Cardiovascular risk stratification in liver transplant patients: Balancing clinical outcomes and resource allocation

Abstract

Cardiovascular diseases are a leading cause of both short-term and long-term complications in patients who are candidates for liver transplantation. The increasing prevalence of cardiovascular risk (CVR) factors like hypertension, diabetes, and dyslipidemia in this population is linked to lower overall survival rates with an increased risk of major cardiovascular events during and after the procedure. However, while guidelines for CVR stratification exist, their clinical application remains inconsistent. A significant challenge is the high cost of comprehensive cardiovascular evaluation, which often involves advanced diagnostic tests, imaging, and multidisciplinary specialist consultations. This issue is especially challenging in public healthcare systems, where the financial burden of thorough cardiovascular examinations can stretch already limited resources. Given the increasing pressures on healthcare sustainability, it is essential to balance careful cardiovascular screening with the efficient use of resources. The rising costs highlight the need for evidence-based updates to practices that optimize patient outcomes while reducing the strain on the healthcare system. Tailored approaches should focus on both managing cardiovascular issues and considering the economic impact. Considering these challenges, adaptable protocols are needed to improve transplantation safety and efficacy while addressing the financial realities of public health systems and minimizing unnecessary costs.

Key Words: Liver transplantation; cardiovascular diseases; Risk assessment; Resource allocation; Cost-benefit analysis

Core Tip: Cardiovascular disease is a leading cause of complications in liver transplant candidates, yet risk assessment remains inconsistent due to high costs, especially in public healthcare systems. Balancing comprehensive screening with resource efficiency is crucial to improving outcomes while minimizing financial strain. Evidence-based, adaptable protocols are needed to enhance patient safety, optimize resource allocation, and ensure the long-term sustainability of healthcare systems.

INTRODUCTION

Liver transplantation (LT) is a life-saving procedure for patients suffering from end-stage liver disease (ESLD), including cirrhosis, hepatocellular carcinoma, and other liver pathologies. Annually, approximately 24000 liver transplants are performed worldwide, with nearly 7000 procedures conducted in the United States alone[1]. However, the distribution of LT procedures varies significantly across countries. The United States performs the highest volume of liver transplants globally, followed by China and Brazil[2]. In Europe and North America, nonalcoholic fatty liver disease (NAFLD) has become the predominant indication for LT, surpassing traditional causes such as hepatitis B and C[3], whereas in regions like Asia, South America, and Africa, viral hepatitis remain the leading indications due to regional differences in disease prevalence[4].

The rising prevalence of NAFLD in Western countries is attributed to increasing rates of obesity, type 2 diabetes, and metabolic syndrome. For example, in the United States, NAFLD-related cirrhosis now accounts for approximately 25% of all liver transplants and is expected to continue rising as the obesity epidemic persists[3]. Similarly, in some European countries, a comparable trend is emerging, where metabolic diseases surpass viral hepatitis as the primary cause of liver failure[5].

Hepatitis B virus (HBV) infection is endemic in many parts of Asia and is a major cause of chronic liver disease and cirrhosis. For instance, in countries like China and Indonesia, HBV remains the principal cause of LT, with studies reporting that approximately 50% of liver transplants in these regions are attributable to HBV-related cirrhosis or hepatocellular carcinoma[6]. Additionally, hepatitis C virus (HCV) is a significant contributor to liver transplants in South America and Africa. Despite advances in antiviral therapies, the global burden of HCV-related liver disease remains substantial, especially in sub-Saharan Africa, where HCV drives the ongoing need for LT[7].

Despite advancements in LT techniques and preoperative care, including comprehensive screening protocols, the management of cardiovascular diseases (CVD) in LT candidates remains a critical concern. Cardiovascular disease is a major contributor to early post-transplant mortality, accounting for up to 40% of deaths within the first 30 days post-transplant[8]. Cardiovascular morbidity can be further exacerbated by several risk factors such as older age, previous cardiovascular events, diabetes, metabolic syndrome, and hyperuricemia. Moreover, immunosuppressive therapies, including mycophenolate or steroids, may increase the likelihood of cardiovascular complications after transplantation[7]. The prevalence of metabolic syndrome among LT recipients, affecting up to two-thirds of patients, further amplifies this risk, with affected individuals being four times more likely to experience cardiovascular events[9]. Therefore, a multidisciplinary approach to preoperative cardiovascular assessment, vigilant postoperative monitoring, and proactive management of modifiable risk factors (including hypertension, hyperlipidemia, and obesity) is essential for optimizing outcomes and reducing the incidence of cardiovascular events.

CARDIOVASCULAR RISK FACTORS IN LIVER TRANSPLANT CANDIDATES

A crucial consideration in LT candidates is the high prevalence of computer-aided detection (CAD), which is a major determinant of perioperative morbidity and mortality. It is estimated that 25% of LT candidates have moderate CAD even when asymptomatic[10]. Several risk factors have been identified as indicators of high risk for CAD: (1) Age ≥ 60 years; (2) Male gender; (3) Body mass index ≥ 30; (4) Diabetes; (5) Dyslipidemia; (6) Smoking; (7) Hypertension; (8) History of CAD; (9) Family history of CAD; (10) Left ventricular (LV) hypertrophy; (11) Renal disease; and (12) Transplant indication for MASH. Despite recognition of these risk factors, the literature remains heterogeneous regarding the diagnostic strategy for identifying CAD in LT candidates; significant variation exists among transplant centers, and no universal threshold determines when further cardiac screening is necessary. Some studies suggest that patients with two or more risk factors and MASH, or those with three or more risk factors, should undergo further assessment using a structured risk score such as CAD-LT[11].

A consensus has emerged that additional testing should be performed in patients at high risk of CAD to identify those who may benefit from cardiac interventions or who possess an unacceptable risk profile for transplantation[12].

The prevalence of cardiovascular risk (CVR) factors in LT candidates remains alarmingly high, with studies showing that up to 35% of LT candidates present with metabolic syndrome or at least one major CVR factor—hypertension, diabetes, dyslipidemia, or obesity. Additionally, as the LT candidate population ages, the prevalence of these risk factors increases, rendering this group particularly vulnerable to postoperative cardiovascular complications. ESLD can affect the cardiovascular system in several ways: (1) Increased systemic inflammation associated with endothelial dysfunction may elevate the risk of CAD; and (2) Particularly in an already susceptible population, the prevalence of CAD is higher than that in the general population[13]. Critical coronary stenosis (> 50%) is found in up to 25% of LT candidates with at least two CVR factors, and subcritical coronary stenosis (< 50%) may remain undetected in preoperative evaluation tests[11].

Failure to diagnose subclinical or undetected CAD preoperatively can have significant clinical consequences, especially under the hemodynamic stress of LT. During LT, the combination of large-volume fluid shifts, fluctuating systemic vascular resistance, and the ischemia-reperfusion response creates an environment of significant myocardial stress, potentially increasing the risk of myocardial ischemia[14]. This can result in intraoperative hypotension, arrhythmias (including atrial fibrillation and ventricular tachycardia), and even perioperative myocardial infarction (MI), all of which have been associated with high morbidity and mortality rates in LT recipients. Furthermore, undiagnosed CAD may predispose patients to postoperative heart failure due to the increased cardiac workload during recovery, potentially leading to hemodynamic instability and poorer long-term outcomes[15].

Recent studies have highlighted the impact of undetected cardiovascular disease on postoperative mortality in LT recipients. Specifically, Reznicek et al[16] showed how patients with preexisting CAD prior to LT are at higher risk of death from any cause—specifically cardiovascular-related death, while Darstein et al[17] found that post-LT MI occurred in 2.8% of patients with a history of CAD, with a 90-day mortality rate of 16.7%. These findings underscore the critical importance of preoperative cardiovascular assessment in LT candidates.

A comprehensive cardiovascular evaluation before LT should always include a thorough history and physical examination. Pre-transplant risk assessment can help predict perioperative events and estimate long-term cardiac survival, thereby enabling proper resource allocation and optimization of clinical outcomes.

In this context, perioperative MI emerges as a serious complication, as it often presents with atypical symptoms in LT recipients due to autonomic dysfunction and anesthetic effects. The incidence of perioperative MI in LT patients may range from 2% to 5%, with significantly higher mortality rates among affected patients[18]. Perioperative MI not only increases the risk of intraoperative cardiac arrest but also leads to prolonged ventilatory support, longer intensive care unit stays, and poor graft survival[19,20].

Undiagnosed CAD can also predispose patients to postoperative heart failure, as rapid changes in preload and afterload, coupled with systemic inflammation, may exacerbate underlying myocardial dysfunction, leading to hemodynamic instability. Furthermore, diastolic dysfunction can complicate post-transplant recovery by impairing LV filling and causing pulmonary congestion[21].

In the long term, undiagnosed CAD and perioperative cardiovascular complications significantly affect patient survival. Vanwagner et al[8] have demonstrated that LT recipients with underlying CAD experience a higher one-year mortality rate, predominantly due to cardiovascular causes. Moreover, recurrent cardiac events post-LT, including heart failure exacerbations and late MI, contribute to long-term morbidity, necessitating close cardiovascular surveillance[22].

Compromised liver function in ESLD can further contribute to the development of cirrhotic cardiomyopathy (CCM), which over time may lead to structural cardiac abnormalities and arrhythmias, thereby compromising the ventricular response to postoperative hemodynamic stress and potentially increasing the risk of cardiac-related death[23]. The pathogenesis of CCM involves systemic inflammation, neurohormonal activation, and alterations in cardiac ion channels, resulting in both systolic and diastolic dysfunction. In the context of LT, patients with CCM face heightened risks during LT due to CCM-related diminished cardiac reserve during major surgery[24].

This increases the risk of complications like organ hypoperfusion or graft failure, potentially aggravating myocardial injury.

CCM-related myocardial dysfunction may also result in alterations in LV and left atrial structures that are independently associated with increased all-cause mortality and prolonged hospitalization due to an increased incidence of infections, partly imputable to longer ventilation times[25].

CURRENT CVR STRATIFICATION GUIDELINES: TOWARD A UNIFIED APPROACH IN LIVER TRANSPLANT CANDIDATE EVALUATION

Preoperative CVR stratification is critical for optimizing outcomes in LT candidates, yet it remains a significant challenge due to the complex interplay between liver disease and the associated metabolic systemic dysfunction.

Current CVR models, such as the Framingham Risk Score and the European Society of Cardiology guidelines[26], were designed for general population and primarily focus on traditional risk factors like age, cholesterol levels, and blood pressure; however, they failed to account for the liver-specific pathophysiology that impacts cardiovascular health, namely, endothelial dysfunction, systemic inflammation, cirrhosis, and the metabolic disturbances common in ESLD[27].

In response to the growing recognition of the unique cardiovascular challenges in LT patients, several LT-specific CVR scores have been developed, such as CAR-orthotopic liver transplantation (OLT), CAD-LT, and Checklist for Assessing Readiness for Implementation (CARI)[28-30]. These scores attempt to capture the complexities of liver disease-related CVR, by factoring in variables such as CCM, portal hypertension, and the effects of immunosuppressive therapy.

The CAR-OLT, CAD-LT, and CARI scores each serve a distinct purpose in the context of preoperative evaluation. Given that LT patients often present with multiple comorbidities, these scores provide a practical and evidence-based approach to identifying those at increased risk for major adverse cardiac events (MACE) and other complications, thereby guiding preoperative management.

CAR-OLT score

The CAR-OLT score is designed to predict MACE in LT candidates by incorporating factors such as age, history of CAD, diabetes mellitus, and functional status. It has demonstrated a sensitivity of approximately 80% and specificity of 70% in predicting perioperative cardiac events[30]. Its simplicity lies in its reliance on readily available clinical parameters, making it an efficient tool for initial CVR stratification. This is particularly valuable in clinical settings where immediate action is required, as it enables the rapid identification of patients at risk for MACE. However, its broad applicability may be limited by its inability to fully capture subclinical CAD, which often does not present with overt clinical symptoms.

CAD-LT score

The CAD-LT score focuses specifically on assessing the risk of significant CAD in LT candidates by incorporating key factors such as age, diabetes mellitus, smoking status, and the presence of metabolic syndrome. It exhibits a sensitivity of 85% and specificity of 75% in detecting significant coronary lesions[7]. This score is particularly effective for identifying LT candidates with underlying CAD—whether asymptomatic or presenting as subclinical atherosclerosis. Given that CAD is a common comorbidity in patients with ESLD, particularly in those with metabolic syndrome or diabetes, the CAD-LT score is an important tool for flagging candidates who may benefit from further noninvasive or invasive coronary evaluations prior to transplantation. For instance, coronary angiography (CA) or stress testing could be considered to evaluate the need for revascularization before proceeding with LT. Additionally, the CAD-LT score’s high sensitivity makes it useful in detecting at-risk patients who might otherwise be overlooked using less sensitive methods[31].

CARI score

The CARI score offers a more comprehensive risk assessment by evaluating both cardiac and renal risks in LT candidates. It incorporates parameters such as LV hypertrophy, diastolic dysfunction, renal function, and electrolyte imbalances. The CARI score has demonstrated a sensitivity of 78% and specificity of 72% in predicting cardiac complications post-LT[32]. This comprehensive approach is particularly beneficial for LT candidates with concomitant cardiac and renal concerns—a common scenario in patients with cirrhosis, especially those with portal hypertension and associated renal dysfunction. By integrating both cardiac and renal assessments, the CARI score provides a holistic risk evaluation, thereby guiding clinicians in managing patients with complex, multi-organ dysfunction[33]. Moreover, it underscores the need for careful perioperative monitoring of both systems, potentially informing decisions regarding transplantation timing, specific perioperative medications, and post-transplant therapies.

Comparative applicability

Choosing the most appropriate risk score for clinical use largely depends on the patient population’s specific characteristics and comorbidities. The CAR-OLT score is advantageous for its ease of use and general applicability; however, it may lack the specificity required to detect subclinical CAD in asymptomatic patients with significant underlying risk. Conversely, the CAD-LT score is highly sensitive and specific for detecting significant CAD, making it an excellent choice for LT candidates with risk factors such as diabetes, metabolic syndrome, or a history of smoking. The CARI score, though less widely used, provides a broader assessment by evaluating both cardiac and renal risks, which is particularly useful for patients with combined issues common in advanced liver disease. This approach enables clinicians to offer a more personalized treatment strategy and potentially improve post-transplant outcomes.

In 2024, the European Association for the Study of the Liver (EASL) clinical practice guidelines advocated for a comprehensive and standardized approach to CVR stratification in LT candidates[34]. Given the significant burden of cardiovascular disease in patients with ESLD, EASL underscored the need for a uniform and evidence-based framework to assess and manage CVR. Recognizing the limitations of traditional CVR models, the guidelines further emphasized the integration of LT-specific CVR scores, multimodal diagnostic strategies, and multidisciplinary collaboration. By standardizing preoperative cardiovascular evaluation, EASL aimed to improve risk stratification, optimize perioperative management, and enhance post-transplant survival.

The guidelines proposed a stepwise, risk-adjusted cardiac work-up algorithm beginning with an initial screening that includes a detailed medical history, physical examination, resting electrocardiogram, and measurement of biomarkers such as natriuretic peptides [N-terminal proBNP (NT-proBNP)] and cardiac troponins to detect subclinical cardiac dysfunction.

While for patients with abnormalities or whenever intermediate CVR is detected, non-invasive testing, including coronary computed tomography angiography (CCTA), may be considered for a more detailed assessment of coronary anatomy, reserving invasive CA only for high risk individuals or in case of signs of significant CAD.

Furthermore, the guidelines highlight the necessity for vigilant perioperative cardiovascular monitoring and management to reduce the risk of MACE, given the increased cardiovascular burden in LT recipients. Post-transplant, ongoing cardiovascular surveillance remains crucial, considering the potential progression of cardiovascular disease and the metabolic impact of immunosuppressive therapy.

Despite the clear recommendations set forth by the EASL 2024 guidelines, real-world clinical practice continues to demonstrate significant variability in the implementation of standardized CVR stratification protocols for LT candidates. A lack of universal adherence to these guidelines can be attributed to several factors, including institutional differences in pretransplant evaluation protocols, limited access to advanced cardiovascular diagnostic tools, and variability in multidisciplinary team expertise across transplant centers. Furthermore, the heterogeneity of LT candidates, many of whom present with complex, multifactorial CVRs, poses challenges in uniformly applying risk stratification models and adhering to predefined assessment algorithms. As a result, despite the efforts to harmonize cardiovascular evaluation in LT recipients, disparities in preoperative cardiac risk assessment persist, underscoring the need for continued efforts to bridge the gap between guideline recommendations and clinical practice. Standardizing CVR assessment remains a critical goal to ensure that all LT candidates receive optimal preoperative evaluation, leading to improved perioperative and long-term outcomes.

CHALLENGES AND OPPORTUNITIES IN STANDARDIZING CVR ASSESSMENT FOR LIVER TRANSPLANT CANDIDATES

The selection of appropriate diagnostic tools for risk stratification of asymptomatic CAD in LT candidates remains a subject of ongoing debate, presenting both challenges and opportunities for enhancing patient outcomes[35]. Traditionally, CA has been considered the gold standard for assessing CAD due to its specific advantages, including precise mapping of coronary lesions, characterization of significant CAD, and the possibility of simultaneous revascularization via stent placement.

However, its invasive nature poses significant risks, particularly in patients with ESLD who may have coagulopathies and other complications. Moreover, CA findings are limited to the coronary lumen and cannot precisely identify lipidic plaques in the coronary wall, further lowering its predictive value in risk stratification for LT recipients[36].

To date, CCTA has become an essential noninvasive tool for CV risk stratification. It exhibited an excellent negative predictive value (95%–100%) for excluding clinically significant CAD[37]. Moreover, due to the ability of CCTA to provide high-resolution imaging that detects both obstructive and nonobstructive coronary lesions, in the general population, this high level of detail allows for a comprehensive anatomical assessment of the coronary arteries, which can be visualized in three dimensions and from multiple spatial orientations thanks to the acquisition of volumetric data sets. Unlike invasive CA, CCTA does not require catheterization, thereby reducing the risk of procedure-related complications—including vascular injury or bleeding—which is particularly relevant in patients with compromised liver function[38].

Furthermore, advancements in CCTA technology, such as improved spatial and temporal resolution, have enhanced its diagnostic accuracy, making it a reliable alternative to traditional invasive methods. Modern CCTA techniques incorporate fractional flow reserve computed tomography (FFR-CT), which allows for a functional assessment of coronary stenoses, providing additional insight into the hemodynamic significance of detected lesions without further invasive testing[39]. Additionally, the ability of CCTA to evaluate coronary artery calcium (CAC) scoring provides valuable prognostic information, helping clinicians refine risk stratification and make more informed decisions regarding pre-transplant cardiovascular management[40].

Another significant advantage of CCTA is its efficiency and accessibility. The procedure is relatively quick—typically completed within minutes—and is well tolerated by patients, thereby minimizing the logistical and physical burdens associated with more invasive evaluations. Ongoing advancements in dose-reduction protocols have also significantly minimized radiation exposure, making CCTA safer for patients who may require repeated imaging. In the context of LT, where timely risk assessment is essential for optimizing outcomes, CCTA provides a rapid and comprehensive evaluation that facilitates early intervention strategies, ensuring that high-risk candidates receive appropriate cardiovascular management before transplant surgery. As a result, CCTA is increasingly integrated into the pre-transplant cardiovascular screening protocols of many transplant centers, reinforcing its role as a valuable and evolving tool for CVR assessment in LT candidates[41].

While CA remains a definitive diagnostic tool, integrating CCTA into the pre-transplant evaluation protocol may offer a noninvasive and effective means of stratifying CVR among LT candidates. This approach not only enhances patient safety by reducing exposure to invasive procedures but also ensures the early detection and management of CAD, ultimately improving transplant outcomes[42].

However, the invasive and resource-intensive nature of traditional cardiovascular assessments has led to a growing shift toward noninvasive alternatives. Techniques such as CAC scoring, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and stress testing—including treadmill exercise and pharmacological stress tests—have emerged as alternative methods for assessing CVR in LT candidates. These noninvasive approaches offer valuable insights into cardiovascular health while minimizing patient discomfort and reducing the burden on healthcare resources[43].

Despite the exploration of various noninvasive methods for CVR assessment in LT candidates, each modality has its limitations. For example, CAC scoring is useful for detecting subclinical atherosclerosis and provides prognostic information regarding CVR. This noninvasive tool is validated for identifying and quantifying calcified plaque in the coronary arteries using computed tomography (CT) scan acquisitions; however, it does not offer direct insight into ischemia or the presence of flow-limiting coronary lesions—both critical for determining the need for further intervention[44]. Moreover, the predictive ability of CAC for perioperative outcomes in patients undergoing LT is still limited, and it should be used in conjunction with other noninvasive techniques to obtain a comprehensive evaluative profile[45].

This limitation renders CAC scoring insufficient as a standalone test in LT candidates, who often have complex cardiovascular profiles requiring a more comprehensive evaluation.

Similarly, stress echocardiography—though widely used for its availability and safety, and recommended by current guidelines for LT candidates with more than three risk factors for CAD—has demonstrated a relatively low sensitivity and low positive predictive value in the LT population when compared to CA[46]. This can be attributed to the unique hemodynamic and metabolic alterations present in patients with ESLD, which may mask underlying coronary pathology and lead to false-negative results. Consequently, stress echocardiography alone may not be adequate for accurately identifying LT candidates at high risk for adverse cardiovascular events.

More advanced imaging modalities, such as myocardial perfusion imaging using SPECT or PET, provide additional functional data on myocardial perfusion and can help detect subclinical ischemia. These techniques offer improved sensitivity in assessing myocardial blood flow abnormalities, making them valuable for refining CVR assessment. PET imaging, in particular, has demonstrated superior accuracy compared to SPECT due to its ability to quantify myocardial blood flow and coronary flow reserve, enabling earlier detection of microvascular dysfunction[12,47]. However, despite these advantages, these modalities face practical challenges—including limited availability, high cost, and the need for specialized expertise—which can restrict their widespread use, especially in public healthcare settings[48].

However, in cases where significant coronary lesions are identified, invasive coronary angiography remains necessary for definitive assessment and potential revascularization[49]. The management of CAD in LT candidates must be individualized based on CAD severity and the degree of liver failure. Revascularization with drug-eluting stents may be performed with a short course (3–6 months) of dual antiplatelet therapy; however, this approach is associated with substantial mortality in candidates with advanced decompensated cirrhosis[50].

It has been demonstrated that the severity or extent of CAD does not adversely impact post-LT survival if appropriate revascularization is achieved. Conversely, failure of revascularization in patients with significant CAD should be considered a contraindication to LT due to the high risk of perioperative mortality and poor midterm outcomes resulting from progressive coronary heart disease. These considerations are reflected in the 2024 EASL guidelines[34], which emphasize the importance of comprehensive cardiovascular assessment and individualized management strategies for LT candidates with CAD.

Given these considerations, a multimodal approach to CVR assessment in LT candidates is often necessary to balance diagnostic accuracy with feasibility. The integration of anatomical and functional imaging techniques—such as combining CCTA with FFR-CT or hybrid PET-CT—has emerged as a promising strategy to enhance risk stratification[51]. These advancements allow for a more precise evaluation of both coronary anatomy and the physiological significance of lesions, ultimately improving pre-transplant decision-making. As technology continues to evolve, efforts to optimize accessibility and cost-effectiveness will be crucial in ensuring that high-risk LT candidates receive appropriate cardiovascular screening and management prior to transplantation.

Ultimately, the evolving landscape of CVR stratification in LT candidates underscores the need for continued research and the development of standardized protocols to enhance patient selection, optimize perioperative outcomes, and improve long-term survival following LT. Despite the availability of validated and specific protocols for evaluating LT candidates, many transplant centers often fail to implement uniform assessment strategies and may continue to rely on outdated guidelines[13]. Variability in local practices leads to inconsistent CVR evaluation, with some centers prioritizing liver function and MELD scores over comprehensive cardiovascular assessments[52]. Even basic CVR factors (including diabetes, age, male sex, obesity, hypertension, and tobacco use), though generally evaluated by all transplant centers, can be interpreted differently. Some centers may implement a holistic approach[53], subjecting all patients to noninvasive testing rather than opting for a risk-based strategy guided by pre-assessment findings[54]. In particular, certain centers may prioritize a tailored approach, focusing on patients with a higher burden of CVR factors, while others may adopt a blanket policy—conducting comprehensive cardiovascular screening on all LT candidates regardless of their baseline risk profile. These practices underscore the necessity for standardized, evidence-based protocols to ensure a thorough and systematic evaluation of CVR in all LT candidates.

This lack of consistency may lead to unnecessary testing in low-risk patients, thereby increasing the financial burden and patient discomfort, while simultaneously failing to adequately assess those at higher risk who may not meet the threshold for second-level diagnostics [including cardiac magnetic resonance imaging (MRI), SPECT, or CA] but are still at significant risk for postoperative major cardiovascular events. Moreover, such variability in practice may result in crucial risk factors—such as subcritical CAD—being overlooked in some centers, leaving patients unprepared for the cardiovascular demands of transplantation. Ultimately, the absence of a standardized, evidence-based approach to CVR stratification leads to suboptimal care, which can have serious implications for both the perioperative management and the long-term outcomes of LT patients.

Furthermore, current guidelines recommend that CVR assessment in LT candidates should involve a multidisciplinary evaluation by various specialists—including hepatologists, cardiologists, and anesthesiologists—to obtain a complete picture of a patient’s health status[55]. However, in many transplant centers, particularly those with high patient volumes, communication between these specialties can be fragmented or inconsistent[56]. A lack of streamlined communication and coordination among these teams can lead to delays in decision-making, misunderstandings about patient management, and potential gaps in care, all of which can negatively affect patient outcomes.

In high-volume transplant centers, multidisciplinary teams often struggle with inconsistent communication, particularly during the perioperative period when timely decision-making is critical. The complexity of LT involves not only surgical intervention but also detailed preoperative assessments including cardiovascular evaluation, renal function monitoring, and the management of comorbid conditions such as diabetes or hypertension. The rapid pace and high patient numbers may lead to less personalized, more hurried interactions, making it difficult for healthcare professionals to keep all relevant parties informed. Failure to integrate communication fully among specialists can result in missed opportunities for timely intervention, potentially increasing the risk of post-transplant complications. For example, if cardiologists and hepatologists do not communicate effectively about the CVRs of an LT candidate, the patient may undergo surgery without sufficient preparation for cardiovascular events, leading to poor outcomes such as heart failure or arrhythmias after transplantation[56].

Poor communication between specialties can also contribute to issues such as medication errors, inappropriate use of immunosuppressants, and delayed or missed follow-up assessments. These issues are particularly concerning in the post-transplant period when close monitoring is essential for the early identification of complications. For example, a lack of coordination between nephrologists and hepatologists may delay the detection of renal dysfunction—a common complication in LT recipients that may require adjustments in immunosuppressive therapy or dialysis[57]. In response, some transplant centers are improving communication by implementing structured protocols and interdisciplinary meetings, including regular case discussions in which all specialists involved in patient care can provide input and agree on management strategies. These efforts aim to reduce fragmentation and ensure that all specialties work together toward the best possible patient outcomes. Additionally, electronic health records (EHR) and shared decision-making platforms are increasingly used to facilitate communication and coordination in high-volume centers, ensuring that patient data is readily accessible to all involved parties and reducing misunderstandings[58].

Furthermore, resource constraints—both in terms of personnel and time—can exacerbate these issues, as specialists may not have the bandwidth to collaborate as effectively as needed[59].

CLINICAL AND FINANCIAL IMPACT OF UNDIAGNOSED CVD

Inadequate preoperative CVR assessment in LT candidates within public health systems can also have significant financial consequences.

Specifically, within Italy's public health system, the costs associated with treating post-transplant cardiovascular complications in liver transplant recipients are particularly concerning[60] and comparative analyses across different healthcare systems give similar results. In the United Kingdom, the National Health Service has made strides in integrating multidisciplinary care teams, which include cardiologists for pre-transplant and post-transplant CVR assessment. However, as in Italy, the financial burden remains significant, particularly for LT candidates who present multiple CVR factors.

Excluding the cost of the procedure itself that may range between £32000 and £45000, an important aspect is represented by the financial burden associated with post-transplant care, which includes ongoing cardiovascular management, immunosuppressive medications, and potential retransplantation due to graft failure for potentially avoidable cardiovascular complications[61].

A similar situation can be observed in Australia and New Zealand, where the increased cost is closely linked to the rising prevalence of metabolic risk factors and concurrent liver diseases. Data from the Australian and New Zealand Liver and Intestinal Transplant Registry highlight a significant shift in the demographic and clinical profile of LT recipients, with an increasing number presenting with multiple liver disease etiologies, particularly metabolic-associated fatty liver disease (MAFLD) and alcohol-related liver disease (ALD). The prevalence of concurrent liver diseases has risen from just 6% in the late 1980s to over 20% in recent years, reflecting broader epidemiological trends in liver disease and metabolic disorders. These conditions often coexist with CVR factors such as hypertension, diabetes, and ischemic heart disease (IHD), which contribute to higher rates of post-transplant complications and an increased demand for specialized cardiovascular care[62].

In this context, a key driver of cost escalation in LT recipients with cardiovascular disease is the need for extended hospitalization and intensive care. Patients with concurrent liver diseases, particularly those with ALD and MAFLD, are more likely to have pre-existing metabolic disorders that heighten the risk of post-transplant cardiovascular events, such as MI and stroke. Howell et al[62] showed also that a higher proportion of LT recipients with concurrent liver diseases had diabetes (28% vs 20% in single-disease recipients, P < 0.001) and hypertension (14% vs 8%, P < 0.001), both of which are major contributors to cardiovascular morbidity. Additionally, IHD was present in 6% of those with multiple liver diseases, further complicating post-transplant recovery and increasing costs associated with cardiac monitoring, medication, and interventions.

Also, the Canadian health system shows an analogous trend. According to data from the University Health Network (UHN) in Toronto, cardiovascular disease is one of the leading causes of post-transplant mortality, with 124 out of 3269 LT recipients (3.8%) in the UHN dataset dying from cardiovascular-related causes. In both Canadian and international cohorts, cardiovascular disease has been identified as a major determinant of long-term survival after LT, with predictive models showing a high area under the receiver operating characteristic curve (0.807 for 1-year and 0.722 for 5-year mortality predictions), reinforcing the significant impact of cardiovascular complications on post-transplant outcomes[63].

Although the implementation of additional pre-transplant cardiovascular investigations may increase initial costs[64], these findings highlight the essential need for comprehensive cardiovascular screening and management strategies in LT candidates. Particularly in publicly funded health systems, where both organ donation and transplantation are government-financed, it is critical for governance to ensure the adoption of current, standardized protocols for LT recipient management. This approach would contribute to achieving optimal one-year and five-year survival rates while simultaneously reducing the incidence of preoperative and postoperative complications and the associated healthcare expenditures[65].

NEW PERSPECTIVE IN PUBLIC HEALTH SYSTEMS AND SCREENING EFFICIENCY

In public healthcare systems where funding is often limited, the need for cost-effective, efficient screening becomes even more pressing. In these settings, the correct preoperative evaluation of CVR factor, since first patient evaluation, and the implementation of a risk-based approach, with a progressive use of first noninvasive modalities (including electrocardiography, dobutamine stress echocardiography, CAC, stress cardiac MRI, and SPECT) and resorting to invasive CA for CAD evaluation only when positive results are obtained, can reduce unnecessary expenditures on advanced imaging while ensuring that individuals most likely to benefit from comprehensive cardiovascular screening receive appropriate care.

Moreover, the wide adoption of validated predictive risk scores such as CAD-LT or CAR-OLT, in conjunction with noninvasive scoring systems, can improve screening efficiency by helping to identify high-risk candidates without the need for extensive testing[66].

Furthermore, as more data become available and personalized medicine continues to evolve, the risk-adjusted screening protocol for LT candidates should be flexible and adaptable. Incorporating genetic predispositions, biomarker profiling, and advanced artificial intelligence (AI)-driven algorithms may further refine risk stratification and enhance the precision of cardiovascular screening. Genetic markers—such as polymorphisms in genes related to inflammation and endothelial function (e.g., interleukin-6, tumor necrosis factor-alpha, and endothelial nitric oxide synthase variants)—could help identify LT candidates at higher risk of developing cardiovascular complications[67]. These genetic predispositions may contribute to the progression of CCM, endothelial dysfunction, and CAD, thereby warranting more aggressive preoperative cardiovascular evaluation.

In addition to genetic factors, several biomarkers have emerged as promising tools for assessing CVR in LT candidates. While B-type natriuretic peptide (BNP) and NT-proBNP have been widely studied for their roles in detecting subclinical cardiac dysfunction, particularly in patients with CCM or heart failure, Galectin-3, a biomarker linked to myocardial fibrosis and inflammation, has been shown to predict adverse cardiac remodeling and heart failure in cirrhotic patients[68]. Higher Galectin-3 levels correlate with worse hemodynamic profiles and poor post-transplant outcomes, highlighting its potential utility in refining CVR assessment.

Beyond these traditional biomarkers, newer markers such as growth differentiation factor-15 (GDF-15) and soluble suppression of tumorigenicity 2 (sST2) have gained attention for their abilities to reflect myocardial stress and fibrosis, respectively[69]. These emerging biomarkers could potentially complement conventional screening tools, improving the detection of early myocardial dysfunction in LT candidates already shown for kidney transplant patients[70]. Additionally, AI-driven algorithms that integrate genetic and biomarker data with clinical and imaging parameters could enhance predictive modeling for MACE[71]. By leveraging machine learning techniques, these models may identify novel risk patterns and automate decision-making in transplant evaluations, ultimately optimizing cardiovascular screening protocols.

As precision medicine continues to advance, incorporating these genetic and biomarker-driven approaches into LT screening algorithms could lead to more personalized risk stratification, minimizing unnecessary testing while ensuring that high-risk patients receive appropriate interventions. Future research should focus on validating these novel markers in large, multicenter cohorts and integrating them into AI-based predictive models to enhance the accuracy and efficiency of CVR assessment in LT candidates.

Additionally, clinical decision support systems (CDSS) could help transplant centers implement these protocols effectively, ensuring consistent and evidence-based decision-making across different healthcare systems and regions[72].

Integrating CDSS into transplant centers offers a promising avenue to enhance protocol implementation and ensure consistent, evidence-based decision-making across diverse healthcare settings. Recent advancements in AI have further augmented the potential of CDSS by enabling the analysis of vast datasets to identify patterns and predict patient outcomes, thus assisting in the early detection of complications such as graft rejection and improving patient prognosis[73]. However, effective implementation requires addressing multiple challenges, including data quality and integration, as AI models rely on comprehensive EHR to generate accurate predictions—necessitating data standardization and interoperability across healthcare systems[74]. Additionally, ensuring a user-centric design is critical for clinical adoption, as intuitive interfaces and alignment with clinical workflows facilitate seamless integration into daily practice. Ethical concerns—particularly potential biases in AI algorithms—require continuous monitoring and refinement to prevent disparities in patient care, with recent efforts highlighting the removal of race-based adjustments in clinical decision-making tools. Furthermore, policy and regulatory support play crucial roles in governing AI-driven CDSS by emphasizing data privacy, security, and ethical compliance, with organizations like the United States Congressional Research Service advocating for comprehensive oversight to ensure safe and effective AI utilization in healthcare. Addressing these challenges through interdisciplinary collaboration among clinicians, AI developers, and policymakers is essential to maximizing the potential of AI-enhanced CDSS in transplant care.

CONCLUSION

Targeted, risk-adjusted cardiovascular screening protocols hold significant potential to optimize cardiovascular care for LT candidates while simultaneously minimizing costs and improving patient outcomes. By stratifying patients according to their individual CVR profiles, healthcare systems can allocate resources more efficiently, ensuring that high-risk individuals receive timely and appropriate interventions while avoiding unnecessary testing in low-risk patients. The integration of advanced CVR scores—such as CAR-OLT, CAD-LT, and CARI—into pretransplant evaluations further refines this stratification, enabling clinicians to balance the need for thorough assessment with streamlined resource utilization. As our understanding of CVRs in LT candidates continues to evolve, screening protocols are expected to become more sophisticated by incorporating emerging biomarkers, innovative imaging modalities, and digital health technologies, thereby enhancing both precision and cost-effectiveness. Novel biomarkers, such as high-sensitivity troponin and NT-proBNP, may facilitate the early detection of subclinical cardiac dysfunction, while advanced echocardiographic techniques—including global longitudinal strain and contrast-enhanced imaging—offer superior sensitivity in assessing myocardial function compared to traditional methods. Additionally, wearable technologies and remote monitoring systems could enable continuous CVR assessment during both the pre-transplant and post-transplant periods, allowing for early intervention and personalized management strategies.

Future research should focus on validating AI–driven models designed to predict MACE in LT candidates, potentially enhancing the accuracy of risk assessment beyond traditional scoring systems. AI-based algorithms have the potential to analyze large-scale patient data by integrating clinical, biochemical, and imaging parameters, thereby increasing predictive power and automating decision-making in transplant evaluations. Moreover, multicenter clinical trials are needed to evaluate the real-world applicability of various cardiovascular screening strategies by comparing outcomes among LT recipients stratified by different risk assessment models; such trials would provide critical evidence regarding effectiveness, cost-benefit ratios, and the necessary refinements to standardize screening protocols across transplant centers globally.

Ultimately, integrating AI, multicenter trial data, and emerging biomarkers into risk-adjusted screening protocols represents a promising avenue for enhancing cardiovascular outcomes in LT candidates. By embracing these advancements, the transplant community can move toward a more personalized and resource-efficient approach to CVR management, ensuring that patients receive the highest standard of care while optimizing healthcare expenditures.