Abstract
Elevated levels of circulating cobalt ions have been linked with a wide range of systemic complications including neurological, endocrine, and cardiovascular symptoms. Case reports of patients with elevated blood cobalt ions have described significant cardiovascular complications including cardiomyopathy. However, correlation between the actual level of circulating cobalt and extent of cardiovascular injury has not previously been performed. This review examines evidence from the literature for a link between elevated blood cobalt levels secondary to metal-on-metal (MoM) hip arthroplasties and cardiomyopathy. Correlation between low, moderate, and high blood cobalt with cardiovascular complications has been considered. Elevated blood cobalt at levels over 250 µg/l have been shown to be a risk factor for developing systemic complications and published case reports document cardiomyopathy, cardiac transplantation, and death in patients with severely elevated blood cobalt ions. However, it is not clear that there is a hard cut-off value and cardiac dysfunction may occur at lower levels. Clinical and laboratory research has found conflicting evidence of cobalt-induced cardiomyopathy in patients with MoM hips. Further work needs to be done to clarify the link between severely elevated blood cobalt ions and cardiomyopathy.
Cite this article: Bone Joint Res 2021;10(6):340–347.
Article focus
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A review of the link between elevated blood cobalt ions and cardiomyopathy.
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A summary of the relevant case reports.
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Analysis of recent clinical and laboratory studies.
Key messages
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Elevated blood cobalt levels greater than 250 µg/l appears to be a risk factor for cardiomyopathy.
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It is not clear if there is a cut-off value and cardiac dysfunction can occur at lower levels of circulating cobalt.
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Cobalt-induced cardiomyopathy is an infrequent but serious complication of metal-on-metal hip arthroplasty.
Strengths and limitations
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A review of case reports and retrospective studies.
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Clinical and laboratory research has found conflicting evidence for cobalt as a risk factor for cardiomyopathy in patients with metal-on-metal hip arthroplasties.
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Further studies required to clarify link between elevated blood cobalt ions and cardiomyopathy.
Introduction
Metal-on-metal (MoM) hip arthroplasties are known to have higher failure rates than metal-on-polyethylene (MoP) or ceramic-on-ceramic (CoC) total hip arthroplasties (THAs).1 As a consequence MoM hip arthroplasties accounted for less than 1% of hip arthroplasties performed in the UK last year,2 down 20% from their peak in 2005.3 When MoM hips fail they release cobalt and chromium ions into the local tissues and the bloodstream. Detection of these ions in samples of whole blood plays an important role in the screening for failing MoM hips.4 Elevated levels of circulating cobalt ions have been linked with a wide range of systemic complications including neurological, endocrine, and cardiovascular symptoms.5,6 There have been isolated case reports of patients with elevated blood cobalt ions suffering considerable cardiovascular complications including cardiomyopathy. However, clinical and laboratory research has found conflicting evidence of cobalt induced cardiomyopathy in patients with MoM hips. Here we present an up-to-date review of the evidence linking elevated blood cobalt ions to cardiomyopathy.
Metal-on-metal ion levels
MoM arthroplasties release cobalt and chromium ions which can cause local tissue damage and are absorbed into the blood stream.7 Laboratory values for metal ions in the blood are given as either parts per billion (ppb) or micrograms per litre (µg/l) and these values are equivalent and interchangeable. Normal blood cobalt levels for the unaffected population are below 0.51 µg/l,8 and well-functioning MoM hips have blood cobalt levels of up to 2 µg/l.9 Higher metal ion levels in the blood reflect a poorly functioning MoM implant10 with an increased risk of complication,11 and the Medicines and Healthcare products Regulatory Agency (MHRA) guidance recommends using whole blood ion levels of 7 ppb (7 µg/l) as a screening tool for failing MoM arthroplasties.4,7 This figure was derived from a 2009 study by Hart et al,12 which analyzed the effect of cobalt and chromium ions on T lymphocytes in well-functioning MoM hips and was later shown to have a specificity of 89% and sensitivity of 52% for detecting an unexplained failing MoM implant.13 Further studies have attempted to validate this figure with various ion levels being suggested as more sensitive or specific screening tools.9,14-16 Implant-specific ion levels have been proposed,17 but the heterogeneity of MoM implants makes this an impractical screening tool. While the MHRA recommends using whole blood to report cobalt levels, serum has been used in most clinical trials.18 While similar, these values are not interchangeable and care should be taken when interpreting values.19,20
Mechanism of cobalt cardiotoxicity
Cobalt is a widespread trace metal, which is the metallic component of Vitamin B12 but can be acutely cytotoxic in larger doses.21 Cobalt-induced cardiomyopathy is a dilated cardiomyopathy similar to idiopathic, non-ischaemic cardiomyopathy,22 and is diagnosed by demonstration of biventricular dilatation and systolic dysfunction in the presence of elevated blood or tissue cobalt and the subsequent normalization of cardiac structure and function when cobalt levels return to normal.23 It has a rapid onset and progression and a high short-term mortality rate, but survivors can experience complete cardiac and clinical recovery once cobalt has been removed from their system.23
The cardiotoxic effects of cobalt have been proposed to be due to cobalt-induced alterations in cardiac calcium handling.21 Cobalt is a divalent cation similar to calcium (Ca2+) and has been shown to interfere with the binding of calcium to sarcolemmal proteins, and the transport of Ca2+ into cardiac myocytes. Several proteins dedicated to transporting divalent cations including Ca2+ into cardiac cells have been considered as a means of cobalt entry and it has been hypothesized that Co2+ may mimic Ca2+ and use similar transport routes.24 Transient receptor potential (TRP) channels belonging to the TRP superfamily of Ca2+ permeable channels have been suggested as a means of cobalt entering cardiac cells.25 Cobalt may also affect Ca2+-dependent intracellular proteins and enzymes that are pivotal to healthy cardiac function. One possible target for the cardiotoxic effects of cobalt could be calcium-/calmodulin-dependent protein kinase II (CaMKII). This Ca2+-dependent enzyme is a key mediator of healthy cardiac function but sustained activation results in adverse cardiac remodelling, inflammation, and dysfunction.26,27 As such it has been highlighted as a promising target for pharmacological inhibition in the treatment of heart disease. If Co2+ can directly or indirectly affect CaMKII activation, then it could exert a broad spectrum of detrimental effects on the heart via this well-recognized route. In addition to altering Ca2+ signalling, cobalt also interrupts the citric acid cycle and the generation of ATP by aerobic cellular respiration.23 It inhibits the activity of respiratory chain enzymes and ATP production in mitochondria,28 producing a net result of depressed cardiac function and altered cardiac cell structure.23,29 The toxic effects of cobalt are reversible as it does not change mitochondrial function30 or cardiac contractility.31
Historical papers
Cobalt induced cardiomyopathy was first described at a March 1965 cardiology conference in Belgium.32 The effects of cobalt were reported in North American beer drinkers who developed acute cardiomyopathy after cobalt was added as a foam stabilizer to their beer of choice.33,34 The amount of cobalt consumed by these patients was less than regularly prescribed nutritional supplements of the time. However, the individual patient’s length of alcohol excess prior to exposure to cobalt35 and their general nutritional deficit, specifically a lack of protein, zinc, and thiamine,34 were bigger predictors of a fatal outcome than the actual dose of cobalt they were exposed to. Cobalt-induced cardiomyopathy has also been reported in patients on haemodialysis receiving cobalt supplementation for anaemia,36 and in patients who handled powdered cobalt in their industrial occupation.37
Cardiomyopathy associated with metal-on-metal implants
Cobalt-induced cardiomyopathy secondary to cobalt chrome hip arthroplasties has been described in case reports (Table I), most of which were summarized in a recent review article.38 Cases of cobalt-induced cardiomyopathy have been reported from primary MoM hip arthroplasties,39-51 revision MoM arthroplasty,39-41 and revision MoP hip arthroplasties following a fracture of a ceramic articulation.52-61 Patients have presented between two months56 and ten years48 postoperatively with a range of cardiac symptoms including dyspnoea,39-44,46,47,49,53,55,58,59,61 heart failure,48,50,51,57 orthopnoea,47,53 fatigue,45,52,53,59,60 and cardiomegaly.62 Blood cobalt levels have also varied greatly, with symptomatic patients having a serum cobalt level as low as 13 µg/l42 and as high as 6,521 µg/l.52 Echocardiographs most commonly demonstrated a decreased left ventricular ejection fraction42,43,45-47,49-51,53,57-59,61 but also a dilated atrium,42 diastolic dysfunction,39-41,47 left ventricular hypertrophy,53,56,62 and a pericardial effusion.52,53 Outcomes have varied from full recovery after revision surgery39-42,44,47,53,56,58,60 or chelation therapy,53,57,61,62 to left ventricular assist device implantation,49,50 to cardiac transplantation43,45,48,53,54 or death.46,51,52,55,56,58
Table I.
A summary of cases reporting cobalt-induced cardiomyopathy. The normal recorded values for left ventricular ejection fraction were 55% to 70%.
| Cardiac presentation | Implant | Sample | Cobalt (µg/l) | Length of follow-up | Echocardiogram results | Outcome |
|---|---|---|---|---|---|---|
| Dyspnoea, neurotoxicity39-41 | Primary MoM arthroplasty | Serum | 122 | 18 months | Diastolic dysfunction | Revision, symptoms resolved |
| Dyspnoea39-41 | Revision MoM arthroplasty | Serum | 23 | 43 months | N/A | Revision, symptoms resolved |
| Dyspnoea, chest pain42 | Primary MoM arthroplasty | Serum | 13 | 6 years | Dilated atrium, decreased LVEF (21%) | Revision, LVEF (45%) |
| Exertional dyspnoea, cough43 | Primary bilateral MoM resurfacings | Serum | 287 | 4 years | Decreased LVEF (10%) | Heart transplant, hip revision |
| Cardiomyopathy62 | Failed CoC revised to MoM | Serum | 506 | N/A | Left ventricular hypertrophy | Chelation therapy, revision, symptoms improved |
| Dyspnoea44 | Primary MoM resurfacing | Serum | 258 | 3 years | N/A | Revision surgery, symptoms resolved |
| Exertional chest tightness, fatigue45 | Primary bilateral MoM arthroplasties | Whole blood | 189 | 11 months | Decreased LVEF (30%) | Heart transplant, bilateral hip revisions |
| Dyspnoea46 | Primary bilateral MoM arthroplasties | Did not specify | 200 to 300 | 2 years | Decreased LVEF (10% to 15%) | Death |
| Fatigue52 | Failed CoC revised to MoP | Whole blood | 6,521 | 6 months | Pericardial effusion | Death |
| Dyspnoea, fatigue53 | Failed CoC revised to MoP | Serum | 489 | 6 years | Left ventricular hypertrophy, pericardial effusion, decreased LVEF (13%) | Chelation, revision normal LVEF (58%). |
| Dyspnoea, orthopnea53 | Failed CoC revised to MoP | Serum | 112 | 6 years | Decreased LVEF (24%), pericardial effusion | Revision surgery, chelation, heart transplantation |
| Cardiogenic shock54 | Failed CoC revised to MoP | Serum | 652 | N/A | N/A | Heart transplant |
| Cardiomyopathy56 | Failed CoP revised to MoP | Serum | 625 | 2 months | Left ventricular hypertrophy | Revision surgery, symptoms resolved |
| Dyspnoea55 | Failed CoC revised to MoP | Whole blood | 641 | 10 months | LVEF 15% to 20% | Death |
| Dyspnoea, orthopnoea47 | MoM | Whole blood | 246 | 4 years | Diastolic dysfunction, decreased LVEF (20%) | Revision surgery, symptoms resolved, LVEF 45% to 50% |
| Heart failure48 | MoM | Serum | 169 | 10 years | N/A | Heart transplantation, revision surgery |
| Exertional dyspnoea49 | Bilateral MoM | Did not specify | 156 | 2 years | Dilated cardiomyopathy with decreased LVEF (20%) | LVAD inserted, no improvement, bilateral hip revisions 1 year later, symptoms resolved |
| Heart failure50 | Bilateral MoM | Serum | 120 | N/A | Decreased LVEF (36%) | Bilateral revision surgery, LVAD |
| Heart failure51 | MoM | Serum | 200 to 300 | N/A | Decreased LVEF (14%) | Death |
| Heart failure57 | Failed CoC revised to MoP | Whole blood | 780 | 2 years | Decreased LVEF (25%) | Chelation therapy, revision surgery, LVEF 40% |
| Dyspnoea, chest tightness58 | Failed CoC revised to MoP | N/A | 45 | 8 years | Dilated cardiomyopathy, reduced LVEF (28%) | Revision surgery, symptoms resolved |
| Dyspnoea, fatigue59 | Failed CoC revised to MoP | Serum | 373 | 3 years | Dilated cardiomyopathy, severe left ventricular dysfunction, LVEF (20%) | Death |
| Fatigue, tachycardia60 | Failed CoC revised to MoP | Did not specify | 788 | 8 years | N/A | Revision surgery, symptoms resolved |
| Dyspnoea61 | Failed CoC revised to MoP | Did not specify | 397 | N/A | Decreased LVEF (25%) | Chelation therapy, revision surgery, symptoms resolved |
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CoC, ceramic-on-ceramic; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MoM, metal-on-metal; MoP, metal-on-polyethylene; N/A, not available.
Discussion
The case reports have shown a correlation between blood cobalt levels and cardiovascular complications63 and mortality (Table II). There is no clear cut-off cobalt level above which risks of complications increase, however an analysis of the published case reports available in 2014 found that ten patients had systemic complications attributable to elevated cobalt and all ten had blood cobalt levels above 250 µg/l.5 Another review of the medical and toxicology literature suggested a cut-off level for blood cobalt of 300 µg/l above which otherwise healthy individuals risk developing serious systemic complications,64 and they suggested that patients with nutritional deficiencies such as a hypoalbuminaemia were at risk of systemic complications below 300 µg/l.
Table II.
A summary of case reports according to documented blood cobalt level. The normal recorded values for left ventricular ejection fraction were 55% to 70%.
| Blood cobalt levels (µg/l) | Patients, n | Mean blood cobalt levels, µg/l (range) | Cardiac presentation | Implants | Echocardiography results | Outcome | References |
|---|---|---|---|---|---|---|---|
| > 250 | 11 | 1,049 (258 to 6521) | Cardiogenic shock (1 case), cardiomyopathy (2 cases), dyspnoea (5 cases), fatigue (4 cases), exertional dyspnoea and cough (1 case), | CoC revised to MoP (7 cases), CoP revised to MoP (1 case), primary MoM resurfacing (1 case), bilateral primary MoM resurfacings (1 case) |
Decreased LVEF (5 cases), mean LVEF reported was 17% (range 10% to 25%), pericardial effusion (2 cases), LVH (3 cases) |
Death (27%, 3 cases), chelation and revision resolved symptoms (27%), revision resolved symptoms (27%), heart transplantation (18%, 2 cases) |
43,44,52-56,59-61 |
| 200 to 300 | 2 | Unknown | Dyspnoea, heart failure | Primary bilateral MoM resurfacing, primary MoM resurfacing |
Decreased LVEF, mean LVEF 13% | Death (100%, both cases) | 46,51 |
| < 250 | 10 | 119.5 (13 to 246) | Heart failure (2 cases), dyspnoea (5 cases), exertional chest pain (3 cases), orthopnoea (1 case) |
Bilateral primary MoM arthroplasties (3 cases), primary MoM arthroplasties (4 cases), CoC revised to MoP (2 cases), revision MoM arthroplasty (1 case) |
Decreased LVEF (7 cases), mean LVEF reported was 24% (range 10% to 36%), diastolic dysfunction (2 cases), dilated cardiomyopathy (2 cases), pericardial effusion (1 case) |
Heart transplantation and revision (30% 3 cases), revision resolved symptoms (60% 6 cases), LVAD and revision (10%, 1 case) |
39-41,45,47-50,53,58 |
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CoC, ceramic-on-ceramic; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MoM, metal-on-metal; MoP, metal-on-polyethylene.
A review of the literature suggests that patients with blood cobalt of all levels are at risk of cobalt-induced cardiomyopathy, however there has been no consistency of findings between clinical studies (Table III). The case reports compiled in this present review demonstrate that reversible cardiac complications confirmed on echocardiogram can be present in patients with blood cobalt levels as low as 13 µg/l.42 Asymptomatic patients with lower levels of circulating cobalt can still suffer cardiac damage. A comparison of patients with and without MoM hip resurfacings using echocardiography and blood tests found a reduced cardiac ejection fraction and increased end diastolic cardiac volume in the MoM patients (mean blood cobalt level of 1.75 µg/l) at a mean of eight years postoperatively. There were no such changes in the control group.65 A separate cohort of MoM patients were assessed by cardiac MRI eight years postoperatively and asymptomatic patients with minimally elevated metal ion levels were found to have statistically significant but clinically insignificant mild cardiac changes. This suggests that adverse cardiac processes may be at work in asymptomatic MoM patients, even when they have normal or minimally elevated blood cobalt levels.66 Population-wide studies have demonstrated cardiac complications in MoM patients without studying individual blood cobalt levels. A retrospective cohort study of the Australian Government Department of Veterans’ Affairs demonstrated that men with an ASR XL THA had a statistically significant higher rate of hospitalization for heart failure than men with a MoP THA. This higher rate of complications was not demonstrated in women or in men with other types of MoM implants.67 The French health insurance database was used to identify all MoP, ceramic-on-polyethylene (CoP), MoM, and CoC THAs performed in France between 2008 and 2011 and follow them up until 2015. All new diagnoses of dilated cardiomyopathy or heart failure in that time were included in the study. Due to the heterogeneity of implants in such a large study the authors performed two separate comparisons: soft-bearing THA MoP versus CoP, and hard-bearing implants MoM versus CoC. A small increase in heart complications in metal bearing surfaces compared to non-metal surfaces was identified after controlling for confounding factors and this was most pronounced in MoM versus CoC in patients over 75 years of age.68 These studies represent a range of different experimental designs including cross-sectional observational studies65,66 and population-based cohort studies,67,68 and they find broadly similar results.
Table III.
A summary of published research into cardiovascular complications of metal-on-metal hip arthroplasties.
| Reference | Study design | Study group | Control group | Study group blood cobalt, µg/l | Findings |
|---|---|---|---|---|---|
| Prentice et al65 | Cross-section associational study | Aymptomatic patients with MoM hip resurfacings | Age- and sex-matched patients with non-MoM hip arthroplasties | Whole blood cobalt 1.75 µg/l compared to 0.38 µg/l in control group | Cardiac ejection fraction reduced and end diastolic volume increased in MoM group |
| Lodge et al69 | Single centre, non-randomized, observational study | Patients with MoM hip arthroplasties in 3 groups, separated by cobalt levels | Age-matched controls with non-MoM hip arthroplasties | Plasma cobalt in 3 study groups 14.6 µg/l, 7.8 µg/l, and 1.3 µg/l compared to 0.6 µg/l in control group | Increasing cobalt values associated with increased heart volume but not with cardiac dysfunction and no clinical difference between groups was demonstrated |
| Berber et al70 | Prospective, single centre, blinded trial | MoM bearing with elevated blood cobalt ions | MoM bearing with low blood cobalt ions and CoC bearing | Whole blood cobalt 30 µg/l and 2.47 µg/l in respective MoM groups compared to 0.17 µg/l in control group | No relationship between cobalt levels and ejection fraction. No differences between groups in the left atrial or ventricle size, B-type natriuretic peptide level, or troponin level, and all values were within normal ranges |
| van Lingen et al71 | Longitudinal cohort study | 10 asymptomatic MoM patients with highest cobalt levels out of a population of 643 MoM patients | None | Whole blood cobalt 18 to 153 µg/l (mean 46.8 µg/l) | No signs or symptoms of cardiomyopathy could be identified |
| Gillam et al67 | Observational cohort study from Australian Government Department of Veteran’s Affairs health claims database | 63 men with an ASR XL THA | 1,502 men with MoP THA, 199 men with other MoM THAs, 2,044 women with MoP, 58 women with ASR XL THA, and 153 women with other MoM THAs | Not recorded | Men with an ASR XL THA had a statistically significant higher rate of hospitalization for heart failure than men with a MoP THA. This higher rate of heart failure was not demonstrated in women or in men with other types of MoM implants |
| Lassalle et al68 | Cohort study in the French National Health Insurance Databases | 11,298 patients with MoM hips | 93,581 patients with MoP, 58,095 patients with CoP, 92,376 patients with CoC | Not recorded | Small increase in heart complications in metal bearing surfaces compared to non-metal surfaces was identified after controlling for confounding factors, most pronounced in MoM vs CoC in women and men over 75 years of age |
| Goodnough et al72 | Analysis of the Standard Analytics Files database in the USA | 29,483 patients with MoM hips | 24,175 patients with non-MoM hips | Not recorded | At 5 years there was no difference in cardiac complications such as cardiac failure, arrhythmia, acute myocardial infarction, or cardiomyopathy |
| Sabah et al73 | Linkage study between the National Joint Registry, Hospital Episodes Statistics and records of the Office for National Statistics on death | 53,529 patients with MoM hips | 482,247 patients with non-MoM hips | Not recorded | At 7 years the risk of cardiac failure was lower in the MoM cohort compared with the non-MoM cohort. When the groups were matched their risk of cardiac failure was similar. |
| Juneau et al66 | Cross-section study using cardiac magnetic resonance | 20 MoM resurfacing patients, 10 bilateral, 10 unilateral | 10 case-matched non-MoM total hip arthroplasty patients | Mean serum cobalt 1.3 µg/l in study group compared to 0.18 µg/l in control group | None of the MoM patients showed clinically significant cardiac functional abnormality. The MoM patients had larger end diastolic volumes. There was a small decrease in T2 time in the MoM patients. Higher metal ion levels were associated with larger LV volumes and with shorter T2 time. |
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CoC, ceramic-on-ceramic; CoP, ceramic-on-polyethylene; LV, left ventricular; MoM, metal-on-metal; MoP, metal-on-polyethylene; THA, total hip arthroplasty.
Other studies have failed to reproduce negative cardiac effects in patients with elevated blood cobalt levels or across MoM populations despite using similar methodology to the previously described research. A total of 95 MoM patients with previously recorded serum cobalt levels of > 7 µg/l were compared to 15 age- and comorbidity-matched patients without a MoM prosthesis. Plasma cobalt levels were rechecked and used to divide the study patients into three groups with mean serum cobalt levels of 14.6 µg/l, 7.8 µg/l, and 1.3 µg/l, respectively. The control group had a mean serum cobalt level of 0.6 µg/l. All patients underwent echocardiography measurements, which found that increasing cobalt levels were associated with increased heart volume but not with cardiac dysfunction, and no clinical difference between groups could be demonstrated.69 No clinically significant correlation between blood ion levels and any cardiac tests were demonstrated when patients with MoM implants with elevated blood ion levels (mean 30 µg/l), MoM implants with low blood ion levels (mean 2.47 µg/l), and CoC implants (mean 0.17 µg/l) were assessed using cardiac MRI and echocardiography.70 Ten Dutch patients with large head MoM hip arthroplasties and a mean whole blood cobalt level of 46.8 µg/l were followed up for a mean of 4.2 years without any signs or symptoms of cardiomyopathy.71 These studies were variously described as a single centre, non-randomized, observational study,69 a prospective, single centre, blinded trial,70 and a longitudinal cohort study,71 but they were all fairly analogous to the cross-sectional observational studies described above and were unable to demonstrate similar findings. Similarly, population-based studies performed in the USA72 and the UK73 did not have similar findings to the Australian67 and French68 studies. An analysis of the Standards Analytics Files database in the USA compared every patient who had undergone a MoM hip arthroplasty between 2005 and 2012 to an age- and sex-matched cohort who had undergone a non-MoM hip arthroplasty in the same period. They found that at five years there was no difference in cardiac complications such as cardiac failure, arrhythmia, acute myocardial infarction, or cardiomyopathy.72 A retrospective analysis of over half a million hip arthroplasty patients in the UK’s National Joint Registry, including 53,529 MoM patients, demonstrated no association between a MoM implant and cardiac failure at seven years postoperatively.73 While there were subtle differences in methodology, none of the population-based studies selected patients for their cobalt levels. Despite the wide range of study designs, none have as yet recreated or studied the population described in the case reports: patients with elevated cobalt over 250 µg/l.
There is a clear requirement for future experimental study design to take a more focused approach with stringent inclusion/exclusion criteria around cobalt levels being considered. Elevated cobalt at levels over 250 µg/l have been shown to be a risk factor for developing systemic complications,5 and published case reports document cardiac transplantation43,45,48,53,54 and death46,51,52,55,59 in patients with severely elevated blood cobalt ions. Currently it is unclear whether there is a hard cut-off value and cardiac dysfunction may occur at cobalt levels less than 250 µg/l (Table II). However, none of the experimental research conducted to date has specifically studied patients with blood cobalt levels over 250 µg/l (Table III). This may account for the inability of previous experimental studies to reproduce the severity of cardiac complications described in the case reports outlined here. Interestingly, a number of animal-/cell-based studies have used higher levels of cobalt to examine potential cardiotoxic effects.24 While these studies may not exactly recreate clinical levels of cobalt, they demonstrate the severe impact that high levels of cobalt may have on cardiac viability and function. Future experimental design needs to include studies that focus only on examining patients with high (> 250 µg/l) cobalt levels. An important aspect of cobalt-induced cardiomyopathy is that the awareness of this phenomenon is low. There may be patients with cardiomyopathy in which the link to failing MoM hip implants has not been acknowledged. This present review presents 24 case reports of cobalt-induced cardiomyopathy following MoM hip arthroplasty, and this is a small proportion of the millions of MoM hips implanted worldwide. Future studies should focus on identifying those patients at risk. In order to do this, cardiac MRI and current biomarkers for cardiac injury, such as Troponin-T and Brain Natriuretic Peptide biomarkers, should be performed to assess for cardiomyopathy in all patients with elevated blood cobalt levels > 250 µg/l. Indeed, cardiologists and orthopaedic surgeons should consider investigating for cardiomyopathy in MoM patients with elevated blood cobalt of all levels. To overcome the design weaknesses in the experimental studies performed to date, and analyze the true incidence of this rare but devastating complication in more detail, future studies should aim to capture all patients in a defined MoM population with cobalt levels greater than 250 µg/l. Due to the small numbers involved this should be on a regional or national basis.
In conclusion, despite a growing number of cases reported in the literature, it remains unclear from experimental studies whether circulating levels of cobalt correlate directly with cardiac dysfunction. Further work needs to be done to clarify the link between elevated blood cobalt above 250 µg/l and cardiomyopathy. Cobalt-mediated effects on cardiac Ca2+ handling proteins should be studied to identify specific cellular changes that occur prior to clinical dysfunction. All patients with blood cobalt levels over 250 µg/l should have thorough, routine cardiological investigation.
References
1. Smith AJ , Dieppe P , Vernon K , Porter M , Blom AW , National Joint Registry of England and Wales . Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National joint registry of England and Wales . Lancet . 2012 ; 379 ( 9822 ): 1199 – 1204 . Crossref PubMed Google Scholar
2. NJR . 16th annual report . 2019 . National Joint Registry . reports.njrcentre.org.uk/portals/0/pdfdownloads/njr%2016th%20annual%20report%202019.pdf (date last accessed 7 April 2021 ). Google Scholar
3. NJR . National joint registry 14th annual report . 2017 . National Joint Registry . www.hqip.org.uk/resource/national-joint-registry-14th-annual-report-2017/#.YGb3t7CSlPY (date last accessed 7 April 2021 ). Google Scholar
4. No authors listed . MHRA (2017) medical device alert: all metal-on-metal (mom) hip replacements: updated advice for follow-up of patients (MDA/2017/018) . https://www.gov.uk/drug-device-alerts/all-metal-on-metal-mom-hip-replacements-updated-advice-for-follow-up-of-patients Google Scholar
5. Bradberry SM , Wilkinson JM , Ferner RE . Systemic toxicity related to metal hip prostheses . Clin Toxicol . 2014 ; 52 ( 8 ): 837 – 847 . Crossref PubMed Google Scholar
6. Finley BL , Monnot AD , Gaffney SH , Paustenbach DJ . Dose-Response relationships for blood cobalt concentrations and health effects: a review of the literature and application of a biokinetic model . J Toxicol Environ Health B Crit Rev . 2012 ; 15 ( 8 ): 493 – 523 . Crossref PubMed Google Scholar
7. Hughes L , Chamberlain K , Sloan A , Choudry Q , Department of Trauma and Orthopaedics, Royal Blackburn Hospital, Blackburn, BB2 3HH, United Kingdom. . Metal-On-Metal hip arthroplasty – development and demise . Int J Orthop . 2018 ; 5 ( 5 ): 961 – 967 . Google Scholar
8. Sampson B , Hart A . Clinical usefulness of blood metal measurements to assess the failure of metal-on-metal hip implants . Ann Clin Biochem . 2012 ; 49 ( Pt 2 ): 118 – 131 . Crossref PubMed Google Scholar
9. Haddad FS , Thakrar RR , Hart AJ , et al. Metal-On-Metal bearings: the evidence so far . J Bone Joint Surg Br . 2011 ; 93-B ( 5 ): 572 – 579 . Crossref PubMed Google Scholar
10. Günther K-P , Lützner J , Hannemann F , et al. [Update on metal-on-metal hip joints] . Orthopade . 2013 ; 42 ( 5 ): 373 – 387 . [Article in German]CrossrefPubMed Google Scholar
11. Hailer NP , Bengtsson M , Lundberg C , Milbrink J . High metal ion levels after use of the ASR™ device correlate with development of pseudotumors and T cell activation . Clin Orthop Relat Res . 2014 ; 472 ( 3 ): 953 – 961 . Crossref PubMed Google Scholar
12. Hart AJ , Skinner JA , Winship P , et al. Circulating levels of cobalt and chromium from metal-on-metal hip replacement are associated with CD8+ T-cell lymphopenia . J Bone Joint Surg Br . 2009 ; 91-B ( 6 ): 835 – 842 . Crossref PubMed Google Scholar
13. Hart AJ , Sabah SA , Bandi AS , et al. Sensitivity and specificity of blood cobalt and chromium metal ions for predicting failure of metal-on-metal hip replacement . J Bone Joint Surg Br . 2011 ; 93-B ( 10 ): 1308 – 1313 . Crossref PubMed Google Scholar
14. Van Der Staeten C , Grammatopoulos G , Gill HS , Calistri A , Campbell P , De Smet KA . The 2012 Otto Aufranc Award: the interpretation of metal ion levels in unilateral and bilateral hip resurfacing . Clin Orthop Relat Res . 2013 ; 471 ( 2 ): 377 – 385 . Crossref PubMed Google Scholar
15. Sidaginamale RP , Joyce TJ , Lord JK , et al. Blood metal ion testing is an effective screening tool to identify poorly performing metal-on-metal bearing surfaces . Bone Joint Res . 2013 ; 2 ( 5 ): 84 – 95 . Google Scholar
16. De Smet K , De Haan R , Calistri A , et al. Metal ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing . J Bone Joint Surg Am . 2008 ; 90-A ( Suppl 4 ): 202 – 208 . Crossref PubMed Google Scholar
17. Matharu GS , Berryman F , Brash L , Pynsent PB , Treacy RB , Dunlop DJ . The effectiveness of blood metal ions in identifying patients with unilateral Birmingham hip resurfacing and Corail-Pinnacle metal-on-metal hip implants at risk of adverse reactions to metal debris . J Bone Joint Surg Am . 2016 ; 98-A ( 8 ): 617 – 626 . Crossref PubMed Google Scholar
18. Hartmann A , Hannemann F , Lützner J , et al. Metal ion concentrations in body fluids after implantation of hip replacements with metal-on-metal bearing-systematic review of clinical and epidemiological studies . PLoS One . 2013 ; 8 ( 8 ): e70359 . Google Scholar
19. Smolders JM , Bisseling P , Hol A , Van Der Straeten C , Schreurs BW , van Susante JL . Metal ion interpretation in resurfacing versus conventional hip arthroplasty and in whole blood versus serum. How should we interpret metal ion data . Hip Int . 2011 ; 21 ( 5 ): 587 – 595 . Crossref PubMed Google Scholar
20. Daniel J , Ziaee H , Pynsent PB , McMinn DJW . The validity of serum levels as a surrogate measure of systemic exposure to metal ions in hip replacement . J Bone Joint Surg Br . 2007 ; 89-B ( 6 ): 736 – 741 . Crossref PubMed Google Scholar
21. Simonsen LO , Harbak H , Bennekou P . Cobalt metabolism and toxicology-a brief update . Sci Total Environ . 2012 ; 432 : 210 – 215 . Google Scholar
22. Hantson P . Mechanisms of toxic cardiomyopathy . Clin Toxicol . 2019 ; 57 ( 1 ): 1 – 9 . Crossref PubMed Google Scholar
23. Packer M . Cobalt cardiomyopathy: a critical reappraisal in light of a recent resurgence . Circ Heart Fail . 2016 ; 9 ( 12 ). Crossref PubMed Google Scholar
24. Laovitthayanggoon S , Henderson CJ , McCluskey C , et al. Cobalt administration causes reduced contractility with parallel increases in TRPC6 and TRPM7 transporter protein expression in adult rat hearts . Cardiovasc Toxicol . 2019 ; 19 ( 3 ): 276 – 286 . Crossref PubMed Google Scholar
25. Clyne N , Persson B , Havu N , Hultman E , Lins LE , Pehrsson SK . The intracellular distribution of cobalt in exposed and unexposed rat myocardium . Scand J Clin Lab Invest . 1990 ; 50 ( 6 ): 605 – 609 . Crossref PubMed Google Scholar
26. Zhang M , Gao H , Liu D , et al. CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair . Nat Cell Biol . 2019 ; 21 ( 9 ): 1152 – 1163 . Crossref PubMed Google Scholar
27. Khoo MS , Li J , Singh MV , et al. Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy . Circulation . 2006 ; 114 ( 13 ): 1352 – 1359 . Crossref PubMed Google Scholar
28. Clyne N , Hofman-Bang C , Haga Y , et al. Chronic cobalt exposure affects antioxidants and ATP production in rat myocardium . Scand J Clin Lab Invest . 2001 ; 61 ( 8 ): 609 – 614 . Crossref PubMed Google Scholar
29. Haga Y , Clyne N , Hatori N , Hoffman-Bang C , Pehrsson SK , Ryden L . Impaired myocardial function following chronic cobalt exposure in an isolated rat heart model . Trace Elem Electrolytes . 1996 ; 13 : 69 – 74 . Google Scholar
30. Endoh H , Kaneko T , Nakamura H , Doi K , Takahashi E . Improved cardiac contractile functions in hypoxia-reoxygenation in rats treated with low concentration Co(2+) . Am J Physiol Heart Circ Physiol . 2000 ; 279 ( 6 ): H2713 – H2719 . Crossref PubMed Google Scholar
31. Clyne N , Persson B , Havu N , Hultman E , Lins LE , Pehrsson SK . The intracellular distribution of cobalt in exposed and unexposed rat myocardium . Scand J Clin Lab Invest . 1990 ; 50 ( 6 ): 605 – 609 . Crossref PubMed Google Scholar
32. Kesteloot H , Roelandt J , Willems J , Claes JH , Joossens JV . An enquiry into the role of cobalt in the heart disease of chronic beer drinkers . Circulation . 1968 ; 37 : 854 – 864 . Crossref PubMed Google Scholar
33. Morin YL , Foley AR , Martineau G , Roussel J . Quebec beer-drinkers' cardiomyopathy: forty-eight cases . Can Med Assoc J . 1967 ; 97 ( 15 ): 881 – 883 . PubMed Google Scholar
34. Alexander CS . Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-eight cases . Am J Med . 1972 ; 53 ( 4 ): 395 – 417 . Crossref PubMed Google Scholar
35. Morin Y , Daniel P . Quebec beer-drinkers' cardiomyopathy . Etiological considerations Can Med Ass J . 1967 ; 97 ( 15 ): 926 – 928 . PubMed Google Scholar
36. Manifold IH , Platts MM , Kennedy A . Cobalt cardiomyopathy in a patient on maintenance haemodialysis . BMJ . 1978 ; 2 ( 6152 ): 1609 . Crossref PubMed Google Scholar
37. Kennedy A , Dornan JD , King R . Fatal myocardial disease associated with industrial exposure to cobalt . Lancet . 1981 ; 317 : 412 – 414 . Crossref PubMed Google Scholar
38. Umar M , Jahangir N , Faisal Khan M , Saeed Z , Sultan F , Sultan A . Cobalt cardiomyopathy in hip arthroplasty . Arthroplast Today . 2019 ; 5 ( 3 ): 371 – 375 . Crossref PubMed Google Scholar
39. Tower SS . Arthroprosthetic cobaltism associated with metal on metal hip implants . BMJ . 2012 ; 344 : e430 . Crossref PubMed Google Scholar
40. Tower SS . Arthroprosthetic cobaltism: neurological and cardiac manifestations in two patients with metal-on-metal arthroplasty: a case report . J Bone Joint Surg Am . 2010 ; 92-A ( 17 ): 2847 – 2851 . Crossref PubMed Google Scholar
41. McLaughlin J . Cobalt toxicity in two hip replacement . Patients State of Alaska Epidemiology Bulletin . 2010 ; 14 . Google Scholar
42. Machado C , Appelbe A , Wood R . Arthroprosthetic cobaltism and cardiomyopathy . Heart Lung Circ . 2012 ; 21 ( 11 ): 759 – 760 . Crossref PubMed Google Scholar
43. Allen LA , Ambardekar AV , Devaraj KM , Maleszewski JJ , Wolfel EE , problem-solving C . Missing elements of the history . N Engl J Med . 2014 ; 370 ( 6 ): 559 – 566 . Google Scholar
44. Mao X , Wong AA , Crawford RW . Cobalt toxicity-an emerging clinical problem in patients with metal-on-metal hip prostheses? Med J Aust . 2011 ; 194 ( 12 ): 649 – 651 . Crossref PubMed Google Scholar
45. Mosier BA , Maynard L , Sotereanos NG , Sewecke JJ . Progressive cardiomyopathy in a patient with elevated cobalt ion levels and bilateral metal-on-metal hip arthroplasties . Am J Orthop . 2016 ; 45 ( 3 ): E132 – E135 . PubMed Google Scholar
46. Martin JR , Spencer-Gardner L , Camp CL , Stulak JM , Sierra RJ . Cardiac cobaltism: a rare complication after bilateral metal-on-metal total hip arthroplasty . Arthroplast Today . 2015 ; 1 ( 4 ): 99 – 102 . Crossref PubMed Google Scholar
47. Tilney R , Burg MR , Sammut MA . Cobalt cardiomyopathy secondary to hip arthroplasty: an increasingly prevalent problem . Case Rep Cardiol . 2017 ; 2017 : 5434571 – 5434574 . Crossref PubMed Google Scholar
48. Moniz S , Hodgkinson S , Yates P . Cardiac transplant due to metal toxicity associated with hip arthroplasty . Arthroplast Today . 2017 ; 3 : 151 – 153 . Crossref PubMed Google Scholar
49. Charette RS , Neuwirth AL , Nelson CL . Arthroprosthetic cobaltism associated with cardiomyopathy . Arthroplast Today . 2017 ; 3 : 225 – 228 . Crossref PubMed Google Scholar
50. Samar HY , Doyle M , Williams RB , Yamrozik JA , Bunker M , Biederman RWW . Novel use of cardiac magnetic resonance imaging for the diagnosis of cobalt cardiomyopathy . JACC Cardiovasc Imaging . 2015 ; 8 : 1231 – 1232 . Crossref PubMed Google Scholar
51. Khan AH , Verma R , Bajpai A , Mackey-Bojack S . Unusual case of congestive heart failure: cardiac magnetic resonance imaging and histopathologic findings in cobalt cardiomyopathy . Circ Cardiovasc Imaging . 2015 ; 8 ( 6 ): e003352 . Crossref PubMed Google Scholar
52. Zywiel MG , Brandt J-M , Overgaard CB , Cheung AC , Turgeon TR , Syed KA . Fatal cardiomyopathy after revision total hip replacement for fracture of a ceramic liner . Bone Joint J . 2013 ; 95-B ( 1 ): 31 – 37 . Crossref PubMed Google Scholar
53. Choi HI , Hong JA , Kim MS , et al. Severe cardiomyopathy due to Arthroprosthetic Cobaltism: report of two cases with different outcomes . Cardiovasc Toxicol . 2019 ; 19 ( 1 ): 82 – 89 . Crossref PubMed Google Scholar
54. Sanz Pérez MI , Rico Villoras AM , Moreno Velasco A , Bartolomé García S , Campo Loarte J . Heart transplant secondary to cobalt toxicity after hip arthroplasty revision . Hip Int . 2019 ; 29 ( 4 ): NP1 – NP5 . Crossref PubMed Google Scholar
55. Fox KA , Phillips TM , Yanta JH , Abesamis MG . Fatal cobalt toxicity after total hip arthroplasty revision for fractured ceramic components . Clin Toxicol . 2016 ; 54 ( 9 ): 874 – 877 . Crossref PubMed Google Scholar
56. Oldenburg M , Wegner R , Baur X . Severe cobalt intoxication due to prosthesis wear in repeated total hip arthroplasty . J Arthroplasty . 2009 ; 24 ( 5 ): 825 : e15 – 825 . Crossref PubMed Google Scholar
57. Dahms K , Sharkova Y , Heitland P , Pankuweit S , Schaefer JR . Cobalt intoxication diagnosed with the help of Dr house . Lancet . 2014 ; 383 : 574 . Crossref PubMed Google Scholar
58. Vasukutty NL , Minhas THA . Systemic effects of cobalt toxicity after revision hip replacement can manifest in intermediate to long term follow-up . Hip Int . 2016 ; 26 : e31 – 34 . Crossref PubMed Google Scholar
59. Gautam D , Pande A , Malhotra R . Fatal Cobalt Cardiomyopathy Following Revision Total Hip Arthroplasty - A Brief Report with Review of Literature . Arch Bone Jt Surg . 2019 ; 7 ( 4 ): 379 – 383 . PubMed Google Scholar
60. Harris A , Johnson J , Mansuripur PK , Limbird R . Cobalt toxicity after revision to a metal-on-polyethylene total hip arthroplasty for fracture of ceramic acetabular component . Arthroplast Today . 2015 ; 1 ( 4 ): 89 – 91 . Crossref PubMed Google Scholar
61. Kim CH , Choi YH , Jeong MY , Chang JS , Yoon PW . Cobalt intoxication heart failure after revision total hip replacement for ceramic head fracture: a case report . Hip Pelvis . 2016 ; 28 ( 4 ): 259 – 263 . Crossref PubMed Google Scholar
62. Pelclova D , Sklensky M , Janicek P , Lach K . Severe cobalt intoxication following hip replacement revision: clinical features and outcome . Clin Toxicol . 2012 ; 50 ( 4 ): 262 – 265 . Crossref PubMed Google Scholar
63. Gessner BD , Steck T , Woelber E , Tower SS . A systematic review of systemic Cobaltism after wear or corrosion of Chrome-Cobalt hip implants . J Patient Saf . 2019 ; 15 ( 2 ): 97 – 104 . Crossref PubMed Google Scholar
64. Paustenbach DJ , Galbraith DA , Finley BL . Interpreting cobalt blood concentrations in hip implant patients . Clin Toxicol . 2014 ; 52 ( 2 ): 98 – 112 . Crossref PubMed Google Scholar
65. Prentice JR , Clark MJ , Hoggard N , et al. Metal-On-Metal hip prostheses and systemic health: a cross-sectional association study 8 years after implantation . PLoS One . 2013 ; 8 ( 6 ): e66186 . Crossref PubMed Google Scholar
66. Juneau D , Grammatopoulos G , Alzahrani A , et al. Is end-organ surveillance necessary in patients with well-functioning metal-on-metal hip resurfacings? a cardiac MRI survey . Bone Joint J . 2019 ; 101-B ( 5 ): 540 – 546 . Crossref PubMed Google Scholar
67. Gillam MH , Pratt NL , Inacio MCS , et al. Heart failure after conventional metal-on-metal hip replacements . Acta Orthop . 2017 ; 88 : 2 – 9 . Crossref PubMed Google Scholar
68. Lassalle M , Colas S , Rudnichi A , Zureik M , Dray-Spira R . Is there a cardiotoxicity associated with metallic head hip prostheses? a cohort study in the French National health insurance databases . Clin Orthop Relat Res . 2018 ; 476 ( 7 ): 1441 – 1451 . Crossref PubMed Google Scholar
69. Lodge F , Khatun R , Lord R , John A , Fraser AG , Yousef Z . Prevalence of subclinical cardiac abnormalities in patients with metal-on-metal hip replacements . Int J Cardiol . 2018 ; 271 : 274 – 280 . Crossref PubMed Google Scholar
70. Berber R , Abdel-Gadir A , Rosmini S , et al. Assessing for cardiotoxicity from metal-on-metal hip implants with advanced multimodality imaging techniques . J Bone Joint Surg Am . 2017 ; 99-A ( 21 ): 1827 – 1835 . Crossref PubMed Google Scholar
71. van Lingen CP , Ettema HB , Timmer JR , de Jong G , Verheyen CC . Clinical manifestations in ten patients with asymptomatic metal-on-metal hip arthroplasty with very high cobalt levels . Hip Int . 2013 ; 23 ( 5 ): 441 – 444 . Crossref PubMed Google Scholar
72. Goodnough LH , Bala A , Huddleston J , Goodman SB , Maloney WJ , Amanatullah DF . Metal-On-Metal total hip arthroplasty is not associated with cardiac disease . Bone Joint J . 2018 ; 100-B ( 1 ): 28 – 32 . Google Scholar
73. Sabah SA , Moon JC , Jenkins-Jones S , et al. The risk of cardiac failure following metal-on-metal hip arthroplasty [published correction appears in Bone Joint J. 2018 Sep;100-B(9):1260] . Bone Joint J . 2018 ; 100-B ( 1 ): 20 – 27 . Google Scholar
Author contributions
M. R. J. Jenkinson: Primary author, Wrote each draft of the manuscript, Performed the literature review.
D. M. Meek: Provided the references for review, Edited each draft of the manuscript.
R. Tate: Provided the references for review, Edited each draft of the manuscript.
S. MacMillan: Provided references for the review, Edited each draft of the manuscript.
H. Grant: Provided references for the review, Edited each draft of the manuscript.
S. Currie: Senior author, Edited each version of the paper, Provided the original idea for the study.
Funding statement
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
ICMJE COI statement
D. M. Meek reports board membership on the Bone & Joint Journal, and payment for lectures including service on speakers bureaus from Palacademy Teaching Lectures, unrelated to this study.
© 2021 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/.
Acknowledgements
The authors would like to acknowledge their colleagues.
