Role of Positron Emission Tomography Cardiac Perfusion Imaging in Clinical Management,Prognosis,and Risk Stratification of Cardiovascular Disease

Abstract

Coronary artery disease (CAD) is an important cause of morbidity and mortality worldwide. Perfusion abnormalities precede wall motion abnormalities, ECG changes, and angina in the etiology of CAD. myocardial perfusion imaging (MPI) can detect perfusion alterations due to pathology at sites such as the endothelium, microvasculature, and epicardial coronary arteries. Thus, it measures the universal burden of ischemic heart disease (IHD). Nuclear medicine MPI is an important noninvasive imaging modality to evaluate the perfusion of the myocardium. Positron Emission Tomography (PET) and single-photon emission computed tomography (SPECT) with or without computed tomography (CT) are 2 primary modalities. PET is a highly sensitive modality with an inherent ability to quantify absolute myocardial blood flow (MBF) and variations in MBF due to various stress agents. PET has immense potential to change clinical management, prognosticate, and risk stratify patients presenting with clinical or preclinical CAD. Evidence shows that early PET detection of myocardial perfusion abnormalities, followed by aggressive intervention for cardiovascular risk factors, can reinstate myocardial perfusion. This may reduce morbidity and mortality. We shall be reviewing the clinical impact of PET in CAD and preclinical CAD patients.

Keywords

Coronary artery disease myocardial perfusion imaging myocardial flow reserve,positron emission tomography myocardial blood flow

Abbreviations

CAD: coronary artery disease

CFR: coronary flow reserve

CVD: Cardiovascular disease

IHD: ischemic heart disease

MBF: myocardial blood flow

MFR: myocardial flow reserve

MPI: myocardial perfusion imaging

PET: positron emission tomography

SPECT: single-photon emission computed tomography

TVD: triple vessel disease

Introduction

Cardiovascular disease (CVD) remains the forerunner cause of mortality all over the world. The prevalence is increasing in the Indian population, with increased risk factors for the disease.^1,2 It has become the leading cause of death in the Indian population.³ Detection of the disease at an early stage of pathology is crucial to reduce disease-related morbidity and mortality. It has been seen that anatomical stenosis correlates poorly with the physiological severity of the lesion, and physiological abnormality precedes anatomical disease. Many clinical trials have shown the superiority of timely detecting physiological abnormality over anatomical lesions in guiding individualized therapy. It may improve clinical outcomes in known, suspected, and at-risk patients of coronary artery disease (CAD). CAD imaging has advanced from only demonstrating epicardial vascular abnormalities to identifying lesions in their earliest pathophysiological phases. This has become possible due to recent advancements in research, clinical trials, and instrumentation. Positron Emission Tomography (PET) myocardial perfusion imaging (MPI) enables true in vivo noninvasive absolute quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR). Hybrid PET/CT is becoming increasingly popular for assessing myocardial perfusion providing excellent diagnostic and prognostic information.

The Diagnostic Criterion of PET MPI: MBF and MFR

The noninvasive assessment of coronary blood flow, MBF measurement, and its responses to several vasomotor stresses have added enormous knowledge to CAD pathophysiology.⁴ Gould et al showed that resting MBF remains unaltered and is proportional to cardiac workload unless epicardial stenosis attains a severity of 90%. This is because of compensatory vasodilation of the coronary microcirculation.⁵ However, during hyperemic flow by pharmacologic vasodilation, epicardial lesions with ≥ 50% luminal obstruction decrease hyperemic flow.⁶ PET/CT, in concert with kinetic tracer modeling, enables measurement of regional MBF in ml/gram/min. The ratio of MBF at rest and pharmacologically stimulated hyperemic state is known as the MFR.⁷ The in vivo and absolute quantification of MBF and MFR provide both diagnostic and prognostic information in the patients (Figure 1).⁷

Figure 1.

N-Ammonia PET/CT myocardial perfusion imaging of a 62-year-old diabetic male. The upper row (stress images) and lower row (rest images) show blood flow in the short axis (a, b), horizontal long-axis (c, d), and vertical long axis view (e, f). A large area of the mild reversible perfusion defect is noted in the left ventricle’s apex, anterior, and anterolateral walls. The corresponding 17-segment model polar maps suggest the extent of perfusion defects (g, h) and myocardial blood flow (i, j). Coronary flow reserve (CFR) is calculated for each vascular territory (table). It shows normal rest perfusion with reduced CFR (<2). CFR is shown as a polar map (j) that depicts reduced CFR.¹³

PET Myocardial Perfusion Imaging (MPI) for Clinical Management

1. Detection of CAD

In addition to identifying advanced and flow-limiting epicardial CAD lesions, PET’s ability to noninvasively quantify absolute MBF also allows for the early detection of atherosclerosis, multivessel disease, and microvascular dysfunction.⁷ A reduction in radiotracer uptake on standard single-photon emission computed tomography (SPECT) or PET MPI during stress-induced hyperemic flows is related to the flow-limiting effects of CAD. The visual and semiquantitative evaluation of regional radiotracer uptake is in “relative” terms. In patients with multivessel CAD, the assigned normal reference region on uptake images may be, in fact, abnormal as well. However, it is the least hypoperfused myocardial region relative to the remaining vascular territories.⁸ In such circumstances, MBF and MFR may unmask the most advanced or “culprit” lesion and the flow-limiting effect of other less severe CAD lesions.⁹ In a study by Fiechter et al, the sensitivity and specificity of MPI for detecting significant CAD were 79% and 80%. The positive predictive value (PPV), negative predictive value (NPV), and accuracy were 91%, 59%, and 79%, respectively (Table 1). At a cut-off of <2.0 for MFR, diagnostic performance was improved to 96% (p = .005), 80%, 93%, 89% (p = .005), and 92% (p = .005), respectively.¹⁰

Table 1.

Diagnostic Performance of Cardiac PET in Various Indications.

Study and Publication	Indication	Modality	Sensitivity	Specificity
Lauerma et al.⁵⁵ (2000)	Assessment of myocardial viability	Dobutamine cine and DE CMR	97%	96%
Lauerma et al.⁵⁵ (2000)	Assessment of myocardial viability	FDG PET	81%	86%
Schmidt et al.⁵⁶ (2004)	18 FDG PET/CT as a predictor in functional recovery of the akinetic but viable infarct region	FDG PET/CT	100%	73%
		Dobutamine Echo	96%	93%
		MRI	100%	53%
Kuhl⁵⁷ (2006)	CE CMR vs combined nuclear imaging using FDG-PET & 99mTc-sestamibi SPECT for the prediction of reversible myocardial dysfunction	CMR	97%	68%
Kuhl⁵⁷ (2006)		PET/SPECT	87%	76%
Wu⁵⁸ (2007)	Compare viability between MRI and nuclear techniques	MRI	92.2%	44.9%
Wu⁵⁸ (2007)	Compare viability between MRI and nuclear techniques	PET/SPECT	60.2%	98.7%
Schinkel et al.⁵⁹ (2007)	18F-FDG PET/CT for the prediction of improved regional left ventricular function after revascularization	FDG PET	92%	63%
Yoshinaga et al.⁶⁰ (2010)	82 -Rubidium PET MPI—From basic aspects to clinical applications	⁸²Rb PET	87.7%	86.8%
Fiechter et al.⁶¹ (2012)	PET MPI for detecting significant CAD	¹³NH₃	79%	80%
Parker et al.⁶² (2012)	Diagnostic Accuracy of Cardiac PET vs. SPECT for Coronary Artery Disease	SPECT	88.3%	76%
Parker et al.⁶² (2012)		PET/PET-CT	92.6%	81.3%
Mc et al.⁶³ (2012)	Rubidium-82 PET over SPECT MPI for the Diagnosing Obstructive Coronary Disease	⁸²Rb PET	90%	88%
Mc et al.⁶³ (2012)		⁹⁹mTc SPECT	85%	85%
Dorbala et al.⁶⁴ (2013)	PET MPI for detecting ≥50% luminal narrowing	⁸²Rb	91%	89%
Caobelli et at⁶⁵ (2021)	18F-FDG cardiac PET/CT for the assessment of myocardial viability in ischemic heart disease	FDG PET/CT	92%	63%
Xu et al. (2021)⁶⁶	Diagnostic Performance of SPECT, CMR, and PET Imaging for the Identification of Coronary Artery Disease: A Meta-Analysis	PET	85%	86%
		SPECT	83%	77%
		CMR	86%	83%

Abbreviations: DE CMR, delayed enhancement cardiac magnetic resonance; PET, positron emission tomography; MRI, magnetic resonance imaging; SPECT, single-photon emission computerized tomography; FDG, fluro-deoxy-glucose; Rb, rubidium; NH3, ammonia.

Dorbala et al demonstrated that PET MPI had sensitivity and specificity of 91% and 89% for more than 50% luminal narrowing.¹¹ In epicardial stenosis ≥ 70%, an MFR of <1.7 is related to increases in epicardial resistance.⁷ A normal MFR carries a very high NPV (97%) for excluding high-risk CAD. It includes multivessel disease (double and triple vessel disease), proximal LAD, or left main CAD (50% stenosis). Being functional imaging, it does not reliably distinguish between diffuse atherosclerosis, epicardial stenosis from nonobstructive CAD, or microvascular dysfunction.¹² In a meta-analysis (12,000 patients), for detection of >50% epicardial stenosis, PET was found to be more sensitive than SPECT (92.6% vs 88.3%, p = .035) with near-identical specificity.¹³

PET has superior diagnostic value and improved risk stratification compared to SPECT due to its ability to assess MBF.¹⁴ Studies have shown that PET-MPI is superior to SPECT in image quality, reliability of interpretation, and diagnostic accuracy. Bateman et al found excellent diagnostic accuracy of PET at stenosis severity of 70% (89% vs 79%, p = .03) and 50% (87% vs 71%, p = .003).¹⁵ A study comparing PET with computed tomography angiography (CTA) has shown a poor PPV of CT angiography to identify functionally significant coronary stenoses as defined by PET. However, CTA is an excellent modality to exclude CAD. However, it has a modest performance in assessing the physiological significance of the degree of luminal narrowing.¹⁶

2. Multivessel disease—“balanced ischemia”

The uniform perfusion deficit in all major vascular territories caused by diffuse myocardial ischemia in significant LMCAD or TVD may lead to false-negative results and go undetected with the routine SPECT MPI.¹⁷ In a study, patients with left main vessel CAD underwent SPECT MPI. Perfusion defects in more than 10% of myocardium were noted in 56% of patients and 59% quantitatively. No perfusion defect (> or = 5% myocardium) was noted in 13% only.¹⁸ Assessing hyperemic MBF and MFR could help prevent a false negative semiquantitative MPI caused by the uniform perfusion deficit in all coronaries. MFR was discovered to be independently predictive of TVD and globally reduced (<2) in 88% of the patients.⁸ This incremental value of flow quantification has been supported by another comprehensive study by Naya et al (Figure 2).¹²

Figure 2.

N-Ammonia PET/CT rest myocardial perfusion imaging of a 71-year-old male. He had severe triple vessel disease with mild left ventricular dysfunction. Myocardial blood flow in the short axis (a), horizontal-long axis (b), and vertical long axis (c) suggest homogenous perfusion in all walls of the left ventricular myocardium. Polar maps (d, f) suggest homogenous uptake and reduced myocardial blood flow pattern in all 3 main coronary arteries.¹³

3. Identification of subclinical CAD

Identifying endothelial dysfunction or preclinical CAD in patients with various risk factors for developing CAD could become clinically relevant.^19–22 PET MPI is evolving in identifying and monitoring the effects of pharmacologic interventions and lifestyle modification in these patients. In patients with risk factors, coronary dysfunction starts at the endothelium. This leads to impaired endothelium-dependent or flow-mediated coronary vasodilation with preserved smooth muscle cell function.⁷ Early coronary artery dysfunction can be detected by assessing MBF and MFR, which provide notable diagnostic and prognostic information.

MBF measurement with the pharmacologically induced hyperemic flow is maintained in asymptomatic insulin-resistant patients with normal stress-rest PET MPI. However, endothelium-related MBF response to cold pressor test (CPT) is impaired.¹⁹ These observations reinforce that the early stages of CAD affect endothelium and could be picked by PET.^20,21 Worsening of CPT MBF response is associated with long-term risk for cardiovascular events.²² As the cardiovascular risk factors and disease progress, oxidative stress burden also increases. This leads to impaired smooth muscle cell vasodilator function in coronary arterioles and arteries.²³

4. PET MPI to guide decisions for coronary angiography and revascularization

As large prospective clinical trial data on the role of PET MPI in guiding coronary angiography and revascularization are lacking, expert opinion and data from observational studies are used for decision-making. Depending upon the extent and severity of reversible perfusion defects, the MPI results are classified as low risk (defect involving <5% of the myocardium), intermediate risk (5–10% of the myocardium), or high risk (>10% of the myocardium).²⁴ Invasive coronary angiography is deemed appropriate for patients with high-risk MPI (>10% ischemic myocardium). Other high-risk markers include transient ischemic dilatation of the left ventricle, significant stress-induced left ventricular dysfunction, discordant and ongoing symptoms, or significant ECG changes during stress. However, it is not considered appropriate in patients with low-risk PET findings (<5% ischemic myocardium).²⁴

5. Monitoring therapy and reductions in cardiovascular risk

Measurements of MBF may be used to monitor the effects of pharmacologic interventions or lifestyle modification in patients with and without manifested CAD.⁷ PET flow studies have verified improved endothelial dysfunction in patients with various cardiovascular risks through regular exercise, preventive medical care, cholesterol-lowering, and antidiabetic medications.^25–28

CAD patients were randomly assigned to receive aggressive risk factor adjustment (low-fat vegetarian diet, exercise, and stress management) or standard medical therapy (primarily anti-anginal medications) by Gould et al. After 5 years, the severity and size of the stress-induced PET perfusion defects improved in the experimental patients and worsened in the control group. In contrast, changes in quantitative coronary angiography were much less apparent.²⁹ PET MPI has also been used to assess the effectiveness of various medical therapies in cardiovascular disease. In diabetic patients, the effect of antidiabetic medications (glyburide and/or metformin) on coronary circulatory function and coronary artery calcifications (CAC) has been studied. There was a lower progression of CAC and increases in endothelium-related MBF responses to CPT with treatment.³⁰ Hormone replacement therapy using estrogen and/or progesterone has been shown to preserve the CPT MBF response and its standard preventive effect on traditional cardiovascular risk factors.³¹

Prognostic Implications

1. Coronary artery disease

Prognostic data on the clinical utility of SPECT is robust in comparison to PET MPI. Absolute quantification of coronary blood flow using PET MPI allows for accurate prognostication in CAD. PET holistically measures ischemic heart disease (IHD) burden from significant CAD, nonobstructive CAD, diffuse atherosclerosis, and microvascular disease. This allows PET to prognosticate over and above SPECT MPI. In a study including 1432 subjects, Rb-82 PET-CT scan showed a low annualized event rate of 0.7% in patients without ischemia. Patients with a large area (>20% of the myocardium) of ischemia had a high event rate of 11%.³²

Ziadi et al. evaluated the MFR as a prognostic marker for ischemia. Based on summed stress scores (SSS) and MFR, patients were divided into 4 groups. Group I included patients with normal SSS (<4) and MFR (>2), whereas group II-IV had normal SSS with MFR <2, abnormal SSS ≥4 with normal MFR ≥2, and abnormal SSS ≥4 with reduced MFR <2, respectively. Patients with decreased MFR (<2) had higher cardiac death and myocardial infarction rates than those with MFR ≥2 (I: 1.3% vs II: 2% [p = .029]; III: 1.1% vs IV: 11.4% [p = .05]). Thus MFR was an independent predictor of cardiac events irrespective of the SSS and other clinical parameters.³³ Murthy et al reported comparable observations in a large cohort (2783 patients). In comparison to the normal MFR (>2), low MFR (< 1.5) was associated with a 16-fold increased risk of CD. At the same time, the intermediate MFR group (1.5-2.0) had a 5.7-fold increased risk for CD. MFR reclassified 35 % of the intermediate-risk patients (CD: 1%-3% per year) into either low or high risk.³⁴

In a normal MPI result, a preserved coronary flow reserve (CFR) > 2.0 strongly predicts event-free survival over 3 years, and an adverse prognosis is seen with reduced CFR.³² Novel parameters such as net reclassification improvement (NRI) and integrated discrimination improvement have better prognostic values than conventional metrics.³⁵ NRI with PET MPI has been demonstrated in a study by Dorbala et al. The author studied PET MPI in patients with risk factors such as age, female sex, body mass index, hypertension, diabetes, dyslipidemia, smoking, angina, beta-blocker use, prior revascularization, and resting heart rate. Even after accounting for risk factors, patients with a grossly abnormal stress PET MPI had a 5-fold higher CD hazard than patients with a normal MPI. This consolidates that PET MPI provided incremental CD risk compared to traditional coronary risk factors.³⁶ It is imperative to emphasize that the incremental clinical value of PET MPI is attained at a lower estimated effective radiation dose in comparison to Technetium-99m MPI.³⁷

2. PET MPI to predict recovery of function after revascularization

Myocardial viability assessment helps to identify patients who may benefit from coronary revascularization. Percent peak perfusion by N-13 Ammonia (> 50%) is considered a viable myocardium and has a high NPV (>86%) to predict improvement in regional wall motion after revascularization.³⁸ An earlier study demonstrated a relationship between cell membrane integrity (by Rb-82 PET) and myocardial glucose utilization as a viability marker. Hypoperfused regions show different Rb-82 kinetics in compromised but metabolically active and irreversibly injured myocardium.³⁹ PET MPI provides incremental prognostic value to clinical variables predicting all-cause mortality and CD in Coronary artery bypass grafting patients.⁴⁰

3. Heart failure (HF)

Approximately two-thirds of HF cases are ischemic, and the rest are nonischemic. However, there is an overlap between these 2. Radionuclide Imaging can differentiate them.⁴¹ Ischemic HF is suggested by a history of MI, revascularization, significant left-main CAD (>75% stenosis), or multiple vessel disease.⁴²

PET helps to detect multivessel CAD.^8,43 It identifies high-risk patients with normal perfusion images.^33,34 Abnormal CFR identifies patients at risk of developing HF.⁴⁴ Many nonischemic HF or cardiomyopathy patients have CFR abnormalities due to microvasculature involvement.⁴⁵ Neglia et al have demonstrated that patients with nonischemic dilated cardiomyopathy and a low MBF (≤ 1.36 mL/min/g is) had an increased risk of CD and 3.5 times progression of HF over other standard clinical and functional variables.⁴⁶

4. Role of PET MPI in special population

Risk factors such as smoking, hypertension, diabetes, hypercholesterolemia, obesity, menopause, or family history, have been associated with attenuated endothelium-dependent vasodilation.⁴ The incremental predictive value of MFR for predicting cardiac death has been reported in patients with diabetes mellitus, chronic kidney disease, and ischemic or idiopathic cardiomyopathy.^46–48

A recent study evaluated the change in MBF in morbidly obese individuals (BMI ≥ 40 kg/m²) after surgical bypass-induced weight loss. The patients did not have other traditional cardiovascular risk. After a median follow-up of 22 months, BMI decreased from a median of 44.8 to 30.8 kg/m². There were changes in lipid profile, reduced plasma markers of the insulin resistance syndrome, chronic inflammatory markers, hyperemic flow reserve, and endothelium-related MBF responses to CPT.⁴⁹ The diagnostic evaluation of women presenting with suspected cardiac symptoms is challenging, with reported lower accuracy, attenuation artifact, and concerns regarding radiation safety. Stress Rb-82 PET provides clinically significant risk stratification in both women and men. It is beneficial in identifying high risk older women.⁵⁰

Risk Stratification—PET MPI Imaging Risk Factors

Imaging and clinical findings on PET MPI stratify patients into low and high risk groups. A few of them are summarized in Table 2.

Table 2.

Various Prognostic Markers on Cardiac Perfusion Imaging.

Imaging Variable	High Risk Finding	Reference
Stress defect size and severity	≥10%	¹¹
Rest defect size and severity	≥10%	¹¹
Reversibility size and severity	≥10%	²⁴
Stress LVEF	<40%	¹¹
Rest LVEF	<40%	¹¹
LVEF reserve1 (stress LVEF-rest LVEF)	Less than +5%	⁵¹
Transient cavity dilation	>1.13	⁵²
Increased lung or right ventricular uptake	Visual estimate
Transient increase in RV tracer uptake	>10% increase in the RV/LV ratio at stress compared to rest	⁵³
Chronotropic response- heart rate reserve (HRR) with pharmacologic stress	≤ 4 beats	⁵⁴

Limitation

In comparison to SPECT, PET perfusion has a few limitations. The main shortcomings of PET are the availability of PET CT scanners, cost, and the need for an on-site cyclotron or generator system. Prognostic data on the clinical utility of SPECT is robust and extensively investigated. Evidence supporting the clinical utility of PET MPI is still limited but rapidly evolving.

Conclusion

PET MPI enables the noninvasive assessment of myocardial perfusion by measuring functional parameters like regional MBF and MFR. The sensitivity of PET is more than SPECT for the identification of CAD, and a normal PET scan effectively rules out CAD with excellent NPV. Understanding MBF and its response to various vasomotor stress has significantly advanced our understanding of CAD pathogenesis. It may detect endothelial dysfunction or preclinical CAD in patients with various CAD risk factors and helps to monitor the effects of lifestyle modification and/or pharmacologic interventions. In short, PET has an “in vivo” holistic capability to image and quantify IHD rather than CAD alone. This capability of PET MPI imaging, if combined with diagnostic CT, may lead to identifying both functional and structural abnormalities in coronary arteries before progression to clinically manifest CAD. Overall cardiac PET/CT may be the next step in the “precision medicine” era.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Vijay Singh

Manish Ora

Aftab Hasan Nazar

References

Shraddha Chauhan, Bani Tamber Aeri. Prevalence of cardiovascular disease in India and its economic impact—a review. Int J Sci Res Publ . 2013;3(10).

Murray

CJL

, Lopez

Eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020: Summary . https://apps.who.int/iris/handle/10665/41864. Accessed August 19, 2019.

Gupta

, Guptha

, Sharma

, Gupta

, Deedwania

. Regional variations in cardiovascular risk factors in India: India heart watch. World J Cardiol . 2012;4(4):112–120. doi:10.4330/wjc.v4.i4.112

Schindler

, Zhang

, Vincenti

, Mhiri

, Lerch

, Schelbert

. Role of PET in the evaluation and understanding of coronary physiology. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2007;14(4):589–603. doi:10.1016/j.nuclcard.2007.05.006

Gould

. Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilatation. I. Physiologic basis and experimental validation. Am J Cardiol . 1978;41(2):267–278. doi:10.1016/0002-9149(78)90165-0

Uren

, Melin

, De Bruyne

, Wijns

, Baudhuin

, Camici

. Relation between myocardial blood flow and the severity of coronary-artery stenosis. N Engl J Med . 1994;330(25):1782–1788. doi:10.1056/NEJM199406233302503

Schindler

, Schelbert

, Quercioli

, Dilsizian

. Cardiac PET imaging for the detection and monitoring of coronary artery disease and microvascular health. JACC Cardiovasc Imaging . 2010;3(6):623–640. doi:10.1016/j.jcmg.2010.04.007

Ziadi

, Dekemp

, Williams

, . Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease? J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2012;19(4):670–680. doi:10.1007/s12350-011-9506-5

Schindler

, Quercioli

, Valenta

, Ambrosio

, Wahl

, Dilsizian

. Quantitative assessment of myocardial blood flow--clinical and research applications. Semin Nucl Med . 2014;44(4):274–293. doi:10.1053/j.semnuclmed.2014.04.002

10.

Fiechter

, Ghadri

, Gebhard

, . Diagnostic value of 13N-ammonia myocardial perfusion PET: added value of myocardial flow reserve. J Nucl Med Off Publ Soc Nucl Med . 2012;53(8):1230–1234. doi:10.2967/jnumed.111.101840

11.

Dorbala

, Hachamovitch

, Curillova

, . Incremental prognostic value of gated Rb-82 positron emission tomography myocardial perfusion imaging over clinical variables and rest LVEF. JACC Cardiovasc Imaging . 2009;2(7):846–854. doi:10.1016/j.jcmg.2009.04.009

12.

Naya

, Murthy

, Taqueti

, . Preserved coronary flow reserve effectively excludes high-risk coronary artery disease on angiography. J Nucl Med Off Publ Soc Nucl Med . 2014;55(2):248–255. doi:10.2967/jnumed.113.121442

13.

Parker

, Iskandar

, Limone

, . Diagnostic accuracy of cardiac positron emission tomography versus single photon emission computed tomography for coronary artery disease: a bivariate meta-analysis. Circ Cardiovasc Imaging . 2012;5(6):700–707. doi:10.1161/CIRCIMAGING.112.978270

14.

Al Badarin

, Malhotra

. Diagnosis and Prognosis of Coronary Artery Disease with SPECT and PET. Curr Cardiol Rep . 2019;21(7):57. doi:10.1007/s11886-019-1146-4

15.

Bateman

, Heller

, McGhie

, . Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2006;13(1):24–33. doi:10.1016/j.nuclcard.2005.12.004

16.

Di Carli

, Dorbala

, Curillova

, . Relationship between CT coronary angiography and stress perfusion imaging in patients with suspected ischemic heart disease assessed by integrated PET-CT imaging. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2007;14(6):799–809. doi:10.1016/j.nuclcard.2007.07.012

17.

Beller

. Underestimation of coronary artery disease with SPECT perfusion imaging. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2008;15(2):151–153. doi:10.1016/j.nuclcard.2008.01.012

18.

Berman

, Kang

, Slomka

, . Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2007;14(4):521–528. doi:10.1016/j.nuclcard.2007.05.008

19.

Quiñones

, Hernandez-Pampaloni

, Schelbert

, . Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med . 2004;140(9):700–708. doi:10.7326/0003-4819-140-9-200405040-00009

20.

Campisi

Roxana

, Czernin

Johannes

, Schöder

Heiko

, Sayre

James W.

, Schelbert

Heinrich R.

l-Arginine normalizes coronary vasomotion in long-term smokers. Circulation . 1999;99(4):491–497. doi:10.1161/01.CIR.99.4.491

21.

Roxana

, Lauren

, Hernandez

, . Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration. Circulation . 2002;105(4):425–430. doi:10.1161/hc0402.102860

22.

Schindler

, Nitzsche

, Schelbert

, . Positron emission tomography-measured abnormal responses of myocardial blood flow to sympathetic stimulation are associated with the risk of developing cardiovascular events. J Am Coll Cardiol . 2005;45(9):1505–1512. doi:10.1016/j.jacc.2005.01.040

23.

Münzel

, Daiber

, Ullrich

, Mülsch

. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol . 2005;25(8):1551–1557. doi:10.1161/01.ATV.0000168896.64927.bb

24.

Patel

, Bailey

, Bonow

, . ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol . 2012;59(22):1995–2027. doi:10.1016/j.jacc.2012.03.003

25.

Czernin

, Barnard

, Sun

, . Effect of short-term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve. Circulation . 1995;92(2):197–204. doi:10.1161/01.cir.92.2.197

26.

Baller

Detlev

, Notohamiprodjo

Gunawan

, Gleichmann

Ulrich

, Holzinger

Jens

, Weise

Reiner

, Lehmann

Joachim.

Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation . 1999;99(22):2871–2875. doi:10.1161/01.CIR.99.22.2871

27.

Gould

, Martucci

, Goldberg

, . Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. Circulation . 1994;89(4):1530–1538. doi:10.1161/01.cir.89.4.1530

28.

Schindler

, Facta

, Prior

, . Improvement in coronary vascular dysfunction produced with euglycaemic control in patients with type 2 diabetes. Heart . 2007;93(3):345–349. doi:10.1136/hrt.2006.094128

29.

Gould

, Ornish

, Scherwitz

, . Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA . 1995;274(11):894–901. doi:10.1001/jama.1995.03530110056036

30.

Schindler

, Cadenas

, Facta

, . Improvement in coronary endothelial function is independently associated with a slowed progression of coronary artery calcification in type 2 diabetes mellitus. Eur Heart J . 2009;30(24):3064–3073. doi:10.1093/eurheartj/ehp482

31.

Schindler

, Campisi

, Dorsey

, . Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors. Eur Heart J . 2009;30(8):978–986. doi:10.1093/eurheartj/ehp013

32.

Herzog

, Husmann

, Valenta

, . Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol . 2009;54(2):150–156. doi:10.1016/j.jacc.2009.02.069

33.

Ziadi

, Dekemp

, Williams

, . Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. J Am Coll Cardiol . 2011;58(7):740–748. doi:10.1016/j.jacc.2011.01.065

34.

Murthy

, Naya

, Foster

, . Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation . 2011;124(20):2215–2224. doi:10.1161/CIRCULATIONAHA.111.050427

35.

Pencina

, D’Agostino

, Vasan

. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med . 2008;27(2):157–172; discussion 207-212. doi:10.1002/sim.2929

36.

Dorbala

, Di Carli

, Beanlands

, . Prognostic value of stress myocardial perfusion positron emission tomography: results from a multicenter observational registry. J Am Coll Cardiol . 2013;61(2):176–184. doi:10.1016/j.jacc.2012.09.043

37.

Einstein

, Moser

, Thompson

, Cerqueira

, Henzlova

. Radiation dose to patients from cardiac diagnostic imaging. Circulation . 2007;116(11):1290–1305. doi:10.1161/CIRCULATIONAHA.107.688101

38.

Gould

, Yoshida

, Hess

, Haynie

, Mullani

, Smalling

. Myocardial metabolism of fluorodeoxyglucose compared to cell membrane integrity for the potassium analogue rubidium-82 for assessing infarct size in man by PET. J Nucl Med Off Publ Soc Nucl Med . 1991;32(1):1–9.

39.

vom Dahl

, Muzik

, Wolfe

, Allman

, Hutchins

, Schwaiger

. Myocardial rubidium-82 tissue kinetics assessed by dynamic positron emission tomography as a marker of myocardial cell membrane integrity and viability. Circulation . 1996;93(2):238–245. doi:10.1161/01.cir.93.2.238

40.

Pen

, Yam

, Chen

, . Prognostic value of Rb-82 positron emission tomography myocardial perfusion imaging in coronary artery bypass patients. Eur Heart J Cardiovasc Imaging . 2014;15(7):787–792. doi:10.1093/ehjci/jet259

41.

Gheorghiade

, Sopko

, De Luca

, . Navigating the crossroads of coronary artery disease and heart failure. Circulation . 2006;114(11):1202–1213. doi:10.1161/CIRCULATIONAHA.106.623199

42.

Felker

, Shaw

, O’Connor

. A standardized definition of ischemic cardiomyopathy for use in clinical research. J Am Coll Cardiol . 2002;39(2):210–218. doi:10.1016/s0735-1097(01)01738-7

43.

Parkash

, deKemp

, Ruddy

, . Potential utility of rubidium 82 PET quantification in patients with 3-vessel coronary artery disease. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2004;11(4):440–449. doi:10.1016/j.nuclcard.2004.04.005

44.

Gewirtz

. Cardiac PET: a versatile, quantitative measurement tool for heart failure management. JACC Cardiovasc Imaging . 2011;4(3):292–302. doi:10.1016/j.jcmg.2010.12.006

45.

Camici

, Crea

. Coronary microvascular dysfunction. N Engl J Med . 2007;356(8):830–840. doi:10.1056/NEJMra061889

46.

Neglia

, Michelassi

, Trivieri

, . Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation . 2002;105(2):186–193. doi:10.1161/hc0202.102119

47.

Murthy

, Naya

, Foster

, . Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation . 2012;126(15):1858–1868. doi:10.1161/CIRCULATIONAHA.112.120402

48.

Murthy

, Naya

, Foster

, . Coronary vascular dysfunction and prognosis in patients with chronic kidney disease. JACC Cardiovasc Imaging . 2012;5(10):1025–1034. doi:10.1016/j.jcmg.2012.06.007

49.

Quercioli

, Montecucco

, Pataky

, . Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines. Eur Heart J . 2013;34(27):2063–2073. doi:10.1093/eurheartj/eht085

50.

Kay

, Dorbala

, Goyal

, . Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: Results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry. J Am Coll Cardiol . 2013;62(20):1866–1876. doi:10.1016/j.jacc.2013.06.017

51.

Dorbala

, Vangala

, Sampson

, Limaye

, Kwong

, Di Carli

. Value of vasodilator left ventricular ejection fraction reserve in evaluating the magnitude of myocardium at risk and the extent of angiographic coronary artery disease: a 82Rb PET/CT study. J Nucl Med Off Publ Soc Nucl Med . 2007;48(3):349–358.

52.

Rischpler

, Higuchi

, Fukushima

, . Transient ischemic dilation ratio in 82Rb PET myocardial perfusion imaging: normal values and significance as a diagnostic and prognostic marker. J Nucl Med Off Publ Soc Nucl Med . 2012;53(5):723–730. doi:10.2967/jnumed.111.097600

53.

Abraham

, Kass

, Ruddy

, . Right and left ventricular uptake with Rb-82 PET myocardial perfusion imaging: markers of left main or 3 vessel disease. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2010;17(1):52–60. doi:10.1007/s12350-009-9153-2

54.

Bellam

, Veledar

, Dorbala

, . Prognostic significance of impaired chronotropic response to pharmacologic stress Rb-82 PET. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2014;21(2):233–244. doi:10.1007/s12350-013-9820-1

55.

Lauerma

, Niemi

, Hänninen

, . Multimodality MR imaging assessment of myocardial viability: combination of first-pass and late contrast enhancement to wall motion dynamics and comparison with FDG PET—initial experience. Radiology . Published online December 1, 2000. doi:10.1148/radiology.217.3.r00dc18729

56.

Schmidt

, Voth

, Schneider

, . F-18-FDG uptake is a reliable predictory of functional recovery of akinetic but viable infarct regions as defined by magnetic resonance imaging before and after revascularization. Magn Reson Imaging . 2004;22(2):229–236. doi:10.1016/j.mri.2003.07.006

57.

Kühl

, Lipke

CSA

, Krombach

, . Assessment of reversible myocardial dysfunction in chronic ischaemic heart disease: comparison of contrast-enhanced cardiovascular magnetic resonance and a combined positron emission tomography–single photon emission computed tomography imaging protocol. Eur Heart J . 2006;27(7):846–853. doi:10.1093/eurheartj/ehi747

58.

, Tadamura

, Kanao

, . Myocardial viability by contrast-enhanced cardiovascular magnetic resonance in patients with coronary artery disease: comparison with gated single-photon emission tomography and FDG position emission tomography. Int J Cardiovasc Imaging . 2007;23(6):757–765. doi:10.1007/s10554-007-9215-y

59.

Schinkel

AFL

, Bax

, Poldermans

, Elhendy

, Ferrari

, Rahimtoola

. Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol . 2007;32(7):375–410. doi:10.1016/j.cpcardiol.2007.04.001

60.

Yoshinaga

, Klein

, Tamaki

. Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging—From basic aspects to clinical applications. J Cardiol . 2010;55(2):163–173. doi:10.1016/j.jjcc.2010.01.001

61.

Fiechter

, Ghadri

, Gebhard

, . Diagnostic value of 13N-ammonia myocardial perfusion PET: added value of myocardial flow reserve. J Nucl Med Off Publ Soc Nucl Med . 2012;53(8):1230–1234. doi:10.2967/jnumed.111.101840

62.

Parker

, Iskandar

, Limone

63.

ABA

, Dowsley

, deKemp

, Wells

, Beanlands

. Does Rubidium-82 PET have superior accuracy to SPECT perfusion imaging for the diagnosis of obstructive coronary disease? J Am Coll Cardiol . 2012;60(18):1828–1837. doi:10.1016/j.jacc.2012.07.038

64.

Dorbala

, Di Carli

, Beanlands

65.

Caobelli

, Kamani

, Nkoulou

, Buechel

; Executive Committee Of The Swiss Society Of Nuclear Medicine Sgnm null. The importance of 18F-FDG cardiac PET/CT for the assessment of myocardial viability in ischaemic heart disease. Swiss Med Wkly . 2021;151:w20511. doi:10.4414/smw.2021.20511

66.

, Sun

, Zhao

, . Ocular metastasis in lung cancer: a retrospective analysis in a single Chinese hospital and literature review. Chin J Lung Cancer . 2017;20(5):326–333. doi:10.3779/10.3779/j.issn.1009-3419.2017.05.05