Bidirectional Relationship Between Cancer and Heart Failure: Old and New Issues in Cardio-oncology

The main focus of cardio-oncology has been the prevention and treatment of the cardiac toxicity of chemotherapy and radiotherapy. Furthermore, several targeted therapies have been associated with unexpected cardiotoxic side-effects. Recently, epidemiological studies reported a higher incidence of cancer in patients with heart failure (HF) compared with individuals without HF. On this basis, it has been proposed that HF might represent an oncogenic condition. This hypothesis is supported by preclinical studies demonstrating that hyperactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which is a hallmark of HF, promotes cancer growth and dissemination. Another intriguing possibility is that the co-occurrence of HF and cancer is promoted by a common pathological milieu characterised by a state of chronic low-grade inflammation, which predisposes to both diseases. In this review, we provide an overview of the mechanisms underlying the bidirectional relationship between HF and cancer

Background Evidence and Research Perspectives

Recent epidemiological analyses suggest that incident cancer may be more common among patients with preexisting heart failure (HF) than in patients without HF. Arguments against this notion have been the increased chance of co-occurrence of 2 high-prevalence conditions and increased tumor detection in patients with HF because of intensified medical observation. However, biological data lend support to the hypothesis that HF is an oncogenic condition. Neurohormonal activation has been related to cancer initiation, progression, and dissemination by studies not specifically focusing on HF, which are now reappraised in the light of the emerging evidence that tumors are diagnosed more often in HF than control cohorts. Furthermore, a thought-provoking scenario to be considered is that a systemically perturbed milieu, where low-grade inflammation plays a primary role, leads to both HF and malignancy, thus connecting 1 disease to another. Postischemic HF has been shown to promote tumor growth in an animal model. Exploring these and other pathways potentially linking HF to malignancy is a new and exciting field of research, with the ultimate goal of answering the question of whether HF does promote cancer

Triggering Endogenous Cardiac Repair and Regeneration via Extracellular Vesicle-Mediated Communication

A variety of paracrine signals create networks within the myocardium and mediate intercellular communications. Indeed, paracrine stimulation of the endogenous regenerative program of the heart, mainly based on resident cardiac progenitor cell (CPC) activation together with cardiomyocyte proliferation, has become increasingly relevant for future cardiac medicine. In the last years, it has been shown that extracellular vesicles (EV), including exosomes (Ex), are powerful conveyors of relevant biological effects. EV have been proposed not only as promising therapeutic tool for triggering cardiac regeneration and improving repair, but also as means of better understanding the physiological and pathological relationships between specific cardiac components, including cardiomyocytes and fibroblasts. Actually, EV from different kinds of exogenous stem cells have been shown to mediate beneficial effects on the injured myocardium. Moreover, endogenous cells, like CPC can instruct cardiovascular cell types, including cardiomyocytes, while cardiac stromal cells, especially fibroblasts, secrete EV that modulate relevant aspects of cardiomyocyte biology, such as hypertrophy and electrophysiological properties. Finally, cardiomyocytes too may release EV influencing the function of other cardiac cell types. Therefore, EV-based crosstalk is thought to be important in both physiology and pathology, being involved in the responses of the heart to noxious stimuli. In this review we will discuss the role of EV in both regulating cardiac homeostasis and driving heart regeneration. In particular, we will address their role in: (i) providing cardio-protection and enhancing cardiac repair mechanisms; (ii) CPC biology; and (iii) influencing adult cardiomyocyte behavior

Distinguishing ventricular septal bulge versus hypertrophic cardiomyopathy in the elderly

The burgeoning evidence of patients diagnosed with sigmoidal hypertrophic cardiomyopathy (HCM) later in life has revived the quest for distinctive features that may help discriminate it from more benign forms of isolated septal hypertrophy often labelled ventricular septal bulge (VSB). HCM is diagnosed less frequently than VSB at older ages, with a reversed female predominance. Most patients diagnosed with HCM at older ages suffer from hypertension, similar to those with VSB. A positive family history of HCM and/or sudden cardiac death and the presence of exertional symptoms usually support HCM, though they are less likely in older patients with HCM, and poorly investigated in individuals with VSB. A more severe hypertrophy and the presence of left ventricular outflow obstruction are considered diagnostic of HCM, though stress echocardiography has not been consistently used in VSB. Mitral annulus calcification is very prevalent in both conditions, whereas a restrictive filling pattern is found in a minority of older patients with HCM. Genetic testing has low applicability in this differential diagnosis at the current time, given that a causative mutation is found in less than 10% of elderly patients with suspected HCM. Emerging imaging modalities that allow non-invasive detection of myocardial fibrosis and disarray may help, but have not been fully investigated. Nonetheless, there remains a considerable morphological overlap between the two conditions. Comprehensive studies, particularly imaging based, are warranted to offer a more evidence-based approach to elderly patients with focal septal thickening

Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway

Indoxyl sulfate (IS) accumulation occurs early during chronic kidney disease (CKD) progression and contributes to renal dysfunction by inducing fibrosis, inflammation, oxidative stress, and tissue remodeling. Renal toxicity of high IS concentrations (250\u2009\u3bcM) has been widely explored, particularly in resident tubular and glomerular cells, while the effect of a moderate IS increase on kidneys is still mostly unknown. To define the effects of IS accumulation on renal fibroblasts, we first analyzed kidneys of C57BL/6 mice receiving IS (0.1%) in drinking water for 12 weeks. As a next step, we treated renal fibroblasts (NRK-49F) with IS (20\u2009\u3bcM) with or without the HSP90 inhibitor 17-AAG (1\u2009\u3bcM). In mouse kidneys, IS increased the collagen deposition and HSP90 and \u3b1-SMA expression (immunohistochemistry) in interstitial fibroblasts and caused tubular necrosis (histological H&E and picrosirius red staining). In NRK-49F cells, IS induced MCP1, TGF-\u3b2, collagen I, \u3b1-SMA, and HSP90 gene/protein expression and Smad2/3 pathway activation. IS had no effects on fibroblast proliferation and ROS production. 17-AAG counteracted IS-induced MCP1, TGF-\u3b2, collagen I, and \u3b1-SMA expression and Smad2/3 phosphorylation. Our study demonstrates that the IS increase promotes renal fibroblast activation by a HSP90-dependent pathway and indicates HSP90 inhibition as a potential strategy to restrain IS-induced kidney inflammation and fibrosis in CKD

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

BACKGROUND: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (KATP). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac KATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells. METHODS: The cardiomyoblast cell line H9c2 was treated for 24 h with glibenclamide or metformin, a known inhibitor of the mitochondrial respiratory chain. Cell viability was evaluated by sulforodhamine B assay. ATP and AMP were measured according to the enzyme coupling method and oxygen consumption by using an amperometric electrode, while Fo-F1 ATP synthase activity assay was evaluated by chemiluminescent method. Protein expression was measured by western blot. RESULTS: Glibenclamide deregulated energy balance of H9c2 cardiomyoblasts in a way similar to that of metformin. It inhibited mitochondrial complexes I, II and III with ensuing impairment of oxygen consumption and ATP synthase activity, ATP depletion and increased AMPK phosphorylation. Furthermore, glibenclamide disrupted mitochondrial subcellular organization. The perturbation of mitochondrial energy balance was associated with enhanced anaerobic glycolysis, with increased activity of phosphofructo kinase, pyruvate kinase and lactic dehydrogenase. Interestingly, some additive effects of glibenclamide and metformin were observed. CONCLUSIONS: Glibenclamide deeply alters cell metabolism in cardiac cells by impairing mitochondrial organization and function. This may further explain the risk of cardiovascular events associated with the use of this drug, alone or in combination with metformin

Advanced Oxidation Protein Products-Modified Albumin Induces Differentiation of RAW264.7 Macrophages into Dendritic-Like Cells Which Is Modulated by Cell Surface Thiols.

Local accumulation of Advanced Oxidation Protein Products (AOPP) induces pro-inflammatory and pro-fibrotic processes in kidneys and is an independent predictor of renal fibrosis and of rapid decline of eGFR in patients with chronic kidney disease (CKD). In addition to kidney damage, circulating AOPP may be regarded as mediators of systemic oxidative stress and, in this capacity, they might play a role in the progression of atherosclerotic damage of arterial walls. Atherosclerosis is a chronic inflammatory disease that involves activation of innate and adaptive immunity. Dendritic cells (DCs) are key cells in this process, due to their role in antigen presentation, inflammation resolution and T cell activation. AOPP consist in oxidative modifications of proteins (such as albumin and fibrinogen) that mainly occur through myeloperoxidase (MPO)-derived hypochlorite (HOCl). HOCl modified proteins have been found in atherosclerotic lesions. The oxidizing environment and the shifts in cellular redox equilibrium trigger inflammation, activate immune cells and induce immune responses. Thus, surface thiol groups contribute to the regulation of immune functions. The aims of this work are: (1) to evaluate whether AOPP-proteins induce activation and differentiation of mature macrophages into dendritic cells in vitro; and (2) to define the role of cell surface thiol groups and of free radicals in this process. AOPP-proteins were prepared by in vitro incubation of human serum albumin (HSA) with HOCl. Mouse macrophage-like RAW264.7 were treated with various concentrations of AOPP-HSA with or without the antioxidant N-acetyl cysteine (NAC). Following 48 h of HSA-AOPP treatment, RAW264.7 morphological changes were evaluated by microscopic observation, while markers of dendritic lineage and activation (CD40, CD86, and MHC class II) and allogeneic T cell proliferation were evaluated by flow cytometry. Cell surface thiols were measured by AlexaFluor-maleimide binding, and ROS production was assessed as DCF fluorescence by flow cytometry. HSA-AOPP induced the differentiation of RAW264.7 cells into a dendritic-like phenotype, as shown by morphological changes, by increased CD40, CD86 and MHC class II surface expression and by induction of T cell proliferation. The cell surface thiols dose dependently decreased following HSA-AOPP treatment, while ROS production increased. NAC pre-treatment enhanced the amount of cell surface thiols and prevented their reduction due to treatment with AOPP. Both ROS production and RAW264.7 differentiation into DC-like cells induced by HSA-AOPP were reduced by NAC. Our results highlight that oxidized plasma proteins modulate specific immune responses of macrophages through a process involving changes in the thiol redox equilibrium. We suggest that this mechanism may play a role in determining the rapid progression of the atherosclerotic process observed in CKD patients

Clinical characteristics and prognostic impact of atrial fibrillation in patients with chronic heart failure

AIMS: To assess the prevalence, clinical characteristics and independent prognostic impact of atrial fibrillation (AF) in chronic heart failure (CHF) patients, and the potential protective effect of disease-modifying medications, particularly beta-blockers (BB). METHODS: We retrospectively reviewed the charts of patients referred to our center since January 2004, and collected all clinical information available at their first visit. We assessed mortality to the end of June 2015. We compared patients with and without AF, and assessed the association between AF and all-cause mortality by multivariate Cox regression and Kaplan-Meyer analysis, particularly accounting for ongoing treatment with BB. RESULTS: A total of 903 patients were evaluated (mean age 68\ub112 years, 73% male). Prevalence of AF was 19%, ranging from 10% to 28% in patients 6460 and 6577 years, respectively. Besides the older age, patients with AF had more symptoms (NYHA II-III 60 vs. 44%), lower prevalence of dyslipidemia (23 vs. 37%), coronary artery disease (28 vs. 52%) and left bundle branch block (9 vs. 16%). On the contrary, they more frequently presented with an idiopathic etiology (50 vs. 24%), a history of valve surgery (13 vs. 4%) and received overall more devices implantation (31% vs. 21%). The use of disease-modifying medications (i.e. BB and ACE inhibitors/angiotensin receptor blockers) was lower in patients with AF (72 vs. 80% e 71 vs. 79%, respectively), who on the contrary were more frequently treated with symptomatic and antiarrhythmic drugs including diuretics (87 vs. 69%) and digoxin (51 vs. 11%). At a mean follow-up of about 5 years, all-cause mortality was significantly higher in patients with AF as compared to those in sinus rhythm (45% vs. 34%, p value <0.05 for all previous comparisons). However, in a multivariate analysis including the main significant predictors of all-cause mortality, the univariate relationship between AF and death (HR 1.49, 95% CI 1.15-1.92) became not statistically significant (HR 0.98, 95% CI 0.73-1.32). Nonetheless, patients with AF not receiving BB treatment were found to have the worst prognosis, followed by patients with sinus rhythm not receiving BB therapy and patients with AF receiving BB therapy, who both had similarly worse survival when compared to patients with sinus rhythm receiving BB therapy. CONCLUSIONS: AF was highly prevalent and associated with older age, worse clinical presentation and underutilization of disease-modifying medications such as BB in a population of elderly patients with CHF. AF had no independent impact on mortality, but the underutilization of BB in this group of patients was associated to a worse long-term prognosis

Exploring the influence of takotsubo syndrome on oncologic patients' mortality

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients

Right ventricular failure in left heart disease: from pathophysiology to clinical manifestations and prognosis

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis