Beyond Traditional Risk Factors: Deconstructing the Burden of Coronary Atherosclerosis in Liver Transplant Recipients

Highlights

• Liver transplant (LTx) recipients exhibit a significantly higher prevalence of coronary atherosclerosis (63% vs. 46%) compared to age- and sex-matched population controls.
• The odds of obstructive (OR: 2.73) and obstructive-extensive (OR: 3.90) coronary atherosclerosis remain markedly elevated in LTx recipients even after adjusting for traditional cardiovascular risk factors.
• LTx recipients are twice as likely to harbor high-risk coronary plaques, suggesting a more vulnerable cardiovascular phenotype.
• Standard risk models like SCORE2 may significantly underestimate the true atherosclerotic burden in the LTx population, necessitating protocolized screening.

Background

Over the past three decades, advances in surgical techniques, organ preservation, and immunosuppressive protocols have transitioned liver transplantation (LTx) from a high-risk experimental procedure to a standard of care for end-stage liver disease and early-stage hepatocellular carcinoma. Consequently, the focus of long-term post-transplant care has shifted from graft survival to the management of chronic comorbidities. Cardiovascular disease (CVD) has emerged as a leading cause of non-graft-related morbidity and mortality in these patients.

Despite the recognized clinical burden, the exact prevalence and morphological severity of coronary atherosclerosis in LTx recipients have remained poorly characterized. Previous data often relied on retrospective analyses of clinically indicated imaging, which introduces significant selection bias. Clinicians have long suspected that the combination of pre-transplant metabolic dysfunction, chronic inflammation, and the metabolic side effects of long-term immunosuppression (such as hypertension, dyslipidemia, and post-transplant diabetes) creates a unique pro-atherogenic environment. The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study was designed to address these gaps using protocolized, prospective imaging.

Key Content

Methodological Advances in the DACOLT Study

The DACOLT study represents a methodological milestone in transplant cardiology. Unlike previous studies, it utilized a cross-sectional design involving 205 LTx recipients aged ≥40 years, matched 1:5 with 1,025 population controls from the Copenhagen General Population Study. Crucially, all participants underwent uniform, protocolized research-coronary computed tomography angiography (CCTA). This approach allowed for the detection of subclinical and non-obstructive disease that would be missed by traditional stress testing or symptom-driven diagnostics.

Quantitative Synthesis: Prevalence and Severity

The findings published in the Journal of the American College of Cardiology (2026) reveal a stark disparity in atherosclerotic burden:

• General Prevalence: 63% of LTx recipients had detectable coronary atherosclerosis compared to 46% of controls (P < 0.0001).
• Obstructive Disease: Defined as ≥50% stenosis, obstructive disease was found in 18% of LTx recipients versus 10% of controls (P < 0.0001).
• Extensive and Obstructive Disease: The most severe category (≥50% stenosis involving >5 coronary segments) was more than twice as common in the LTx group (13% vs 6%; P < 0.0001).

Risk Adjustment and the “Transplant Factor”

One of the most significant aspects of this research is the persistence of risk after robust statistical adjustment. Despite having similar SCORE2 (Systematic COronary Risk Evaluation 2) baseline risks (P = 0.20), the LTx recipients showed much higher actual disease rates. Logistic regressions adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking, and obesity demonstrated that the status of being a liver transplant recipient was independently associated with:

• Any Atherosclerosis: OR 2.19 (95% CI: 1.48–3.27)
• Obstructive Disease: OR 2.73 (95% CI: 1.43–5.16)
• Obstructive-Extensive Disease: OR 3.90 (95% CI: 1.76–8.55)

This suggest that the transplant state itself, likely mediated by chronic immunosuppression (e.g., calcineurin inhibitors) and historical inflammatory insults, acts as a potent multiplier of cardiovascular risk.

Plaque Morphology and High-Risk Features

The study also delved into the qualitative aspects of coronary plaques. Among those with detectable atherosclerosis, LTx recipients had significantly higher odds of possessing high-risk plaques (OR: 2.10; 95% CI: 1.29–3.45). These features—such as low-attenuation plaque, positive remodeling, and spotty calcification—are strongly associated with acute coronary syndromes and plaque rupture, suggesting that the LTx population is not only more diseased but also more vulnerable to clinical events.

Expert Commentary

The DACOLT study challenges the adequacy of current cardiovascular risk stratification tools in the transplant setting. The finding that SCORE2 scores did not differ significantly between groups despite vastly different CCTA results implies that conventional calculators are calibrated for the general population and fail to capture the unique pathophysiology of the transplant recipient. This “residual risk” may be attributed to several factors:

1. Immunosuppressive Toxicity: Long-term use of cyclosporine or tacrolimus is associated with nephrotoxicity, hypertension, and metabolic derangements that accelerate vascular aging.
2. Systemic Inflammation: Even in the absence of rejection, LTx recipients may maintain a state of low-grade systemic inflammation that promotes atherogenesis.
3. Pre-Transplant History: Many LTx recipients have a history of non-alcoholic steatohepatitis (NASH), now termed MASH, which is inherently linked to metabolic syndrome and coronary disease.

Clinically, these results argue for a more aggressive approach to primary prevention. The high prevalence of obstructive and extensive disease in asymptomatic LTx recipients suggests that protocolized CCTA might be a valuable tool in the long-term follow-up of these patients, moving beyond the standard pre-transplant workup.

Conclusion

Liver transplant recipients harbor a disproportionately high burden of coronary atherosclerosis and high-risk plaque that cannot be fully explained by traditional risk factors. As survival after LTx continues to improve, managing the atherosclerotic consequences of the transplant state becomes paramount. Future research should focus on whether aggressive statin therapy, more metabolic-neutral immunosuppressive regimens, or early CCTA-based intervention can improve cardiovascular outcomes in this vulnerable population. For now, clinicians must maintain a high index of suspicion for coronary artery disease in all LTx survivors, regardless of their standard risk scores.

References

• Knudsen AD, Kühl JT, Schultz NA, et al. Coronary Atherosclerosis in Liver Transplant Recipients and Population Controls: A Nationwide Study Using Protocolized CT Angiography. Journal of the American College of Cardiology. 2026-03-04. PMID: 41778959.
• Libby P, Kobashigawa J. The Heart of the Matter in Liver Transplantation. J Am Coll Cardiol. 2026. (Editorial Comment).
• Mancia G, et al. 2024 ESC Guidelines for the management of cardiovascular risk in patients with chronic diseases. Eur Heart J. 2024.