Abstract
Cardiotoxicity, or the development of unwarranted cardiovascular side-effects of oncologic therapies, can involve all aspects of cardiovascular disease. The development of cardiac fibrosis is a dreaded complication that leads to cardiac mechanical dysfunction, tachyarrhythmias, and an increase in cardiovascular mortality. This review details established and putative mechanisms leading to fibroblast activation, myofibroblast transdifferentiation, and the development of replacement or interstitial cardiac fibrosis as a consequence of cancer treatments. Clinical and imaging strategies for cardiac fibrosis assessment as well as emerging antifibrotic therapeutics will also be addressed.
Introduction
The adult mammalian heart has a negligeable ability to regenerate – estimated at no more than ~ 1% replacement of cardiomyocytes per year [1–4] – and thus rather heals through cardiac repair mechanisms leading to scar tissue formation. In adult hearts, fibroblasts account for ~25% of the cell population [5], provide support to cardiomyocytes, and contribute to multiple signaling processes [6]. The majority of the cardiac extracellular matrix (ECM) is constituted by type I and III collagen [7,8]. Cardiac fibrosis requires the activation of cardiac fibroblasts – abundant in the interstitial and perivascular space – and transdifferentiation to myofibroblasts, resulting in the excess deposition of ECM proteins, which may play a reparative role but also negatively impact cardiac function [9]. In addition to activation of the renin-angiotensin-aldosterone system [10,11], β-adrenergic stimulation [12,13], and the Wnt pathway [14,15], key mediators of fibrogenic activation include growth factors, e.g. transforming growth factor (TGF)-β and platelet-derived growth factors (PDGF), and cytokines, e.g. tumor necrosis factor (TNF)-α, and interleukin (IL)-1, -4, -6, and -10 [16].
Cardiac fibrosis may occur as a consequence of epicardial and microvascular ischemic heart disease, inherited cardiomyopathies, pressure overload such as aortic valve stenosis or systemic hypertension, and certain oncologic treatments, amongst others. There are three main types of cardiac fibrosis based on histopathology, namely replacement fibrosis, interstitial fibrosis, and perivascular fibrosis [9]. Whether interstitial and perivascular fibrosis have distinct pathobiological mechanisms remains controversial and is addressed elsewhere [9]. Others also distinguish infiltrative interstitial fibrosis as observed in Fabry disease with diffuse cellular glycolipid accumulation [17].
Replacement or reparative cardiac fibrosis occurs as a result of sudden cardiomyocyte necrosis as observed following acute myocardial infarction and also reported in the setting of radiation therapy. Given the negligeable ability of cardiomyocytes to regenerate, the collagen-rich scar in this setting serves a critical role, i.e. maintaining the structural integrity of the heart, albeit at the price of a deterioration in left ventricular systolic function. However, in other pathologies such as systemic hypertension, diabetes mellitus, and obesity, interstitial cardiac fibrosis occurs in the absence of significant cardiomyocyte death, likely as a result of prolonged activation of fibrogenic stimuli, and predominantly involves the interstitium and perivascular space. Interstitial fibrosis can develop insidiously [9], and initially manifests as heart failure with preserved ejection fraction (HFpEF) due to increased interstitial stiffness leading to a reduction in ventricular compliance and diastolic filling. Finally, perivascular fibrosis is most prominent in hypertensive heart disease, and is associated with impaired microvascular function leading to perturbation of myocardial blood flow [18].
The end-result of replacement, interstitial, and perivascular fibrosis is often cardiac dysfunction, either diastolic, systolic, or their combination, leading to heart failure with reduced and/or preserved ejection fraction, and an increased propensity for both atrial and ventricular tachyarrhythmias most notably atrial fibrillation [19], ventricular tachycardia [20], and sudden cardiac death [21]. Indeed, excess ECM proteins, most prominently collagen, act as ‘scars’ from a functional standpoint, and are centrally implicated in the occurrence of focal electrical re-entry circuits, which may deteriorate to potentially life-threatening ventricular tachy-arrhythmias [22], and further contribute to the degradation of ventricular function.
Expansion of the ECM leading to cardiac fibrosis is associated with increased mortality [23]. Cardiac remodeling, defined as a change in geometry with ensuing worsening function following injury, occurs as a result of crosstalk between cardiac cells and the ECM: on the one hand, cells secrete ECM molecules with regulatory properties, on the other, changes in the ECM lead to cellular responses [9,24].
This review details known and putative associations between oncologic therapies and the development of cardiomyocyte injury, fibroblast activation, and subsequent deposition of excess ECM proteins leading to cardiac fibrosis.
Anthracyclines
Severe anthracycline-induced cardiotoxicity resulting in depressed systolic function and heart failure can afflict up to 25% of patients [25,26]. Ample evidence supports that anthracycline-induced cardiac injury is multi-factorial and -genic, with no single mechanism fully explaining all aspects of the injury process. Prior studies indicate anthracycline-induced cardiotoxicity results from a combination of deoxyribonucleic acid (DNA) damage, oxidative stress, and metabolic perturbations, leading to the activation of all forms of cell death [27,28].
Anthracycline chemotherapy intercalates in the DNA and induces single- and double-strand DNA breaks in target cells in a topoisomerase (Top)-2-dependent manner [29]. By producing temporary single- or double-stranded DNA breaks, Top regulates topological changes during DNA replication, transcription, or recombination [30]. Top-2α is overexpressed in tumors and is the molecular basis of anthracycline anticancer activity [31,32]. Adult cardiomyocytes express Top-2β but not Top-2α [31], and Top-2β is also an anthracycline target, forming a Top-2β–anthracycline–DNA ternary cleavage complex that induces DNA strand breaks and ensuing cell death [33,34]. Furthermore, anthracycline/Top-2β bind to selective promoters, significantly affecting the cardiomyocyte transcriptome [34,35]. Ensuingly, key antioxidative enzymes are reduced, providing a mechanism linking anthracycline-induced reactive oxygen species (ROS) production (O2•− superoxide anion, H2O2 hydrogen peroxide, and OH• hydroxyl radical) [36,37] in a Top-2β-dependent manner. An additional major pathway of anthracycline-induced cardiotoxicity is through mitochondrial complex I NADH dehydrogenase mediated redox cycling with the quinone moiety of anthracyclines, leading to the generation of excess reactive oxygen species (ROS) [36,38] with ensuing DNA damage [36,38–40]. Furthermore, anthracyclines can interact directly with iron to form complexes, catalyzing a Fenton reaction, i.e. the Fe2+ mediated conversion of H2O2 to OH•, supported by experimental studies in which excess iron accumulation worsens anthracycline-induced cardiotoxicity [41,42].
Anthracyclines such as doxorubicin are known to lead to cardiac fibrosis (Fig. 1) [40,43,44]. In particular, anthracycline-induced cardiomyocyte injury and death leads to an inflammatory response that induces fibroblast activation [45]. Indeed, anthracyclines damage mitochondria, causing the release of mitochondrial DNA, peptides, and lipids, that become damage-associated molecular patterns (DAMPs) resulting in innate immune system activation [46]. Given the abundance of mitochondria required to maintain cardiac energy consumption and function, these mitochondrial DAMPs can lead to a significant response amplification, mediated by pattern recognition receptors, primarily Toll-like receptor (TLR) -9 [47]. In turn, this activates the pro-inflammatory transcription factor nuclear factor (NF)-κB, induces the expression of inflammatory cytokines such as TNF-α, and the recruitment of inflammatory cells [48,49]. The ensuing chronic inflammation triggers TGF-β1 activation which promotes the conversion of fibroblasts to myofibroblasts with ensuing collagen synthesis and deposition [9,50,51]. Both TGF-β1 and its signal transducer SMAD (similar to mothers against decapentaplegic) -3 are consistently induced by anthracyclines in the heart, and during all phases of the injury process [52].
Figure 1. Progression of anthracycline cardiotoxicity from cardiomyocyte injury and death to fibroblast activation and interstitial fibrosis.
Anthracycline chemotherapy affects the heart in a ‘patchy’ manner. (A) Segment of normal left ventricular myocardium prior to chemotherapy. (B) In the setting of anthracycline treatment, cardiomyocyte injury develops with ensuing inflammatory infiltration, primarily macrophages. (C) With progression of anthracycline toxicity, cardiomyocyte death occurs, leading to activation of fibroblasts and myofibroblasts that produce excess extracellular matrix proteins, primarily collagen. (D) In the chronic phase of anthracycline cardiotoxicity, scattered dead cardiomyocytes have been replaced with collagen leading to interstitial cardiac fibrosis, setting the stage for ensuing cardiac mechanical complications.
ECM: extracellular matrix. PDGF: platelet-derived growth factor. TGF-β: transforming growth factor-β. TNF-α: tumor necrosis factor-α. Wnt: wingless and int-1.
In addition to cardiomyocyte injury and death, anthracyclines also directly promote the release of pro-fibrotic factors from the myocardium. Experimental evidence suggests that low-dose doxorubicin exposure can lead to fibroblast activation and perivascular fibrosis in the absence of cardiomyocyte injury [53]. Indeed, anthracyclines induce TGF-β release from cardiac endothelial cells [54] and fibroblasts [55]. Furthermore, PDGF-A and -B are induced 4-5-fold in the ventricles of doxorubicin treated mice [56]. Doxorubicin also increases plasma angiotensin-II levels 3-fold [57], mediated in part by enhanced renin [58] and angiotensin-converting enzyme [59,60] activities. Importantly, anthracyclines promote the trans-differentiation of cardiac fibroblasts to myofibroblasts [55]. Further research established the expression of additional fibroblast activation markers in response to anthracyclines. Indeed, daunorubicin treatment is associated with increased cardiac fibroblast expression of vimentin [61], a protein previously implicated in fibroblast proliferation and differentiation [62]. Tenascin-C, another marker of fibroblast activation, is induced in doxorubicin-treated pigs [63]. Similarly, connective tissue growth factor (CTGF) is a matricellular protein secreted by activated fibroblasts to mediate TGF-β activity during the fibrotic response to anthracycline therapy (64), and further has an autocrine function by amplifying fibroblast activation, thus creating a positive feedback loop [65].
Following fibroblast/myofibroblast activation, there is increased deposition of collagen type I and III in the ECM, leading to cardiac interstitial fibrosis [52]. In addition, doxorubicin also results in fibronectin deposition in the ECM [66]. Importantly, tissue inhibitor of metalloproteinase (TIMP) -1 that hinders matrix metalloproteinase (MMP) activity, is induced by anthracycline treatment, thus impeding ECM degradation and indirectly promoting collagen accumulation [53]. Similarly, the matricellular protein thrombospondin (TSP) -2 – released mainly by fibroblasts – is induced by doxorubicin, and also inhibits MMP proteolytic activity [67]. The net effect of these molecular actions caused by anthracyclines is ECM accumulation, leading to interstitial fibrosis. It is important to note that the cardiac injury process induced by anthracyclines and ensuing interstitial fibrosis is spatially heterogeneous (Fig. 1), with unaffected regions of the myocardium compensating through augmentation of function, thus ‘masking’ early cardiotoxicity from a functional standpoint [68].
Trastuzumab
Trastuzumab cardiotoxicity is mediated by inhibition of cardiomyocyte human epidermal growth factor receptor-2 (also known as ErbB2) which interferes with mitochondrial integrity through Bcl-x proteins, leading to adenosine triphosphate (ATP) depletion, interference with the repair and survival of cardiomyocytes, and mechanical failure [69,70]. In mice, treatment with an anti-ErbB2 antibody further leads to ventricular myofibril disarray [71]. Additional animal studies demonstrate trastuzumab-mediated activation of cardiomyocyte apoptosis [72] which – similar to anthracyclines – leads to cardiac interstitial fibrosis [73,74] that can be characterized by cardiac magnetic resonance imaging (MRI) [75,76].
VEGF Signaling Inhibitors
Angiogenesis inhibitors, or vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSPi), block VEGF signaling through various mechanisms, i.e. (i) anti-VEGF antibodies (e.g., bevacizumab), (ii) anti-VEGF receptor antibodies (e.g., ramucirumab), and (iii) VEGFR intracellular domain tyrosine kinase inhibitors (TKIs, e.g., sorafenib, sunitinib) [77]. VSPi are implicated in the onset of hypertension in up to 80% of patients [78,79]. Dissecting the mechanisms thereof is of paramount importance given treatment of hypertension associated with VSPi is challenging as demonstrated by its abrupt onset and requirement for multiple anti-hypertensive medications [78]. Whereas the exact pathobiology leading to severe hypertension remains to be determined, putative pathways include endothelial dysfunction with decreased nitric oxide production [80,81], and glomerular injury with podocyte apoptosis [82,83]. Refractory hypertension is a well-known risk factor for the development of cardiac interstitial fibrosis [9] and has been reported in certain animal studies of VSPi-induced cardiotoxicity [84,85]. In addition, VSPi have been associated with accelerated atherosclerosis [86] as well as coronary microvascular dysfunction (sunitinib) [87], however the contributions thereof to the development of ischemic heart disease and subsequent cardiac fibrosis have not been investigated to date. Importantly, cardiotoxicity by VSPi is reversible in up to 80% of patients upon withdrawal [88].
Bruton’s Tyrosine Kinase Inhibitors
Bruton’s tyrosine kinase inhibitors (BTKi) are increasingly used in B lymphocyte malignancies [89]. A first-generation BTKi, ibrutinib, has been implicated in cardiac fibrosis, a consequence of its lack of selectivity leading to frequent off-target actions [90]. Indeed, mice treated with ibrutinib develop left atrial fibrosis with increased deposition of fibronectin, collagen-I and -III, left atrial enlargement, and atrial fibrillation [90,91]. Using chemo-proteomic profiling and genetically modified mice, the cardiotoxic effect of ibrutinib was demonstrated to be due to the inhibition of CSK (C-terminal Src kinase), itself a non-receptor tyrosine kinase that functions as a master negative regulator of Src family tyrosine kinases (SFKs) [92]. Second-generation BTKi (e.g. acalabrutinib, zanubrutinib) are more selective, leading to fewer cardiovascular off-target effects. A recent meta-analysis indicated an 87% decrease in symptomatic or life-threatening atrial fibrillation, and a 38% decrease in severe hypertension (defined as ≥ 160/110 mmHg or malignant hypertension) with second- vs. first-generation BTKi [93]. To date, second-generation BTKi have not been implicated in cardiac fibrosis [94].
Immune Checkpoint Inhibitors
Cardiac complications of immune checkpoint inhibitors (ICI) that act on different co-stimulatory molecules expressed by T lymphocytes and antigen-presenting cells are rare – with the caveat of likely being under-recognized [95–97] – but potentially fatal [98]. The pathobiology of cardiac fibrosis in the setting of ICI treatment has not been explored [99,100]. Putative mechanisms leading to fibroblast activation, transdifferentiation to myofibroblasts, and replacement fibrosis – not demonstrated to date in experimental models – may involve ICI-induced (i) direct cytotoxic T-cell mediated cardiomyocyte death [101], (ii) chronic inflammation with ensuing oxidative stress [102], and (iii) accelerated coronary atherosclerosis [103] leading to ischemic heart disease and cardiomyocyte death. Whether ICI also has a direct effect on fibroblasts should also be scrutinized. Cardiac fibrosis is overall a very rare complication in ICI [98,104].
Radiation Therapy
Radiation therapy is an integral part of the armamentarium against multiple chest cancers, including lymphomas, lung cancer, and breast cancer [105]. However, radiotherapy may lead to a myriad of cardiovascular complications, including accelerated coronary artery disease, conduction system abnormalities, valvular disease, pericardial disease, and cardiac fibrosis. Whereas the underlying pathobiological mechanisms leading to cardiac fibrosis following radiotherapy are not entirely understood, certain features of the disease process have been explored (Fig. 2).
Figure 2. Radiation therapy-induced endothelial and cardiomyocyte injury leading to fibroblast activation and cardiac fibrosis.
Mechanisms leading to cardiac fibrosis following radiation therapy. (A) Following radiation, endothelial cells rapidly express adhesion molecules, leading to the recruitment of leukocytes. ROS-mediated release of leukotrienes and prostaglandins further induce capillary permeability and leukocyte extravasation. Leukocytes, mainly monocytes and neutrophils, subsequently release pro-inflammatory cytokines, stimulating cardiomyocytes and fibroblasts to secrete pro-fibrotic mediators with ensuing fibroblast activation, ECM production, and cardiac fibrosis. (B) Radiation therapy is complicated by collagen exposure in the sub-endothelial matrix, with ensuing binding of von Willebrand Factor, platelet adhesion, and thrombus formation. Downstream, hypoxia occurs, leading to endothelial cell and fibroblast release of HIF-1α, in turn promoting the secretion of pro-fibrotic factors, and fibroblast activation. (C) Radiation can also directly injure cardiomyocytes, albeit at a later time-point. Three mechanisms have been proposed, namely an increase in ROS production, ER stress leading to excess calcium accumulation in the mitochondria, and increased Bax expression which translocates to the mitochondrial membrane and opens the mitochondrial membrane transition pore. Combined, these lead to mitochondrial swelling and rupture, cytochrome c release, and activation of cell death pathways. Following cardiomyocyte death, replacement cardiac fibrosis occurs.
Bax: Bcl-2 associated X-protein. CTGF: connective tissue growth factor. ECM: extracellular matrix. ER: endoplasmic reticulum. HIF-1α: hypoxia-inducible factor-1α. ICAM-1: intercellular adhesion molecule-1. IGF: insulin-like growth factor. IL: interleukin. mPTP: mitochondrial membrane transition pore. NF-κB: nuclear factor-κB. PDGF: platelet-derived growth factor. RNS: reactive nitrogen species. ROS: reactive oxygen species. TGF-β: transforming growth factor-β. TNF-α: tumor necrosis factor-α. VCAM-1: vascular cell adhesion molecule-1. vWF: von Willebrand Factor.
Endothelial injury of the dense myocardial capillary network and ensuing microvascular dysfunction plays a central role. Following radiation, there is a rapid rise in endothelial ROS production, mediated in part by the up-regulation of the NADPH oxidases NOX-2 and -4 [106], with ensuing NO scavenging and peroxynitrite (ONOO−) formation, implicated in protein nitrosylation [107]. This endothelial dysfunction leads to the release of eicosanoids such as leukotrienes and prostaglandins that increase capillary permeability and leukocyte extravasation [108]. In addition, irradiated endothelial cells express adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), promoting the recruitment of neutrophils and monocytes [109,110]. These leukocytes secrete inflammatory mediators, including TNF-α, IL-1, -6, and -8, and signal to neighboring cardiomyocytes and fibroblasts, rapidly promoting the release of pro-fibrotic cytokines such as TGF-β, PDGF, insulin-like growth factor (IGF), and basic fibroblast growth factor (FGF), as well as myofibroblast transdifferentiation [105,111,112].
Furthermore, endothelial injury results in exposure of the sub-endothelial matrix, permitting binding of von Willebrand factor via its collagen interaction sites, followed by a conformational change that enables platelet glycoprotein binding and ensuing thrombus formation and vascular occlusion [113,114]. This decrease in endothelial and capillary density results in microvascular disease, ischemia, cardiomyocyte death, and cardiac fibrosis [105]. In addition, chronic hypoxia leads to the expression of hypoxia-inducible factor (HIF) -1α, implicated in the stimulation of pro-fibrotic mediators such as TGF-β, endothelin-1, and CTGF, thus further contributing to replacement cardiac fibrosis [115,116].
Cardiomyocytes are relatively resistant to radiation injury due to their very low rate of proliferation [1–4], however direct radiation-induced cardiomyocyte injury has been reported. First, radiation induces ROS [117] which interact with the transcription factor NF-κB, resulting in its nuclear translocation and proinflammatory cytokine production, leading to chronic inflammation [118,119]. Second, radiation induces the cardiomyocyte endoplasmic reticulum to release excess calcium ions, leading to mitochondrial swelling, mitochondrial membrane permeabilization, and oxidative phosphorylation uncoupling [120,121]. Third, experimental studies have described an increase in Bax levels following radiation [120,122]. Bax then translocates from the cytoplasm to the mitochondrial membrane where it opens the mitochondrial membrane transition pore (mPTP), leading to membrane depolarization and rupture, release of cytochrome c into the cytoplasm, and cardiomyocyte death [123]. Although less well characterized, these direct radiation-induced cardiomyocyte death mechanisms also implicate replacement fibrosis, as above [119].
Strategies for Cardiac Fibrosis Assessment
Animal studies present the distinct advantage of direct tissue collection and histological staining at predefined timepoints [124], in addition to targeted genetic manipulation and controlled environmental factors. Following histology staining, for example with picrosirius red, and digital scanning, the fraction of cardiac fibrosis may be quantified using pixel-based segmentation and clustering [125].
Whereas endomyocardial biopsies in humans are the gold standard for visualization of fibrosis, this approach is limited by its invasive nature [126]. Circulating biomarkers [127] including galectin-3, secreted by inflammatory cells and fibroblasts, and soluble ST-2 (suppression of tumorigenicity-2), a member of the IL-1 receptor family, correlate with the degree of cardiac fibrosis [128–130]. The carboxy-terminal pro-peptide of pro-collagen type I and the amino-terminal pro-peptide of pro-collagen type III are additional circulating biomarkers that correlate with the collagen volume fraction in cardiac fibrosis [131]. However, this strategy is not used in routine clinical practice, in part due to a lack of validation.
Echocardiography may be used for the rapid assessment of cardiac structure, dimensions, function, and remodeling. 2-D [132] or 3-D speckle [133] tracking echocardiography with strain measurement further permits the assessment of segmental ventricular function, reported to correlate with cardiac fibrosis [134]. Whereas echocardiography does not have the spatial resolution to directly image interstitial fibrosis, ensuing changes in diastolic function can be readily measured and help unmask the disease, albeit with limited specificity [135].
For in vivo characterization, cardiac MRI is the reference modality for detection of cardiac fibrosis in both human and animal studies [136]. Two cardiac magnetic resonance imaging (MRI) methods are routinely used for fibrosis detection; (i) late gadolinium enhancement, and (ii) T1 mapping, alone or in combination with an extracellular contrast agent to determine the extracellular volume fraction calculated by pre- and post-contrast T1 measurements [137–139]. Whereas late gadolinium enhancement is ideally suited for the assessment of replacement (or reparative) cardiac fibrosis, T1 mapping is favored for the detection of diffuse interstitial fibrosis, for example in the setting of anthracycline-induced cardiotoxicity, and quantification of the ECM expansion by measurement of the extracellular volume fraction (Fig.1) [140–142]. Using serial cardiac MRI, Farhad et al. demonstrated in a chronic doxorubicin mouse injury model that 10 weeks after the first dose of chemotherapy, left ventricular ejection fraction (LVEF) deteriorated and cardiac fibrosis developed, as measured by T1 mapping and validated histologically using Masson’s trichrome staining [143]. Importantly, cardiac fibrosis also predicted late mortality in mice, whereas the deterioration in LVEF did not [143]. Similar experiments and findings in mice [144], rats [145,146], rabbits [125,147], and pigs [148] have been reported by other groups.
These experimental observations indicating a strong correlation between cardiac fibrosis and left ventricular dysfunction [23,141,149] have translational implications. Whereas on the one hand abnormal T1 mapping and extracellular volume expansion in anthracycline treated patients may warrant closer follow-up and/or changes in chemotherapy, on the other hand normal T1 mapping may allow for longer surveillance intervals [142].
Nuclear imaging permits molecular targeting of cellular and molecular contributors to cardiac fibrosis. Mostly studied in the setting of replacement cardiac fibrosis following myocardial infarction, nuclear imaging molecular strategies should be explored further in experimental models of oncologic treatments. Such radiotracers include 99mTc-labeled cyanine-5.5 RGD imaging peptide (99mTc-CRIP) [150,151] and 18F-labeled RGD [152,153]. The RGD peptide (containing the arginine-glycine-aspartate motif) binds to integrins such as αvβ3, expressed on the cell membrane of myofibroblasts [154]. Caution must be exerted however given these integrins are also expressed by endothelial cells, particularly during neo-angiogenesis [155], decreasing their specificity for cardiac fibrosis assessment.
Recently, fibroblast activation protein (FAP) has gained significant traction in nuclear imaging, with expanding applications in oncologic diseases. 68Ga-fibroblast activation protein inhibitor (FAPI) positron emission tomography (PET) was initially developed to detect FAP-expressing, cancer-associated fibroblasts. Retrospective studies have indicated potential applicability in cardiac diseases, with myocardial FAPI signals correlating with underlying metabolic disease [156], coronary artery disease, and LVEF [157] in patients with cancer. Interestingly, a small prospective study observed an association between right ventricular 68Ga-FAPI signals and the severity of right ventricular dysfunction and pulmonary hypertension, suggesting detection of right ventricular fibrosis [158]. Furthermore, 68Ga-FAPI predicts the degradation of ventricular dysfunction following acute myocardial infarction, and may provide a novel biomarker of left ventricular remodeling [159]. In this setting, experimental and clinical studies evaluating 68Ga-FAPI PET in oncologic therapies implicated in the development of cardiac fibrosis warrant evaluation.
Limitations
The scientific literature retraced here is heterogeneous in nature, with limited studies conducted using pertinent genetically modified models. Thus, definitive results are currently lacking in this field. This review may provide a framework for further evaluation of the molecular mechanisms culminating in fibroblast activation and cardiac fibrosis in the context of established and emerging oncologic therapies. As such, additional work is needed in fibroblast-specific gene editing models to determine whether well-established pro-fibrotic signaling pathways, e.g. the mitogen-activated protein kinase p38α [160] or the TGF-β downstream mediator SMAD-3 [161] can protect from oncologic treatment mediated cardiac fibrosis and dysfunction.
Conclusions and Future Directions
Improved long-term cancer survival has led to an increase in the incidence of adverse cardiac side-effects of cancer treatments [25,26]. The exponential growth of cancer therapies warrants (i) monitoring of adverse cardiovascular side-effects such as cardiac fibrosis, (ii) developing pertinent experimental strategies to dissect underlying pathobiological mechanisms leading to cardiac fibrosis, and (iii) exploring novel therapeutic strategies targeting cardiac fibrosis [162].
Once established, the direct targeting of cardiac fibrosis has proven difficult in the clinical setting [163–165]. Beyond previously explored antifibrotic therapeutics, a promising new development involves targeting of the epigenetic machinery, particularly inhibition of histone acetyltransferases (HATs) and histone deacetylases (HDACs) [162]. This breakthrough advance centered on chromatin-level modification permits gene expression changes – independent of gene editing – downstream of cellular activation pathways and upstream of transcriptional changes leading to ECM protein production and deposition. HAT p300 is targeted by curcumin [166,167], leading to decreased cardiac fibrosis, however with the caveat of a lack of curcumin target specificity [162]. Recently, a novel compound A-485 was identified with high p300 specificity [168], setting the stage for its evaluation in cardiac fibrosis models. Furthermore, HDAC inhibition with compound ITF2357/givinostat mitigates cardiac fibrosis in experimental models [169,170].
Another shift in therapeutic strategy involves engineered CD8+ T-cells [171,172]. By directing T-cell specificity using a chimeric antigen receptor (CAR-T cells) towards cardiac fibroblasts expressing FAP – a cell surface glycoprotein minimally expressed in normal heart tissue but significantly induced in activated fibroblasts – immunotherapy may successfully target pathological cardiac fibrosis [171]. These results bear great promise given CAR-T cells are already approved by the FDA in patients with leukemia or lymphoma [173], thus setting the stage for clinical trial evaluation in patients with cardiac fibrosis. Given the dynamic nature of FAP expression by fibroblasts, i.e. during ‘active’ ECM deposition, patient selection will be critical to increase the likelihood of trial success [174]. Specifically, patients undergoing active cancer therapy, particularly those with limited therapeutic options in whom the chemotherapeutic and/or radiotherapeutic strategies necessitate continuation despite the development of off-target cardiac fibrosis, as opposed to patients with fully established excess cardiac ECM deposition where cardiac fibroblasts have returned to a more quiescent state, may stand to benefit the most from a CAR-T cell strategy. This will almost certainly require an imaging-based patient selection process, either by cardiac MRI or FAPI PET imaging, for the early and accurate identification of cardiac fibrosis prior to randomization to CAR-T cell immunotherapy.
Acknowledgements
The author thanks Jeremy Jong for assistance with the figure which was created with BioRender.com.
Funding
Supported by VA Merit BX004558, UCLA Cardiovascular Discovery Fund/Lauren B. Leichtman and Arthur E. Levine Investigator Award, and NIH NCATS UCLA CTSI UL1TR00188.
Footnotes
Disclosures
None.
References and recommended reading
• of special interest
• • of outstanding interest
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