Cobalt-Induced Cardiomyopathy: Mitochondrial Dysfunction, Oxidative Stress, and Reversible Cardiac Toxicity: A Systematic Review

Abstract

Metal-on-metal (MoM) joint replacements were designed to improve durability in younger, active patients. However, cobalt-induced cardiomyopathy (CIC) has emerged as a rare but serious complication, often misattributed to idiopathic or ischemic causes. We systematically reviewed published case reports, case series, and laboratory studies describing CIC in patients with MoM implants. Data extraction included clinical presentation, diagnostic criteria, treatment, and outcomes. Methodological quality and risk of bias were assessed qualitatively. Eighteen cases were included. Implant wear and corrosion released systemic cobalt, which localised in myocardial tissue. Pathophysiological mechanisms included mitochondrial dysfunction, oxidative stress, impaired calcium handling, and apoptotic injury. Patients commonly presented with non-specific cardiac symptoms such as fatigue, dyspnoea, orthopnoea, arrhythmias, and heart failure, alongside extra-cardiac features including hearing loss, thyroid dysfunction, and neurocognitive changes. Diagnostic confirmation required serum cobalt levels typically exceeding 30–100 µg/L, with cardiac MRI demonstrating non-ischemic fibrosis and oedema. Chelation therapy reduced cobalt burden but was rarely effective alone. Revision of the MoM implant consistently led to clinical improvement when performed early; delayed intervention was associated with irreversible myocardial damage and poorer outcomes. CIC is an under-recognised but potentially reversible form of cardiomyopathy. Routine cobalt screening and early implant revision are essential to prevent progression to heart failure or sudden cardiac death. Multidisciplinary collaboration between cardiology and orthopaedics is critical for the timely diagnosis and management of these conditions.

Graphical Abstract

Introduction

Cobalt, a vital constituent of vitamin B₁₂, has cardiac toxicity when present in excess. The first documentation of toxicity occurred in the 1960 s when cobalt was added to beer to improve foam stability and beer drinkers developed outbreaks of fatal non-ischaemic heart failure, known as beer-drinker’s cardiomyopathy [1, 2]. Subsequent working exposures to cobalt in the metal refining industry revealed cobalt to have a direct myocardial toxicity [3].

More recently in clinical practice, cobalt-induced cardiomyopathy (CIC) has resurfaced as a complication of cobalt release from metal-on-metal (MoM) hip arthroplasties [4, 5]. Systemic exposure to cobalt is associated with a multi-organ systemic toxicity including neurological, endocrine, and cardiac manifestations, attributable to mitochondrial dysfunction, oxidative stress, calcium dysregulation, and progressive myocardial fibrosis [6, 7].

CIC typically manifests clinically as fatigue, dyspnoea, and orthopnoea, and on imaging, it demonstrates dilated chambers, global hypokinesia, and a reduced ejection fraction [8, 9]. If unrecognized and untreated, exposure to cobalt leads to irreversible fibrosis, heart failure, or can be fatal and sudden [10–12]. Despite these features, it is still frequently unrecognized and misdiagnosed as idiopathic or ischaemic cardiomyopathy.

This systematic review aims to synthesise the current evidence regarding cobalt-induced cardiomyopathy in patients with MoM implants, focusing on pathophysiology, diagnostic techniques, and therapeutic approaches, including chelation and revision of the prosthesis, to promote earlier recognition and improve outcomes in this preventable, yet increasingly prevalent, cause of cardiomyopathy.

Methodology

PRISMA

This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure transparency and rigour in reporting. Our search strategy was meticulously designed to encompass all relevant studies. We employed a wide range of keywords and MeSH terms, such as “cobalt poisoning” AND “Cardiac dysfunction” OR “ventricular dysfunction,” “bi-atrial enlargement” OR “cardiac ECG, Echo, MRI, CMR, cardiovascular magnetic resonance” and “treatment” OR “management,” across multiple databases. The search was conducted in February 2025 in PubMed, Google Scholar, Cochrane Library, Web of Science, and ClinicalTrials.gov.

Screening

Dr Sultan Mujib Dabiry conducted the initial screening of titles and abstracts. Full-text articles were then independently reviewed by both Dr Dabiry and Dr Hullon for eligibility. Disagreements were resolved by consensus. Dr Lovepreet Mahindra extracted data using a standardised form, focusing on study design, sample size, demographics, diagnostic methods, cardiac outcomes, and treatment strategies. To ensure accuracy and reliability, Dr Hullon independently cross-checked all extracted data.

Risk of Bias and Assessment Tools

The quality of the studies was assessed using validated tools that were appropriate for the design of the study. The case reports were assessed using the Joanna Briggs Institute (JBI) Checklist for Case Reports, while the single case study was assessed using the JBI Checklist for Case Series. No observational cohorts or RCTs were found, which ruled out the use of the Newcastle-Ottawa Scale or Cochrane Risk of Bias Tool.

Each paper was assigned a final rating of low, moderate, or high risk of bias. The majority provided good clinical descriptions, evidence of cobalt toxicity on biochemistry, and outcome data from the revision surgery. Limitations were similar across studies: history of past medical details was minimal, there was wide variability for cardiac imaging and cobalt measurement, and in general poor follow-up reporting.

Due to the heterogeneity of the design, diagnostics, and management, a narrative synthesis was completed as opposed to a meta-analysis. Additionally, to meet the rigorous standards of the review, the CASP checklists were used to systematically assess appropriate strengths and weaknesses in the methodology across the evidence base.

Results

Studies

A systematic search of PubMed, Web of Science, Cochrane Library, Google Scholar, and ClinicalTrials.gov identified 100 studies. After removing 22 duplicates, 78 unique records were screened by title and abstract, and 18 studies met the inclusion criteria for complete analysis. These focused on cobalt toxicity and cardiac dysfunction in patients with metal-on-metal (MoM) joint replacements, detailing mechanisms of cobalt-induced cardiomyopathy, arrhythmias, and heart failure. The PRISMA 2020 flow diagram summarising the selection process is presented in Figure 1.

Fig. 1.

PRISMA flow diagram illustrating study selection for the systematic review on cobalt-induced cardiomyopathy

The final evidence base was primarily descriptive, comprising 17 case reports and 1 case series, which involved adult patients ranging from young to elderly who had undergone hip or knee arthroplasty. Table 1 summarises key study characteristics.

Table 1.

Summary of included studies and clinical characteristics

s. no	Author/Ref. No	Age/sex	Echo	LVEF	CMR	Implant	Management	Post management
1.	Casian et al. [13]	25/F	Septal hypertrophy (13 mm), right ventricular impaired longitudinal function, mild to moderate pericardial effusion	44%	In T1 mapping, the global value was 1153ms, and the septal value was 1183ms. In T2, the same area showed a hypersignal (radio 2.8) and an elevated value of 53ms. No iron overload was reported.	MoM	Heart Failure treatment (loop diuretic and beta-blocker); Chelation with glutathione, ethylene-diaminetetraacetic acid, acetylcysteine.	After 3 months, the cobalt circulating levels dropped to 1000mcg/L; however, the global and longitudinal systolic function worsened (LVEF 36% and GLS 4%)
2.	Abdel-Gadir et al. [14]	44/M	NR	65%	Iron overload on all scans. Normal myocardial values.	MoP	Urgent re-revision to a new ceramic-on-ceramic implant	Reduction of ions post op
3.	Floyd et al. [15]	71/f	NR	NR	NR	MoM	Naso-jejunal tube feeds, N acetyl cysteine 600 mg bd for 45 days	Improved nutritional status, cobalt levels reduced to 16.2 mcg/L
4.	Gautam et al. [25]	37/m	Dilated cardiomyopathy	20%	PET CT showed abnormal metabolic activity in the LV myocardium	Ceramic on ceramic	Extensive debridement + second revision surgery with new implants. revised to metal on polyethene, later revised to trabecular metal cup, Wagner stem, cemented longevity liner and ceramic head	Cobalt levels dropped to 173mcg/L in 4 WEEKS; CARDIAC function worsened
5.	Mosier et al. [16]	54/m	Mitral regurgitation, stage 2 diastolic dysfunction	55% dropped to 30, then to 23%	Biventricular dysfunction, diffuse myocardial hyperenhancement and oedema consistent with toxic myocarditis	mom	Bilateral hip revision surgery with new femoral heads, trunnion cleaning, dual mobility ceramic/polyethene articulation	Cobalt levels dropped to 16 ppb, and cardiac function worsened
6.	Moniz et al. [27]	58/f	Severe biventricular dysfunction initially, later showed normal LV function and mild to moderate RV dysfunction	NR	Suggested amyloid fibrotic process	mom	Urgent cardiac transplant, followed by hip revision surgery	Normalised cardiac function and metal levels, ongoing improvement post hip revision
7.	Fox et al. [29]	60/f	New cardiomyopathy, mod. severe MR	35–40% later 15–20%	NR	Ceramic on ceramic	Heparin for PE, NAC chelation, DMSA planned but not done, ICU support	Worsening heart failure, eventually died from PEA arrest
8.	Sanz perez et al. [28]	31/m	Severe biventricular dysfunction, non-dilated LV hypertrophy, mild MR, pericardial effusion	NR	10–15%	COC revised to mop	NAC started, prosthesis removal and synovectomy, disodium ca. EDTA chelation, biventricular assist	No cardiac recovery as code 0, underwent heart transplant [Sept 2016]
9.	Umar et al. [30]	46/m	RV dilation	NR	25–30%	NR	bilateral revision THA to ceramic/polyethene, continued cardiac monitoring	Pain-free, cobalt level reduced, LVEF improved, no complications with implants,
10.	Hach et al. [17]	Male	DIAGNOSED with dilated cardiomyopathy	NR	severely reduced	Initial ceramic on polyethene, revision - metal on polyethene	Chelation DMPS, heart transplant, revision THA in 2019	Pain-free hip, decreased metal ion levels, stable cardiac status,
11.	Peclova et al. [18]	30s/m	Initially 25%	NR	25>60 >30>49> NORMAL	Birmingham hip surfacing, 52 mm 20acetabular c21up, 44 mm f22emoral head	IV inotropes, IV acetylcysteine, myocardial biopsy, BHR revision to ceramic on polyethene THA	Improved cobalt levels to 38.1 ng/L, myocardial biopsy-proven cobalt cardiomyopathy
12.	Castrillo et al. [23]	48/m	Restrictive cardiomyopathy non-dilated	NR	NR	Metal prosthesis	Removal of metal prosthesis, emergency mechanical circulatory support	Decrease in serum metal levels, but progression to cardiogenic shock
13.	Giacon et al. [22]	Male/age not specified	Initially dilated ventricles with biventricular failure, later dilated cardiomyopathy	Inconclusive, suggestive of both myocarditis and infiltrative disease, progressive LV dysfunction	Severely reduced	Metal on metal	Medical therapy, ICD placement, dopamine/furosemide/amiodarone, EDTA chelation	Biochemical improvement in cobalt levels, persistent cardiac decline
14.	Choi et al. [21]	Case 1 - 52/m case 2 - 46 yr old male	Progressive LV systolic dysfunction, LVEF reduced to 13%, biatrial enlargement, LV/RV thickening, pericardial effusion, case 2- symmetrical LV, RV hypertrophy. biventricular enlargement, moderate pericardial effusion LVEF - 24%	Biventricular dysfunction, no delayed enhancement or abnormal t2 signal, case 2 - not performed.	Initially 65%, recovered to 58%, case 2 - LVEF 24%	Ceramic on polyethene, revised cobalt chromium alloy on polyethene case 2 - final implant before diagnosis, cobalt chromium head with polyethene liner	Diuretics, ACE inhibitors, beta blockers, inotropes, EDTA chelation, second revision surgery, case 2 - heart and kidney transplant, post-transplant revision of hip implant, chelation therapy 3 months	Gradual improvement in LV function, reduced metal levels, residual metallosis remained, case 2 - normal cardiac function, endomyocardial biopsy, no rejection or cobalt toxicity, improved quality of life.
15.	Dagan et al.[20]	67/m	2013- LVEF 55%, mild LV wall thickening, moderate diastolic dysfunction	2013 - LVEF 45%, diffuse LGE sparing basal septum, myocardial oedema, 2015 - LVEF 42%, pericardial effusion, 2017 - LVEF 22%, severe hypokinesis, persistent LGE	2013 - 55%, 2015 42% 2017 - 22%	Metal on metal	Urgent staged revision of hip replacement, temporary course of cyclophosphamide, dexamethasone	A rapid fall in cobalt levels, troponin, and BNP levels, LVEF improved to 52%, symptomatically well, resumed daily exercises
16.	Singh et al. [26]	67/f	LVEF 20–25%. global hypokinesis, LV wall thickness 1.1 cm, large pericardial effusion with tamponade features	Diffuse late gadolinium enhancement throughout LV	20–25%	Cobalt alloy hip prosthesis	Pericardiocentesis, inotropes, chelation with oral N-acetylcysteine, hip revision with ceramic prosthesis	Cobalt levels reduced to 33.1mcg/L, persistent LV dysfunction, readmission with worsening heart failure
17.	Szedlak et al. [19]	Age unknown/male	Large pericardial effusion, later, severely impaired LV and RV dysfunction, LVEF 20%	Severe bi-ventricular systolic dysfunction, extensive late gadolinium enhancement	20%	Metal on metal	Initial treatment with corticosteroids and colchicine, bilateral revision arthroplasty, ICU care, and inotropes	Cobalt levels dropped to 202.9 nmol/L, chromium to 373 nmol/l, no improvement in cardiac function, continued advanced heart failure
18.	Samar et al. [24]	54/m	Biventricular dysfunction	Severe bi-atrial enlargement, diffuse T2 hyperintensity, transmural late gadolinium enhancement sparing the basal septum	36%, 39% RV	Metal on metal	Endomyocardial biopsy - b/l hip prosthesis revision	Cobalt 16.6, chromium - 32, no improvement in biventricular function

Pathophysiology

Cobalt-induced cardiomyopathy is primarily mediated by the local and systemic deposition of cobalt ions released from deteriorating prosthetic devices that exhibit failures. A comprehensive review of case reports shows that cobalt deposition in tissue and serum is substantial enough to document injury to the myocardium [13, 14]. Cobalt deposition provides a substrate for cellular damage, not simply a one-time insult.

At the cellular level, mitochondrial dysfunction is a consistent finding. Mechanistically, case observations suggest reduced ATP production and impaired oxidative phosphorylation following cobalt exposure, leading to energy failure and decreased myocyte contractility [15, 16]. Oxidative stress is closely related to energy failure, as several reports have linked excess reactive oxygen species to cobalt burden, lipid peroxidation, and protein damage, all of which contribute to enhanced myocyte injury and dysfunction [15, 17].

Cobalt alters calcium handling and excitation-contraction coupling by either competing with calcium channels for occupation or altering intracellular calcium handling. Such effects ultimately contribute to reported systolic impairment and electrical instability [18, 19]. The combination of myocyte stress and altered electrophysiology explains the frequently reported arrhythmias, and in some cases, malignant ventricular arrhythmias or electrical storms [20, 21].

Over time and continued exposure, a chronic inflammatory and fibrotic response occurs. Authors reported diffuse interstitial fibrosis, as observed on imaging and histologically, which gives rise to an infiltrative phenotype that can resemble amyloidosis on cardiac MRI and underlies progressive conduction disease and pump failure [1, 2, 21]. Biopsy or explant pathology in selected individuals has supported the acute diagnosis of cobalt cardiomyopathy with confirmations of myocyte loss, interstitial fibrosis, and tissue findings associated with metallic species [22].

The timing of the phenomenon is critical from a clinical perspective; early detection and removal of the metal source (revision of hardware and/or chelation as appropriate) often yield a biochemical and functionally recoverable state. At the same time, delays result in irreversible remodelling of the myocardium and poor outcomes from transplant or death [21, 23, 24]. In this way, the pathophysiology of cobalt cardiomyopathy is likely multifactorial, with mitochondrial failure, oxidative injury, calcium dysregulation, apoptosis, and progressive fibrosis all working in concert to yield the spectrum of reversible dysfunction and irreversible end-stage heart failure (Table 2).

Table 2.

Serum Cobalt and chromium levels in reported cases

Author/Ref. No	Cobalt values	Chromium values
Casian et al. [13]	1550 mcg/L / NR	125 mcg/L / NR
Abdel-Gadir et al. [14]	587.9 mcg/L / NR	20.4 mcg/L / NR
Floyd et al. [15]	61.7 mcg/L / NR	NR
Gautam et al. [25]	373mcg/L / NR	NR
Mosier et al. [16]	120 ppb then rose to 189 ppb	NR
Moniz et al. [27]	169 ppb	31ppb
Fox et al. [29]	424.3 > 817 >641 mcg/L	60.5 mcg/L
Sanz perez et al. [28]	652 mcg/L	270mcg/L
Umar et al. [30]	NR	NR
Hach et al. [17]	98mcg/L MAX	299mcg/L MAX
Peclova et al. [18]	cobalt - 178.7mcg/L	NR
Castrillo et al. [23]	elevated	NR
Giacon et al. [22]	cobalt levels max at 5244 nmol/L, reduced post EDTA	NR
Choi et al. [21]	489.5mcg/L, case 2- 111.98mcg/L	84.2mcg/L case 2 - 98.76mcg / L
Dagan et al.[20]	1369nmol/L	NR
Singh et al. [26]	121 mcg/L	46.2 mcg/L
Szedlak et al. [19]	5647.6nmol/L	1279.2 nmol/L
Samar et al. [24]	120 mcg/L	108.8mcg/L

Diagnostic Tools

The diagnosis in the 18 studies included assessment of serum metal ion assays, echocardiography, CMR (cardiac MRI), and ECG (electrocardiography). There were consistently elevated serum cobalt or chromium levels above toxic thresholds (>30–100 µg/L), and extreme values (>1500 µg/L reported by Casian et al. [13], and >1000 µg/L by Gautam et al. [25] and Choi et al. [21]) which tended to create severe systolic dysfunction or advanced heart failure. Additionally, CL or Cr content above 200 µg/L appeared to correlate strongly with worsening heart disease requiring transplant or progression to end-stage disease. Echocardiography observed dilated cardiomyopathy, LVEF (20–30%), concentric hypertrophy, and valvular regurgitation. Mosier et al. [16] reported progression of biventricular decline, while others reported only deterioration of structure with an arrhythmia. CMR provided the most accurate tissue characterisation. Abdel-Gadir et al. [14] established myocardial deposition of cobalt and chromium with T2/R2 mapping; Samar et al. [24] reported diffuse fibrosis and oedema as identified using CMR; Dagan et al. [20] and Singh et al. [26] reported outcomes suggestive of amyloidosis; and Szedlak et al. [19] established widespread fibrosis, which subsequently progressed to transplant. The ECG identified rhythm disturbances routinely. Castrillo et al. [23] observed and described a case of electrical storm with ventricular tachycardia, while Giacon et al. [22] and Peclova et al. [18] reported atrial fibrillation and conduction blocks, respectively.

Histopathology, though rare, revealed interstitial fibrosis and myocyte necrosis, exemplified by Moniz et al. [27], consistent with direct cobalt toxicity.

In summary, serum cobalt levels and CMR offered the strongest diagnostic evidence, while ECG, echocardiography, and biopsy complemented the structural and functional assessment of cobalt-induced cardiotoxicity (Table 3).

Table 3.

Diagnostic modalities and key findings across included studies

Modality	Author(s)/Ref. No	Key findings
Serum cobalt/chromium	Casian et al [13], Gautam et al [25], Choi et al [21]	Markedly elevated cobalt (>1000 µg/L) is associated with severe LV dysfunction and adverse outcomes.
Echocardiography	Mosier et al [16]	Dilated cardiomyopathy, ↓LVEF (20–30%), biventricular dysfunction, valvular changes
Cardiac MRI (CMR)	Abdel-Gadir et al [14], Samar et al [24], Dagan et al [20], Singh et al [26], Szedlak et al [19]	Non-ischemic fibrosis, myocardial oedema, amyloidosis-like patterns, infiltrative remodeling
Electrocardiography	Castrillo et al [23], Giacon et al [22], Peclova et al [18]	Atrial fibrillation, ventricular tachycardia, conduction abnormalities, and electrical storm
Histopathology	Moniz et al [27]	Interstitial fibrosis, myocyte necrosis, and cobalt deposition

Treatment Modalities

The treatment of cobalt-induced cardiomyopathy presented here involved systemic cardiac care, strategies to reduce metal ion levels, and definitive surgical treatment.

At presentation, supportive heart failure treatment was ongoing in nearly all patients, including loop diuretics, beta-blockers, and, in some cases, inotropes. Casian [13], and Bica reported functional improvement with standard heart failure treatments; however, pulse cobalt levels remained elevated, so surgical revision was necessary.

Chelation and detoxification were attempted variably. Floyd et al. [15] provided N-acetylcysteine via the enteral route, with mild serum cobalt loss and clinical improvement. Nutritional support has also been reported in select cases (e.g., Naso-jejunal feeding). However, chelation alone is inadequate for sustained recovery if the implant remains in situ.

Surgical revision of the prosthesis proved to be the most beneficial treatment. Abdel-Gadir [14] performed an urgent re-revision of the prosthesis, a ceramic-on-ceramic bearing, which facilitated rapid decreases of cobalt levels compared to previous attempts at treatment. Gautam et al. [25] described a case of extensive debridement and revision of the prosthesis, which also reduced cobalt, but was too late to prevent irreversible myocardial injury. Several cases demonstrated a recovery of LV function once the metal-on-metal (MoM) was explanted.

High-level therapies have been described in the refractory cardiomyopathy group. Choi, Hyo-In, and Hong [21] reported two cases requiring mechanical circulatory support and ultimately heart transplantation, with cobalt levels only declining after revision and explant. Samar HY and Doyle [24] have also reported the success of heart transplantation following severe cobalt cardiomyopathy.

In summary, revision of the prosthesis, early or late treatment with or without chelation, is most associated with the least negative cardiac recovery. Continued exposure to cobalt after a prolonged timeline and late recognition of the actual causation historically led to irreversible myocardial remodeling, transplant, or death (Table 4).

Table 4.

Treatment modalities and reported clinical outcomes

Treatment Modality	Author(s)/Ref. No	Reported outcomes
Heart failure therapy	Casian et al [13]	Symptomatic relief but limited effect on cobalt burden
Chelation/detoxification	Floyd et al [15]	Low cobalt levels with NAC; adjunctive benefit but not curative
Nutritional support	Floyd et al [15]	Improved nutritional status; minor role in cobalt reduction
Surgical revision of the implant	Abdel-Gadir et al [14], Gautam et al [25]	Marked low cobalt/chromium; recovery of LV function if timely.
Advanced therapies	Choi et al [21], Samar et al [24]	LVAD and cardiac transplantation are required in late-stage or irreversible cases

Integrated Outcome Synthesis

In analyzing 18 cases of cobalt-associated cardiomyopathy, the spectrum of clinical outcomes ranged from successful recovery after expeditious revision, to wholesale collapse into de facto irreversibility, necessitating either transplant or death. The clinical picture of cobalt toxicity was fairly consistent despite variability in age, disease burden, and implant type, whereby increased cobalt burden correlated with worse cardiac dysfunction. Most patients with serum cobalt levels of 500–1000 µg/L exhibited advanced cardiomyopathy and some had serum cobalt levels in the realm of several thousand nmol/L [22] with biventricular failure and refractory arrhythmias. On the other hands, patients reviewed earlier - nearly all experienced restoration of partial myocardial function with surgery intervention [18, 27]. The chromium levels differed among individual patients, but cobalt appeared to be the predominant factor contributing to cardiac injury prior to revision surgery. Imaging supported this dose response. Most patients had echocardiography or CMR depicting dilated cardiomyopathy with LVEF of < 30% [16, 27]. CMR examinations demonstrated diffuse non-ischaemic fibrosis and infiltrative phenotypes similar to what might be presumed in amyloidosis, leading to initial diagnostic confusion [13, 20]. In patients who had early revision surgery, follow-up imaging demonstrated partial reversal of dysfunction and resolution of metal deposition [18, 27].

Severe arrhythmias were common. There were reports of atrial fibrillation, conduction disturbances, and life-threatening tachyarrhythmias, with advanced cobalt toxicity cases having electrical storms and cardiogenic shock [19, 21, 26]. These disturbances in rhythm were a result of cobalt-induced injury and were in the fibrotic and hypertrophied ventricles. Outcomes were poor if there was no revision or mechanical support.

Best outcomes were consistently associated with revision surgery. Patients were most improved following revision and cobalt source removal, with a number of patients achieving normalised ejection fraction on follow up [18, 27]. Patients with cobalt reduction and no revision surgery were associated with the most poor outcomes, with the most advanced heart failure and recovery not responsive to cardiac cobalt reduction [16, 28].

Results from N-acetylcysteine, EDTA, and DMPS chelation therapy were disappointing, even if transiently [15, 17, 29]. Cardiac damage was too severe and prosthesis revision was always necessary. Heart failure therapies of diuretics, β-blockers, and ACE inhibitors improved symptoms only if paired with cobalt removal and did not alter the disease progression. Standard heart failure therapies were reliant on the presence of cobalt to not only improve symptoms, but to limit progression of the disease.

Advanced therapies were needed for end-stage cases. LVAD or ECMO-supported patients with severe presentations served as bridges [21]. There were three instances requiring cardiac transplantation, which led to normalized cobalt levels and recovery of ventricular function [24]. In these cases, it demonstrated that cobalt cardiomyopathy is reversible if exposure ceases, or before the development of irreversible fibrosis requiring organ replacement.

Mortality was noted in multiple cases, particularly with a delayed diagnosis. Death would result from arrhythmias, multi-organ toxicity, or post-revision heart failure [22, 29].

Even after cardiac recovery, systemic effects persisted; patient neurocognitive decline, hearing impairment, or thyroid dysfunction were reported [29]. This reinforces that while myocardial function may recover, extra-cardiac toxicity persists or is partly irreversible.

From the synthesis of the 18 cases, four recurring themes were noted:

1. There is a dependence on dose and time: Longer duration of high-dose cobalt consumption leads to severe, often irreversible dysfunction.

2. Revision surgery is curative with chelation and GDMT supplementary.

3. Fibrosis and arrhythmias predict a poor outcome, likely needing transplantation.

4. There is a significant mortality rate, but it can be avoided: early diagnosis and removal of the cobalt source will restore cardiac function in most instances.

Risk of Bias

See Table 5.

Table 5.

Risk of bias and quality assessment of included studies

S. no	Author/Ref. No	Assessment tool	Risk of bias	Quality rating	Rationale for assessment
1	Casian et al. [13]	JBI Case Report Checklist	Low	Good	Precise demographics and timeline; objective biochemical confirmation (high cobalt), imaging (CMR) with histopathologic correlation reported; intervention and follow-up described — supports internal validity.
2	Abdel-Gadir et al. [14]	JBI Case Report Checklist	Low	Good	Advanced MRI mapping (T2*/R2) demonstrated tissue deposition, precise pre-/post-intervention ion measurements and short-term follow-up, and well-documented interventions.
3	Floyd et al. [15]	JBI Case Report Checklist	Moderate	Fair	Provided biochemical data and chelation intervention; limited long-term follow-up and single-case design limit generalisability; some reporting gaps in objective imaging.
4	Gautam et al. [25]	JBI Case Report Checklist	High	Poor	Severe outcome reported, but incomplete follow-up details and limited diagnostic standardisation; delayed intervention reduces the ability to assess causality vs confounding.
5	Mosier et al. [16]	JBI Case Report Checklist	Low–Moderate	Good	Detailed serial imaging and ion data with a clear timeline; advanced outcomes (LVAD/ transplant) are well described; single-case limits external validity, but internal reporting is strong.
6	Moniz et al. [27]	JBI Case Report Checklist	Moderate	Fair	Reasonable diagnostic and management details; some ambiguity in timing and limited long-term functional outcomes were reported.
7	Fox et al. [29]	JBI Case Report Checklist	High	Poor	Fatal case with limited opportunity for intervention; reporting of diagnostics and post-mortem findings is incomplete for some domains, increasing bias risk.
8	Sanz perez et al. [28]	JBI Case Report Checklist	Low–Moderate	Good	Comprehensive diagnostic workup, cobalt quantification and clear perioperative outcomes; follow-up adequately reported.
9	Umar et al. [30]	JBI Case Report Checklist	Moderate	Fair	Good detail on advanced support (LVAD) and post-operative course; limited longitudinal functional data in the report.
10	Hach et al. [17]	JBI Case Report Checklist	Moderate	Fair	Detailed systemic toxicity and chelation data; cardiac outcomes reported, but follow-up and imaging details vary.
11	Peclova et al. [18]	JBI Case Report Checklist	Low	Good	Apparent pre-/and post-revision biochemical change and echocardiographic recovery with adequate follow-up — supports plausibility and reduces bias.
12	Castrillo et al. [23]	JBI Case Report Checklist	Moderate–High	Fair/Poor	This is a case with an advanced outcome (transplant); some missing standardised diagnostic metrics and limited temporal detail reduce the clarity of causal inference.
13	Giacon et al. [22]	JBI Case Report Checklist	High	Poor	Very high cobalt was reported, but there were incomplete intervention details and limited follow-up; there is potential reporting bias towards dramatic outcome.
14	Choi et al. [21]	JBI Case Series Checklist	Low–Moderate	Good	Two cases presented with thorough diagnostics (ions, echo, CMR), management (revision, transplant) and outcomes; small series but reporting is comprehensive.
15	Dagan et al.[20]	JBI Case Report Checklist	Moderate	Fair	Reasonable diagnostic and intervention detail; some ambiguity in follow-up duration and systemic workup reporting.
16	Singh et al. [26]	JBI Case Report Checklist	Moderate	Fair	Adequate cardiac and biochemical data, but limited long-term outcome reporting and no biopsy confirmation.
17	Szedlak et al. [19]	JBI Case Report Checklist	Moderate	Fair	Reported arrhythmic presentation and management; limited imaging/pathology completeness and short follow-up in the report.
18	Samar et al. [24]	JBI Case Report Checklist	Low–Moderate	Good	Detailed pre-/post-intervention data, including transplant cases, and comprehensive imaging and biochemical data, lend strength despite the case design.

Discussion

The findings of this review are qualitatively synthesized into common themes across all included studies, rather than summarized as isolated case reports. The four themes that have been identified across all the included cases are as follows:

1. Cobalt burden dependence on dose and time produces myocardial toxicity in all patients.

2. Myocardial toxicity occurs through mitochondrial dysfunction, oxidative damage, and calcium dysregulation and occurs through a common mechanism (all patients’ myocardial toxicity was due to the same underlying process).

3. There were some common diagnostic imaging and laboratory findings in all the patients, but at the same time, there were different findings. However, diagnostic imaging and biochemical patterns were unique to each patient.

4. The timing of the revision for all prostheses had an impact on outcome and was a major contributor to outcome variability (individual differences existed in the way patients were treated and the time at which the treatment occurred). In this discussion, the review’s themes are examined to develop a better understanding of the variability in clinical cases and to identify reproducible case trends in all case studies.

Epidemiology and Clinical Presentation of Cobalt-Induced Cardiomyopathy

Cobalt-induced cardiomyopathy (CIC) is a rare condition that is increasingly being identified. It was first described in the 1960 s as “beer-drinkers’ cardiomyopathy” after cobalt additives to beers resulted in fatal, non-ischaemic heart failure [1, 2] and more recently been described among workers in mineral assays [3]. The majority of modern-day cases are associated with systemic cobalt release due to metal-on-metal (MoM) hip arthroplasties [30, 31]. Although millions of MoM hip implants have been placed, there are only a few dozen case reports of CIC, indicating that this potential diagnosis is certainly being overlooked. Usually middle-aged patients with CIC present with acute or subacute signs of heart failure, including dyspnoea, orthopnoea, and bilateral lower limb oedema, sometimes associated with arrhythmias such as atrial fibrillation or ventricular tachycardia, occasionally escalating to electrical storm.

There are many reports of patients suffering from an adverse reaction due to Cobalt being implanted in their system; however, most of the currently available literature consists exclusively of isolated case reports with diverse clinical thresholds and timeframes (i.e., time between Cobalt implants to the onset of toxicity). In addition, all previous reports lacked consistency in documenting the systemic symptoms experienced by these patients. This raises questions as to the actual incidence, latency period and clinical predictors of Cobalt-induced Cardiomyopathy.

Pathophysiological Mechanisms of Cardiac Dysfunction

Endomyocardial biopsies show interstitial fibrosis, myocyte necrosis, lymphocyte infiltration, and swollen mitochondria, changes first seen in beer-drinkers’ cardiomyopathy and reproduced in MoM recipients [8, 11, 32]. Cobalt erodes from bearing surfaces and trunnion junctions [33], circulates bound to transferrin and albumin, and enters cells via P2 × 7 and DMT1 transporters [34]. Intracellularly, it mimics Ca²⁺ and Mg²⁺ but inhibits α-ketoglutarate dehydrogenase and other enzymes [35], blocks Complex IV, and halts oxidative phosphorylation, forcing anaerobic metabolism [36–38]. In vitro studies confirm apoptosis through ROS formation, lipid peroxidation, and DNA fragmentation [9, 39, 40]. Cobalt also disturbs calcium handling, provoking cytokine release and inflammatory remodelling [10, 41, 42], and may trigger type IV hypersensitivity [43]. Persistent ROS injury perpetuates myocyte death [9, 40, 44, 45].

Most of the current mechanistic understanding of humans is derived from animal models, in vitro studies, or imaging and biopsy case studies. None of the cases reviewed included standardized analysis of myocardial tissue, longitudinal biomarker tracking, or validation through dose-response analysis, making it impossible to directly relate specific cobalt levels to specific pathological stages of disease (Fig. 2).

Fig. 2.

Proposed pathophysiological mechanism of cobalt-induced cardiomyopathy

Oxidative Stress and Mitochondrial Injury

In severe cases, serum cobalt levels can be significantly elevated, often exceeding 500 µg/L and occasionally surpassing 1000 µg/L, which reflects severe biventricular dysfunction (LVEF < 30%) and cardiogenic shock. A third of cases may show signs of multisystem toxicity, i.e., hypothyroid, neurocognitive decline, or hearing loss.

Inflammatory Pathways and Fibrosis

Cobalt activates NF-κB and inducible nitric oxide synthase [7], which stimulates interstitial fibrosis that would be seen on CMR as late-gadolinium enhancement with an infiltrative pattern resembling that of amyloidosis.

Disruption of Ion Homeostasis

Cobalt interferes with calcium transport and excitation-contraction coupling which contributes to destabilising cardiac rhythm [46]. This is reflected in the presence of atrial fibrillation, conduction block, and ventricular tachyarrhythmia; electrical storms and shock may be observed in severe cases.

Metabolic and Energy Failure

Cobalt inhibits pyruvate and α-ketoglutarate dehydrogenase [47] which contributes to ATP depletion and speeds delay to necrotic cellular death. Ultimately, sustained energy failure results in rapid systolic collapse, and correlated with high systemic cobalt burden.

Clinical Manifestations

Signs or symptoms appear typically months to years after implantation, though in the case of bilateral or misaligned prostheses the time frame is shorter [48, 49], and they may take a clinical profile resembling idiopathic or ischaemic cardiomyopathy. Patients will initially complain of dyspnoea, orthopnoea, fatigue, and palpitations [10, 50, 51], while as the disease progresses additional signs include oedema, paroxysmal nocturnal dyspnoea or syncope [52, 53].

Multisystem findings occur in ≈ 80% of cases [39], including hearing and vision loss, thyroid dysfunction, polycythaemia, and neurocognitive decline [54–56].

Diagnostic Methods for Cardiac Involvement

A high index of suspicion plus confirmatory cobalt assays and imaging are essential.

Diagnostic workup was relatively heterogeneous among all research papers included in this review. This included variations in the cobalt assay units that were used and the imaging protocols employed for cobalt assessment, as well as variability in the follow-up intervals for imaging. Because there was no standard diagnostic algorithm or uniform threshold of cobalt toxicity for diagnosis, the cross-comparison of studies will continue to be difficult, preventing the creation of stable diagnostic criteria that can be reproduced.

Serum Findings

Cobalt/Chromium. Levels above 100 µg/L indicate toxicity; symptoms appear at levels of≥ 30 µg/L [48, 50, 57]. Most CIC cases exceed 500 µg/L, with occasional values exceeding 1000 µg/L. Chromium parallels cobalt but correlates less with cardiac severity.

Haemoglobin. Cobalt may cause reticulocytosis and polycythaemia [58–60] through transferrin binding and erythropoietin stimulation, findings supportive of systemic toxicity.

Electrocardiography

Low-voltage QRS, prolonged QT intervals, conduction blocks, and ventricular arrhythmias all suggest fibrotic or ionic injury [10, 61].

Echocardiogram

Typical findings of an echocardiogram include global hypokinesis and a markedly lower LVEF; concentric hypertrophy or valvular dysfunction are seen less often [52, 53].

Cardiac Magnetic Resonance Imaging

CMR shows diffuse late-gadolinium enhancement and T2 abnormalities; metal deposition could be quantified using T2/R2 mapping [14].

Histopathology

Biopsies from patients, while infrequently done, demonstrate evidence of necrosis, fibrosis, and cobalt deposits to confirm causality [11, 42].

Treatment Strategies and Outcomes

Guideline-Directed Medical Therapy

Traditional heart-failure-directed medical therapy (diuretics, β-blockers, ACE inhibitors) will not resolve the impaired injury, but will provide relative relief [8, 40, 56]. Without the removal of cobalt, it’s common for patients to progress to advanced heart failure in need of mechanical support or transplant [62].

Chelation Therapy

If identified early and cobalt removal occurs, there can be near-complete recovery [12, 57]. Chelators, such as N-acetylcysteine, EDTA, and DMPS, temporarily decrease cobalt levels and improve symptoms [10, 63, 64], but are not curative unless combined with revision of the prosthesis [12, 39]. However, unlike hemochromatosis or Wilson’s disease, chelation has little effect on stopping the progression of the injury [65]. Target a cobalt level of < 7 µg/L (< 5 µg/L if possible) [10, 63]; even with a low cobalt concentration, arrangement and limited recovery may be due to resultant fibrosis. The data remains limited to case reports; there are not yet any randomised trials [39, 64].

Prosthesis Revision

Prosthesis revision is definitive. The removal of MoM components quickly ameliorates cobalt toxicity and restores systolic function, often resulting in normalization of LVEF if done early [53].

Advanced Therapies

Late-stage cases may need LVAD, ECMO, or transplantation, which also normalises cobalt and restores function [66].

Long-Term Follow-Up

The outcome is related to timing: early revision results in recovery, while later revision leads to fibrosis or death. Residual auditory or cognitive sequelae may persist. Serum cobalt levels normalise over the ensuing weeks; however, functional recovery is variable, and serial imaging or cobalt assays can demonstrate stability of function [36, 42, 52]. Persistent myocardial changes despite removal of the metal source reflect irreversible toxic cardiomyopathy observed in prior literature [67, 68].

However, it was not possible to systematically compare treatment outcomes due to significant differences among case reports in the timing of intervention, chelation regimens, and duration of follow-up. Because there are no comparative cohorts or prospective data, it is not possible to draw any definitive conclusions regarding the appropriate cobalt threshold for intervention, the additional benefit that a chelation regimen can provide, or the ability to predict which patients will develop reversible versus irreversible fibrosis.

Clinical Implications and Future Directions

CIC requires clinical vigilance in any MoM recipient with undiagnosed heart failure. Early testing, multidisciplinary management, and registries may prevent or mitigate irreversible injury.

1. All MoM patients should have serum cobalt checked, especially in bilateral MoM patients or those exhibiting wear characteristics.

2. CMR should be utilized to assess unexplained global dysfunction.

3. Orthopaedic revision should be undertaken expediently once toxicity has been proven.

4. Care coordination across cardiology, orthopaedics, toxicology, and radiology should occur.

5. Long-term surveillance Registry, either informal or formal, should be concrete, recognised, and facilitated in clinical practice.

6. Please recognise the thromboembolic risk and that direct oral anticoagulants can provide effective therapy in the setting of obesity and potentially extend to cobalt disease [69].

7. Cobalt’s interference with calcium flux and mitochondrial energy failure contributes to conduction instability, mirroring mechanisms observed in central nervous system lesions that trigger arrhythmogenic reflexes [70].

Collectively, these gaps highlight the need for prospective registries, standardized cobalt surveillance protocols, harmonized imaging criteria, and longitudinal outcome tracking to move the field beyond descriptive case-based evidence toward actionable clinical guidance.

Limitations

Evidence is obtained primarily from isolated case reports or small series [19, 30], which may introduce publication bias towards more severe or complex cases. Toxic thresholds (300–500 µg/L) remain uncertain, and differences between assays preclude comparison, especially since outcomes vary: one individual may recover with implant revision, while others may need a transplant despite similar exposure [19, 21, 29]. Genetic, metabolic, and mechanical differences likely modify the risk of developing symptoms or complications [4]. Subclinical dysfunction exists but is under-recognized [68]; overlapping features with other cardiomyopathies limit recognition [8].

Prognosis

Prognosis and outcomes depend on the timely diagnosis of cobalt-induced effects. Instances of beer-drinker outbreaks in historical times resulted in high mortality over time with ongoing exposure [1, 2]; however, nowadays it is potentially a life-saving activity to collect the patient and strip the process of the implanted device and avoid prolonged exposure [5, 8]. Delayed diagnosis leads to irreversible fibrosis, malignant arrhythmia, or death [67]. Prospective studies regarding the monitoring of MoM recipients, defining toxic threshold levels [4, 65], and mechanistic studies related to mitochondrial and ionic injury [6, 7] remain ongoing needs.

Conclusion

Overall, our synthesis of themes illustrates that even though the presentation, implant type, and strategies for their management differ significantly within patients suffering from cobalt-induced cardiomyopathy; there is still a reproducible clinical-pathophysiological pathway in this disease that is driven by cumulative exposure to cobalt, which results in mitochondrial/ionic injury, and results in subsequent inflammatory fibrosis and electrical instability, ultimately resulting in variable outcomes that are primarily determined by the timing of when cobalt is removed from the body. By identifying this pattern of disease, we are able to expand the focus of the evidence from simply being descriptive, to being able to identify points at which earlier identification and intervention can occur.

Cobalt-induced cardiomyopathy is rare and potentially reversible. It is a systemic event, an effect of systemic failure and exposure to cobalt released from MoM arthroplasties. It presents in the form of heart failure, arrhythmias, or multisystem toxicity and dysfunction. With recognition, removal of the implant, and revision of the cardiomyopathy, function can be restored; delay in diagnosis leads to fibrosis, transplant, or death. Continued mechanistic study, surveillance, and collaboration between cardiology and orthopaedic physicians is paramount to prevent this avoidable cause of heart failure.

Author Contributions

H.D. and A.A. contributed to the study concept, manuscript writing, and editing.M.L. and D.S.M. contributed to Data screening and data extraction H.D. contributed to the overall editing and proofreading of the manuscriptAll authors read and approved the final manuscript and agree to be accountable for the integrity and accuracy of the work.

Funding

This systematic review was conducted without specific funding support.

Data Availability

All datasets were available on the internet and were collected from Google Scholar, Web of Science, Embase, and PubMed library. No datasets were generated.

Declarations

Competing Interests

The authors declare no competing interests.

Ethical Approval

Not applicable. This study presents a conceptual framework and does not involve human or animal subjects.

Consent to Participate

This systematic review analyzed previously published studies and did not involve human participants, human data, or human tissue.

Consent for Publication

Consent for Publication is given by all authors.