YKL-40: Revolutionizing cardiac risk prediction and therapy in liver transplantation

Table 1 Essential perioperative strategies in liver transplantation

Key perioperative considerations	Core objectives	Clinical strategies	Relevance to LT outcomes
Anesthetic management	Optimize hemodynamic stability while minimizing cardiovascular depression	Use of balanced anesthesia with reduced myocardial depressants, individualized ventilation strategies	Reduces intraoperative cardiovascular instability and improves early graft function
Hemodynamic monitoring and support	Maintain adequate perfusion, prevent hypotension, and manage fluid shifts	Continuous invasive hemodynamic monitoring (arterial line, CVP), vasoactive drug titration	Prevents hemodynamic collapse, improves organ perfusion, and reduces renal dysfunction
Intraoperative transfusion strategies	Reduce bleeding risk, optimize coagulation, and prevent transfusion-related complications	Goal-directed transfusion strategies using viscoelastic tests (ROTEM/TEG), use of antifibrinolytics	Minimizes need for massive transfusion, reduces clotting disorders, and improves recovery
Metabolic and electrolyte management	Correct metabolic derangements and optimize acid-base balance	Perioperative glucose control, electrolyte replacement, correction of metabolic acidosis/ alkalosis	Prevents metabolic crises, reduces acidosis-related cardiac dysfunction, and stabilizes electrolytes
Surgical techniques	Enhance graft implantation, reduce ischemia-reperfusion injury, and optimize surgical technique	Use of minimally invasive techniques, normothermic regional perfusion. and/ or veno-venous bypass	Optimizes graft survival, reduces ischemic complications, and improves surgical efficiency
Immunosuppressive strategies	Prevent rejection while minimizing cardiovascular and metabolic toxicity	Induction therapy with IL-2 receptor antagonists, tailored CNI minimization in high-risk patients	Enhances long-term graft survival while mitigating CVD, metabolic, and renal adverse effects

CNI: Calcineurin inhibitor; CVD: Cardiovascular disease; CVP: Central venous pressure; IL-2: Interleukin-2; LT: Liver transplantation; ROTEM: Rotational thromboelastometry; TEG: Thromboelastography.

Table 2 Non-graft-related causes of mortality in liver transplantation

Cause of mortality	Condition	Pathophysiology and clinical impact
CVD and related complications	CAD	Accelerated atherosclerosis, endothelial dysfunction, and pre-existing metabolic risk factors contribute to higher rates of MI, IHD, and HF post-LT
	HF and cirrhotic cardiomyopathy	Many LT candidates have underlying myocardial dysfunction due to cirrhosis-related hyperdynamic circulation, leading to increased HF risk after LT
	Arrhythmias and sudden cardiac death	Post-LT arrhythmias, particularly AF, increase the likelihood of stroke, thromboembolic events, and sudden cardiac death, contributing to long-term mortality
Renal dysfunction and CKD	CNI-induced nephrotoxicity	Prolonged exposure to CNIs (tacrolimus, cyclosporine) can lead to progressive renal dysfunction, increasing the risk of ESKD and cardiovascular mortality
	Cardiorenal syndrome	Many LT recipients develop concurrent renal and cardiac dysfunction, further complicating post-LT management
Metabolic disorders and graft function decline	DM and metabolic syndrome	PTDM, dyslipidemia, and obesity contribute to long-term cardiovascular risk, exacerbating non-graft-related mortality
	Late graft dysfunction and chronic rejection	While primary graft failure is a well-recognized early risk, chronic rejection and immune-mediated injury can lead to progressive hepatic dysfunction, affecting long-term survival
Infections and sepsis	Opportunistic infections	CMV, fungal infections, and multidrug-resistant bacterial infections are frequent causes of morbidity and mortality in immunosuppressed LT recipients
	Sepsis and multi-organ failure	Infection-related complications, particularly in the first year post-LT, remain a significant cause of non-graft-related mortality
Malignancies: De novo and recurrent cancers	HCC recurrence	While LT is a curative treatment for selected patients with HCC, recurrence occurs in 10% to 20% of cases, significantly affecting survival
	PTLD	Linked to chronic immunosuppression, PTLD and other malignancies increase the risk of non-graft-related mortality
	De novo cancers	Immunosuppressive therapy contributes to higher rates of skin cancers, gastrointestinal malignancies, and hematologic malignancies, impacting long-term outcomes

AF: Atrial fibrillation; CAD: Coronary artery disease; CKD: Chronic kidney disease; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CVD: Cardiovascular disease; DM: Diabetes mellitus; ESKD: End-stage kidney disease; HCC: Hepatocellular carcinoma; HF: Heart failure; IHD: Ischemic heart disease; LT: Liver transplantation; MI: Myocardial infarction; post-LT: Post liver transplantation; PTDM: Post-transplant diabetes mellitus; PTLD: Post-transplant lymphoproliferative disorder.

Table 3 Cardiovascular risk factors in liver transplantation: Traditional and transplant-specific considerations

Risk factor	Description	Category	CVD risk level
HTN	Prevalent in up to 70% of LT candidates, often secondary to cirrhosis-related hemodynamic changes and renal dysfunction. Increased after LT due to CNI therapy	Traditional	High
DM	Strongly associated with CAD in LT candidates. Increases post-LT MACE risk, especially in patients with NAFLD/ NASH-related cirrhosis	Traditional	High
HLP	Often masked by cirrhosis, where severe liver disease leads to low LDL and cholesterol levels. Becomes evident post-LT due to immunosuppressive drugs (CNIs, steroids, mTOR inhibitors)	Traditional	Moderate
Obesity and metabolic syndrome	Increasingly common due to the rising prevalence of NAFLD/NASH, which is now a leading LT indication. Contributes to insulin resistance, HTN, and CAD	Traditional	High
Smoking and CKD	Smoking doubles post-LT cardiovascular risk. CKD is a strong predictor of post-LT cardiovascular events, often worsened by CNI nephrotoxicity	Traditional	High
Cirrhotic cardiomyopathy	Subclinical cardiac dysfunction due to chronic cirrhosis-related myocardial remodeling. Manifests as blunted cardiac response to stress, leading to increased perioperative cardiovascular instability	Nontraditional	High
Portal hypertension and hyperdynamic circulation	Characterized by low SVR and high CO, which can mask underlying cardiac disease. Contributes to high-output HF and pulmonary hypertension in advanced cirrhosis	Nontraditional	Moderate
NAFLD/ NASH-related cardiovascular risk	Strongly associated with CAC and subclinical atherosclerosis. NAFLD-related CVD risk persists post-LT, even after resolution of liver disease	Nontraditional	High
HRS and ESLD	Worsens fluid overload and increases cardiovascular complications, especially in patients requiring pre-transplant renal replacement therapy	Nontraditional	High
Inflammation and endothelial dysfunction	Chronic systemic inflammation in cirrhosis promotes accelerated atherosclerosis. Circulating pro-inflammatory cytokines impair vascular function, increasing CAD risk	Nontraditional	Moderate
QT prolongation and arrhythmias	Common in cirrhosis due to electrolyte imbalances, autonomic dysfunction, and beta-adrenergic receptor desensitization. Increases perioperative arrhythmic risk, particularly in ALD patients	Nontraditional	Moderate

ALD: Alcohol-related liver disease; CAC: Coronary artery calcification; CAD: Coronary artery disease; CKD: Chronic kidney disease; CNI: Calcineurin inhibitor; CO: Cardiac output; CVD: Cardiovascular disease; DM: Diabetes mellitus; ESLD: End-stage liver disease; HF: Heart failure; HLP: Hyperlipidemia; HRS: Hepatorenal syndrome; HTN: Hypertension; LDL: Low density lipoprotein; LT: Liver transplant; LT: Liver transplantation; MACE: Major adverse cardiovascular events; mTOR: Mammalian target of rapamycin; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; post-LT: Post liver transplantation; SVR: Systemic vascular resistance.

Table 4 Predictive tools and scoring systems designed to assess cardiovascular risk in liver transplant recipients

Scoring system	Description	Risk categories	Clinical factors considered	Applicability to LT patients
RCRI	Developed for the general surgical population to predict perioperative cardiac complications	Low risk: 0-1 factors. Moderate risk: 2 factors. High risk: ≥ 3 factors	History of IHD. History of CHF. History of CVD. Insulin-dependent DM. CKD (creatinine > 2 mg/dL). Undergoing high-risk surgery	Limitations: Does not account for cirrhosis-specific hemodynamic alterations, potentially underestimating risk in LT candidates
CVROL score	Tailored specifically for LT candidates to predict post-LT cardiovascular events	Low risk: Score ≤ 2. Moderate risk: Score 3-5. High risk: Score ≥ 6	Age history of CAD DM hypertension Smoking status LVH elevated serum troponin levels	Strengths: Incorporates factors prevalent in LT candidates, providing a more accurate risk assessment
Framingham risk score	Estimates 10-year cardiovascular risk in the general population	Low risk: < 10% risk. Intermediate risk: 10%-20% risk. High risk: > 20% risk	Age gender total cholesterol. HDL cholesterol. SBP treatment for hypertension. Smoking status	Limitations: May not accurately reflect the altered cardiovascular physiology in LT candidates
CAR-OLT score	Developed to predict cardiovascular complications post-LT, incorporating cirrhosis-specific factors	Low risk: Score ≤ 10. Moderate risk: Score 11-15. High risk: Score > 15	Age history of CAD DM Beta-blocker use. Serum creatinine. LVH. Non-sinus rhythm. Low serum albumin	Strengths: Addresses cirrhosis-specific hemodynamic changes, offering improved predictive accuracy for LT recipients
CAD-LT score	Predicts the risk of significant CAD in LT candidates	Low risk: Score ≤ 2. High risk: Score ≥ 3	Age DM hypertension. Smoking status. Dyslipidemia	Strengths: Assists in identifying LT candidates at higher risk for CAD, guiding further cardiac evaluation

CAD: Coronary artery disease; CAD-LT: Coronary artery disease in liver transplantation; CAR-OLT: Cardiac risk in orthotopic liver transplantation; CHF: Congestive heart failure; CKD: Chronic kidney disease; CVD: Cerebrovascular disease; CVROL: Cardiovascular risk in orthotopic liver transplantation; DM: Diabetes mellitus; HDL: High-density lipoprotein; IHD: Ischemic heart disease; LVH: Left ventricular hypertrophy; post-LT: Post liver transplantation; RCRI: Revised cardiac risk index; SBP: Systolic blood pressure.

Table 5 Diagnostic tests for cardiovascular disease detection in liver transplant candidates

Diagnostic test	Purpose	Risk stratification	Key clinical parameters
Stress echocardiography	Assesses myocardial function under stress conditions to detect ischemia and evaluate contractile reserve	Low risk: Normal stress echocardiography findings. High risk: Inducible ischemia or significant wall motion abnormalities	Utilizes exercise or pharmacologic agents to induce stress. Non-invasive functional assessment. May have limitations in cirrhotic patients due to hyperdynamic circulation leading to false-negative results
Myocardial perfusion scintigraphy (nuclear stress test)	Evaluates myocardial perfusion at rest and under stress to identify areas of reduced blood flow, aiding in the detection of silent ischemia	Low risk: No perfusion defects; High risk: Reversible perfusion defects indicating ischemia	Involves administration of radioactive tracers. Non-invasive imaging technique. Accuracy may be compromised in cirrhotic patients due to splanchnic vasodilation and hyperdynamic circulation
CCTA	Provides detailed anatomical visualization of coronary arteries to detect obstructive CAD	Low risk: No or minimal coronary artery disease. High risk: Presence of significant coronary artery stenosis	High-resolution imaging modality. Non-invasive anatomical assessment. Effective in detecting CAD in LT candidates
CAC scoring	Quantifies the burden of coronary artery calcification to stratify cardiovascular risk	Low risk: CAC score of 0. Moderate risk: CAC score 1-100. High risk: CAC score > 100	Derived from CCTA or dedicated calcium scoring CT. Non-invasive quantification of calcified plaque. Higher scores associated with increased risk of perioperative MACE
Cardiac MRI	Provides detailed images of cardiac structures and function, aiding in the assessment of myocardial viability, fibrosis, and overall cardiac function	Low risk: Normal cardiac MRI findings; High risk: Presence of myocardial fibrosis, reduced ejection fraction, or other significant abnormalities	Offers high spatial resolution images without ionizing radiation. Superior tissue characterization capabilities. Useful in detecting myocardial fibrosis and assessing ventricular function. Limited availability and higher cost may restrict widespread use

CAC: Coronary artery calcium; CAD: Coronary artery disease; CCTA: Coronary computed tomography angiography; CT: Computed tomography; LT: Liver transplant; MACE: Major adverse cardiac events; MRI: Magnetic resonance imaging.

Table 6 Clinical applications of artificial intelligence in liver transplantation

	Clinical application	Description
1	Personalized preoperative risk stratification	Machine learning enables data-driven candidate selection, identifying subclinical cardiovascular risk markers that traditional scoring systems may overlook
2	Optimized post-LT monitoring	AI-driven models facilitate early detection of cardiovascular decompensation, allowing for proactive, patient-specific management with tailored follow-up protocols
3	AI-assisted decision support	Integrating predictive models into EHRs can generate automated alerts, guiding transplant teams on cardiology referrals, prehabilitation strategies, and medication adjustments
4	Resource allocation in low-resource settings	In regions with limited access to advanced cardiac testing, AI-based risk prediction provides a cost-effective alternative to conventional cardiac workups, ensuring efficient resource distribution without compromising patient safety

AI: Artificial intelligence; EHRs: Electronic health records; post-LT: Post liver transplantation.

Table 7 YKL-40 as a biomarker in adverse cardiovascular events: Associations and clinical implications

	Adverse cardiovascular event	Cardiovascular condition overview	YKL-40 association	Ref.
1	AF	A common cardiac arrhythmia characterized by rapid and irregular beating of the atria, leading to inefficient blood flow and increasing the risk of stroke and HF	General population studies have reported that elevated YKL-40 Levels are associated with an approximately two-fold increased risk of AF. Findings from Kjaergaard et al[50] largely align with these observations. However, the lack of a significant association with AF in this study challenges previous hypotheses linking YKL-40 to thromboembolism. Notably, the prognostic value of YKL-40 for AF appears to be influenced by pre-existing CVEs, as no association was observed in individuals without prior CVEs at enrollment. This discrepancy with previous general population studies, which identified a stronger relationship between YKL-40 and AF in otherwise healthy cohorts, may be attributed to differences in study design. Specifically, earlier research did not adjust for age- and sex-related variations in YKL-40 Levels, potentially leading to overestimation of its predictive value for AF	Kjaergaard et al[50]. Marott et al[55]
2	IS	Occurs when an artery supplying blood to the brain is obstructed, typically by a thrombus or embolus, leading to brain tissue ischemia and potential infarction	General population studies have shown that elevated YKL-40 Levels are associated with an approximately two-fold increased risk of IS. The study by Kjaergaard et al[50] reinforces this association, suggesting that YKL-40 may serve as a more effective prognostic biomarker for IS in individuals with lower CVE risk. This highlights the potential utility of YKL-40 in identifying subclinical vascular inflammation and endothelial dysfunction before overt CVEs develop	Kjaergaard et al[48]. Kjaergaard et al[50]
3	VTE	Includes DVT, where blood clots form in deep veins (commonly in the legs), and PE, where such clots travel to the lungs, causing potentially life-threatening complications	General population studies have reported that elevated YKL-40 Levels are associated with an approximately two-fold increased risk of VTE. Findings from Kjaergaard et al[50] partially align with these observations. However, the lack of a significant association between YKL-40 and VTE in this study challenges previous hypotheses linking YKL-40 to thromboembolic risk. This discrepancy suggests that while YKL-40 is a marker of systemic inflammation, its role in VTE pathogenesis may be less pronounced than previously thought, possibly influenced by differences in study populations or underlying risk factors	Kjaergaard et al[50]. Kjaergaard et al[54]
4	MI	MI occurs when blood flow to a part of the heart muscle is blocked, leading to tissue damage or necrosis	General population studies have found no significant association between elevated YKL-40 Levels and MI. This suggests that YKL-40 may be more closely linked to thromboembolic processes rather than atherosclerotic plaque formation. Its role in CVD appears to be stronger in conditions driven by endothelial dysfunction and systemic inflammation rather than direct arterial occlusion	Chou et al[49]. Kjaergaard et al[50]
5	HF	A clinical syndrome where the heart is unable to pump sufficient blood to meet the body's needs, resulting in symptoms like shortness of breath, fatigue, and fluid retention	YKL-40 has been associated with increased mortality in HF populations. Elevated YKL-40 Levels have also been linked to a higher risk of HF, as demonstrated in a meta-analysis of population-based studies. The study by Kjaergaard et al[50] suggests that YKL-40 may serve as a more effective prognostic biomarker for HF in individuals with lower CVE risk, indicating its potential role in early disease identification and risk stratification	Kjaergaard et al[50]. Henry et al[56]
6	PAD	A circulatory condition characterized by narrowed arteries, reducing blood flow to the limbs, often leading to leg pain and mobility issues	Elevated YKL-40 Levels have been observed in individuals with PAD, particularly among those with prediabetes or diabetes. However, no prospective studies have specifically evaluated YKL-40 as a risk factor for PAD development. The study by Kjaergaard et al[50] suggests that YKL-40 may serve as a more reliable prognostic biomarker for PAD in individuals with lower CVE risk, highlighting its potential role in early vascular risk assessment	Wu et al[46]. Chou et al[49]. Kjaergaard et al[50]

AF: Atrial fibrillation; CAD: Coronary artery disease; CVD: Cardiovascular disease; CVEs: Cardiovascular events; DVT: Deep vein thrombosis; HF: Heart failure; IS: Ischemic stroke; MI: Myocardial infarction; PAD: Peripheral artery disease; PE: Pulmonary embolism; VTE: Venous thromboembolism.