obtuse marginal territory (arrows). Rest myocardial perfusion and FDG uptake are normal in the LAD and RCA territories. The blackout myocardial perfusion (left), FDG (middle), and comparison viability (right) polar maps confirm the extent of nonviable myocardium in the LCX/OM territory

Findings

• The images demonstrate a severely dilated LV and normal tracer uptake in the lungs. They also demonstrate a mildly dilated RV with normal RV tracer uptake at rest. The rest perfusion images show a large and severe perfusion defect throughout the inferior and inferolateral walls.

• On the FDG images, glucose uptake is concordantly reduced in all hypoperfused LV segments (perfusion-FDG matched defect), consistent with nonviable myocardium in the LCX/obtuse marginal territory.

• Rest myocardial perfusion and FDG uptake are normal in the LAD and RCA territories.

• The ECG-gated images demonstrated a rest LV ejection fraction of 34% with severely dilated LV volumes. There was moderate global hypokinesis with akinesis of the inferior and inferolateral walls.

Differential Diagnosis

• None

Correlative Imaging

• None

Management

• This patient was continued to be managed medically.

Teaching Points

• PET metabolic imaging is one of the most accurate techniques for the assessment of myocardial viability. Glucose uptake in dysfunctional myocardial areas with a perfusion defect is indicative of viability, whereas the absence of FDG uptake like in this case is consistent with nonviable myocardium.

• A perfusion-FDG match has a high negative predictive value for predicting functional recovery after revascularization.

Further Reading

• Mc Ardle B, Shukla T, Nichol G, deKemp R, Bernick J, Guo A, et al. Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging–Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease. Circulation: Cardiovascular Imaging. 2016;9.

• Bax J, Di Carli M, Narula J, Delgado V. Multimodality imaging in ischaemic heart failure. The Lancet. 2019;393:1056–1070.

2.7.4 Match + Stress-Induced Ischemia

Case 44

History

• 71-year-old male with a history of ischemic cardiomyopathy, remote multivessel CABG, and ICD placement for sustained ventricular tachycardia, presented with congestive heart failure and recurrent ventricular arrhythmias.

• He was referred for a PET/CT scan to assess the degree of stress-induced ischemia and myocardial viability (Fig. 2.82).

PET/CT Imaging

Fig. 2.82

Stress-rest ¹³N-ammonia myocardial perfusion and rest ¹⁸F-deoxyglucose (FDG) PET images. There is severe LV dilatation and increased lung uptake on both the rest and stress images

There is a large perfusion defect of severe intensity involving the mid anterior, anterolateral and anteroseptal walls, the apical LV segments and the LV apex, showing near complete reversibility. FDG uptake in this area is normal, except in the anteroseptal wall, which is reduced compared to perfusion (so-called reversed perfusion-FDG mismatched defect).

Findings

• There is severe LV dilatation and increased lung uptake on both the rest and stress images.

• The stress perfusion images demonstrate a large perfusion defect of severe intensity throughout the inferior and inferolateral and basal inferoseptal walls, which is essentially fixed. FDG uptake in this area is concordantly reduced (perfusion-FDG matched defect).

• In addition, there is a large perfusion defect of severe intensity involving the mid anterior, anterolateral and anteroseptal walls, the apical LV segments and the LV apex, which shows near complete reversibility. FDG uptake in this area is normal, except in the anteroseptal wall, which is reduced compared to perfusion (so-called reversed perfusion-FDG mismatched defect).

• The ECG-gated images demonstrated a rest LV ejection fraction of 12% at rest with minimal change post stress with end-stage LV remodeling. There was severe global hypokinesis with akinesis of the inferior and inferolateral walls. Perfusion-reversed mismatched defects can also be seen in the context of conduction abnormalities with LBBB. This patient did not have a LBBB.

Differential Diagnosis

• None

Management

• Invasive coronary angiography demonstrated:

  • Left main: LMCA has a focal 80% stenosis.

  • The proximal LAD has a focal 90% stenosis.

  • The first obtuse marginal branch has a focal 100% stenosis.

  • The mid RCA is totally occluded.

  • The LIMA graft to mid LAD is patent.

• Given the results of the PET scan and his ventricular arrhythmias and worsening heart failure, the patient underwent PCI of his native LAD coronary artery.

Correlative Imaging

• None

Teaching Points

• The study demonstrates the clinical utility of stress perfusion and viability imaging for a comprehensive evaluation of patients with ischemic LV dysfunction. In this case, the stress test uncovered a large area of stress-induced ischemia in the LAD territory that would have been missed with only the rest viability protocol.

• If there are no contraindications for stress testing, stress imaging should always be considered as part of the myocardial viability evaluation.

• In addition to the classic perfusion-FDG matched defect in the RCA territory, the study shows the presence of another perfusion-metabolic pattern often seen in patients with ischemic cardiomyopathy: the perfusion-FDG reversed mismatch defect in which FDG uptake is reduced compared to the rest perfusion. This pattern is often the expression of viable but stunned myocardium. The clue to diagnosis in this case is the extensive evidence of severe stress-induced ischemia in the area of reduced FDG.

Further Reading

• Bax J, Di Carli M, Narula J, Delgado V. Multimodality imaging in ischaemic heart failure. The Lancet. 2019;393:1056–1070.

• Di Carli M, Prcevski P, Singh TP, Janisse J, Ager J, Muzik O, et al., Myocardial blood flow, function, and metabolism in repetitive stunning. J Nucl Med. 2000;41:1227–1234.

2.8 Evaluation of Medical Therapy

Case 45

History

• 64-year-old male with a history of type 2 diabetes mellitus and hypercholesterolemia was admitted for atrial fibrillation with rapid ventricular response.

• He is undergoing hormonal replacement following surgery for a pituitary adenoma.

• His coronary angiogram demonstrated total occlusions of the RCA and LCX coronary arteries and an intermediate stenosis of the mid LAD artery. He underwent successful PCI of the occluded LCX artery (Fig. 2.83).

• He was referred for a myocardial perfusion PET scan for evaluation of viability and residual ischemia (Fig. 2.84 and Table 2.33).

Fig. 2.83

Selective coronary angiographic views demonstrating total occlusion of RCA (left panel) and LCX (middle panel), and successful recanalization of the LCX total occlusion (right panel)

Fig. 2.84

Stress-rest ¹³N-ammonia PET images demonstrating a medium sized perfusion defect of moderate severity in the inferior wall showing complete reversibility

Table 2.33 Quantitative analysis shows relatively preserved stress MBF and normal MFR in the LAD and LCX territories. Stress MBF and MFR are both reduced in the RCA territory

Findings

• The myocardial perfusion PET scan demonstrated a moderate amount of stress-induced ischemia with complete viability in the territory of the occluded RCA, with relatively preserved stress MBF and MFR in the LAD and LCX territories.

Management

• The patient underwent optimization of medical therapy.

• He returned a year after the index PET scan for re-assessment of ischemic burden for potential myocardial revascularization (Fig. 2.85 and Table 2.34).

Fig. 2.85

Stress-rest ¹³N-ammonia PET images demonstrating near complete resolution of the inferior perfusion defect seen on the index PET scan

Table 2.34 Summary of quantitative blood flow data showing normal stress and MFR in the LAD and LCX territories, with mild reduction of stress MBF with normal MFR in the RCA territory

Findings

• The follow-up PET myocardial perfusion scan a year after optimization of medical therapy demonstrates significant interval improvement in myocardial perfusion in all vascular territories including near complete resolution of the area of ischemic in the territory of the occluded RCA.

Management

• Given the results of the follow-up PET scan, consideration for PCI of the RCA was deferred.

Differential Diagnosis

• None

Teaching Points

• This case illustrates the benefits of optimized medical therapy for the management of ischemic heart disease.

• The addition of the quantitative blood flow data by PET permits the assessment of treatment efficacy especially in areas that do not show regional perfusion deficit.

Further Reading

• Ohira H, Dowsley T, Dwivedi G, deKemp R, Chow B, Ruddy T, et al. Quantification of myocardial blood flow using PET to improve the management of patients with stable ischemic coronary artery disease. Future Cardiology. 2014;10:611–631.

2.9 Evaluation of CAV After Heart Transplantation

Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins. CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV.

Keywords

CAV, ⁸²Rb myocardial perfusion PET images

2.9.1 Severe CAV

Case 47

History

• 51-year-old man with prior orthotopic heart transplant 14 years prior for severe idiopathic dilated cardiomyopathy. He has diabetes mellitus and end-stage kidney disease on hemodialysis for the past 12 years. He is an active smoker.

• A recent transthoracic echocardiogram demonstrated a new wall motion abnormality in the anterior wall.

• Because of unresponsiveness to vasodilator stress on a prior study, he was referred for dobutamine-stress ⁸²Rb PET/CT to assess for cardiac allograft vasculopathy (CAV (Fig. 2.86 and Table 2.35).

PET/CT

Fig. 2.86

Stress and rest ⁸²Rb myocardial perfusion PET images. There is transient ischemic dilatation of the left ventricle during stress. There is increased tracer uptake of the free wall of the right ventricle on both stress and rest images. The stress images show a large perfusion defect of severe intensity involving the mid and apical anterolateral and anterior walls, and the LV apex, showing complete reversibility. In addition, there is a small perfusion defect of moderate intensity in the mid lateral wall with minimal reversibility

Table 2.35 Summary of quantitative flow data showing severely reduced stress flows in the LCX and LAD territories. MFR is reduced in the LAD. The relatively preserved MFR in the LCX territory is related to the presence of a prior nontransmural scar in this area. Stress MBF and MFR were normal in the RCA territory

Findings

• Transient ischemic dilatation of the left ventricle during stress

• Increased uptake of the free wall of the right ventricle on both stress and rest images

• A large perfusion defect of severe intensity involving the mid and apical anterolateral and anterior walls, and the LV apex, showing complete reversibility

• Small perfusion defect of moderate intensity in the mid lateral wall with minimal reversibility

• Normal LV systolic function with a rest LVEF of 53% with normal LV volumes which increased to 56% during stress

Differential Diagnosis

• Grade 3 cardiac allograft vasculopathy

Correlative Imaging

• Coronary angiography (Fig. 2.87)

Fig. 2.87

Selective view from coronary angiography showing complete occlusion of the mid LAD (yellow circle) and proximal first obtuse marginal coronary artery (red circle)

Management

• Patient was referred for revascularization of the LAD and LCX coronary arteries.

Teaching Points

• Quantitative PET is a useful alternative to coronary angiography to delineate the presence of CAV, especially in patients with renal dysfunction as in this case example.

• The presence of RV tracer uptake is common in heart transplant recipients due to their restrictive physiology and increased pulmonary vascular resistance.

• The relatively normal flow reserve in the LCX territory is caused by a very low rest flow in this patient with a prior nontransmural infarction in this area.

Further Reading

• Michael Weis and Wolfgang von Scheidt. Cardiac Allograft Vasculopathy. A Review. Circulation. 1997;96:2069–2077.

• Mc Ardle B, Dowsley T, Cocker M, Ohira H, deKemp R, DaSilva J. et al. Cardiac PET: Metabolic and Functional Imaging of the Myocardium. Seminars in Nuclear Medicine. 2013;43:434–448.

• Bravo P, Bergmark B, Vita T, Taqueti V, Gupta A, Seidelmann S. et al. Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy. European Heart Journal. 2017;39:316–323.