Matters of the Heart: The Case of TNFα-Targeting Drugs

  1. Fabio Cacciapaglia1,4,
  2. Pierantonio Menna2,4,
  3. Luca Navarini3,4,
  4. Antonella Afeltra3,4,
  5. Emanuela Salvatorelli2,4 and
  6. Giorgio Minotti2,4
  1. 1 Internal Medicine and Rheumatology, “N. Melli” Hospital, San Pietro Vernotico, Brindisi
  2. 2 Drug Sciences and Clinical Pharmacology, University Campus Bio-Medico of Rome
  3. 3 Clinical Medicine and Rheumatology, University Campus Bio-Medico of Rome
  4. 4 Center for Integrated Research and Alberto Sordi Foundation for Research on Aging, University Campus Bio-Medico of Rome, Italy

Drugs targeted at tumor necrosis factor–alpha (TNFα) have paved new avenues for treating chronic inflammatory diseases such as rheumatoid arthritis and many others. Anti-TNFα drugs have been also considered as therapeutics to treat heart failure or other cardiovascular events that are caused or accompanied by high circulating levels of TNFα. Surprisingly, however, anti-TNFα therapies caused both beneficial and detrimental cardiovascular effects. Here, we suggest that the disappointing cardiovascular outcome of pharmacological interventions with TNFα-targeted drugs could be reconciled with the Janus-like behavior of TNFα, a molecule that conveys both negative and positive stimuli to the heart.

Many drugs developed and approved to treat noncardiovascular diseases are known to cause cardiovascular effects that range from arrhythmias to blood pressure disorders, ischemia, heart failure (HF), thromboembolism, or combinations thereof. Drugs labeled as possibly cardiotoxic belong to such diverse classes as antineoplastics, nonsteroidal anti-inflammatory drugs, antihistamines, psychoactive drugs, antibiotics, and antiretrovirals (1). This viewpoint paper aims at familiarizing the reader with a potential new family of cardiotoxic drugs, the tumor necrosis factor–alpha (TNFα)-targeted drugs.

In comparison to noncardiovascular drugs known or suspected to cause cardiotoxicity, TNFα-targeted drugs provide a case for more complexity and ambiguity. Complexity exists because TNFα-targeted drugs were developed to treat patients with inflammatory diseases known to be promoted or sustained by TNFα. In such patients, however, TNFα-targeting drugs caused no effect on cardiovascular events associated with systemic inflammation, or they caused reduced incidence in some studies or a trend toward increased incidence in other studies. Ambiguity exists because TNFα-targeted drugs were repurposed as cardiovascular drugs. In fact, patients who had not had rheumatic disease but were affected by heart failure (HF) have long been known to carry high serum concentrations of TNFα, which suggests that drugs able to antagonize TNFα could be of benefit to these patients (2). Unfortunately, studies that probed “anti-TNFα” drugs in nonrheumatic patients showed clinical worsening or no improvement of HF.

Complexity and ambiguity might be reconciled if we take into consideration that patients who apparently share TNFα as a marker of disease may have differing underlying disease etiologies. Although reasonable and clinically sound, this conclusion would neglect the supposition that the subtleties of TNFα concentration and localization may exert influences that add complexity and ambiguity to the conclusions drawn from research on this cytokine. Therefore, defining the risk:benefit of anti-TNFα drugs in cardiovascular settings requires a brief reppraisal of what TNFα does in healthy or diseased conditions.

TNFα is a pleiotropic cytokine that participates in many aspects of the innate immune system, regulates the responses of immune cells, and thus stimulates the acute-phase reaction that occurs as a response to inflammation (3). Infectious or inflammatory stimuli induce the release of large amounts of TNFα into the systemic circulation, which allows TNFα to modulate the expression of a constellation of factors involved in the inflammatory reaction [interleukin-1 (IL-1), IL-6, platelet-derived growth factor (PDGF), tumor growth factor–beta (TGFβ), eicosanoids, platelet-activating factor (PAF), and adrenaline]. TNFα activates and promotes leucostasis by inducing increased expression of adhesion molecules at sites of inflammation. These effects are seen at TNFα plasma concentrations below 10−9 M and denote the physiological role of TNFα (4). At higher plasma concentrations, however, TNFα induces less benign endocrine- and exocrine-like effects observed in endotoxemia and shock (i.e., metabolic wasting, microvascular clotting, and hypotension). TNFα also causes diverging effects on tissue integrity and turnover. On the one hand, TNFα may assist tissue repair by stimulating fibroblast and mesenchymal cell proliferation, either directly or through inducing expression of growth factors; on the other hand, TNFα causes dysfunction or apoptosis of endothelial cells, increases the expression of collagenases and proteases, and thus contributes to tissue damage. Supraphysiological levels of reactive oxygen species (ROS) and cyclooxygenase metabolites of arachidonic acid (prostaglandins) usually accompany the untoward effects of TNFα (5, 6). Thus, overproduction of TNFα appears to cause or accompany autoimmunity and inflammation and has been implicated in rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel diseases, vasculitis, multiple sclerosis, and sarcoidosis.

In the era of DNA recombination and protein engineering, anti-TNFα drugs presented as an unprecedented option to treat inflammatory diseases caused or sustained by TNFα. Currently approved anti-TNFα drugs can be subgrouped as monoclonal antibodies (i.e., infliximab, adalimumab, and golimumab), chemically modified Fab’ fragments of TNFα-specific monoclonal antibodies (i.e., certolizumab-pegol), or fusion proteins that carry the ligand-binding moiety of TNFαreceptor 2 (i.e., etanercept) (Table 1). TNFα-targeting drugs can be used as single agents in patients who failed to respond to disease-modifying antirheumatic drugs (DMARD) like methotrexate, leflunomide, or sulphasalazine, but there are regimens that combine anti-TNFα drugs with DMARDs and show higher efficacy than anti-TNFα drugs alone. Anti-TNFα drugs are only available in parenteral formulations; attempts to improve patient compliance by designing orally bioavailable drugs are still in their infancy.

View this table:
Table 1

Anti-TNFα Drugs and Approved Indications

The clinical development of other anti-TNFα drugs has been less favorable. Testing of CDP 571, a humanized antibody to TNFα, was halted after a disappointing Phase II study of patients with Crohn’s disease, whereas the clinical development of onercept, a recombinant, unmodified, fully humanized, soluble type 1 TNF receptor (p55), was stopped because of its lack of efficacy in Crohn’s disease and its unfavorable risk:benefit in patients with moderate-to-severe psoriasis. Nonetheless, anti-TNFα drugs introduced long-awaited improvements in the clinical management of chronic inflammatory diseases and expanded a pharmacological repertoire that for too long had remained bound to the relatively nonspecific DMARDs. To some extent, anti-TNFα drugs could be compared to the so-called targeted drugs that revolutionized pharmacological approaches to anticancer therapy. That is, in oncologic settings, targeted drugs were developed to overcome limitations of nonspecific cytostatics and cytotoxics and specifically to inhibit receptors, receptor-associated kinases, intracellular kinases, or other enzymes that were thought to be crucial to the growth and survival of cancer cells but not of normal cells (7).

Cardiovascular events represent the main cause of death in patients with rheumatoid arthritis (RA). These RA patients are at a twofold greater risk for myocardial infarction (MI) and stroke, which jumps to nearly threefold in patients who have had the disease for ten years or more (8, 9). The risk of cardiovascular disease and mortality is largely independent of traditional risk factors (such as obesity or smoking) but relates to chronic inflammation and consequent accelerated atherosclerosis (9, 10). Anti-TNFα drugs were therefore anticipated to protect RA patients from cardiovascular events, but unfortunately this was not the case. Studies that looked at the incidence of any cardiovascular event showed that the effects of anti-TNFα drugs varied from reducing the risk to lacking any measurable influence (11). Regarding MI (whether primary or recurrent), anti-TNFα drugs were reported to lack an effect, to reduce the risk, or to increase it (11). And finally, studies that looked at HF as the major contributor to cardiovascular mortality in RA patients showed a very disappointing blending of reduced risk, no effect, or increased risk (11).

In the late 1990s, preclinical studies showed that TNFα inhibition could protect against cardiac dysfunction (12). These observations, and the aforesaid correlation of HF severity with the circulating amounts of TNFα, paved the road to exploratory clinical studies and placebo-controlled phase II trials that probed etanercept in patients with New York Heart Association (NYHA) class III or IV HF (Box 1). All such studies were quite consistent in demonstrating improvements in left ventricular function and remodeling and clinical composite scores (13, 14). Etanercept also caused a remarkable improvement of endothelium-dependent vasodilation, which was consistent with a possible role of TNFα in inducing endothelial dysfunction in HF patients (15, 16). Everything looked promising and well set to move toward larger studies, but once again ambiguity and complexity surfaced. In the phase IIB study of anti-TNFα Therapy Against Chronic Heart failure (ATTACH), 150 patients with NYHA class III-IV were randomized to receive placebo or low- or high-dose infliximab. Left ventricular ejection fraction was only transiently improved by infliximab; at a longer follow-up, both infliximab groups showed a trend toward increasing mortality or hospitalization for HF (17, 18). Infliximab-associated deterioration of cardiac function occurred in the presence of diminished serum levels of acute-phase proteins (i.e., C-reactive protein and interleukin-6) (Figure 1). The unexpected results of ATTACH could only suggest a contraindication to using infliximab in patients with HF.

Figure 1
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    Figure 1 Cardiovascular outcome of pharmacological interventions with infliximab or etanercept in patients with NYHA class III or IV heart failure (HF)

    The graph in the upper section shows increasing circulating levels of TNFα in HF patients as a function of disease severity (NYHA class). The central section represents NYHA class III or IV patients that were recruited in trials that probed infliximab or etanercept. In the bottom section, infliximab decreased circulating levels of acute phase proteins (IL-6, CRP) but caused increased cardiac events, while etanercept lacked effects or caused increased cardiac events. Solid circles indicate circulating TNFα. NYHA, New York Heart Association; IL-6, interleukin 6; CRP, C–reactive protein. Based on (2, 17–19).

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      ATTACH was not the only study to uncover deleterious effects of anti-TNFα drugs (Figure 1). Two larger studies, RENAISSANCE (Randomised Etanercept North American Strategy to Study Antagonism of Cytokines) and RECOVER (Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction), were terminated because of a lack of efficacy or a true negative result of low- or high-dose etanercept in patients with NYHA class III-IV. Analysis of RENEWAL, which merged the results from RENAISSANCE and RECOVER, showed that in RECOVER, high-dose etanercept demonstrates only slightly better results than low-dose etanercept, whereas in RENAISSANCE, the risk of death or hospitalization for HF is increased at both low- and high-dose etanercept (16, 19). These results led to contraindicate etanercept in nonrheumatic patients with HF and raised caution against using etanercept in RA patients with HF.

      The diverging effects of anti-TNFα drugs on cardiovascular events in RA patients could at least in part be attributed to study-to-study differences in patient selection and evaluation (e.g., retrospective versus prospective studies, data retrieval from national registries or insurance records, absence or presence of preexisting comorbidities, timing and length of anti-TNFα therapy, monotherapy versus combination with DMARDs, and type of DMARD). Nonetheless, it is quite evident that TNFα dysregulation and systemic inflammation by no means anticipate that anti-TNFα drugs are salutary for the heart. This concept is echoed in the studies of non-rheumatic patients with HF: high TNFα concentrations do not always translate into a cardioprotective effect from anti-TNFα drugs, regardless of whether these drugs also decrease the serum levels of other reactive proteins. We have described that in many RA or nonrheumatic patients, anti-TNFα drugs actually caused more damage to the heart, particularly in the presence of HF. So, what is wrong with anti-TNFα drugs? We suggest that the experience gained with anti-TNFα drugs calls for revisiting the axiom “TNFαsynonymous to cardiac dysfunction”: this should be tempered and reshaped to incorporate appreciation of both detrimental and beneficial effects of TNFα. The unexpectedly negative effects of anti-TNFα drugs on cardiac function would accommodate the dual behavior of TNFα.

      There are several proposed mechanisms that attest to the dual role of TNFα in the heart: 1) activation or increased expression of proapoptotic proteins like caspases and Bax (20, 21) but also increased transcription of genes related to cellular survival and proliferation (22, 23), and 2) activation of apoptosis signal–regulating kinase 1 but also of antiapoptotic Btk nonreceptor tyrosine kinases (24). The balance of cellular life versus death is governed by two distinct receptors, TNFα receptor 1 (TNFR1, also referred to as p55) and TNFα receptor 2 (TNFR2 or p75). The two receptors share significant sequence similarity in their extracellular domains but not in their cytoplasmic domains, which suggests that activation of one receptor or the other could result in different downstream effects. Accordingly, TNFR1 has been reported to signal apoptosis and fibrosis or remodeling, whereas TNFR2 has been reported to signal survival, repair, and angiogenesis (“cell survival receptor”) (25). Such opposing functions of TNFR1 and TNFR2 have been proposed to explain improved versus exacerbated post-infarction remodeling in TNFR1−/− or TNFR2−/− mice, respectively (26, 27), or mitigation versus aggravation of HF in TNFR1−/− or TNFR2−/− mice (28), respectively. In cardiomyocytes, TNRF1 is expressed more abundantly than TNRF2, which, in principle, would only suggest bad news for the heart (24); however, TNFα shows higher affinity for TNFR2, from which it may eventually “pass” to TNFR1 (29). Furthermore, there is compelling evidence that both TNFR1 and TNFR2 might be required to protect isolated cardiomyocytes or whole-heart preparations against hypoxia and reoxygenation or ischemia and reperfusion, as if TNFR1 and TNFR2 shared one or more cytoprotective repertoires (30, 31). TNFα receptor-associated factor 2 (TRAF2), a scaffolding protein that is common to TNFR1 and TNFR2, propagates cardiac survival effects in experimental models of ischemia-reperfusion injury (32). The binding interface of TRAF2 and other scaffolding proteins for TNFR1 is being investigated in depth (33). These studies will further clarify how TNFR1, previously reported to signal apoptosis, may assist TNFR2 in signaling survival and resistance to stressor agents.

      The aforesaid beneficial effects of TNFα were seen in genetically manipulated mice that express different amounts of TNFR1 or TNFR2; however, similar effects had been seen in wild-type cells or in animals exposed to exogenous TNFα, particularly when low-dose TNFα was used to treat cardiomyocytes or to perfuse (i.e., precondition) isolated heart prior to subjecting it to ischemia-reperfusion (23, 34). High-dose TNFα did, in fact, suppress contractility in working isolated heart, or it made the heart more vulnerable by subsequent ischemia-reperfusion (35). Such a concentration dependence of the effects of exogenous TNFα is not too different from that observed with endogenous TNFα: in wild-type mice, ischemia-reperfusion evoked protective synthesis and release of TNFα from cardiomyocytes whereas mice that over-expressed TNFα exhibit accelerated ventricular inflammation and dysfunction (23, 36).

      On balance, there seems to be a window of opportunity for endogenous or exogenous TNFα to convey cardioprotective signals, particularly when the concentration of either source of TNFα is low enough to preferentially activate TNFR2 or to drive the TNFR1-TNFR2 couple toward cytoprotective processes only. How these mechanisms precisely work is uncertain. For example, increased ROS formation and NF-κB activation were reported to transduce TNFα-mediated stimulation into both cardiac protection and injury (37–39). Nonetheless, linking “some TNFα” (i.e., low concentrations of TNFα) with cardioprotection twists our perception of TNFα antagonism in RA or nonrheumatic patients: it raises the possibility that intercepting TNFα would leave cardiac dysfunction unchanged or more aggressive.

      The cardioprotective role of low concentrations of TNFα was inferred by comparing data from disparate experimental models of ischemia-reperfusion or HF. Can we next assume that “some TNFα” struggles to protect the heart against high TNFα concentrations that occur in patients with cardiac disease or are at risk for it? In other words, can we consider low TNFα to offer preconditioning benefits against high TNFα? The observation that anti-TNFαdrugs did not always diminish but actually increased the incidence of cardiac events might in fact be explained by assuming that they intercepted those discrete amounts of TNFα that heralded cardiomyocyte preconditioning and survival to high concentrations of TNFα.

      Testing this hypothesis requires experimental and conceptual considerations. On experimental grounds, there is a need for unambiguous models that explore “low TNFα” against “high TNFα.” We have found that TNFα causes concentration-dependent death of isolated cardiomyocytes; however, pre-exposing cardiomyocytes to nontoxic concentrations of TNFα (one-sixth of its IC50 value) made them resistant to a rechallenging with high concentrations of TNFα (40). TNFα preconditioning offered a net survival effect over a broad range of otherwise toxic concentrations of TNFα and peaked at TNFα concentrations ~20 times higher than its IC50 value in unpreconditioned cells. Interestingly, low TNFα could also protect cardiomyocytes that were subsequently challenged with bolus H2O2 or etoposide to cause oxidative stress or apoptosis, respectively (41); however, TNFα was much better at protecting against etoposide rather than H2O2 (survival effect at concentrations ~ 40 times higher than or equal to respective IC50 values in unpreconditioned cells, respectively) (42). On balance, the effect of low TNFα against high TNFα was much similar to that of low TNFα against etoposide, which supports a prevailing role of apoptosis in TNFα cardiotoxicity.

      The untoward cardiac effects of anti-TNFα drugs were previously explained by immunologic mechanisms that nonetheless await direct demonstration. Worsening of NYHA III-IV class HF by infliximab was tentatively attributed to complement fixation on cardiomyocytes that expressed TNFα-TNFR complexes, similar to what occurs in post-ischemic heart that expresses self-antigens and evokes autoimmune myocarditis (43). In the case of etanercept, however, a more complex and self-repeating mechanism has been tentatively put forward: rapid binding of TNFα to etanercept and equally rapid or faster dissociation of TNFα results in longer-lived circulating levels TNFα in a biologically active form (43). Both mechanisms may be valid if one only looked at the high levels of TNFα in the bloodstream and considered anti-TNFα drugs from immunologic viewpoints only.

      We suggest that the failing heart is a pharmacologic sanctuary where ischemia or hemodynamic overload triggers an autocrine loop that protects cardiomyocytes from attack by circulating high TNFα. The loop begins with cardiomyocyte synthesis and release of discrete amounts of TNFα, and proceeds with the binding of such TNFα to TNFR1-TNFR2 and activation of downstream survival-oriented cell responses. Potentially toxic “high” TNFα that came from systemic dysregulation of cytokine sources (44) and penetrated the sanctuary would find cardiomyocytes protected by preconditioning (Figure 2A); in contrast, treatment with infliximab or etanercept disrupts the autocrine loop and leaves cardiomyocytes unprotected against high TNFα (Figure 2B). In progressive HF, altered permeability of coronary microvasculature should, in fact, be accompanied by an increasing penetration of the sanctuary by high molecular mass anti-TNFα drugs (45, 46).

      Figure 2
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        Figure 2 Proposed mechanism for cardiac protection by low TNFα and cardiac toxicity by anti-TNFα

        A. Cardiomyocytes may synthetize and release discrete amounts of TNFα that bind to TNFR2 and eventually pass to TNFR1, activating survival-oriented cell responses that protect against higher levels of TNFα. B. Penetration of anti-TNFα drugs through discontinuous endothelium of the failing heart interrupts the autocrine loop and eventually shifts TNFR1–2 to signaling apoptosis. Solid blue circles represent circulating TNFα; solid green circles represent TNFα released by cardiomyocytes. INF, infliximab; ETA, etanercept; TNFR1–2, TNFα receptor 1–2; TRAF2, TNFα receptor–associated factor 2; TRADD, TNFR1-associated death domain.

        The story we suggest is in part reminiscent of cardiotoxicity from trastuzumab, a humanized epidermal growth factor receptor 2 (ErbB2)-specific antibody that was developed to kill ErbB2-overexpressing breast cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC) (46). Trastuzumab causes HF by binding to ErbB2 that is constitutively expressed in cardiomyocytes, but cardiotoxicity is not mediated by ADCC: trastuzumab halts survival signals that are relayed by ErbB2 and helps cardiomyocytes to withstand toxicity from other drugs or hemodynamic overload or other comorbidities (7, 47, 48). In principle, there are other intersections or similarities between our story and the lessons from trastuzmab. ErbB2 activation makes the heart more responsive to vagal stimulation (49), which is known to increase TNFR2 expression and TNFR2-mediated protection against ischemia-reperfusion (25). Furthermore, patients with HF exhibit circulating levels of soluble forms of both TNFR1–2 and ErbB2 (50); unfortunately, however, uncertainties about the mechanisms of receptor shedding and the pathophysiologic role of circulating receptors do not justify much speculation in this setting. With that said, the time is right to explore anti-TNFα drugs from the broader perspective of other drugs that decrease cardiotrophic signals.

        Anti-TNFα drugs have now been used in more than two million patients with RA or other chronic inflammatory diseases. Investigational indications ranging from Kawasaki’s disease to steroid-refractory acute graft-versus-host disease and dermatomyositis (or polymyositis) or many others will conceivably surface in clinical practice in the next years and will further expand the marketing of anti-TNFα drugs. Concerns about cardiac events should guide or limit, when appropriate, the prescribing of these agents.

        In this article we have challenged facts and controversies about cardiotoxicity induced by anti-TNFα drugs. Looking at TNFα as a Janus-like molecule that brings life or death to cardiomyocytes as a function of its levels in cardiac sanctuaries or in the bloodstream may help drug developers, pharmacologists, and clinicians to redefine the appropriateness and safety of these drugs in a given patient or another. Defining the cardiovascular risk of an individual should not be confined to measuring plasma levels of TNFα but probably should be extended to probe the capability of the heart to capture trophic signals from “some TNFα” and other factors, whether in absence or presence of anti-TNFα drugs. These concepts call for diagnostic measures or provocative tests that can only be surmised at this time. We conclude that anti-TNFα drugs should be included in the list of potentially cardiotoxic drugs. Putting these drugs on that list calls for research—and good sense—that go from bench to bedside.

         
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        Acknowledgments

        Work in the authors’ laboratories was supported by University Campus Bio-Medico Special Project “Cardio-Oncology” (to GM).

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        References

        1. ↵
          1. Minotti G
          (2010) Cardiotoxicity of Non-Cardiovascular Drugs, John Wiley & Sons, Ltd, Chichester, UK.

          The authors discuss contemporary issues in cardiotoxicity from non-cardiovascular drugs, with in-depth analyses of regulatory matters, preclinical research, and clinical correlates.

          .
        2. ↵
          1. Koller-Strametz J,
          2. Pacher R,
          3. Frey B,
          4. Kos T,
          5. Woloszczuk W,
          6. Stanek B
          (1998) Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor II, interleukin-6, and neurohumoral variables. J Heart Lung Transplant 17:356–362.
          Medline
        3. ↵
          1. Apostolaki M,
          2. Armaka M,
          3. Victoratos P,
          4. Kollias G
          (2010) Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr Dir Autoimmun 11:1–26.
          CrossRefMedline
        4. ↵
          1. Abbas AK,
          2. Lichtman AH
          (2009) Basic Immunology: Functions and Disorders of the Immune System, 3rd ed, Saunders, Philadelphia, PA.
        5. ↵
          1. Lorente JA,
          2. Marshall JC
          (2005) Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock 1:107–119.
        6. ↵
          1. Kollias G
          (2005) TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum 34:3–6.
          CrossRefMedline
        7. ↵
          1. Minotti G,
          2. Salvatorelli E,
          3. Menna P
          (2010) Pharmacological foundations of cardio-oncology. J Pharmacol Exp Ther 334:2–8.
          Abstract/FREE Full Text
        8. ↵
          1. Bartoloni E,
          2. Alunno A,
          3. Luccioli F,
          4. Moscatelli S,
          5. Biscontini D,
          6. Santoboni G,
          7. Gerli R
          (2010) Atherosclerotic vascular damage and rheumatoid arthritis: a complex but intriguing link. Expert Rev Cardiovasc Ther 8:1309–1316.

          The authors properly describe the increased risk for cardiovascular events in rheumatoid arthritis (RA) patients, summarizing the reasons for this condition.

          .
          CrossRefMedline
        9. ↵
          1. Sanders S,
          2. Geraci SA
          (2010) Cardiovascular disease in rheumatoid arthritis: disease and treatment interactions and their implications on treatment decisions. J Miss State Med Assoc 51:75–80.
          Medline
        10. ↵
          1. Myasoedova DJM 3rd.,
          2. Crowson CS,
          3. Gabriel SE
          (2010) Epidemiology of rheumatoid arthritis: rheumatoid arthritis and mortality. Curr Rheumatol Rep 12:379–385.
          CrossRefMedline
        11. ↵
          1. Westlake SL,
          2. Colebatch AN,
          3. Baird J,
          4. Curzen N,
          5. Kiely P,
          6. Quinn M,
          7. Choy E,
          8. Ostor AJK,
          9. Edwards CJ
          (2011) Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology 50:518–531.

          The authors review of the articles that reported on the effects of anti-tumor necrosis factor (TNF) agents on the risk of cardiovascular diseases in RA patients.

          .
          Abstract/FREE Full Text
        12. ↵
          1. Stamm C,
          2. Friehs I,
          3. Cowan DB,
          4. Moran AM,
          5. Cao-Danh H,
          6. Duebener LF,
          7. del Nido PJ,
          8. McGowan FX Jr.
          (2001) Inhibition of tumor necrosis factor-alpha improves postischemic recovery of hypertrophied hearts. Circulation 104:I350–I355.
          Medline
        13. ↵
          1. Deswal A,
          2. Bozkurt B,
          3. Seta Y,
          4. Parilti-Eiswirth S,
          5. Hayes FA,
          6. Blosch C,
          7. Mann DL
          (1999) Safety and efficacy of a soluble p75 tumor necrosis fa:ctor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 99:3224–3226.

          In this clinical trial, the authors were the first to assess the efficacy and safety of etanercept in patients with advanced heart failure.

          .
          Abstract/FREE Full Text
        14. ↵
          1. Bozkurt B,
          2. Torre-Amione G,
          3. Warren MS,
          4. Whitmore J,
          5. Soran OZ,
          6. Feldman AM,
          7. Mann DL
          (2001) Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103:1044–1047.
          Abstract/FREE Full Text
        15. ↵
          1. Mann DL
          (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 91:988–998.
          Abstract/FREE Full Text
        16. ↵
          1. Capria A,
          2. De Nardo D,
          3. Baffetti FR,
          4. Barbini U,
          5. Violo A,
          6. Tondo T,
          7. Fontana L
          (2010) Long-term anti-TNF-alpha treatments reverse the endothelial dysfunction in rheumatoid arthritis: the biological coherence between synovial and endothelial inflammation. Int J Immunpathol Pharmacol 23:255–262.
        17. ↵
          1. Anker SD,
          2. Coats AJ
          (2002) How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 86:123–130.
          CrossRefMedline
        18. ↵
          1. Chung ES,
          2. Packer M,
          3. Lo KH,
          4. Fasanmade AA,
          5. Willerson JT
          Anti-TNF Therapy Against Congestive Heart Failure Investigators (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107:3133–3140.

          The authors report on the phase IIB clinical trial that evaluated the effects of infliximab in heart failure (HF). According to the results, infliximab was contraindicated in HF treatment.

          .
          Abstract/FREE Full Text
        19. ↵
          1. Mann DL,
          2. McMurray JJ,
          3. Packer M,
          4. Swedberg K,
          5. Borer JS,
          6. Colucci WS,
          7. Djian J,
          8. Drexler H,
          9. Feldman A,
          10. Kober L,
          11. et al.
          (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109:1594–1602.

          The authors present the result of the clinical trial that probed etanercept in HF. Based on these results, etanercept was contraindicated in HF treatment.

          .
          Abstract/FREE Full Text
        20. ↵
          1. Dent MR,
          2. Das S,
          3. Dhalla NS
          (2007) Alterations in both death and survival signals for apoptosis in heart failure due to volume overload. J Mol Cell Cardiol 43:726–732.
          CrossRefMedline
        21. ↵
          1. Kewalramani G,
          2. Puthanveetil P,
          3. Wang F,
          4. Kim MS,
          5. Deppe S,
          6. Abrahani A,
          7. Luciani DS,
          8. Johnson JD,
          9. Rodrigues B
          (2009) AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death. Cardiovasc Res 84:42–53.
          Abstract/FREE Full Text
        22. ↵
          1. Lecour S,
          2. Suleman N,
          3. Deuchar GA,
          4. Somers S,
          5. Lacerda L,
          6. Huisamen B,
          7. Opie LH
          (2005) Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase). Circulation 112:3911–3918.

          The authors explore the in vitro effects of TNFα preconditioning and demonstrate that activation of canonical prosurvival kinases (Akt and Erk 1/2) is not essential to preconditioning, possibly indicating the involvement of alternative protective pathways (e.g., STAT-3).

          .
          Abstract/FREE Full Text
        23. ↵
          1. Sack MN,
          2. Smith RM,
          3. Opie LH
          (2000) Tumor necrosis factor in myocardial hypertophy and ischaemia: An anti-apoptotic perspective. Cardivasc Res 45:688–695.
          FREE Full Text
        24. ↵
          1. Al-Lamki RS,
          2. Brookes AP,
          3. Wang J,
          4. Reid MJ,
          5. Parameshwar J,
          6. Goddard MJ,
          7. Tellides G,
          8. Wan T,
          9. Min W,
          10. Pober JS,
          11. et al.
          (2009) TNF receptors differentially signal and are differentially expressed and regulated in the human heart. Am J Transplant 9:2670–2696.
        25. ↵
          1. Katare RG,
          2. Ando M,
          3. Kakinuma Y,
          4. Arikawa M,
          5. Yamasaki F,
          6. Sato T
          (2010) Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. J Mol Cell Cardiol 49:234–244.
          CrossRefMedline
        26. ↵
          1. Hamid T,
          2. Gu Y,
          3. Ortines RV,
          4. Bhattacharya C,
          5. Wang G,
          6. Xuan YT,
          7. Prabhu SD
          (2009) Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 119:1386–1397.
          Abstract/FREE Full Text
        27. ↵
          1. Monden Y,
          2. Kubota T,
          3. Inoue T,
          4. Tsutsumi T,
          5. Kawano S,
          6. Ide T,
          7. Tsutsui H,
          8. Sunagawa K
          (2007) Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am J Physiol Heart Circ Physiol 293:H743–753.

          The authors characterize, in a murine model of myocardial infarction (MI), the differences between TNFα receptor 1 and 2 effects (toxic and beneficial, respectively), and suggested selective blockade of TNFR1 as a therapeutic option in MI.

          .
          Abstract/FREE Full Text
        28. ↵
          1. Higuchi Y,
          2. McTiernan CF,
          3. Frye CB,
          4. McGowan BS,
          5. Chan TO,
          6. Feldman AM
          (2004) Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy. Circulation 109:1892–1897.

          The authors appropriately describe, in transgenic mice, the different roles of TNF receptors 1 and 2 in cardiac hypertrophy, dilation, and reduced cardiac function. They were the first to consider the cardioprotective role of TNFR2 signalling in cytokine-mediated heart failure.

          .
          Abstract/FREE Full Text
        29. ↵
          1. Medvedev AE,
          2. Espevik T,
          3. Ranges G,
          4. Sundan A
          (1996) Distinct roles of the two tumor necrosis factor (TNF) receptors in modulating TNF and lymphotoxin alpha effects. J Biol Chem 271:9778–9784.
          Abstract/FREE Full Text
        30. ↵
          1. Flaherty MP,
          2. Guo Y,
          3. Tiwari S,
          4. Rezazadeh A,
          5. Hunt G,
          6. Sanganalmath SK,
          7. Tang XL,
          8. Bolli R,
          9. Dawn B
          (2008) The role of TNF-alpha receptors p55 and p75 in acute myocardial ischemia/reperfusion injury and late preconditioning. J Mol Cell Cardiol 45:735–741.
          CrossRefMedline
        31. ↵
          1. Nakano Y,
          2. Imagawa S,
          3. Matsumoto K,
          4. Stockmann C,
          5. Obara N,
          6. Suzuki N,
          7. Doi T,
          8. Kodama T,
          9. Takahashi S,
          10. Nagasawa T,
          11. et al.
          (2004) Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood 104:4300–4307.
          Abstract/FREE Full Text
        32. ↵
          1. Burchfield JS,
          2. Dong JW,
          3. Sakata Y,
          4. Gao F,
          5. Tzeng HP,
          6. Topkara VK,
          7. Entman ML,
          8. Sivasubramanian N,
          9. Mann DL
          (2010) The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart. Circ Heart Fail 3:157–164.
          Abstract/FREE Full Text
        33. ↵
          1. Terry Powers JL,
          2. Mace KE,
          3. Parfrey H,
          4. Lee SJ,
          5. Zhang G,
          6. Riches DW
          (2010) TNF receptor-1 (TNF-R1) ubiquitous scaffolding and signaling protein interacts with TNF-R1 and TRAF2 via an N-terminal docking interface. Biochemistry 49:7821–7829.
          CrossRefMedline
        34. ↵
          1. Baxter GT,
          2. Kuo RC,
          3. Jupp OJ,
          4. Vandenabeele P,
          5. MacEwan DJ
          (1999) Tumor necrosis factor-alpha mediates both apoptotic cell death and cell proliferation in a human hematopoietic cell line dependent on mitotic activity and receptor subtype expression. J Biol Chem 274:9539–9547.

          The authors, in this timely editorial, summarized current experimental knowledge on TNFα and its receptors, and described their ambivalent role in heart damage or protection in the light of the disappointing results from TNFα antagonism in clinical practice.

          .
          Abstract/FREE Full Text
        35. ↵
          1. Schulz R,
          2. Heusch G
          (2009) Tumor necrosis factor-alpha and its receptors 1 and 2: Yin and Yang in myocardial infarction?. Circulation 119:1355–1357.
          FREE Full Text
        36. ↵
          1. Kubota T,
          2. McTiernan CF,
          3. Frye CS,
          4. Demetris AJ,
          5. Feldman AM
          (1997) Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Card Fail 3:117–124.
          CrossRefMedline
        37. ↵
          1. Burchfield JS,
          2. Dong JW,
          3. Sakata Y,
          4. Gao F,
          5. Tzeng HP,
          6. Topkara VK,
          7. Entman ML,
          8. Sivasubramanian N,
          9. Mann DL
          (2010) The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart. Circ Heart Fail 3:157–164.
          Abstract/FREE Full Text
          1. Khaper N,
          2. Bryan S,
          3. Dhingra S,
          4. Singal R,
          5. Bajaj A,
          6. Pathak CM,
          7. Singal PK
          (2010) Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure. Antioxid Redox Signal 13:1033–1049.
          CrossRefMedline
        39. ↵
          1. Lacerda L,
          2. Smith RM,
          3. Opie L,
          4. Lecour S
          (2006) TNFalpha-induced cytoprotection requires the production of free radicals within mitochondria in C2C12 myotubes. Life Sci 79:2194–2201.
          CrossRefMedline
        40. ↵
          1. Cacciapaglia F,
          2. Menna P,
          3. Salvatorelli E,
          4. Buzzulini F,
          5. Arcarese L,
          6. Margiotta D,
          7. Minotti G,
          8. Afeltra A
          (2009) Tumor necrosis factor alpha and cardiomyocytes: evidence for a self-protective preconditioning. Ann Rheum Dis 68:194.

          The authors first described in H9c2 cardiomyocytes that TNFα preconditioning affords protection against rechallenging with high concentrations TNFα.

          .
        41. ↵
          1. Menna P,
          2. Salvatorelli E,
          3. Minotti G
          (2007) Doxorubicin degradation in cardiomyocytes. J Pharmacol Exp Ther 322:408–419.
          Abstract/FREE Full Text
        42. ↵
          1. Cacciapaglia F,
          2. Menna P,
          3. Navarini L,
          4. Salvatorelli E,
          5. Lo Vullo M,
          6. Vernuccio A,
          7. Minotti G,
          8. Afeltra A
          (2010) TNF-alpha induced cardioprotection: effects on reactive oxygen species (ROS) and apoptosis. Ann Rheum Dis 69:170.
        43. ↵
          1. Sarzi-Puttini P,
          2. Atzeni F,
          3. Shoenfeld Y,
          4. Ferraccioli G
          (2005) TNF-alpha, rheumatoid arthritis, and heart failure: a rheumatological dilemma. Autoimmun Rev 4:153–161.

          The authors reviewed the possible roles of TNFα in the development of atherosclerosis and described several possible explanations for the disappointing results of TNFα antagonism in HF patients.

          .
          CrossRefMedline
        44. ↵
          1. Niebauer J,
          2. Volk HD,
          3. Kemp M,
          4. Dominguez M,
          5. Schumann RR,
          6. Rauchhaus M,
          7. Poole-Wilson PA,
          8. Coats AJ,
          9. Anker SD
          (1999) Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353:1838–1842.
          CrossRefMedline
        45. ↵
          1. Hansen PR
          (1998) Inflammatory alterations in the myocardial microcirculation. J Mol Cell Cardiol 30:2555–2559.
          CrossRefMedline
        46. ↵
          1. Dongaonkar RM,
          2. Stewart RH,
          3. Geissler HJ,
          4. Laine GA
          (2010) Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function. Cardiovasc Res 87:331–339.
          Abstract/FREE Full Text
        47. ↵
          1. Cheng H,
          2. Force T
          (2010) Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res 106:21–34.

          The authors make an authoritative analysis of cardiotoxicity induced by targeted antitumor drugs. In demonstrating that “tumor-specific” targets may in fact be constitutively expressed in the heart, this review provides the readers with analogies to the mechanisms of cardiotoxicity from anti-TNFα drugs.

          .
          Abstract/FREE Full Text
        48. ↵
          1. Menna P,
          2. Salvatorelli E,
          3. Minotti G
          (2008) Cardiotoxicity of antitumor drugs. Chem Res Toxicol 21:978–989.
          CrossRefMedline
        49. ↵
          1. Lemmens K,
          2. Doggen K,
          3. De Keulenaer GW
          (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960.

          The results critically reviewed the role of ErbB signaling in the heart. They described that the neuregulin 1/ErbB2 machinery facilitates cardiac responses to cholinergic (vagal) stimulation. This anticipates similarities with the TNFα story, as vagal stimulation also increases expression of “protective” TNFR2.

          .
          Abstract/FREE Full Text
        50. ↵
          1. Perik PJ,
          2. de Vries EGE,
          3. Gietema JA,
          4. van der Graaf TA,
          5. Smilde TDJ,
          6. Sleijfer DT,
          7. van Veldhuisen DJ
          (2007) Serum HER2 levels are increased in patients with chronic heart failure. Eur J Heart Fail 9:173–177.

          The authors published an original investigation on the elevation of soluble forms of both HER2 and TNFR1 and TNFR2 in patients with chronic HF and high levels of TNFα. It denotes complex interactions between cardiac trophic signals from neuregulin 1-HER2 and TNFα-TNFRs.

          .
          Abstract/FREE Full Text

        Fabio Cacciapaglia, MD, received his degree in medicine (2004) and boarded in clinical immunology (2008) at the University Campus Bio-Medico of Rome. He currently attends a Research Doctorate Program in Sciences of Organ Plasticity and Tissue Regeneration for Functional Recovery at the University Campus Bio-Medico of Rome. A member of the Italian Society of Rheumatology, he is an attending physician of Internal Medicine at the “N. Melli” Hospital of San Pietro Vernotico (Brindisi) and participates in pre-clinical and clinical trials of anti-rheumatic therapies with TNFα targeted drugs or disease modifying anti-rheumatic drugs. E-mail f.cacciapaglia{at}unicampus.it; fax +39-0831-670377.


        Pierantonio Menna, PhD, graduated in pharmaceutical chemistry in 2000 and was granted a doctoral research degree in 2005 from the G. d’Annunzio University of Chieti School of Pharmacy and the Center of Excellence on Aging. From 2004 to 2005, he was Visiting Scientist at the Cancer Pharmacology Center of the University of Pennsylvania School of Medicine, Philadelphia. He is presently a Clinical Pharmacologist at the University Hospital of Campus Bio-Medico of Rome. His main interest is in drug metabolism, therapeutic drug monitoring, and investigational pharmacokinetics and biomarkers.


        Luca Navarini, MD, works in the Department of Clinical Medicine and Rheumatology at the Campus Bio-Medico University of Rome. His research is focused on cardioprotection and cardiotoxicity induced by TNFα, in collaboration with the laboratory of Drug Sciences of the same Institute.


        Antonella Afeltra, MD, is Professor of Rheumatology and Chief of Clinical Medicine and Rheumatology at the University Campus Bio-Medico of Rome. Her scientific areas of interest include the pathogenesis of systemic autoimmune diseases and their cardiovascular involvement, the pathophysiology of neuropsychiatric disorders in connective tissue diseases, and the role of biologic agents in the treatment of arthritis.


        Emanuela Salvatorelli, PhD, graduated in pharmacy in 2000 and was granted a doctoral research degree in 2005 from the G. d’Annunzio University of Chieti School of Pharmacy and the Center of Excellence on Aging. She is presently Assistant Professor of Pharmacology and Head of Laboratory at the Center for Integrated Research of the University Campus Bio-Medico of Rome. Her main interest is in drug metabolism and bioactivation mechanisms of toxicity. She developed translational models of human heart to probe the metabolic determinants of cardiotoxicity from antitumor anthracyclines and investigational analogues.


        Giorgio Minotti, MD, PhD, is Professor of Pharmacology and Chief of Clinical Pharmacology at the University Campus Bio-Medico of Rome. He graduated in medicine in 1981 and boarded in oncology in 1984. He was a Fulbright Scholar at the Department of Biochemistry of Michigan State University, Lansing (1985–1987) and a Fulbright Visiting Professor at the Department of Physiology and Biophysics of Case Western Reserve University, Cleveland. He is member of the Italian Society of Pharmacology, the Italian Society of Toxicology, the American Society of Oncology, and the American Society of Pharmacology and Experimental Therapeutics, and an honorary member of the International Society of Cardio-Oncology. His main research interest is in preclinical models and clinical correlates of cardiotoxicity from antitumor drugs and other noncardiovascular drugs.


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        1. doi: 10.1124/mi.11.2.4 MI April 2011 vol. 11 no. 2 79-87
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