Incidental Detection of Severe LAD Stenosis by FAPI PET/CT in a Patient Under Evaluation for Solitary Pulmonary Nodule – Correlation with Coronary Flow Velocity and Coronary Angiogram

INTRODUCTION

⁶⁸Gallium labelled Fibroblast activation protein inhibitor (FAPI) is a promising Positron Emission Tomography/Computed Tomography (PET/CT) agent which targets fibroblast activation protein (FAP)^[1] and is being extensively used in oncology, especially in patients with low metabolically active tumours and those scheduled for FDG PET/CT with uncontrolled diabetes. Use of FAPI in non-oncological indications, especially myocardial pathologies, is still evolving. Although ¹⁸F-Fluorodeoxyglucose (FDG) is an established metabolic tracer for myocardial viability and sarcoidosis assessment, patient preparation is different for both these clinical conditions. Overnight fasting, glucose loading, combined with insulin management for diabetic patients on the day of the viability test is important. As fatty acid is the normal substrate for myocardium, we need to alter the normal substrate by performing a glucose loading to induce myocardial glucose transporters (GLUT-4) to take up both glucose and FDG into the myocytes. Only when patient prepartion is optimal, a confident report for viability/other inflammatory cardiac pathologies is feasible. Focal areas of pathological ¹⁸F FDG uptake from normal physiologic myocardial uptake need to be delineated. FAPI has been used to study inflammatory changes, but its use in myocardial ischemia and fibrosis is not establised. Technological advances like transthoracic doppler echocardiography (TTDE) are upcoming non-invasive investigations for evaluating coronary blood flow in suspected coronary artery disease patients.^[2] We wanted to present the incidental detection of FAPI positive LAD fibrosis and document any coronary flow reduction corresponding to FAPI-positive myocardial segments.

CASE REPORT

A 57-year-old diabetic male presented with cough for 4 weeks and haemoptysis on two occasions. CT chest done elsewhere reported a soft tissue nodule in the apical segment of the right lung upper lobe. Whole body ¹⁸F FDG PETCT was suggested to characterise the right lung lesion [Fig 1A]. Whole body and chest images [Fig 1B and C] showed a FDG non-avid well-circumscribed soft tissue lesion in the right upper lobe apical segment measuring 1.9 x 1.4 cm with surrounding ground glassing. In the presence of a strong malignancy history in the family, ⁶⁸Gallium FAPI -04 PETCT was performed to look for FAPI positivity, especially in an event of a low metabolically active lung malignancy [Fig 2A and B]. Similar to FDG PETCT, there was no FAPI uptake in the right lung lesion [Fig 2C] with no nodal or distant lesions. However, abnormal FAPI uptake seen in myocardium, localised to the left anterior descending artery (LAD)-supplied coronary territory, was incidentally detected (SUV max 7.4) [Fig 3A and B]. Being a diabetic patient with no prior coronary events, rest myocardial perfusion single photon emission computed tomography (SPECT) was performed on the next day using 10 millicuries of ^99mTc SestaMIBI IV injection. Rest ^99mTc MIBI gated SPECT images were acquired 1-hour post injection on an ECAM gamma camera. Images showed severe perfusion defects in the anterior, apical, and septal LV segments, confirming the diagnosis of a large LAD territory infarct with a left ventricular ejection fraction of 46% [Fig 3C]. The case was discussed in the tumour board, and a lung biopsy was planned in view of the patient’s anxiety and family history. As part of preanaesthetic clearance for lung biopsy, the patient was evaluated by an echocardiogram and finally confirmed with a coronary angiogram. Another new parameter was evaluated in this patient using transthoracic doppler. Reports say that LAD velocities demonstrate high sensitivity and specificity for the evaluation and prediction of severe angiographic stenosis in unsuspected cases. Thus, we wanted to study whether transthoracic doppler measurement of coronary flow velocity can identify LAD stenosis in this patient prior to a coronary angiogram.

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Fig 1: Whole body Fluorodeoxyglucose PETCT; (A) MIP; (B) Inspiratory CT and (C) Fused PET/CT in lung window: images show no abnormal myocardial FDG uptake and no uptake in a well-circumscribed soft tissue lesion in the right upper lobe apical segment (arrow) measuring 1.9 x 1.4 cm with surrounding ground glassing. No FDG avid nodal or distant lesions noted. PET/CT: Positron emission tomography/computed tomography; CT: Computed tomography; MIP: Maximum intensity projection

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Fig 2: (A) ⁶⁸Gallium fibroblast activation protein inhibitor (FAPI) – 04 PETCT MIP (star) indicating site of right lung lesion and arrow shows the FAPI uptake in LAD supplied LV territories (SUV Max 7.7); (B) CT; (C) Fused PET/CT showed no FAPI uptake in the right upper lobe lesion. FAPI: Fibroblast activation protein inhibitor; PET/CT: Positron emission tomography/computed tomography; MIP: Maximum intensity projection

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A 3.5-7 MHz transducer was used with a colour doppler Nyquist limit set at 17 cm/sec. LAD colour flow recording was meticulously performed, starting from the low parasternal short-axis view. The search for diastolic colour velocity was tried starting from the anterior interventricular groove, followed by clockwise rotation to achieve alignment of the colour jet.^[2] Doppler revealed a flat diastolic velocity profile with long diastolic pressure half-time and large systolic velocity component, indicating severe LAD stenosis in our patient [Fig 3]. The peak diastolic and systolic velocities and their ratios were obtained using colour doppler (transthoracic approach). Time-velocity integrals in diastole and systole were measured, and their ratios were calculated. Pressure half-time was obtained from the diastolic component of the LAD velocity profile. Measurements were averaged from three consecutive beats. The LAD diameter was measured from the colour flow two-dimensional image [Fig 4A and B].

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Fig 3: (A) Myocardial segmentation model and assignment to the coronary territories for analysis of scintigraphy images; SSA = short axis; VLA = vertical long axis; LAD = left anterior descending artery; RCA = right coronary artery; LCx = left circumflex artery; (B) Fibroblast activation protein inhibitor (FAPI) quantitative myocardial segmentation highlighting significant abnormal FAPI uptake confined to LAD territory supplying myocardial segments; C) 99mTc SestaMIBI rest myocardial SPECT study showing severe perfusion defects involving apex, major part of anterior and septal LV segments, indicating LAD infarct (arrows).

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Fig 4: (A) Colour jet of diastolic flow velocity in the left anterior descending (LAD) coronary artery; (B and C) Quantitative coronary angiography: 80.6% diameter stenosis; 96.2% area stenosis.

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LAD cross-sectional area was calculated as:

Area = Diameter (cm)²s

LAD Flow was calculated as follows:

Flow = (heart rate) x (LAD area) x (time velocity integral).

Quantitative coronary angiography revealed 80.6% LAD diameter stenosis and 96.2% area stenosis which was compatible with our FAPI finding indicating chronic phase of ischemia with associated fibrosis [Fig 4C]. Uptake of FAPI may be linked to the FAP expression driven by proliferating fibroblasts laying down a new extracellular matrix. Inactive myocardial fibroblasts (during apoptosis phase) may show low or negligible FAPI uptake, and provides a basis for the possible differentiation between fresh and mature ischemia.

DISCUSSION

⁶⁸Ga-FAPI-04 is a newly developed PET agent that targets fibroblast activation protein (FAP).^[3] Unlike ¹⁸F-FDG that accumulates in both cancer and active inflammatory cells due to upregulation of glycolytic flux and GLUT receptor overexpression, uptake of FAPI is directly associated with the degree of fibrosis.^[4] Therefore, comparing FAPI with FDG imaging, one may achieve better information for differentiating scarred, fibrosed myocardial tissue using FAPI, which is a marker of chronic inflammation^[5] with no cumbersome patient preparation as evident in this case.

Similarly, studies have established a high degree of correlation between invasively derived flow measurements and parameters provided by transthoracic doppler echocardiography (TTDE) with angiography.^[6-8] This technique is considered promising as a screening modality in most of the suspected cases of coronary artery disease, and we found it feasible and accurately correlated with our case post-angiogram.

CONCLUSION

FAPI 04 PETCT was found to be an accurate indicator for assessing the presence and extent of myocardial fibrosis. Therefore Myocardial PET studies using FAPI may be undertaken to get an insight into its diagnostic potential. Similarly, Doppler LAD flow velocity was a feasible and robust marker for identifying LAD stenosis, especially in unsuspected coronary artery disease patients.