Cardiovascular Toxicity of Immune Checkpoint Inhibitors: Clinical Risk Factors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors, such as monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1, have improved the outcome of many malignancies, but serious immune-related cardiovascular adverse events have been observed. Patients' risk factors for these toxicities are currently being investigated. RECENT FINDINGS: Interfering with the CTLA-4 and PD-1 axes can bring to several immune-related adverse events, including cardiotoxic events such as autoimmune myocarditis, pericarditis, and vasculitis, suggesting that these molecules play an important role in preventing autoimmunity. Risk factors (such as pre-existing cardiovascular conditions, previous and concomitant cardiotoxic treatments, underlying autoimmune diseases, tumor-related factors, simultaneous immune-related toxic effects, and genetic factors) should be always recognized for the correct management of these toxicities.

New-Onset Cancer in the HF Population: Epidemiology, Pathophysiology, and Clinical Management.

PURPOSE OF REVIEW: Oncological treatments are known to induce cardiac toxicity, but the impact of new-onset cancer in patients with pre-existing HF remains unknown. This review focuses on the epidemiology, pathophysiological mechanisms, and clinical implications of HF patients who develop malignancies. RECENT FINDINGS: Novel findings suggest that HF and cancer, beside common risk factors, are deeply linked by shared pathophysiological mechanisms. In particular, HF itself may enhance carcinogenesis by producing pro-inflammatory cytokines, and it has been suggested that neurohormonal activation, commonly associated with the failing heart, might play a pivotal role in promoting neoplastic transformation. The risk of malignancies seems to be higher in HF patients compared to the general population, probably due to shared risk factors and common pathophysiological pathways. Additionally, management of these patients represents a challenge for clinicians, considering that the co-existence of these diseases significantly worsens patients' prognosis and negatively affects therapeutic options for both diseases.

Mechanisms underlying the cross-talk between heart and cancer.

Cardiovascular diseases and cancer remain the leading cause of death worldwide. Despite the fact that these two conditions have long been considered as distinct clinical entities, recent epidemiological and experimental studies suggest that they should be contemplated and treated as co-morbidities. Heart failure represents nowadays a well-established complication of cancer, primarily as a consequence of the aggressive use of cardiotoxic anti-cancer treatments. On the other hand, the provocative idea that heart failure can prime carcinogenesis has started to emerge, though the molecular basis is still to be fully elucidated. This review summarizes the current knowledge on the mechanisms underlying the bidirectional communication between the failing heart and the cancer. We will discuss and/or speculate on the role of molecular mediators released by either the tumour or the heart that can potentially link heart failure and cancer.

Cancer Risk in the Heart Failure Population: Epidemiology, Mechanisms, and Clinical Implications.

PURPOSE OF REVIEW: Along with population aging, the incidence of both heart failure (HF) and cancer is increasing. However, little is known about new-onset cancer in HF patients. This review aims at showing recent discoveries concerning this subset of patients. RECENT FINDINGS: Not only cancer and HF share similar risk factors but also HF itself can stimulate cancer development. Some cytokines produced by the failing heart induce mild inflammation promoting carcinogenesis, as it has been recently suggested by an experimental model of HF in mice. The incidence of new-onset cancer is higher in HF patients compared to the general population, and it significantly worsens their prognosis. Moreover, the management of HF patients developing new-onset cancer is challenging, especially due to the limited therapeutic options for patients affected by both cancer and HF and the higher risk of cardiotoxicity from anticancer drugs.

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.

Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth.

BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.

Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs.

Heart failure (HF) is a complication of oncological treatments that may have dramatic clinical impact. It may acutely worsen a patient's condition or it may present with delayed onset, even years after treatment, when cancer has been cured or is in stable remission. Several studies have addressed the mechanisms of cancer therapy-related HF and some have led to the definition of disease models that hold valid for other and more common types of HF. Here, we review these models of HF based on the cardiotoxicity of antineoplastic drugs and classify them in cardiomyocyte-intrinsic, paracrine, or potentially secondary to effects on cardiac progenitor cells. The first group includes HF resulting from the combination of oxidative stress, mitochondrial dysfunction, and activation of the DNA damage response, which is typically caused by anthracyclines, and HF resulting from deranged myocardial energetics, such as that triggered by anthracyclines and sunitinib. Blockade of the neuregulin-1/ErbB4/ErbB2, vascular endothelial growth factor/vascular endothelial growth factor receptor and platelet-derived growth factor /platelet-derived growth factor receptor pathways by trastuzumab, sorafenib and sunitinib is proposed as paradigm of cancer therapy-related HF associated with alterations of myocardial paracrine pathways. Finally, anthracyclines and trastuzumab are also presented as examples of antitumor agents that induce HF by affecting the cardiac progenitor cell population.

Arterial wave reflections and ventricular-vascular interaction in patients with left ventricular systolic dysfunction.

Central aortic pressure waveform (AoPW) is the summation of a forward-traveling wave generated by the left ventricle and a backward-traveling wave caused by the reflection of the forward wave. The aim of this study was to evaluate the effect of ventricular-vascular coupling on the morphology of AoPW in chronic heart failure patients with different degrees of left ventricular systolic dysfunction (LVSD) using pulse wave analysis (PWA). PWA of AoPW and left ventricular (LV) function were evaluated by applanation tonometry in 26 control subjects, in 12 patients with left ventricular ejection fraction (LVEF) ≤ 30%, and in 14 patients with LVEF > 30%. Augmentation pressure, augmentation index, wasted energy, and ejection duration were lower in patients with LVEF ≤ 30% than in those with LVEF > 30% and in control subjects. Furthermore, augmentation index showed an inverse correlation with Doppler mitral E-wave amplitude (r = -0.40; P = 0.04) and E/A ratio (r = -0.42; P = 0.03) and a direct correlation with deceleration time of mitral E-waves (r = 0.39; P = 0.04). In patients with severe LVSD (LVEF ≤ 30%), aortic wave reflections negatively interfere with LV function and induce a shortening of ejection duration. In contrast, AoPW is similar in patients with moderate LVSD (LVEF > 30%) and in control subjects.

A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.

Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as ß2-adrenergic receptor (ß2-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by ß2-ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a ß2-AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.

How can we manage the cardiac toxicity of immune checkpoint inhibitors?

Introduction: Cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints (i.e. CTLA-4 and PD-1/PD-L1) have revolutionized antineoplastic treatments. Immune checkpoint inhibitors (ICIs) approved for cancer immunotherapy are mAbs anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab, and cemiplimab), and anti-PD-L1 (atezolizumab, avelumab, and durvalumab). Treatment with ICIs can be associated with immune-related adverse events (irAEs), including an increased risk of developing myocarditis. These findings are compatible with the observation that, CTLA-4, PD-1, and PD-L1 pathways play a central role in the modulation of autoimmunity.Areas covered: In this paper, we start from examining the pathogenesis of cardiovascular adverse events from ICIs, and then we focus on risk factors and strategies to prevent and manage this cardiotoxicity.Expert opinion: There is a growing need for a multidisciplinary approach of ICI-associated cardiotoxicity, involving oncologists, cardiologists, and immunologists. Prevention and effective management of ICIs cardiotoxicity starts with an in-depth screening and surveillance strategies of high-risk patients, in order to improve early detection and appropriate management in a personalized approach.

Oxidative stress in anticancer therapies-related cardiac dysfunction.

Redox abnormalities are at the crossroad of cardiovascular diseases, cancer and cardiotoxicity from anticancer treatments. Indeed, disturbances of the redox equilibrium are common drivers of these conditions. Not only is an increase in oxidative stress a fundamental mechanism of action of anthracyclines (which have historically been the most studied anticancer treatments) but also this is at the basis of the toxic cardiovascular effects of antineoplastic targeted drugs and radiotherapy. Here we examine the oxidative mechanisms involved in the different cardiotoxicities induced by the main redox-based antineoplastic treatments, and discuss novel approaches for the treatment of such toxicities.

Autophagy and cancer therapy cardiotoxicity: From molecular mechanisms to therapeutic opportunities.

Cardiotoxicity is a major drawback of anticancer therapies, often hindering optimal management of cancer. Among the most cardiotoxic agents are anthracyclines (AC) that, despite being cardiotoxic, are highly effective in the treatment of a wide variety of cancers, spanning from hematological malignancies to solid tumors. Modern imaging techniques can identify patients at risk of developing cardiotoxicity, but treatment options are still limited and ineffective, partly because the molecular mechanisms underlying AC cardiac side effects are still incompletely understood. Although AC cardiotoxicity was initially ascribed to the trigger of cell-damaging oxidative stress, antioxidants fail to prevent anthracycline-induced cardiotoxicity (AIC), suggesting the involvement of additional mechanisms. Among these, the cellular recycling process, named autophagy, recently emerged to play a key role in AIC, but whether autophagy activation is beneficial or detrimental in this context is still controversial. This review will summarize recent evidence on the role of autophagy in AIC in the attempt to reconcile the controversial findings in the field. Finally, we will describe major regulator of cardiac autophagy that may represent good candidates for therapeutic intervention in AIC.

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes.

The development of therapeutic approaches based on direct cardiac reprogramming of fibroblasts into induced-cardiomyocytes (iCM) has emerged as an attractive strategy to repair the injured myocardium. The identification of the mechanisms driving lineage conversion represents a crucial step toward the development of new and more efficient regenerative strategies. To this aim, here we show that pre-treatment with the Bmi1 inhibitor PTC-209 is sufficient to increase the efficiency of Chemical-induced Direct Cardiac Reprogramming both in mouse embryonic fibroblasts and adult cardiac fibroblasts. PTC-209 induces an overall increase of spontaneously beating iCM at end-stage of reprogramming, expressing high levels of late cardiac markers Troponin T and myosin muscle light chain-2v. The inhibition of Bmi1 expression occurring upon PTC-209 pre-treatment was maintained throughout the reprogramming protocol, contributing to a significant gene expression de-regulation. RNA profiling revealed that, upon Bmi1 inhibition a significant down-regulation of genes associated with immune and inflammatory signalling pathways occurred, with repression of different genes involved in interleukin, cytokine and chemokine pathways. Accordingly, we observed the down-regulation of both JAK/STAT3 and MAPK/ERK1-2 pathway activation, highlighting the crucial role of these pathways as a barrier for cardiac reprogramming. These findings have significant implications for the development of new cardiac regenerative therapies.

Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty.

AIMS: The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF). METHODS AND RESULTS: We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow-up visit after 2 years of follow-up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO2 max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m2 , and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow-up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO2 max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E', VE/VCO2 slope, and NT-pro-BNP decreased. At right heart catheterization performed after 1 year of follow-up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow-up (P < 0.001), with a reduction in all PF domains. CONCLUSIONS: Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together with an NT-pro-BNP reduction constant over the follow-up.

PI3K Signaling in Chronic Obstructive Pulmonary Disease: Mechanisms, Targets, and Therapy.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Currently available therapies are not able to block disease progression and to reduce mortality, underlying the need for a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets. Recent studies demonstrated that phosphoinositide 3-kinase (PI3K) signaling is prominently activated in COPD and correlates with an increased susceptibility of patients to lung infections. PI3Ks have thus emerged as promising alternative drug targets for COPD and a wide array of pan-isoform and isoform-selective inhibitors have been tested in preclinical models and are currently being evaluated in clinical studies. Here, we summarize the recent knowledge on the involvement of PI3K enzymes in the pathophysiology of COPD, and we discuss the most recent results arising from the preclinical as well as the clinical testing of PI3K inhibitors as novel therapeutics for COPD.

What Is the Cardiac Impact of Chemotherapy and Subsequent Radiotherapy in Lymphoma Patients?

Anthracyclines are widely used in anticancer protocols, but can induce cardiotoxicity by mechanisms that mainly involve oxidative damage and mitochondrial dysfunction. Radiotherapy (RT) can also impair cardiac function by promoting myocardial fibrosis, microvascular damage, and decreased density of myocardial capillaries. Hence, we aim at investigating prospectively whether RT impacts heart function in lymphoma patients who had been already treated with anthracyclines. Twenty-nine consecutive patients with Hodgkin or non-Hodgkin lymphomas underwent echocardiography at baseline (before antineoplastic treatments), and then every 2 months, until 6 months after treatment completion. Echo evaluation included standard two-dimensional and speckle tracking. Twenty-two patients treated with anthracycline-based regimens were eligible. Out of the 22 patients, 8 received chemotherapy (CT) only (subgroup 1), while 14 underwent RT after CT [subgroup 2 (S2)]. At the end of CT, ejection fraction was significantly reduced in the whole population. At 6 months after completion of therapies, E/E' increased and global longitudinal strain was compromised in S2, suggesting additional damage induced by RT after CT. On the basis of the data from our small prospective study, we can hypothesize that in lymphoma patients, anthracyclines can worsen cardiac function, and RT may have an additional unfavorable myocardial impact.

Depression and chronic heart failure in the elderly: an intriguing relationship.

Chronic heart failure and depressive disorders have a high prevalence and incidence in the elderly. Several studies have shown how depression tends to exacerbate coexisting chronic heart failure and its clinical outcomes and vice versa, especially in the elderly. The negative synergism between chronic heart failure and depression in the elderly may be approached only taking into account the multifaceted pathophysiological characteristics underlying both these conditions, such as behavioural factors, neurohormonal activation, inflammatory mediators, hypercoagulability and vascular damage. Nevertheless, the pathophysiological link between these two conditions is not well established yet. Despite the high prevalence of depression in chronic heart failure elderly patients and its negative prognostic value, it is often unrecognized especially because of shared symptoms. So the screening of mood disorders, using reliable questionnaires, is recommended in elderly patients with chronic heart failure, even if cannot substitute a diagnostic interview by mental health professionals. In this setting, treatment of depression requires a multidisciplinary approach including: psychotherapy, antidepressants, exercise training and electroconvulsive therapy. Pharmacological therapy with selective serotonin reuptake inhibitors, despite conflicting results, improves quality of life but does not guarantee better outcomes. Exercise training is effective in improving quality of life and prognosis but at the same time cardiac rehabilitation services are vastly underutilized.

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective.

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

Nanotechnology-Based Cardiac Targeting and Direct Cardiac Reprogramming: The Betrothed.

Cardiovascular diseases represent the first cause of morbidity in Western countries, and chronic heart failure features a significant health care burden in developed countries. Efforts in the attempt of finding new possible strategies for the treatment of CHF yielded several approaches based on the use of stem cells. The discovery of direct cardiac reprogramming has unveiled a new approach to heart regeneration, allowing, at least in principle, the conversion of one differentiated cell type into another without proceeding through a pluripotent intermediate. First developed for cancer treatment, nanotechnology-based approaches have opened new perspectives in many fields of medical research, including cardiovascular research. Nanotechnology could allow the delivery of molecules with specific biological activity at a sustained and controlled rate in heart tissue, in a cell-specific manner. Potentially, all the mediators and structural molecules involved in the fibrotic process could be selectively targeted by nanocarriers, but to date, only few experiences have been made in cardiac research. This review highlights the most prominent concepts that characterize both the field of cardiac reprogramming and a nanomedicine-based approach to cardiovascular diseases, hypothesizing a possible synergy between these two very promising fields of research in the treatment of heart failure.