Heart Failure with Targeted Cancer Therapies: Mechanisms and Cardioprotection

Abstract

Over the past two decades, oncology has seen growing use of newly developed targeted therapies, with less emphasis on traditional chemotherapy based regimens. Although this has resulted in dramatic improvements in progression free and overall survival, challenges in the management of toxicities related to longer term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and non-cancer cells, overlap in fundamental signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities of targeted therapies are of important concern. In this review, we highlight a number of targeted therapies commonly used across a variety of cancer types, including HER2+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK/BRAF inhibitors. We present the oncologic indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity and potential mechanistic rationale for specific cardioprotective strategies (Table 1). Regarding our overview of the mechanisms of cardiotoxicity, we focused primarily on studies that evaluated the specific cardiotoxicity of these therapies, rather than the basic science evidence to support effects of a particular signaling pathway on the cardiovascular system.

Introduction

Over the past two decades, oncology has seen growing use of targeted therapies, with lesser emphasis on traditional chemotherapy-based regimens. Although this has resulted in improvements in progression-free and overall survival, challenges in the management of toxicities related to longer term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and non-cancer cells, overlap in fundamental signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities, and specifically heart failure (HF) with targeted therapies are of important concern. In this review, we highlight a number of targeted therapies commonly used across a variety of cancer types, including HER2+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK/BRAF inhibitors. We present the oncologic indications, HF incidence, hypothesized mechanisms of cardiotoxicity and potential mechanistic rationale for specific cardioprotective strategies (Table 1). Regarding our overview of the mechanisms of cardiotoxicity, we focused primarily on studies that evaluated the specific cardiotoxicity of these therapies, rather than the basic science evidence to support effects of a particular signaling pathway on the cardiovascular system.

Table 1:

Cardiotoxicity of Targeted Therapies and Proposed Mechanistic Basis

Targeted Therapy	Signaling Pathways Hypothesized to be Central to Cardiotoxicity Mechanisms	Cardiovascular Toxicities Directly or Indirectly Related to Heart Failure	Potential Cardioprotective Strategies
HER2+ Targeted Therapies	NRG-1 HER2/ERBB2 HER4/ERRB4 PI3K/Akt MEK/ERK AMPK mTOR	LVEF declines Heart failure	Beta-blockers (BB) RAAS inhibitors Metformin Bivalent NRG-1
VEGF Signaling Pathway Inhibitors	Raf/MEK/ERK VEGFR PDGFR c-kit fms-like tyrosine kinase 3 AMPK PI3K/Akt	Hypertension Heart failure	Afterload reduction Beta-blockers (BB) Dihydropyridine Calcium channel blockers ACE-I Endothelin receptor antagonists Mitochondrial ROS scavengers
Immunotherapy	CTLA-4 PD-1 PD-L1 T cell and macrophage infiltration of myocardium	Myocarditis Heart Failure Arrhythmias Heart block Accelerated atherosclerosis Cardiac arrest	Steroids Statins CTLA-4 agonists
Proteasome inhibitors	Ubiquitin/proteasome system	Heart Failure LVEF declines Cardiac arrest Arrhythmia	Neurohormonal therapy Possible effects with metformin
Androgen Deprivation Therapy	Androgen receptors Effects on FSH levels Mineralocorticoid excess Cardiometabolic effects	Ischemic heart disease Hypertension Metabolic syndrome Heart failure	Anti-hypertensive therapy Statins Metformin Anti-platelet therapy Aldosterone antagonists
MEK/BRAF Inhibitor	MEK/ERK	LVEF declines Heart failure Hypertension	Beta-blockers (BB) RAAS inhibitors

HER2- human epidermal growth factor receptor 2; NRG-1- Neuregulin-1; PI3K- phosphoinositide 3-kinase; Akt- Ak transforming factor; MEK- Ras/Raf/mitogen-activated-protein kinase kinase; ERK- extracellular signal-regulated kinase; AMPK- adenosine monophosphate-activated protein kinase; mTOR- mammalian target of rapamycin; LVEF- left ventricular ejection fraction; BB- beta-blockers; RAAS- renin-angiotensin-aldosterone system; VEGF- vascular endothelial growth factor; RAF- Raf-1; VEGFR- vascular endothelial growth factor receptor; PDGFR- platelet derived growth factor receptor; ACE-I- Angiotensin converting enzyme inhibitors; ROS- reactive oxygen species; CTLA-4- cytotoxic T lymphocyte associated antigen 4; PD-1- programmed death 1; PD-L1- programmed death 1 ligand; FSH- follicle-stimulating hormone; BRAF v-raf murine sarcoma viral oncogene homolog B1

Anthracyclines

Anthracyclines are amongst the most well established classes of cancer therapies to cause HF. The incidence of HF and asymptomatic left ventricular ejection fraction [LVEF] declines is approximately ~10 to 15% with systematic screening.^{1, 2} Mechanisms of cardiotoxicity include direct cardiomyocyte cytotoxicity via topoisomerase II-mediated DNA damage, generation of reactive oxygen species, and impaired mitochondrial function. ^{3, 4}. Potential strategies for cardioprotection include concurrent treatment with dexrazoxane, ⁵ liposomal doxorubicin, or slow infusion. ⁶ Small studies with neurohormonal therapy, including angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), aldosterone antagonists, and beta blockers have shown benefit in reducing declines in LVEF.^{7, 8} Expert consensus recommend prophylactic use of ACEi/ARB and/or beta blockers in patients with normal LVEF and established cardiovascular risk factors who will receive known cardiotoxic agents. ⁹ Once patients develop a LVEF decline, guideline directed medical therapy for HF is indicated.

HER2+ Targeted Therapies

Oncologic Indications

Amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) drives tumorigenesis through downstream oncogenic signaling and promotion of cellular proliferation, survival, and angiogenesis.¹⁰ HER2 is an established target in breast and gastric/gastroesophageal cancers, and is an emerging target in other tumor types. Approximately 1 in 5 patients with breast cancer have HER2-overexpressing tumors; HER2-directed therapies have led to dramatic improvements in oncologic outcomes.¹¹

Multiple classes of HER2-targeted therapies are currently in clinical use. The monoclonal antibodies trastuzumab and pertuzumab are approved for both localized and advanced breast cancer. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1), which consists of a HER2 monoclonal antibody connected to a cytotoxic antimicrotubule agent, and small molecule tyrosine kinase inhibitors lapatinib, tucatinib, and neratinib, are most commonly used in later-line settings for HER2+ metastatic breast cancer. Trastuzumab deruxtecan is another HER2 monoclonal antibody connected to a cytotoxic topoisomerase I inhibitor that is used in metastatic breast cancer.

Heart Failure Events

Cardiotoxicity with targeted anti-HER2 therapy was recognized in the seminal trials of trastuzumab in breast cancer, with a marked increase risk of HF and LVEF declines with concurrent administration of trastuzumab and anthracyclines. The incidence of LVEF declines has been reported to be 19% in patients with sequential anthracycline therapy.¹² A meta-analysis of nearly 12,000 patients enrolled in 10 randomized clinical trials of trastuzumab noted the incidence of asymptomatic LVEF declines was 7.5% and symptomatic HF 1.9%;¹³ and others have shown that LVEF declines do place patients at an increased risk of subsequent HF.¹⁴ Generally speaking, with careful clinical management, there is a high likelihood of recovery from cardiotoxicity related to trastuzumab alone. The HF risk with trastuzumab deruxtecan appears to be low but measurable;¹⁵ clinical experience with this drug is still evolving.

Mechanisms of Cardiotoxicity

HER2 is a transmembrane tyrosine kinase receptor that belongs to the epidermal growth factor receptor (EGFR) family. Homo or hetero-dimerization leads to downstream signaling that promotes cell growth, proliferation, survival, and angiogenesis (Figure 1). These effects are largely mediated via augmented phosphoinositide 3-kinase (PI3K)/Ak transforming factor (Akt) and Ras/Raf/mitogen-activated-protein kinase kinase (MEK)/extracellular signal-regulated kinases (ERK) signaling (Figure 1). Trastuzumab and pertuzumab bind to the extracellular domain of HER2 and disrupt downstream HER2 signaling via reduced dimerization, antibody-dependent cytotoxicity, and downregulation of the HER2 receptor.¹⁶ Neuregulin-1 (NRG-1) is a HER2 ligand secreted by the endothelium that activates pro-survival and growth signaling in cardiomyocytes.¹⁷

Figure 1:

Human Epidermal Growth Factor Receptor Targeted Therapies: Mechanisms of Cardiotoxicity and Potential Cardioprotective Mechanisms. Left side: Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase that dimerizes with other members of the epidermal growth factor receptor family to activate downstream signaling that promotes cell survival and proliferation. Ligands of HER2 include epidermal growth factor (EGF) and neuregulin-1 (NRG-1). Trastuzumab and pertuzumab inhibit HER2 signaling, leading to downstream downregulation of PI3K/AKT, mTOR, and Ras/RAF/MEK/ERK signaling. In the cardiovascular system this leads to reduced growth and survival of cardiomyocytes, altered metabolism, reduced angiogenesis, altered calcium handling, reduced autophagy, and mitochondrial dysfunction. Right side: Potential cardioprotective mechanisms include beta-blockers that transactivate β-arrestin, promoting PI3K/Akt signaling in the cardiomyocyte. Additional cardioprotective mechanisms include ACE inhibitors/ARBs that reduce angiotensin-II mediated downregulation of NRG-1, and bivalent NRG-1. HER2- human epidermal growth factor receptor 2; EGF- epidermal growth factor; NRG-1- Neuregulin-1; PI3K- phosphoinositide 3-kinase; Akt- Ak transforming factor; mTOR- mammalian target of rapamycin; RAS- Ras GTPase; RAF- Raf-1; MEK- Ras/Raf/mitogen-activated-protein kinase kinase; ERK- extracellular signal-regulated kinase; ACEi- angiotensin converting enzyme inhibitor; ARB- angiotensin II receptor blocker (Illustration credit: Ben Smith).

The cardioprotective role of NRG-1/HER2 signaling has been studied extensively in animal models and induced pluripotent stem-cell derived cardiomyocytes (iPSC-CM). HER2 and HER4 levels are stable early after pressure overload in vivo, but later decrease by 40–50% as decompensated cardiomyopathy develops. ¹⁸ Mice with cardiomyocyte-specific HER2 knockdown developed dilated cardiomyopathy and isolated cardiomyocytes were more susceptible to anthracyclines.¹⁹ Recent studies using human iPSC-CMs have demonstrated altered metabolism as a potential mechanism of trastuzumab cardiotoxicity ²⁰. iPSC-CMs treated with trastuzumab or lapatinib, a small molecule inhibitor of HER1/HER2, downregulated genes involved in small molecule metabolism, and had reduced glucose uptake. iPSC-CMs treated with trastuzumab and iPSC-CMs from patients treated with trastuzumab showed impaired contractile and calcium handling after trastuzumab treatment, but no change in sarcomere organization or cell viability as seen in anthracycline cardiotoxicity.²¹ Functional assays in trastuzumab treated iPSC-CMs demonstrated reduced autophagy, glucose uptake, and mitochondrial function as measured by Seahorse assay. RNAseq identified differentially expressed genes that were enriched in mitochondrial oxidative phosphorylation and cardiac dysfunction/enlargement pathways, including key metabolism genes.²¹ Treatment with the mTOR inhibitor rapamycin did not ameliorate trastuzumab-induced contractile dysfunction, while multiple pharmacologic agents that augment adenosine monophosphate-activated protein kinase (AMPK) activity (e.g. metformin) improved contraction velocity and metabolism. Other studies have supported the role of reduced autophagy²² and mitochondrial dysfunction²³ in trastuzumab-mediated cardiotoxicity. These findings highlight potential mechanisms that can be targeted to prevent and treat trastuzumab cardiotoxicity.

Rationale for Cardioprotective Therapies

Angiotensin converting enzyme inhibitors (ACE-I) and beta-blockers (BB) are the most well-studied agents in trastuzumab cardiotoxicity, and there is mechanistic rationale for their use. The sympathetic nervous and renin-angiotensin-aldosterone systems (RAAS), specifically angiotensin II, downregulate NRG-1 expression in vitro.¹⁷ Reduction in angiotensin II levels with RAAS inhibition may promote cardiomyocyte survival pathways in patients receiving HER2 inhibitor therapy. Certain BB (carvedilol, nebivolol, alprenolol) block the beta-1 adrenergic receptor and transactivate β-arrestin.²⁴ β-arrestin, an intracellular protein that transactivates epidermal growth factor receptors (EGFR) such as HER2 in cardiomyocytes, promotes activation of ERK1/2 and AKT kinase and signals through HER1/EGFR.²⁵ β-arrestin-mediated EGFR transactivation has been associated with reduced cardiomyocyte apoptosis under in vivo conditions of cardiac stress. Carvedilol increases recruitment of β-arrestin to cardiac β-adrenergic receptors in vitro thereby stimulating β-arrestin-mediated cellular signaling and cardioprotective pathways. Beta-1 receptors are predominantly found in the heart, kidney, and adipose tissue, representing an opportunity to exploit tissue-specific differences. Interestingly, BB usage has been associated with improved disease specific survival in a meta-analysis including 46,000 breast cancer patients.²⁶ To date, clinical studies of RAAS inhibitors and BB for prevention of HER2 inhibitor-related cardiac dysfunction have shown mixed results, though clinical practice guidelines support their use in high risk patients.^27–30 There are also data to support the continuation of HER2+ therapy with neurohormonal therapy in the setting of modest LVEF declines. ³¹

Novel cardioprotective agents deserve further study. As noted above, multiple pharmacologic agents that augment adenosine monophosphate-activated protein kinase (AMPK) activity have resulted in improved contractile function and metabolism in vitro. Moreover, recombinant NRG-1 merits further investigation as a novel therapeutic for HER2 inhibitor-related cardiac dysfunction. Recombinant NRG-1 has been tested as treatment for systolic HF, and improves cardiac function in animal models of HF.³² Small, early phase clinical trials of recombinant NRG-1 in patients with chronic systolic HF have shown improvement in LV ejection fraction and LV volumes over short-term follow-up.³⁴ Dedicated clinical studies are needed in patients with HER2-inhibitor cardiac dysfunction, with careful attention to cancer outcomes.

EGFR Signaling Pathway Tyrosine Kinase Inhibitors

Oncologic Indications

Since the introduction of imatinib for the molecularly-targeted treatment of chronic myelogenous leukemia nearly two decades ago, use of receptor tyrosine kinase inhibitors (TKIs) has rapidly expanded.³⁵ Small molecule TKIs share potent and efficient competitive inhibition of catalytic binding sites of tyrosine kinase enzymes.³⁶ However, TKI therapies target a wide variety of oncogenic receptor tyrosine kinases, including the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), c-kit, bcr-abl, and fms like tyrosine kinase 3 (FLT3), among others.

TKIs targeting the EGFR include gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. They are generally used to treat lung cancers that have EGFR mutations. Osimertinib is a third generation EGFR TKI that irreversibly targets the EGFR. This therapy prolongs progression-free survival in patients with EGFR mutation-positive advanced lung cancer.^{37, 38}

Heart Failure Events

In the initial clinical trials for efficacy, 3–5% percent of patients treated with osimertinib had a significant LVEF decline.^{37, 38} Review of the Federal Drug Administration Adverse Events Reporting System demonstrated a reporting odds ratio of 2.2 (1.5–3.2) for cardiac failure with osimertinib versus first- and second-generation EGFR TKIs.³⁹ Another study noted LVEF declines in 3% and HF in 2%, ⁴⁰ while case reports have noted HF with reduced ejection fraction.^{41, 42}

Mechanisms of Cardiotoxicity and Rationale for Cardioprotective Therapies

The mechanisms of EGFR TKI cardiotoxicity are hypothesized to be shared with that of HER2-targeted therapies, as they affect the same pro-survival signaling pathways. However, more data are needed regarding the unique mechanisms of osimertinib cardiotoxicity and efficacy of cardioprotective therapies. Currently, there is dearth of data specific to appropriate screening and cardioprotective strategies.

VEGF Signaling Pathway Tyrosine Kinase Inhibitors

Oncologic Indications

TKIs targeting the VEGFR, including sunitinib, pazopanib, axitinib, and cabozantinib, remain a fundamental therapy for many patients with clear cell renal cell carcinoma (ccRCC). The vast majority of ccRCC tumors harbor inactivating mutations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia inducible factor (HIF) and inappropriate upregulation of hypoxia-responsive angiogenic genes, including VEGF. Moreover, owing to their multi-kinase inhibitory properties, such TKIs are also commonly utilized for the treatment of thyroid cancers, hepatocellular carcinoma, and pancreatic neuroendocrine tumors.^{43, 44} In addition to these biomarker agnostic settings, TKI therapies have similarly improved clinical outcomes for molecularly-defined advanced malignancies, including Philadelphia chromosome-positive leukemias, EGFR mutation-positive non small-cell lung cancer, and FLT3-mutated acute myeloid leukemia.^{45, 46}

Heart Failure Events

The most common CV side effect of VEGF signaling pathway inhibitors (VSPI) is hypertension, with an estimated incidence of 20–25% with sunitinib or sorafenib.^{47, 48} In a prospective study of vascular function during sunitinib treatment, sunitinib led to increased large artery stiffness, resistive load, and pulsatile load.⁴⁹ Baseline resistive load was associated with diastolic function and elevation of estimated filling pressures over time. Asymptomatic LVEF declines and clinical HF due to left ventricular (LV) dysfunction are prevalent, with an estimated incidence of symptomatic HF and LVEF declines in 2–15%.⁵⁰ A meta-analysis of ~10,000 patients treated with VEGF signaling pathway inhibitors (VSPI) noted an incidence of all grade HF of 2.4% in those who received TKIs, and 0.75% in those who did not.⁵¹ This study included trials of sorafenib, sunitinib, vandetanib, axitinib, and pazopanib. A recent clinical trial of 1900 patients with non-metastatic renal cell carcinoma treated with sunitinib, sorafenib, or placebo in the adjuvant setting noted asymptomatic LV dysfunction was relatively rare with an incidence of 1.9% with sunitinib, 1.4% with sorafenib, and 0.9% with placebo.⁵² Most of the patients (76%) recovered their LVEF. The lower incidence of LV dysfunction in this study may be secondary to differences in patient population, as most studies of VSPI have been performed in patients with metastatic disease.

Mechanisms of Cardiotoxicity

LV dysfunction observed with VSPI is hypothesized to be due to a combination of increased LV pressure overload, combined with the reduction of cardioprotective signaling mechanisms. The most well-studied VSPI in the context of HF are sorafenib and sunitinib. Sorafenib was originally developed as an inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway, but was found to also inhibit the VEGF receptor, the platelet derived growth factor (PDGF) receptor, c-Kit, and fms-like tyrosine kinase-3 (Figure 2).⁵³ Sunitinib inhibits at least 50 kinases in vitro, including the VEGF receptor, PDGF receptor, c-Kit, colony-stimulating factor 1, RET, and fms-like tyrosine kinase-3.⁵⁴

Figure 2:

Vascular Endothelial Growth Factor Signaling Pathway Inhibitors: Mechanisms of Cardiotoxicity and Potential Cardioprotective Mechanisms. Sunitinib and sorafenib are the most commonly used targeted VEGF pathway signaling inhibitors. They both target multiple tyrosine kinase receptors including the VEGFR, PDGFR, cKit, FLT3, and sunitinib targets RET. Inhibition of these receptors leads to downregulation of pro-survival signaling and angiogenesis, with additional effects on nitric oxide (NO) and calcineurin/NFAT. This leads to hypertension, cardiomyocyte apoptosis, contractile dysfunction, mitochondrial dysfunction, and oxidative stress. Potential cardioprotective mechanisms include dihydropyridine calcium channel blockers, ACE inhibitors, endothelin receptor antagonists, and scavengers of mitochondrial ROS. VEGFR- vascular endothelial growth factor receptor receptor; PDGFR- platelet derived growth factor receptor; FLT3- fms like tyrosine kinase 3; PLCgamma- phospholipase C gamma; NFAT- nuclear factor of activated T cells; PI3K- phosphoinositide 3-kinase; Akt- Ak transforming factor; eNOS- endothelial nitric oxide synthase; NO- nitric oxide; RAS- Ras GTPase; RAF- Raf-1; MEK- Ras/Raf/mitogen-activated-protein kinase kinase; ERK- extracellular signal-regulated kinase; ACEi- angiotensin converting enzyme inhibitor. (Illustration credit: Ben Smith).

Inhibition of the VEGF signaling pathway in animal models of pressure overload contributes to capillary rarefaction, reduced contractile function, and development of HF. Upregulation of VEGF in a large animal model of tachycardia-induced cardiomyopathy led to reduced apoptosis, reduced oxidative stress, prevention of capillary rarefaction, and delayed HF progression. ⁵⁵ Animals treated with sunitinib developed hypertension and reduced LVEF, and demonstrated proteomic signatures that suggested impaired oxidative metabolism, reduced fatty acid beta-oxidation, and increased reliance on glycolysis.⁵⁶ These metabolic changes occurred early in the treatment course and improved over time. Histologic analysis demonstrated lipid accumulation in the cardiomyocytes, while mitochondrial structure was preserved. Early in the treatment course, myocardial perfusion defined by myocardial positron emission tomography (PET) imaging was reduced, but improved over time. In other studies, human iPSC-CMs treated with sunitinib exhibited increased apoptosis, decreased contractile force generation, and mitochondrial dysfunction.⁵⁷ Apoptosis was increased in the setting of increased afterload. Reduced AMPK activity has been postulated as an off-target effect of sunitinib leading to cardiotoxicity, though treatment with an AMPK activator did not improve mitochondrial function. Others have demonstrated worsened mitochondrial function, increased mitochondrial reactive oxygen species, and cardiomyocyte apoptosis with sunitinib, which improved after treatment with a mitochondrial ROS scavenger. ⁵⁸

PDGF can be cardioprotective, especially in the setting of CV stress. Expression of PDGF increases after pressure overload and genetic deletion of PDGF leads to worsened left ventricular remodeling, HF, apoptosis, and reduction in cardioprotective Akt and ERK signaling.⁵⁹ ERK is the downstream target of MEK, and plays an important role in proliferation, survival, and cardiac hypertrophy (both pathologic and physiologic). Neurohormonal activation upregulates MEK/ERK signaling, most likely as a protective stress response.⁶⁰

Rationale for Cardioprotective Therapies

Treatment with afterload reducing agents is the mainstay of therapy for VSPI related hypertension and prevention and management of VSPI related cardiac dysfunction. There are limited data regarding the most effective agents for management of VSPI-induced hypertension. Based on the data noting increased cardiomyocyte apoptosis with sunitinib, beta-blockers that transactivate β-arrestin and augment pro-survival MEK/ERK signaling might have mechanistic rationale. Efforts to target oxidative stress in HF have thus far been unsuccessful, but two strategies to target mitochondrial derived ROS (mitoTEMPO and thioredoxin-2 signaling) have shown promise in animal models of HF.^{61, 62}

In vivo and clinical studies suggest that dihydropyridine calcium channel blockers (CCB), such as amlodipine or felodipine, and ACE-I may be preferred. Sunitinib therapy led to increased arterial stiffness, worse resistive load, and abnormal arterial compliance suggesting that an arterial vasodilators may be beneficial.⁴⁹ In mice treated with sunitinib, amlodipine mitigated VSPI induced hypertension while sildenafil did not.⁶³ Nondihydropyridine CCBs are not recommended for treatment of VSPI related hypertension due to a CYP3A4 drug interaction. A separate in vivo study found that increases in afterload, concentric LV remodeling, and plasma angiotensin II levels on VSPI were all prevented by treatment with ramipril.⁶⁴ Retrospective clinical studies suggest dihydropyridine CCBs and ACE-I are effective for treatment of VEGF-inhibitor related hypertension,^65–68 though prospective studies are needed. While the endothelin receptor antagonists macitentan and tezosentan have prevented VSPI related hypertension in vivo, these agents have not been studied in patients.⁶⁹

Immunotherapy

Oncologic Indications

Immunotherapy including immune checkpoint inhibitors (ICIs) activate the immune system to recognize cancer cells, and have revolutionized the management of many cancers. Many tumors express immune checkpoint molecules including cytotoxic T lymphocyte associated antigen 4 (CTLA-4), programmed death 1 (PD-1) and its ligand (PD-L1) in order to evade anti-tumor immunosurveillance and immune-mediated cytotoxicity. ICIs are monoclonal antibodies against these molecules that disrupt this inhibitory signaling and “unleash the brakes” on anti-tumor immunity ⁷⁰. These agents have been incorporated into standard first-line therapy for advanced melanoma, head and neck squamous cell carcinoma, lung cancer, and renal cell carcinoma.^{71, 72} For other solid malignancies, ICIs are approved for use in later line or restricted to patients with biomarkers that predict for efficacy of immunotherapy, such as PD-L1 expression, mismatch repair deficiency, or mutations in DNA repair pathway genes.

Chimeric antigen receptor T cell therapies (CAR-T), another type of immune cancer-directed therapy, have shown remarkable success in treating highly refractory hematologic malignancies. In this process, autologous T cells are collected from a patient and genetically modified via a viral vector and transduction of a chimeric receptor antibody (CAR) that recognizes a tumor-specific antigen such as CD19. After ex-vivo expansion, this genetically modified CAR-T cell population is infused back to the patient. Currently, two CD19-specific CAR-T cell therapies (axicabtagene ciloleucel/Yescarta, Gilead Sciences; tisangenleclucel/Kymriah, Novartis) have been approved for use in relapsed/refractory lymphomas,^{73, 74} and others are in development. CAR-T therapy is generally administered in a monitored setting due to high risk for serious toxicities including neurotoxicity and cytokine release syndrome, which can require intensive care.

Heart Failure Events

CV toxicity from ICIs include myocarditis, pericarditis and pericardial effusion, HF, arrhythmias, heart block, accelerated atherosclerosis and cardiac arrest. Studies of the incidence of CV toxicities are heterogeneous due to differences in cardiotoxicity monitoring. A recent meta-analysis reported a cumulative incidence of cardiotoxicity as 7%, including an atrial fibrillation incidence of 4.6%.⁷⁵ Other studies have reported a myocarditis incidence as ~1%. ⁷⁶ Though myocarditis is rare, it accounted for 25% of deaths due to combination ICI therapy in a recent meta-analysis. ⁷⁷

CV toxicities with CAR-T still remain to be fully elucidated, but arrhythmias, systolic dysfunction, and hypotension have been reported.⁷⁸ In a retrospective review of 145 patients with B cell malignancies, 31 patients developed adverse CV events, including 21 who developed HF, and 11 atrial fibrillation. ⁷⁹ The development of CV events typically was associated with severe cytokine release syndrome (CRS).

Mechanisms of Cardiotoxicity

ICIs work by driving an anti-tumor CD4+ and CD8+ T cell response, by antagonizing the inhibitory function of CTLA-4 and PD-1 (Figure 3). Several mechanisms work in concert to ensure immune tolerance. Central tolerance is the process by which T cells that recognize self undergo apoptosis in the thymus. Peripheral tolerance is mediated by apoptosis of autoreactive T cells, and regulation of the co-stimulatory signals required to activate T cells in the periphery. Both CTLA-4 and PD-1 inhibit co-stimulatory signals necessary for activation of T cells.

Figure 3:

Immune Checkpoint Inhibitors: Mechanisms of Cardiotoxicity and Potential Treatments. Inhibitors of CTLA-4 and PD-1/PD-L1 are designed to activate anti-tumor T lymphocytes to harness the immune system to attack cancer cells. This leads to several autoimmune off-target effects including cardiotoxicity affecting the myocardium, pericardium, and conduction system. Immune checkpoint inhibitors can cause myocarditis, heart failure, cardiogenic shock, heart block, arrhythmias, pericarditis, pericardial effusion, cardiac arrest, and accelerated atherosclerosis. Potential treatment options include high dose steroids, abatacept (a CTLA-4 agonist), and anti-thymocyte globulin, while statins may be cardioprotective via pleiotropic effects. CTLA-4- cytotoxic T lymphocyte associated antigen 4; PD-1- programmed death 1; PD-L1- programmed death 1 ligand; TCR- T cell receptor; MHC- major histocompatibility complex. (Illustration credit: Ben Smith)

The impact of ICIs on the heart and other organs in animal models has been known for decades. Mice lacking CTLA-4 develop profound T cell and macrophage infiltration of multiple organs, leading to severe myocarditis and increased mortality.⁸⁰ While CTLA-4 deficient mice develop a fatal lymphoproliferative disorder with systemic organ involvement, mice with PD-1 deficiency exhibit more targeted autoimmunity, particularly in the heart. Mice with genetic knockdown of PD-1 or PD-L1 spontaneously develop dilated cardiomyopathy and expressed autoantibodies to cardiac troponin I.⁸¹ Mice had increased mortality and exhibited myocarditis with dense infiltration of macrophages and T cells.⁸²

Early case reports of fulminant ICI myocarditis noted significant infiltration of the myocardium with T lymphocytes (both CD4+ and CD8+) and macrophages, affecting the conduction system as well.⁸³ Skeletal muscle, but not smooth muscle, were also affected. Transcriptomics demonstrated expression of muscle-specific transcripts in the tumors, suggesting that there may be shared epitopes between the tumor and striated muscle.

Rationale for Cardioprotective Therapies

Optimal strategies to prevent ICI-induced cardiac dysfunction and CV adverse events are currently unknown, although it is hypothesized that vasculoprotective therapies may be beneficial. The PD-1/PD-L1 pathway downregulates proatherogenic T cell responses within atherosclerotic plaque, and PD-1 deficiency is associated with increased aortic atherosclerotic burden and lesional T cell infiltration in murine models.⁸⁴ Similarly, CTLA-4 overexpression is associated with reduced atherosclerotic lesion formation and reduced lesional accumulation of macrophages and T-cells.⁸⁵ Studies of ICI on atherosclerosis in animal models have suggested that combination ICI therapy results in T-cell mediated plaque progression. ⁸⁶ A retrospective study reported an increased risk of atherosclerotic CV events on ICI therapy, and statins or corticosteroids reduced plaque volume.⁸⁷ Statins reduce production of pro-inflammatory cytokines and increase regulatory T cells in atherosclerotic plaques,⁸⁸ while dexamethasone reduces aortic atherosclerotic plaque burden and lesional T-cell burden.⁸⁹ Prospective studies are needed to determine the clinical and translational relevance of these findings. Treatment of ICI-induced myocarditis consists of potent anti-inflammatory therapy, as detailed in recent reviews.⁷⁰

CAR-T cell therapy has been associated with adverse CV events including symptomatic HF in observational studies, particularly in patients who suffer CRS after CAR-T cell infusion.^79,91 Treatment of severe CRS can include tocilizumab, an anti-IL6 monoclonal antibody, approved for treatment of CRS.⁹² Early treatment of CRS with tocilizumab and/or corticosteroids has been shown to improve outcomes and mitigate the toxicity profile without compromising anti-cancer efficacy. Additionally, delay in tocilizumab administration from CRS onset is associated with increased risk of adverse CV events.⁹¹

Proteasome Inhibitors

Oncologic Indications

The proteasome, a multicatalytic protein complex, is involved in the degradation of a majority of intracellular proteins. Through the highly regulated ubiquitin/proteasome system (UPS) pathway, targeted proteins are tagged with ubiquitin, recognized by the proteasome complex, unfolded, and cleaved into peptide products. Many oncogenic proteins involved in tumorigenesis and cancer progression, including p53, cyclins, and cyclin-dependent kinases, are degraded by the proteasome complex.⁹³ Proteasome inhibitors (PIs), which target the catalytic subunits of the proteasome, are believed to significantly affect protein turnover, which proves toxic to malignant cells. While the anti-cancer effects of PIs remain unclear, this may occur through the faulty degradation of tumor suppressors, impairment of cell division and resultant cell death, and the accumulation of misfolded proteins which incite the unfolded protein response and cellular apoptosis.⁹³ Over the last two decades, multiple PIs, including bortezomib, carfilzomib, and ixazomib, have been approved for the treatment of hematologic malignancies, including multiple myeloma and mantle cell lymphoma.^94–96

Heart Failure Events

The incidence of cardiotoxicity with bortezomib is 2.6–5.6% for all-grade cardiotoxicity, based on a recent meta-analysis of 25 clinical trials and 5718 patients.⁹⁷ Cardiotoxicity included LVEF declines, LV dysfunction, HF, cardiomyopathy, cardiac arrest, and arrhythmia. The majority of the events were HF related. A recent meta-analysis of 29 clinical trials of 4164 patients noted an incidence of carfilzomib cardiotoxicity, defined as acute coronary syndromes, acute HF or cardiomyopathy, arrhythmia, and cardiac arrest, of 6.1–11.6%, with an odds ratio of 2 for any cardiotoxicity. ⁹⁸ The investigators separately reported the incidence of hypertension as 7.7–16.0% based on an analysis of 1905 patients. The incidence of HF alone secondary to carfilzomib is 4–7%^100,101, although a more precise understanding of the predominant HF subtype (i.e., reduced or preserved LVEF) is needed.^102,103 The risk with carfilzomib versus bortezomib appears to be greater, potentially due to carfilzomib’s irreversible inhibition. Ixazomib is an oral, reversible PI and is not known to increase the risk of HF; however, clinical experience is more limited.

Mechanisms of Cardiotoxicity

Bortezomib is a reversible inhibitor of the 26S proteasome, specifically targeting the proteolytic β-type subunits of the core particle, ¹⁰⁴ while carfilzomib is an irreversible inhibitor of the same complex (Figure 4). The UPS plays an important role in protein homeostasis, degrading misfolded or damaged proteins. Patients with end-stage HF and hypertrophic cardiomyopathy have reduced proteasome activity in the myocardium, particularly patients with a sarcomere mutation. ¹⁰⁵ Unloading of the LV with a ventricular assist device improved proteasome activity. ¹⁰⁶ PIs may lead to endothelial dysfunction that underlies the vascular and blood pressure effects. ¹⁰⁷ Cardiomyocytes are particularly susceptible to proteotoxicity due to their high protein turnover of the contractile proteins in the sarcomere. In vitro studies demonstrate direct cardiomyocyte toxicity after treatment with carfilzomib or bortezomib, leading to cardiomyocyte apoptosis. ¹⁰⁸ In vivo studies of mice treated with carfilzomib have shown a reduction in proteasome activity in the heart and peripheral blood cells, along with a reduction in left ventricular function. Carfilzomib significantly increased PP2A phosphatase activity and reduced activation or expression of adenosine monophosphate kinase (AMPK), Raptor, LC3-II, PI3K, Akt, and eNOS. Other studies of genetically modified proteasome activity have demonstrated similar contractile dysfunction, particularly in the setting of other stressors. ^{109, 110} Many patients treated with proteasome inhibitors have pre-existing CV comorbidities, likely increasing susceptibility to cardiotoxic effects of PIs.

Figure 4:

Proteasome Inhibitors: Mechanisms of Cardiotoxicity and Potential Treatments. Carfilzomib and bortezomib inhibit the catalytically active beta-subunits of the 26S proteasome, impairing its ability to break down and recycle misfolded proteins. This leads to the accumulation of misfolded proteins and cellular proteotoxicity. This leads to abnormal protein homeostasis, accumulation of misfolded proteins, endothelial dysfunction, abnormal vasomotor tone, cardiomyocyte apoptosis, and contractile dysfunction. Clinical manifestations of proteasome inhibitor cardiotoxicity include hypertension, heart failure with preserved or reduced ejection fraction, left ventricular ejection fraction decline, arrhythmias, and cardiac arrest. Activators of protein kinase G (PKG) may counter these effects by activating the proteasome. Other potentially cardioprotective therapies include beta-blockers, ACE inhibitors, ARBs, apremilast, and metformin. PKG-protein kinase G; ARNI- angiotensin receptor-neprilysin inhibitor; sGC-soluble guanylate cyclase; ACEi- angiotensin converting enzyme inhibitor; ARB- angiotensin II receptor blocker; PDE4-phosphodiesterase 4; LVEF, left ventricular ejection fraction

Rationale for Cardioprotective Therapies

Multiple myeloma and light chain amyloidosis are among the most common indications for PIs, and patients with these conditions are at increased risk for HF in part due to light chain deposition within the myocardium. BB and RAAS inhibitors are currently the standard of care for patients with proteasome inhibitor-related cardiac dysfunction but these therapies are typically not well tolerated by patients with light chain amyloidosis. There are no data to support their use for primary prevention of LVEF declines. Carfilzomib, an irreversible inhibitor of the proteasome, is associated with increased vascular tone and impaired vasodilation,¹¹¹ and strict blood pressure control is warranted though the optimal antihypertensive agent is not known. In mouse models, metformin prevented carfilzomib-induced cardiac dysfunction and improved vascular function by restoring AMPKα phosphorylation and autophagic signaling in cardiomyocytes and smooth muscle cells.^112,113 However, the effect of metformin in humans receiving carfilzomib has not been studied. The bioflavinoid rutin and phosphodiesterase-4 inhibitor apremilast were found in vivo to mitigate carfilzomib-induced increases in expression of caspase-3, which participates in apoptosis signaling, suggesting possible utility for cardioprotection.^{114, 115}

Protein kinase G is a cardioprotective kinase with pleotropic effects on the CV system, including enhancement of proteasome activity via phosphorylation and activation of key components of the proteasome.^116,117 This signaling pathway is manipulated by multiple HF therapies, including vericiguat and neprilysin inhibitors, both of which have demonstrated a beneficial effect in the reduction of CV events in the general HF population, however these have never been tested in proteasome inhibitor cardiotoxicity.

Androgen Deprivation Therapy and Androgen Receptor Signaling Inhibitors

Oncologic Indications

Systemic androgen deprivation, most commonly through the use of gonadotropin-releasing hormone (GnRH) agonists or antagonists, has remained the mainstay therapy for men with advanced prostate cancer and those receiving curative-intent radiation therapy. Testosterone, and its potent metabolite dihydrotestosterone, bind to prostate cancer intracellular androgen receptors, upregulating expression of oncogenic target genes.¹¹⁹ Given this androgen-dependence, lifelong androgen deprivation therapy (ADT) remains standard practice for most men with advanced prostate cancer.

GnRH agonists, also called luteinizing hormone-releasing or LHRH agonists, are the most commonly used form of androgen deprivation therapy (Figure 5). More recently, an improved understanding of androgen-dependent ADT resistance mechanisms has led to the development of secondary androgen-receptor signaling inhibitors (ARSIs), including androgen biosynthesis inhibitors, which blunt production of extragonadal androgens, and potent androgen receptor antagonists. Abiraterone reduces the production of androgens by inhibiting CYP17A, which is expressed in adrenal and prostate tumor cells and required for androgen biosynthesis. By inhibiting CYP17A1 enzymes, abiraterone results in a compensatory increase in ACTH and potential treatment-induced symptoms of mineralocorticoid excess (hypertension, hypokalemia, fluid retention). In contemporary prostate cancer clinical management, ARSI therapies, including abiraterone, enzalutamide, apalutamide, and darolutamide, are often utilized earlier in the disease course and for prolonged durations to further attenuate androgen signaling and to enhance oncologic outcomes.^120–122

Figure 5:

Androgen Deprivation Therapy and Androgen Receptor Signaling Inhibitors. GnRH agonist and GnRH agonists lead to increased risk of cardiometabolic traits of diabetes, hypertension, hyperlipidemia, and ultimately atherosclerotic cardio- and cerebrovascular disease. Abiraterone inhibits the CYP17A enzyme that leads to conversion of pregnenolone to 17-hydroxyl-pregnenalone, and then to dehydroepiandrosterone (DHEA), ultimately leading to reduced estrogen and testosterone levels. This also leads to accumulation of pregnenolone, which is ultimately converted to aldosterone, contributing to the mineralocorticoid excess seen with abiraterone. Direct androgen receptor antagonists such as enzalutamide, do not have this mineralocorticoid excess, but can still lead to hypertension. Androgen receptor signaling inhibitors also increase the risk of atherosclerotic cardio- and cerebrovascular events. GnRH-gonadotropin-releasing hormone; FSH- follicle-stimulating hormone; LH- luteinizing hormone; Gen- generation

Heart Failure Events

With GnRH agonists and ARSI therapies, there is risk of the development of HF, ischemic heart disease and the worsening of CV risk factors.¹²³ GnRH agonists demonstrated increased risk of atherosclerotic CV events, HF, and sudden cardiac death.¹²⁴ Several meta-analyses have found an increased risk of cardiac events (1.3–1.4 fold increase, incidence ~14%) with abiraterone but not with enzalutamide, while both increase the risk of hypertension significantly (2 fold increase, overall incidence ~20%).^{125, 126} Cardiac events were defined in these studies as ischemic heart disease, myocardial infarction, tachyarrhythmia, and HF. ^127–130 A large retrospective observational analysis including >45,000 patients treated with androgen deprivation therapy noted an incidence of HF of 1–2% with enzalutamide and abiraterone. ¹³¹

In a large randomized phase 3 trial, the oral GnRH antagonist relugolix demonstrated a lower incidence of major adverse cardiovascular events (defined as non-fatal MI, non-fatal stroke, and all-cause mortality) compared to the GnRH agonist leuprolide (2.9% vs 6.2%).¹³² This difference was most pronounced in patients with underlying cardiovascular disease (3.6% vs 17.8%). The cardiovascular safety of these therapies is being studied in advanced prostate cancer populations. ¹³³

Mechanisms of Cardiotoxicity

Androgen deprivation, through the use of GnRH agonists or antagonists, is associated with several detrimental cardiometabolic effects. Androgen receptor signaling in myocytes is important for maintenance of muscle mass,¹³⁸ and normal levels of androgens are generally considered protective against atherosclerosis. ¹³⁹ The mechanisms of atheroprotection in men with normal endogenous levels of testosterone are unclear and complex given its multi-organ, pleiotropic effects. Recent prospective evidence has indicated potential differences in CV risk between GnRH agonist and GnRH antagonist therapies. ¹⁴⁰ While the explanatory mechanisms for this CV risk difference are unclear, hypotheses include differential effects on FSH levels post-treatment, atherosclerotic plaque instability, and the presence of GnRH receptors on cardiomyocytes and infiltrating leukocytes. Reduced estrogen synthesis with abiraterone may also play a role, as estrogen has beneficial effects on the cardiovascular system.

Animal models have demonstrated increased blood pressure with androgen supplementation.¹³⁷ Enzalutamide is an androgen receptor antagonist, while abiraterone selectively inhibits the CYP17 enzyme (17α-hydroxylase and C_17,20-lyase), leading to reduced estrogen and testosterone synthesis, reduced cortisol synthesis, increased adrenocorticotropic hormone (ACTH) levels, and secondary mineralocorticoid excess. Abiraterone is co-administered with prednisone in order to limit this positive feedback loop and attenuate mineralocorticoid side effects; the difference in mechanisms of action may explain why abiraterone is associated with increased risk of cardiovascular events compared to enzalutamide, though further study is warranted.

Rationale for Cardioprotective Therapies

Aggressive treatment of CV risk factors, including hypertension, is believed to be important to prevent HF in patients treated with androgen deprivation therapy. Specific therapies have not been tested. Mechanistically, mineralocorticoid receptor antagonists would appear to be appropriate for prevention of abiraterone-induced hypertension. Prospective studies suggest that eplerenone alone may be insufficient to prevent hypertension associated with mineralocorticoid excess syndrome in patients receiving abiraterone acetate,¹⁴⁶ and combination antihypertensive therapy may be necessary. Given the association between ADT and arterial vascular events, especially in men with more comorbidities,¹⁴⁷ standard primary and secondary prevention approaches to prevent atherosclerotic events are indicated, including statin therapy.¹⁴⁸ Aspirin, metformin, and BB therapy have all been associated with reduced mortality in observational studies of men with prostate cancer, though it is unclear if the risk reduction is related to mitigating adverse effects of androgen deprivation therapy or prostate cancer signaling pathways.^148–151

MEK/BRAF Inhibitors

Oncologic indication

Mutations in BRAF, a key gene in the mitogen-activated protein kinase (MAPK) pathway involved in cellular growth and proliferation, occur in ~50% of patients with melanoma, 2–8% of patients with non-small cell lung cancer, and ~25% of patients with anaplastic thyroid cancer¹⁵². The most common activating BRAF mutations occur at position V600 and lead to constitutive activation of BRAF. BRAF inhibitors including vemurafenib, dabrafenib, and encorafenib are ATP-competitive drugs that selectively bind to the kinase domain of mutant BRAF, rendering it incapable of binding to ATP and phosphorylating MEK, its downstream target¹⁵³. Alterations in MEK can lead to bypass MAPK pathway activation and resistance to BRAF inhibitor therapy. Thus, dual inhibition of BRAF and MEK maximizes MAPK pathway inhibition and helps to prevent treatment resistance, leading to improved survival outcomes¹⁵⁴. MEK inhibitors including trametinib, cobimetinib, and binimetinib are non-ATP competitive drugs that bind to a unique pocket adjacent to the ATP binding site, triggering conformational changes to lock MEK in an inactive state¹⁵⁵.

Currently, three BRAK/MEK inhibitor combinations (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) are approved for metastatic or unresectable BRAF V600-mutated melanoma; dabrafenib/trametinib is also approved for advanced non-small cell lung cancers and anaplastic thyroid cancers harboring BRAF V600E mutation¹⁵⁶.

Heart Failure Events

CV events in patients treated with BRAF/MEK inhibitors on clinical trials included decreased LVEF and arterial hypertension^{157, 158}. A meta-analysis including over 2300 patients found dual BRAF and MEK inhibitors were associated with a 4-fold increased risk of pulmonary embolism, 4-fold increased risk of a significant decline in LVEF, and 1.5-fold increased risk of arterial hypertension compared to BRAF inhibitor monotherapy¹⁵⁹. In total, 8% of patients treated with dual therapy had LVEF decline, and 20% had hypertension. Another meta-analysis focused on MEK inhibitors (with or without BRAF inhibitors) noted similar relative risk of hypertension and decline in ejection fraction compared to the control arms. ¹⁶⁰

Mechanisms of Cardiotoxicity

MAPK pathways are highly conserved across many cell types, and play a fundamental role in cancer and the CV system. There are four main MAPK subfamilies relevant to the heart- extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNK 1, 2, and 3), p38 kinase, and big MAP kinase (BMK or ERK5). In response to growth factors and other stimuli binding to receptor tyrosine kinases, a cascade of kinases phosphorylate downstream targets leading to MEK1/2 activation.¹⁶¹ ERK1/2 is the main downstream target of MEK and plays an important role in proliferation, survival, and cell cycle progression through phosphorylation of several targets. In the CV system, ERK1/2 is an important mediator of the hypertrophic response, and plays a role in pathologic and physiologic hypertrophy.¹⁶² It also confers cardioprotection after ischemia-reperfusion injury. ¹⁶³ Neurohormonal activation via Gαq agonism leads to downstream activation of MEK/ERK signaling. ⁶⁰ In response to mechanical unloading after LVAD, ¹⁶⁴ there is decreased ERK activity, and increased endogenous ERK inhibitor. ¹⁶⁵ In summary, MEK/ERK signaling is stimulated by CV stress and is cardioprotective.

Rationale for Cardioprotective Therapies

Neurohormonal blockade with RAAS inhibitors and BB reduce maladaptive hypertrophy signaling and have mechanistic rationale in MEK inhibitor cardiotoxicity, though have never been studied in this patient population. Carvedilol has potential benefit as it triggers a conformational change that favors inhibitory GαI signaling, leading to β-arrestin activation and promotion of pro-survival MEK/ERK and Akt signaling. ²⁴ Other RAAS inhibitors have mechanistic rationale via downregulation of maladaptive Gαq signaling. Another agonist of pro-survival signaling is apelin. Apelin is an adipokine that is upregulated in the plasma of patients with HF. ¹⁶⁶ Apelin binds to the apelin receptor and stimulates β-arrestin but also stimulates contractility and systemic vasodilation. ¹⁶⁷ The increased contractility and vasodilation are potentially mediated by nitric oxide and antagonism of RAAS. ¹⁶⁸ Apelin also exerts some of its beneficial effects through upregulation of ERK signaling.¹⁶⁹ The apelin receptor is predominantly found in the heart; however, apelin signaling has also been implicated in cancers so its cardioprotective benefits would need to be weighed with potential reduced anti-cancer efficacy of MEK inhibitors. ¹⁷⁰

Conclusions and Future Directions

The field of oncology continues to evolve with the development of newer targeted therapies. Critical to the continued successes of these therapies is the mitigation of treatment-related adverse events, including cardiovascular toxicities. As such, there is first an important need to advance our understanding of the basic mechanisms of toxicities. This understanding is necessary to inform and improve the design of oncologic therapeutics to increase specificity and minimize multi-organ toxicities. Many of the anti-cancer mechanisms that dampen growth, survival, and angiogenesis are cardiotoxic. Moreover, this knowledge can be translated to the development of mechanistic biomarkers to aid in cardiotoxicity risk prediction and prognosis. Second, there is an important need to advance our understanding and the development of targeted cardioprotective strategies. The hypothesized mechanisms of cardiotoxicity can be used to best inform the rationale for cardioprotective therapies, and these mechanisms must not augment oncogenic signaling cascades. Targeted cardioprotection includes the use of personalized approaches, including those involving clinical risk scores, genomics, and biomarkers to identify high cardiovascular risk individuals who may benefit the most from cardioprotection. ¹⁷¹ Biomarkers have played a longstanding role in prediction and prognosis both in cancer and cardiovascular medicine, and there is rationale for their use in cardio-oncology as well. Third, the application of existent and newer HF therapies, including SGLT2 inhibitors and neprilysin inhibitors, and discovery of therapies relevant to cardio-oncology to prevent and treat cancer related HF need to be clarified. There is a growing body of basic science data that support a protective cardiometabolic effect of SGLT2 inhibitors and beneficial effects of sacubitril/valsartan¹⁷² as it relates to traditional chemotherapeutics, and clinical trials investigating the use of neprilysin inhibitors (NCT03760588) with conventional chemotherapies. Their application to targeted therapies, and the application of the additional strategies in metabolic modulation and attenuating inflammation are promising avenues for additional research. However, for any of these to be realized, there is an imperative need for continued multi-disciplinary and multi-center collaboration and adequately powered clinical trials targeting the at-risk population.

Abbreviations

HER2

human epidermal growth factor receptor 2

MEK

Ras/Raf/mitogen-activated-protein kinase kinase

BRAF

v-raf murine sarcoma viral oncogene homolog B1

LVEF

left ventricular ejection fraction

HF

heart failure

EGFR

epidermal growth factor receptor

PI3K

phosphoinositide 3-kinase

Akt

Ak transforming factor

ERK

extracellular signal-regulated kinase

NRG-1

Neuregulin-1

iPSC-CMs

induced pluripotent stem cell cardiomyocytes

mTOR

mammalian target of rapamycin

AMPK

adenosine monophosphate-activated protein kinase

ACE-I

Angiotensin converting enzyme inhibitors

BB

beta-blockers

RAAS

renin-angiotensin-aldosterone system

LV

left ventricle

TKIs

tyrosine kinase inhibitors

VEGFR

vascular endothelial growth factor receptor

PDGFR

platelet derived growth factor receptor

FLT3

fms like tyrosine kinase 3

ccRCC

clear cell renal cell carcinoma

VHL

von Hippel-Lindau

HIF

hypoxia inducible factor

VSPI

VEGF signaling pathway inhibitors

RAF

Raf-1

PET

positron emission tomography

CV

cardiovascular

ROS

reactive oxygen species

CCB

calcium channel blocker

ICI

immune checkpoint inhibitors

CTLA-4

cytotoxic T lymphocyte associated antigen 4

PD-1

programmed death 1

PD-L1

programmed death 1 ligand

CAR-T

Chimeric antigen receptor T cell

CRS

cytokine release syndrome

UPS

ubiquitin/proteasome system

eNOS

endothelial nitric oxide synthase

GDMT

guideline directed medical therapy

PI

proteasome inhibitor

GnRH

gonadotropin-releasing hormone

LHRH

luteinizing hormone-releasing hormone

ADT

androgen deprivation therapy

ARSI

androgen-receptor signaling inhibitor

ACTH

adrenocorticotropic hormone

MI

myocardial infarction

FSH

follicle-stimulating hormone

MAPK

mitogen-activated protein kinase

ATP

adenosine triphosphate

SGLT2

sodium-glucose cotransporter-2