Emerging molecular imaging targets and tools for myocardial fibrosis detection

Abstract

Myocardial fibrosis is the heart's common healing response to injury. While initially seeking to optimize the strength of diseased tissue, fibrosis can become maladaptive, producing stiff poorly functioning and pro-arrhythmic myocardium. Different patterns of fibrosis are associated with different myocardial disease states, but the presence and quantity of fibrosis largely confer adverse prognosis. Current imaging techniques can assess the extent and pattern of myocardial scarring, but lack specificity and detect the presence of established fibrosis when the window to modify this process may have ended. For the first time, novel molecular imaging methods, including gallium-68 (68Ga)-fibroblast activation protein inhibitor positron emission tomography (68Ga-FAPI PET), may permit highly specific imaging of fibrosis activity. These approaches may facilitate earlier fibrosis detection, differentiation of active vs. end-stage disease, and assessment of both disease progression and treatment-response thereby improving patient care and clinical outcomes.

Keywords: fibroblast activation protein inhibitor; fibrosis imaging; molecular fibrosis imaging; myocardial fibrosis; positron emission tomography and cardiovascular magnetic resonance.

Graphical Abstract

Myocardial fibrosis occurs when various forms of myocardial injury affect previously healthy myocardium. Various existing imaging techniques including cardiovascular magnetic resonance, computed tomography, echocardiography, and nuclear imaging (single-photon emission computed tomography and 18F-FDG PET) assess the extent and pattern of myocardium scar. However, they are not specific to fibrosis and detect established fibrosis that may no longer be modifiable with treatment. Novel molecular fibrosis imaging methods may for the first time allow highly specific imaging of fibrosis activity. Benefits over existing modalities may include detection of the earliest stages of fibrogenesis, differentiation between active and end-stage disease, assessment of response to treatment in vivo as well as determination of the anti-fibrotic potential of existing and novel agents. These new techniques remain under investigation to determine their clinical utility. CMR images of myocardial infarction courtesy of Dr Trisha Singh. ⁶⁸Ga-FAPI-04 Images courtesy of Dr Zohreh Varasteh.

Figure 1

Potential triggers for myocardial fibrosis. A variety of cardiovascular conditions can cause myocardial injury and induce fibrogenesis within the myocardium.

Figure 2

Composition of the normal myocardium and pathological changes of fibrosis. Following myocardial injury, fibroblasts are activated to instigate the transformation from normal myocardium to fibrosis. In interstitial fibrosis, myocyte membranes are not compromised, there is no myocyte death, and a more diffuse pattern of potentially reversible fibrosis ensues. Other more intense forms of injury cause myocyte cell death from the outset, triggering replacement fibrosis seen as focal regions of irreversible cardiac scarring. Interstitial fibrosis can progress to replacement fibrosis in the presence of persistent exposure to myocardial injury. In reality, significant overlap exists between these types but they remain useful when considering the different imaging techniques.

Figure 3

Molecular imaging assessments of myocardial fibrosis activity. Positron emission tomography (PET) radiotracers fused with either computed tomography (CT; PET/CT) or cardiovascular magnetic resonance (CMR; PET/MR) to detect active myocardial damage in a range of conditions. Panels A and B: late gadolinium enhancement (LGE) (left panel) and ¹⁸F-fluciclatide PET/CT (right panel) 8 and 13 days following anterior myocardial infarction respectively with intense tracer uptake within the infarct. Panel C: intense 68-gallium fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) uptake on PET/MR within an inferior myocardial infarct in a patient with out-of-hospital cardiac arrest and cardiopulmonary resuscitation. Intense tracer uptake within multiple ribs, representing healing rib fractures (lower panel, ⁶⁸Ga-FAPI PET image). Panel D: increased ⁶⁸Ga-FAPI PET/MR uptake within regions of posterior (upper panels) and anteroseptal (lower panels) scar following myocardial infarction in two patients imaged at Days 3 and 8, respectively. Panel E: ⁶⁸Ga-FAPI PET (top image), CT (middle image), and fused PET/CT image (bottom image) demonstrating right heart ⁶⁸Ga-FAPI uptake in idiopathic pulmonary artery hypertension and right heart failure. Adapted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Wang et al. Panel F: ⁶⁸Ga-FAPI PET (left image), and fused PET/CT (right images) demonstrate left ventricular ⁶⁸Ga-FAPI uptake in a patient with chemotherapy-induced cardiotoxicity (ejection fraction 41%). Reprinted from Totzeck et al.

Figure 4

Potential therapeutic targets in myocardial fibrosis. Relevant pathways involved in fibrosis formation include Angiotensin-II, transforming growth factor-β, and interleukin-11 making them key treatment targets. Other targets include the renin–angiotensin–aldosterone system, sympathetic and immune systems, endothelin 1, stem cell therapy, CAR-T therapy, and theranostic FAP inhibitor agents. AngII, angiotensin-II; ACE-i, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; AT1, Angiotensin receptor; CAR-T, chimeric antigen receptor-modified T cells; ET-1, endothelin-1; FAPI, fibroblast activation protein inhibitor; FAP, fibroblast activation protein; IL, interleukin; PDGF, platelet-derived growth factor; RAAS, renin–angiotensin–aldosterone system; SGLT2i, sodium-glucose cotransporter-2 inhibitor; TGF-β, transforming growth factor (beta).