Advertisement
Canadian Journal of Cardiology

Cardiovascular Pathophysiology: Is It a Tumour Necrosis Factor Superfamily Affair?

  • Brendan N. Putko
    Affiliations
    Division of Cardiology, Department of Medicine and the Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
  • Haran Yogasundaram
    Affiliations
    Division of Cardiology, Department of Medicine and the Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
  • Gavin Y. Oudit
    Correspondence
    Corresponding author: Dr Gavin Y. Oudit, Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: +1-780-407-8569; fax: +1-780-407-6452.
    Affiliations
    Division of Cardiology, Department of Medicine and the Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
Published:September 14, 2014DOI:https://doi.org/10.1016/j.cjca.2014.09.006
      Dysregulated inflammation plays a central role in the pathophysiology of cardiovascular diseases. For instance, dysregulated interleukin-1, tumour necrosis factor (TNF), and interleukin-6 pathways, master regulators of the inflammasome, drive pathological vascular and myocardial remodelling.
      • Braunwald E.
      Biomarkers in heart failure.
      • Ridker P.M.
      • Luscher T.F.
      Anti-inflammatory therapies for cardiovascular disease.
      Heart failure (HF), which often develops as a consequence of conditions like atherosclerosis, has also been linked to dysregulation of inflammation mediated by TNF.
      • Marti C.N.
      • Khan H.
      • Mann D.L.
      • et al.
      Soluble tumor necrosis factor receptors and heart failure risk in older adults: Health, Aging, and Body Composition (Health ABC) Study.
      • Putko B.N.
      • Wang Z.
      • Lo J.
      • et al.
      Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.
      • Paulus W.J.
      • Tschope C.
      A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
      Interestingly, TNF and its 2 receptors, TNFR1 and TNFR2, are only 3 members of a group of ligands and receptors, called the TNF superfamily, that have been linked to cardiovascular pathophysiology. Among the members of the TNF superfamily, the osteoprotegerin (OPG)/receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) axis has been implicated in the pathophysiology of various cardiovascular disorders that involve a vascular component, such as atherosclerosis and diabetes.
      • Van Campenhout A.
      • Golledge J.
      Osteoprotegerin, vascular calcification and atherosclerosis.
      OPG is a circulating decoy receptor that binds RANKL, thereby inhibiting its interaction with RANK (Fig. 1). Interaction between RANKL and RANK can produce pathological effects on a number of organ systems, such as vascular calcification, bone resorption, and cardiac extracellular matrix remodelling (Fig. 1). There is a positive correlation between OPG and cardiovascular morbidity and mortality
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      • Montagnana M.
      • Lippi G.
      • Danese E.
      • Guidi G.C.
      The role of osteoprotegerin in cardiovascular disease.
      • Gupta S.
      • Drazner M.H.
      • de Lemos J.A.
      Newer biomarkers in heart failure.
      and OPG can be used as a biomarker of left ventricular (LV) systolic dysfunction.
      • Gupta S.
      • Drazner M.H.
      • de Lemos J.A.
      Newer biomarkers in heart failure.
      Figure thumbnail gr1
      Figure 1Systemic effects mediated by osteoprotegerin (OPG) and the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) systems that can result in remodelling heart failure with preserved ejection fraction after myocardial infarction (MI). ECM, extracellular matrix; MMP, matrix metalloproteinase; TNF, tumour necrosis factor.

      The Use of OPG as a Diagnostic, Prognostic, and Therapeutic Biomarker

      Because OPG, unlike RANK, is a circulating receptor, its use has been developed as a blood-borne biomarker for use in cardiovascular disease assessment. The interplay between RANKL and OPG and their ligand, RANKL, is of utmost importance when evaluating the OPG/RANK/RANKL axis for diagnostic, prognostic, and therapeutic benefit.
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      Unfortunately, RANKL and RANK are difficult to measure in vivo,
      • Gupta S.
      • Drazner M.H.
      • de Lemos J.A.
      Newer biomarkers in heart failure.
      rendering an accurate assessment of the OPG/RANK/RANKL axis via serum analysis problematic. Before OPG can be used for diagnostic or prognostic purposes, the relationships between OPG and various demographic factors and clinical outcomes must be investigated further. The relationships between OPG and age, sex, and obesity remain unresolved, because several studies have reported conflicting findings.
      • Montagnana M.
      • Lippi G.
      • Danese E.
      • Guidi G.C.
      The role of osteoprotegerin in cardiovascular disease.
      In addition, OPG was negatively correlated with fasting plasma glucose in healthy subjects but there was no such correlation in diabetic patients,
      • O’Sullivan E.P.
      • Ashley D.T.
      • Davenport C.
      • et al.
      Osteoprotegerin and biomarkers of vascular inflammation in type 2 diabetes.
      adding to the observed heterogeneity of OPG across various cohorts of patients. OPG concentrations might reflect changes in different OPG sources, such as the liver, skeletal bone, and endothelial cells, which might confer varying degrees of risk and have their own clinical implications.
      • Montagnana M.
      • Lippi G.
      • Danese E.
      • Guidi G.C.
      The role of osteoprotegerin in cardiovascular disease.
      Because OPG expression and release are stimulated by various inflammatory cytokines and an increase in RANKL/OPG ratio is observed in inflamed tissues, the potential of therapeutic OPG to limit inflammation, and subsequent intimal atherosclerotic lesions, should be considered.
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      If such treatments prove efficacious, OPG might be used in other systemic diseases with major inflammatory components leading to cardiovascular morbidity and mortality, such as HF with preserved ejection fraction, rheumatoid arthritis, and systemic lupus erythematosus. In murine models, exogenous OPG administration blocks arthritic bone loss,
      • Kong Y.Y.
      • Feige U.
      • Sarosi I.
      • et al.
      Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
      reverses osteoporosis, and prevents vascular calcification.
      • Min H.
      • Morony S.
      • Sarosi I.
      • et al.
      Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.
      Although promising, much work remains to translate these findings into clinical applications in patients. Several other aspects need to be more adequately investigated before the prospect of therapeutic OPG can be considered. It is unknown whether therapies that manipulate OPG will have ensuing changes in RANKL and RANK activity through feedback mechanisms. OPG itself is regulated via several pathways such as angiotensin II, interleukin-1, TNF, and peroxisome proliferator-activated receptor-γ ligands, which might affect endogenous OPG release.
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      In the presence of significant negative feedback, exogenous administration of OPG could potentially be deleterious because systemic effects would be seen and endogenous OPG is more localized via cell-mediated expression. Another complicating factor to therapeutic OPG use is that it binds and neutralizes TNF-related apoptosis-inducing ligand (TRAIL).
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      TRAIL induces apoptosis in multiple types of cancers
      • Zauli G.
      • Secchiero P.
      The role of the trail/trail receptors system in hematopoiesis and endothelial cell biology.
      and OPG interaction with TRAIL promotes the survival of these cancerous cells, thereby limiting its use as a therapeutic agent.
      • Zauli G.
      • Secchiero P.
      The role of the trail/trail receptors system in hematopoiesis and endothelial cell biology.
      Moreover, long-term OPG therapy will likely be needed to prevent atherosclerosis and progression of existing atherosclerotic lesions.
      • Min H.
      • Morony S.
      • Sarosi I.
      • et al.
      Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.
      RANKL is important for dendritic cell survival and, therefore, antigen surveillance, T-cell memory formation, and immunomodulatory effects.
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      As a result, long-term inhibition of RANKL might predispose patients to autoimmune diseases. RANKL also regulates endothelial cell survival and proliferation; disruption along the OPG/RANK/RANKL axis could result in endothelial dysfunction and impaired angiogenesis.
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.

      Contributions and Limitations of 2 Studies in This Issue of the Canadian Journal of Cardiology

      In this issue of the Canadian Journal of Cardiology, 2 clinical studies of OPG are presented: Kalaycıoğlu et al. examine OPG as a marker of subclinical LV systolic dysfunction in diabetic patients,
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      and Lindberg et al. examine OPG as a biomarker of LV systolic dysfunction in the peri-percutaneous coronary intervention (PCI) period and longitudinal follow-up in patients with ST-elevation myocardial infarction (STEMI).
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      In a single-centre cross-sectional study, Kalaycıoğlu et al.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      recruited 86 consecutive diabetic hypertensive individuals as their study group, and 30 consecutive nondiabetic hypertensive individuals as their control group and found that serum OPG levels were significantly higher and LV systolic function, assessed according to global longitudinal strain, was significantly lower in the diabetic hypertensive cohort.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      Global longitudinal strain is representative of subendocardial ischemia and is therefore more sensitive to coronary artery disease.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      After adjusting for covariates such as blood pressure and estimated glomerular filtration rate, OPG remained a significant predictor of LV systolic dysfunction, defined as a global longitudinal strain cutoff of ≤ 18.5%.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      Importantly, the study cohorts were generally well matched for demographic characteristics and medical history, and inclusion of a control group with a known cardiovascular risk factor served to reduce selection bias. Kalaycıoğlu et al. concluded that OPG might be a good biomarker for detecting early diabetic cardiomyopathy and/or subsequent HF in diabetic hypertensive patients.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      Because diabetes itself is correlated with increased serum OPG levels,
      • Collin-Osdoby P.
      Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
      a diabetic nonhypertensive cohort would have provided valuable information on a potential synergistic interaction between diabetes and hypertension that could contribute to increased OPG levels seen in systolic dysfunction. As it currently stands, it is impossible to know if the observed correlation of OPG with systolic dysfunction in diabetic hypertensive patients relative to nondiabetic hypertensive patients is due to diabetes or an interaction between diabetes and hypertension. In addition, the lack of a healthy cohort limits the strength of the study findings.
      Lindberg et al. examined the acute setting of vascular pathophysiology by recruiting 42 patients with significant STEMI to measure plasma OPG before PCI, immediately after PCI, 1 day after PCI, and 2 days after PCI.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      They found that OPG levels peaked immediately after PCI and then declined thereafter. Interestingly, mean OPG levels were significantly higher in patients with LV ejection fraction (LVEF) ≤ 40% than in patients with LVEF > 40%, even after adjusting for cofactors, such as age and sex.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      Lindberg et al. observed a mean increase in LVEF over the 7-month median follow-up period, and did not find that increased OPG was reflected in reduced LVEF at follow-up.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      Their study might have been underpowered to detect a long-term relationship between OPG and LVEF, and it might be that OPG could be useful for identifying patients who have initially compromised systolic function, and could therefore benefit from rigourous interdisciplinary follow-up and treatment.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      Administration of unfractionated heparin causes the release of OPG from vascular smooth muscle cells.
      • Nybo M.
      • Rasmussen L.M.
      Osteoprotegerin released from the vascular wall by heparin mainly derives from vascular smooth muscle cells.
      In vivo studies have shown that OPG levels after an intravenous bolus of 50 IU/kg unfractionated heparin normalized within 1-2 hours, but an intravenous bolus of 5,000 IU followed by a 24-hour infusion of 450 IU/kg led to a return to baseline of OPG values at 8 hours.
      • Nybo M.
      • Rasmussen L.M.
      Osteoprotegerin released from the vascular wall by heparin mainly derives from vascular smooth muscle cells.
      • Vik A.
      • Brodin E.
      • Sveinbjornsson B.
      • Hansen J.B.
      Heparin induces mobilization of osteoprotegerin into the circulation.
      Because of this effect of heparin on serum OPG levels, clear tracking of heparin use within studies is especially important. In the study by Lindberg et al., 10,000 IU of heparin was used in the ambulance before PCI.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      In this case, the increase in OPG might or might not resolve before sampling just before PCI, depending on symptom-to-balloon time. Lindberg et al. noted this potential pitfall and explained that there was a lack of association between OPG and symptom-to-balloon time.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      However, it is unclear whether heparin was used during the PCI, which would cause an increase in OPG in the time period after PCI. In addition, it is unclear whether heparin was used as part of antithrombotic therapy after PCI, which could cause an increase in OPG in the day 1 and day 2 samples. Although the conclusion of the study, that circulating OPG levels are altered during STEMI treated with PCI is still entirely reasonable, the mechanism behind these altered OPG levels needs to be elucidated. Although much more work is needed to understand the pathophysiological mechanisms behind these associations, OPG is worth considering for its potential to fulfil the major characteristics of a good biomarker: to enhance diagnosing, prognosticating, or treating a given condition.
      • Braunwald E.
      Biomarkers in heart failure.
      • Putko B.N.
      • Yogasundaram H.
      • Oudit G.Y.
      The harbinger of mortality in heart failure with preserved ejection fraction: do GDF-15 levels reflect tandem, deterministic effects of fibrosis and inflammation?.

      Potential Implications and Conclusions

      Although the studies by Kalaycıoğlu et al.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      and Lindberg et al.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      are interesting additions to the growing evidence that the TNF superfamily is one of the major players in cardiovascular pathophysiology, more general questions that are common to biomarker studies emerge. Biomarker studies, especially of circulating biomarkers, provide limited mechanistic insights: multiple biomarkers might be observed in tandem, but the complex interplay of feedback loops, genetic modifiers, and cofactors makes elucidating pathophysiology difficult. Much of the evidence gleaned from biomarker studies is thus correlative in nature, and must be complemented by basic investigations to determine the order of pathophysiological events, or the significance of observed changes in biomarkers. Another potential pitfall with biomarkers is their use as surrogates of gold-standard measures. The suggestion that OPG, or other biomarkers, be used as surrogates for echocardiographic measures is not entirely agreeable. Echocardiography epitomizes a gold-standard technology in cardiovascular medicine that should not be replaced by surrogates: it is relatively inexpensive, safe, and widely available, does not expose patients to ionizing radiation, and practice guidelines exist for its application in the evaluation of various cardiovascular disorders.
      In conclusion, the question posed in the title of this editorial should be pause for scientists and clinicians alike to be cautiously optimistic about how much we can learn from biomarkers. Although the reports by Kalaycıoğlu et al. and Lindberg et al.
      • Kalaycıoğlu E.
      • Gökdeniz T.
      • Aykan AÇ
      • et al.
      Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
      • Lindberg S.
      • Jensen J.S.
      • Hoffmann S.
      • et al.
      Osteoprotegerin levels change during STEMI and reflect cardiac function.
      and reports from our group and others
      • Marti C.N.
      • Khan H.
      • Mann D.L.
      • et al.
      Soluble tumor necrosis factor receptors and heart failure risk in older adults: Health, Aging, and Body Composition (Health ABC) Study.
      • Putko B.N.
      • Wang Z.
      • Lo J.
      • et al.
      Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.
      have implicated various members of the TNF superfamily in cardiovascular disorders and their common outcome, HF, questions remain before confirming that cardiovascular pathophysiology is indeed a TNF superfamily affair.

      Acknowledgements

      Brendan N. Putko and Haran Yogasundaram contributed equally to this work.

      Funding Sources

      Gavin Y. Oudit is supported by operating grants from the Canadian Institute of Health Research, Heart and Stroke Foundation of Canada , and Alberta Innovates-Health Solutions.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Braunwald E.
        Biomarkers in heart failure.
        N Engl J Med. 2008; 358: 2148-2159
        • Ridker P.M.
        • Luscher T.F.
        Anti-inflammatory therapies for cardiovascular disease.
        Eur Heart J. 2014; 35: 1782-1791
        • Marti C.N.
        • Khan H.
        • Mann D.L.
        • et al.
        Soluble tumor necrosis factor receptors and heart failure risk in older adults: Health, Aging, and Body Composition (Health ABC) Study.
        Circ Heart Fail. 2014; 7: 5-11
        • Putko B.N.
        • Wang Z.
        • Lo J.
        • et al.
        Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.
        PLoS One. 2014; 9: e99495
        • Paulus W.J.
        • Tschope C.
        A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
        J Am Coll Cardiol. 2013; 62: 263-271
        • Van Campenhout A.
        • Golledge J.
        Osteoprotegerin, vascular calcification and atherosclerosis.
        Atherosclerosis. 2009; 204: 321-329
        • Collin-Osdoby P.
        Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.
        Circ Res. 2004; 95: 1046-1057
        • Montagnana M.
        • Lippi G.
        • Danese E.
        • Guidi G.C.
        The role of osteoprotegerin in cardiovascular disease.
        Ann Med. 2013; 45: 254-264
        • Gupta S.
        • Drazner M.H.
        • de Lemos J.A.
        Newer biomarkers in heart failure.
        Heart Fail Clin. 2009; 5: 579-588
        • O’Sullivan E.P.
        • Ashley D.T.
        • Davenport C.
        • et al.
        Osteoprotegerin and biomarkers of vascular inflammation in type 2 diabetes.
        Diabetes Metab Res Rev. 2010; 26: 496-502
        • Kong Y.Y.
        • Feige U.
        • Sarosi I.
        • et al.
        Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
        Nature. 1999; 402: 304-309
        • Min H.
        • Morony S.
        • Sarosi I.
        • et al.
        Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.
        J Exp Med. 2000; 192: 463-474
        • Zauli G.
        • Secchiero P.
        The role of the trail/trail receptors system in hematopoiesis and endothelial cell biology.
        Cytokine Growth Factor Rev. 2006; 17: 245-257
        • Kalaycıoğlu E.
        • Gökdeniz T.
        • Aykan AÇ
        • et al.
        Osteoprotegerin is associated with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study.
        Can J Cardiol. 2014; 30: 1529-1534
        • Lindberg S.
        • Jensen J.S.
        • Hoffmann S.
        • et al.
        Osteoprotegerin levels change during STEMI and reflect cardiac function.
        Can J Cardiol. 2014; 30: 1523-1528
        • Nybo M.
        • Rasmussen L.M.
        Osteoprotegerin released from the vascular wall by heparin mainly derives from vascular smooth muscle cells.
        Atherosclerosis. 2008; 201: 33-35
        • Vik A.
        • Brodin E.
        • Sveinbjornsson B.
        • Hansen J.B.
        Heparin induces mobilization of osteoprotegerin into the circulation.
        Thromb Haemost. 2007; 98: 148-154
        • Putko B.N.
        • Yogasundaram H.
        • Oudit G.Y.
        The harbinger of mortality in heart failure with preserved ejection fraction: do GDF-15 levels reflect tandem, deterministic effects of fibrosis and inflammation?.
        Can J Cardiol. 2014; 30: 264-266