Visualization of fibroblast activation using 68Ga-FAPI PET/CT after pulmonary vein isolation with pulsed field compared with cryoballoon ablation

This retrospective study is the first comparing FAPI uptake as surrogate for fibroblast activation in patients after single shot non-thermal ablation with PFA to thermal ablation with CBA. Patients treated with PFA had significantly lower FAPI uptake compared to individuals treated with CBA indicating less pronounced fibroblast activation after non-thermal ablation by electroporation.

Tracer uptake after nonthermal vs thermal ablation

Our study found that visual tracer uptake was significantly lower in patients after PFA compared to CBA procedures, as only 3/15 (20%) of PFA patients had a positive visual uptake compared to 10/11 (90.9%) CBA patients who had intense-to moderate visual uptake. These results were in line with quantitative analyses showing significantly lower quantitative uptake in PVs after PFA in comparison to CBA-treated individuals.

The significantly lower extent of tracer uptake as a surrogate for a lower degree of fibrotic remodeling after PFA in comparison to CBA could be explained through different mechanism of energy delivery. PFA, using a predefined protocol, causes selective electroporation of cardiomyocytes leading to apoptosis, thereby sparing the surrounding vascularized connective tissue, which seems to be less sensitive for the used set-up of electroporation.4,12,13 In contrast, CBA results in a non-selective coagulatory necrosis of both the target area and the surrounding tissue, affecting both cardiomyocytes as well as nearby microvascular structures which may translate in different magnitude/pathways of inflammatory vs fibrotic reactive processes in terms of tissue remodeling/healing.14,15 As PFA has only recently been introduced published data in regard to imaging is scarce. A recent MRI study of patients after ablation with both non-thermal and thermal modalities identified a large area of late-gadolinium enhancement (LGE) in PFA patients directly after ablation, which, however, almost disappeared in the 3-months follow up scan.16 This was in complete contrast to an initially small non-homogenous LGE after CBA which then persisted three months later.16 The authors suggested that the initial (extensive) LGE after PFA was induced by acute disintegration of the sarcolemma, resulting in tissue oedema. The regredient LGE after 3 months was explained by the lack of development of chronic fibrosis.16 The chronic disappearance of LGE after PFA is an interesting finding and in accordance with our results as we observed significantly lower amount of FAPI uptake in PFA patients compared to CBA within the first weeks post PVI suggesting a lower degree of activation of fibroblasts in PFA and in consequence lack of fibrosis or absence of LGE as a surrogate of fibrosis. We hypothesize that cardiomyocyte apoptosis after PFA, opposed to general tissue necrosis after CBA, does not trigger an inflammatory cascade that ultimately causes fibroblast activation by the transformation from inflammation to fibrosis by stimulating collagen synthesis.16,17,18 In contrast, CBA, as a thermal modality causing coagulatory necrosis, is suggested to trigger an inflammatory response, hence activating fibroblasts that may be responsible for LGE persistence as well as significantly increased FAPI uptake in these patients.14,16 Further, the disruption of structural integrity as a consequence of thermal ablation due to microvascular obstruction or intramural hemorrhage may lead to mechanical strain on fibroblasts, stimulating their activation, while after an ablation with PFA the structural integrity of extracellular matrix is preserved, preventing the additional mechanical stress on fibroblasts.7,14,16,19

Fibroblast activation after thermal/non-thermal ablation vs controls

The finding of significantly higher fibroblast activation after CBA, which seems to further increase over time, has been reported and discussed elsewhere.8 Here we report a positive visual uptake in 3/15 (20%) of PFA patients and the finding that FAPI uptake in PFA patients tended to be higher compared to ablation-naïve controls in SUVmean and SUVpeak parameters. This finding suggests divergent extent of fibroblast activation in patients after PVI with a clear increase after CBA and a less pronounced, but still to some degree enhanced level of fibroblast activation after PFA. At the moment one can only speculate about this finding. Preclinical studies have shown that although apoptosis is the dominant pathway of cell death in PFA, some degree of immediate cell necrosis after PFA energy delivery may be present, possibly triggering a low-level inflammation cascade that further results in activation of fibroblasts.5,18,20 Another reason for this finding could be found in the direct contact of the PFA device. Especially the olive configuration where the PV ostium is deeply intubated with the PFA device might lead to the triggering of a local fibroblast activation by mechanical stimulation as a consequence of a direct myocardial contact.21,22

Last, the increased FAPI uptake in PFA vs controls could be suggested in the pathophysiologic characteristics of the AF itself, as chronic inflammation and increased fibrotic atrial burden have been increasingly recognized as an important pathomechanism for AF in terms of an atrial cardiomyopathy and no serial pre-ablation imaging was performed in the PFA patients to determine the pre-ablation/baseline FAPI status in these patients.23,24,25,26,27 Both chronic atrial inflammation as well as atrial fibrosis may explain the increased level of FAPI uptake in PFA patients, opposed to non-AF controls.

As an incidental finding, a diffuse left ventricular FAPI uptake was observed in one PFA patient with dilated cardiomyopathy (DCM) and reduced LVEF, possibly reflecting ongoing cardiac remodeling in the setting of DCM, which is further highlighted by the diffuse pattern of ventricular uptake.28 This would be in line with reports of previous studies which associated decreased LVEF with FAPI uptake as well as recent preclinical study, where in rats with heart failure a positive FAPI uptake was observed as a result of an ongoing myocardial fibrosis development.9,11,29

Temporal relation of FAPI uptake depending on the imaging timepoint after PFA/CBA

The MRI study on PFA patients observed LGE disappearance after 3 months post PFA.16 Analogous to this study we tried to evaluate if there is a trend of lower FAPI uptake after PFA procedures over time. After stratifying the PFA cohort according to the time of the imaging we observed only a trend of higher FAPI uptake within the early phase without significant changes in tracer uptake between the time points of imaging. However, preclinical data do suggest that activation of fibroblasts happens within the first 28 days following myocardial injury due to myocardial infarction,30 and published preclinical data suggest peak FAPI uptake to be 6 days after myocardial injury.31 Although the results of our study might have been hampered by the small patient cohort and/or the overall low uptake, due to the specific tissue response following PFA, there might be a trend of decreasing fibroblast activation after PFA. On the other side in CBA patients there was a clear increase after PVI and even a sign of further increase in FAPI uptake over time in the late vs early CBA cohort further underlying a different effect of the ablation technologies on the cellular level.

Clinical implication and future perspectives

Despite the lack of chronic LGE or fibroblast activation, the follow-up data of PFA studies and the results of our 6-month follow-up suggest that recurrence rate is not inferior to thermal ablation.6,16 This is also underlined by the first reported 1-year outcome data of PFA compared to thermal PVI.6 This is an encouraging finding suggesting that PFA is simultaneously a noninferior modality with respect to AF recurrence while simultaneously being a safer modality with respect to adverse effects of increased fibrosis and its complications observed after thermal ablation including PV stenosis, substrate for macro-reentry arrhythmias or atrial stiffness due to adverse remodeling.5,6,32

Protocols of PFA utilization regarding the use of either monophasic or biphasic waveforms have been modified according to the increasing experience and while results of PFA have been promising in regard to safety and outcomes, we still don´t know its possibilities in regard to overpowering.5 Imaging with FAPI may offer a chance to monitor different PFA protocols in regard to their configuration through level of FAPI uptake as surrogate for fibroblast activation. Further, FAPI imaging, especially in combination with LGE-MRI and functional follow-up parameters of myocardial function may allow to better understand subsequent myocardial remodeling due to both thermal and non-thermal ablation caused lesions as well as mechanisms behind AF recurrence. The question if there could be a direct effect of the electroporation on the fibroblast activity, which could in consequence alter the progress of atrial fibrosis, remains completely speculative and has to be elucidated by future studies.

Limitations

This was an observational study of small cohorts with no histological validation, nor a pre-ablation imaging in the ablation patients. Larger prospective studies with repeat hybrid imaging with PET and LGE-MRI in combination with electrophysiological studies, histological validation, longer follow-up and cardiac biomarkers as well as concentration of fibroblast activation protein in serum are needed to further explore the significance of this tracer in evaluation of structural changes following different PVI modalities.

留言 (0)

沒有登入
gif