Calcified coronary artery disease: Mechanisms, risk factors and clinical consequences

Abstract

Coronary artery calcification is a common manifestation of advanced atherosclerosis and an important determinant of cardiovascular risk and procedural complexity during percutaneous coronary intervention (PCI). Calcification evolves from microcalcifications within the intima to larger fragmented, sheet-like or nodular deposits. Although extensive calcification often reflects stable plaque, specific patterns such as spotty calcification and eruptive calcified nodules are associated with plaque vulnerability and thrombotic events. In calcified lesions, PCI is technically challenging because calcium impairs balloon expansion, stent delivery and optimal stent deployment, increasing the risk of under-expansion and adverse outcomes. Intracoronary imaging with intravascular ultrasound and optical coherence tomography enables detailed calcium characterization and guides lesion preparation. This review summarizes the mechanisms, prevalence, risk factors, clinical consequences and contemporary management of calcified coronary artery disease.

Key Words: Coronary artery calcification; Atherosclerosis; Intravascular imaging; Calcified nodule; Percutaneous coronary intervention

Core Tip: Coronary artery calcification reflects both atherosclerotic burden and lesion complexity. While extensive sheet-like calcium is often associated with stable plaque, spotty calcification and eruptive calcified nodules may increase thrombotic risk. Intracoronary imaging with intravascular ultrasound and optical coherence tomography enables accurate calcium assessment and guides appropriate lesion preparation. A phenotype-driven approach may improve stent expansion and outcomes in patients undergoing percutaneous coronary intervention for calcified coronary artery disease.

INTRODUCTION

Atherosclerosis is an increasingly important contributor to global morbidity and mortality, while cardiovascular disease was responsible for approximately 18 million deaths worldwide[1,2]. Atherosclerosis is the principal underlying mechanism of ischemic heart disease and coronary artery disease (CAD). Coronary artery calcification (CAC) commonly develops as a feature of advanced atherosclerosis and both its presence and extent serve as objective indicators of coronary atherosclerotic burden[1,2]. CAC also predicts future cardiovascular events independently of traditional risk factors and has shown stronger prognostic value than other noninvasive biomarkers of CAD. Consequently, several clinical guidelines now recognize CAC as an additional tool for refining cardiovascular risk assessment and guiding preventive management[1,2]. Its prevalence increases with age and is indicative of a greater burden of atherosclerotic plaque[2-4]. The process typically evolves from early microcalcification within the intimal layer to the formation of broad, concentric calcium sheets. When these sheets fracture, they may give rise to calcified nodules (CN). Microcalcifications are believed to be markers of unstable CAD, whereas a higher overall volume of calcified plaque tends to correlate with more stable lesions[5]. Among calcification subtypes, nodular forms, particularly eruptive nodules represent severe yet potentially unstable plaque morphology and are implicated in triggering acute coronary syndromes (ACS) and other major adverse cardiac events (MACE)[6].

Performing percutaneous coronary intervention (PCI) in the presence of calcified atherosclerotic plaques presents numerous challenges[1,2]. These rigid lesions are resistant to mechanical expansion, often leading to inadequate plaque modification, stent under-expansion and ultimately, increased rates of stent failure. Moreover, calcified coronary lesions are associated with higher risks of PCI-related complications, including flow-limiting dissections and vessel perforations[1,2]. Despite these concerns, PCI in calcified arteries is becoming more routine, with approximately 25% of elective PCI cases showing angiographic evidence of coronary calcium[7-9]. As interventional cardiology continues to evolve, managing patients with calcified disease has become unavoidable. Therefore, a thorough understanding of the underlying disease mechanisms and their clinical implications is essential. This review aims to provide a comprehensive overview of CAC, including its underlying pathophysiological mechanisms, epidemiology, risk factors, morphological patterns and clinical consequences. In addition, it discusses the prognostic significance of different calcification phenotypes and summarizes contemporary imaging-guided strategies for the assessment and management of CAC lesions during PCI.

BIOLOGICAL MECHANISMS AND PLAQUE PHENOTYPES OF CAC

CAC results from the deposition of crystals within the vascular wall (Figure 1)[10]. According to the anatomical location of calcium deposition, vascular calcification is generally classified as intimal or medial. Intimal calcification predominates in the coronary arteries and is closely linked to atherosclerosis, endothelial injury, lipid accumulation and chronic vascular inflammation. In contrast, medial calcification is more commonly observed in peripheral arteries and is particularly associated with chronic kidney disease (CKD), diabetes mellitus (DM) and disturbances in mineral metabolism[10].

Figure 1 Evolution of coronary atherosclerotic plaque and calcification patterns. Representation of the progression of coronary artery disease from pathologic intimal thickening to fibroatheroma and ultimately fibrocalcific plaque. Early stages are characterized by microcalcifications, which evolve into punctate and fragmented deposits, eventually forming sheet-like and nodular calcification. Plaque destabilization may occur at the fibroatheroma stage, leading to thin-cap fibroatheroma and plaque rupture, followed by healing and transition to fibrocalcific plaque. Plaque erosion may arise from earlier stages, while calcified nodules typically develop from advanced fibrocalcific plaques and may contribute to thrombotic events (10).

The development of CAC is a dynamic course. It begins within atherosclerotic plaques, where endothelial dysfunction allows low-density lipoprotein cholesterol to accumulate in the intima. Oxidative modification of these lipoproteins promotes an inflammatory response, leading to monocyte recruitment, macrophage infiltration, foam cell formation and progressive plaque development. Within this inflammatory environment, vascular smooth muscle cells, macrophages, extracellular matrix components and matrix vesicles interact to promote calcium deposition[10-12].

Several mechanisms contribute to the transition from lipid-rich atherosclerotic plaque to calcified plaque. Vascular smooth muscle cells may undergo osteogenic differentiation under the influence of oxidative stress, inflammatory cytokines, and bone morphogenetic proteins, including BMP-2 and BMP-4, leading to the expression of bone-related proteins and hydroxyapatite deposition within the extracellular matrix. In parallel, apoptosis of vascular smooth muscle cells and macrophages generates matrix vesicles and apoptotic bodies that may act as nucleation sites for microcalcification, if they are not efficiently cleared. Under physiological conditions, calcification inhibitors such as matrix Gla protein and fetuin-A limit mineral deposition and support the clearance of apoptotic cells. However, during chronic inflammation and advanced atherosclerosis, the balance between pro-calcific and anti-calcific mechanisms is disrupted, resulting in progressive calcium accumulation within the vessel wall. CAC usually begins with microcalcifications measuring approximately 0.5-15 μm, which may enlarge into punctate calcifications ranging from 15 μm to 1 mm and subsequently merge into fragmented calcific deposits greater than 1 mm. With disease progression, these deposits can coalesce into broad sheet-like calcium plates extending across multiple quadrants of the vessel circumference, reducing vascular compliance, increasing lesion rigidity, impairing balloon dilatation and contributing to the technical complexity of PCI[10-15].

The progression from microcalcification to larger calcium sheets also reflects changes in plaque behavior. Early microcalcifications and spotty calcifications are commonly associated with plaque vulnerability, particularly when located within a thin fibrous cap, where they may increase local mechanical stress and contribute to plaque rupture. In contrast, extensive sheet-like calcification is generally associated with more advanced fibrocalcific plaques and a relatively more stable plaque phenotype. However, advanced calcified plaques may still become clinically relevant when calcium sheets fracture and protrude into the lumen, forming nodular calcification or CN. When these protruding nodules disrupt the fibrous cap and are associated with thrombus formation, they may contribute to ACS[15,16].

Plaque erosion is one of the major pathological mechanisms underlying ACS and differs substantially from plaque rupture. Unlike plaque rupture, which is characterized by disruption of a thin fibrous cap overlying a large necrotic core, plaque erosion involves endothelial denudation with preservation of the underlying fibrous cap. It can develop in both fibroatheromas and areas of pathological intimal thickening and is often associated with plaques rich in smooth muscle cells and proteoglycans. It can develop in both fibroatheromas and areas of pathological intimal thickening[2].

Calcification is uncommon in eroded plaques, but if present, it generally appears as fragmented deposits. This is because plaque erosion typically develops over plaques rich in smooth muscle cells and proteoglycans, with less prominent necrotic core formation and less advanced fibrocalcific remodeling than plaques that undergo rupture. Therefore, when calcium is present in eroded lesions, it is usually limited and discontinuous rather than forming large sheet-like deposits[7,8]. This pattern likely reflects the underlying biology of plaque erosion, which typically develops over plaques rich in smooth muscle cells and proteoglycans, with less prominent necrotic core formation and less advanced fibrocalcific remodeling than plaques that undergo rupture. In contrast, healed plaques are generally considered the consequence of previous plaque rupture and are often characterized by an embedded or previously disrupted fibrous cap surrounded by a collagen-rich matrix. These lesions frequently contain more extensive calcification, often in fragmented deposits or continuous sheets, sometimes exceeding what would be expected relative to the size of the necrotic core. Small microcalcifications within the fibrous cap may increase localized mechanical stress and contribute to plaque rupture, although current intracoronary imaging modalities and most computed tomography (CT) scanners cannot reliably detect these deposits. However, intracoronary imaging can identify spotty calcification, which has been linked to plaque instability. In an intravascular ultrasound (IVUS) study by Ehara et al[17], spotty calcification, defined as a calcium arc < 90°, was significantly more frequent in culprit lesions of patients presenting with myocardial infarction (MI) than in those with unstable or stable angina, and these plaques were also associated with fibrofatty components and positive vascular remodeling[3,4,16-18].

CT-based plaque characterization studies further support the concept that calcium morphology, rather than calcium burden alone, determines plaque behavior. However, CN represent an important exception to this pattern. Despite their high calcium content, they have been associated with ACS, particularly when they become eruptive. CN are classified as non-eruptive or eruptive according to their morphology and are commonly found in areas exposed to high mechanical stress or repetitive motion, such as the proximal right coronary artery (RCA) and the circumflex artery (LCx). Non-eruptive nodules are typically covered by a thick fibrous cap, whereas eruptive nodules show fibrous cap disruption and are frequently associated with thrombus formation, explaining their stronger association with ACS[6,19-23]. These morphological differences often result in distinct clinical outcomes. Eruptive nodules, with their fibrous cap damage, are strongly associated with ACS[6]. To clarify the distinction between these entities, the main histological, intracoronary imaging and clinical features of non-eruptive nodular calcification and eruptive CN are summarized in Table 1[24].

Table 1 Comparison between non-eruptive nodular calcification and eruptive calcified nodules.

Feature	Non-eruptive nodular calcification	Eruptive calcified nodule
Histological characteristics	Nodular calcium protrusion covered by an intact fibrous cap; usually reflects advanced fibrocalcific plaque remodeling	Disrupted fibrous cap overlying protruding nodular calcium, frequently associated with endothelial denudation and luminal thrombus
OCT characteristics	Protruding calcific mass with an irregular surface but preserved overlying fibrous tissue; absence of definite thrombus	Protruding calcific mass with surface disruption, signal-rich thrombus, and irregular luminal contour
IVUS characteristics	Superficial convex calcific protrusion with acoustic shadowing; preserved luminal continuity	Protruding superficial calcium with marked acoustic shadowing, irregular luminal surface, and possible thrombotic material
Usual clinical context	Often associated with stable or healed fibrocalcific plaques; may contribute to lesion rigidity and PCI complexity	Associated with acute coronary syndromes, coronary thrombosis, and higher risk of recurrent events
Procedural implications	May impair balloon expansion and stent apposition; often requires lesion modification	High-risk lesion requiring careful thrombus assessment, intracoronary imaging, and adequate calcium modification before stenting

IVUS: Intravascular ultrasound; OCT: Optical coherence tomography; PCI: Percutaneous coronary intervention.

EPIDEMIOLOGY AND DETERMINANTS OF CAC

CAC is highly prevalent in both asymptomatic and symptomatic populations and increases progressively with age and cumulative exposure to cardiovascular risk factors[2,25]. This longitudinal cohort enrolled over 5000 asymptomatic individuals from four major ethnic groups (White, Black, Hispanic and Chinese) across six United States cities and followed them with serial CT calcium scoring every two years. The annual incidence of newly identified CAC in this cohort was 6.6%. Age had a strong influence, only 5% of participants under 50 showed CAC, compared to 12% of those over 80[2]. Men had a higher prevalence of CAC than women, likely due to estrogen’s protective role[2,26]. These studies exhibited a strong correlation between CAC and cardiovascular outcomes over long-term follow-up[27-29]. This aligns with the understanding that CAC reflects total atherosclerotic plaque burden[19].

DM has been consistently linked to higher levels of CAC in numerous investigations[30]. Moreover, diabetic individuals exhibit increased mortality at any given calcium score compared to non-diabetics[31]. The extent of glycemic control, as indicated by HbA1c levels, is closely associated with CAC severity. In the CARDIA study, serial calcium scoring was performed over a five-year period in more than 2,000 participants. Those with higher HbA1c levels showed greater likelihood of incident CAC[32].

CKD is another important factor[33,34]. Serial CT calcium scoring showed that 60% of participants with CKD had CAC at baseline. Even once addressed for conventional cardiovascular risk factors, a decreased estimated glomerular filtration rate was independently related to CAC presence and progression[35]. Given the frequent co-occurrence of DM and CKD, the compounded risk of CAC in these individuals is not unexpected[36]. Patients with end-stage renal disease undergoing dialysis experience even greater threat and faster development of CAC compared to those not on dialysis[37]. Autopsy and imaging studies, including CT, have demonstrated that dialysis patients tend to have more extensive CAC[38-41]. Strategies such as phosphate control and the utilization of low-calcium dialysate have shown potential in slowing CAC progression in dialysis patients[42,43].

Interestingly, while statins are known to reduce plaque burden and mitigate the threat of MACE, they additionally appear to promote the production of calcium, potentially contributing to plaque stabilization[44]. In a trial by Hiro et al[45], serial IVUS in individuals treated with statins after an ACS showed reduced plaque volume alongside increased calcification[45,46]. Another conducted substudy confirmed that patients on high-intensity statin therapy experienced both reduced atheroma volume and increased CAC[44]. CT studies have corroborated these findings.

Lipoprotein(a) (Lp-a) has also emerged as an important cardiovascular risk factor associated with CAC. Elevated Lp-a levels have been linked to higher CAC scores, particularly in middle-aged individuals at increased cardiovascular risk. Beyond its association with calcific atherosclerosis, Lp-a may also contribute to thrombotic risk through pro-inflammatory and pro-thrombotic mechanisms, including interference with fibrinolysis and promotion of platelet activation[19,25,26]. Individuals with high levels of Lp-a face an increased likelihood of arterial thrombotic events, prompting recommendations for earlier initiation of antiplatelet therapy in this population. From a pathophysiological standpoint, when the integrity of the intimal layer is compromised and the anti-thrombotic function of the endothelium is impaired, platelets may adhere to the subintimal layer, triggering thrombus development. Predictably, the emergence of eruptive CNs has been associated with overlying thrombus, ACS and even sudden cardiac death[28].

The potential link between calcium supplementation and CAC remains unclear due to the observational nature of most available studies, which are prone to confounding[47]. In the ARIC study, an observational cohort of adults aged 45-64, no association was found between dietary calcium intake and vascular calcification[48]. Likewise, MESA investigators observed no relationship with dietary calcium, but did note a higher risk of CAC in individuals using calcium supplements[49]. However, randomized trials (RCTs) on this topic are lacking[7-9].

RELATIONSHIP BETWEEN SPECIFIC CALCIFIED LESION TYPES AND THROMBOTIC RISK

The initiation of MI in individuals with CAD involves complex processes. Although CAC often reflects healed plaque, it is also closely connected to an increased tendency for thrombus formation. Segments showing endothelial dysfunction often exhibit features of plaque instability alongside more extensive calcific deposits[23,24,29]. However, the extent of calcification alone does not consistently reflect plaque vulnerability. Autopsy investigations have revealed that plaques most prone to rupture are typically thin-cap fibroatheromas featuring large necrotic cores. These plaques often contain small-scale calcifications, such as microcalcifications, punctate deposits, or fragmented calcium. Microcalcifications exceeding 5 μm in diameter have been implicated in plaque instability, possibly due to localized increases in shear stress[31].

Supporting this, IVUS has shown that MI often involves culprit lesions with “spotty” calcification, defined as calcium arcs less than 90 degrees[32]. In contrast, plaques characterized by extensive sheet-like calcification or fibrocalcific morphology, though indicative of high plaque burden, are generally more stable. One notable exception is the CN, which has emerged as a significant cause of ACS in older populations, particularly those over the age of 65[32,50].

ANATOMIC DISTRIBUTION AND VESSEL-SPECIFIC PATTERNS OF CORONARY CALCIFICATION

Although CNs are the least frequent cause of MI, they are disproportionately found in certain coronary segments, specifically, the left main (LM) bifurcation and tortuous, heavily calcified portions of the RCA. Torii et al[6] proposed that CNs in the proximal to mid-RCA are more likely to form at anatomical “hinge points,” where mechanical stress from cardiac motion is highest[6]. These regions are typically surrounded by stiffened vessels due to adjacent fibrocalcific plaques and sheet-like calcium deposits. Similarly, the higher incidence of CNs in the LM bifurcation may be explained by the presence of larger underlying necrotic cores. In a broader evaluation of CAC, Torii et al[6] reported that nodular and eruptive CN were predominantly observed in the LAD and the RCA vessels, while layer calcification occurred extra frequently in the LCx[33].

CLINICAL CONSEQUENCES OF CAC

CAC has important clinical consequences that extend beyond its role as a marker of atherosclerotic burden. In asymptomatic individuals, CAC detected by CT provides incremental prognostic information and improves cardiovascular risk stratification beyond traditional risk factors. Higher CAC scores are associated with an increased risk of MACEs, including MI, cardiovascular death and the need for future revascularization. In symptomatic patients, the presence and severity of CAC are associated with more extensive CAD, higher lesion complexity and worse long-term clinical outcomes.

From an interventional perspective, CAC substantially increases procedural complexity during PCI. Calcified lesions are less compliant and more resistant to balloon dilatation, which may result in inadequate lesion preparation, impaired stent delivery, stent under-expansion, malapposition and increased risk of restenosis or stent thrombosis. Severe calcification is also associated with a higher risk of procedural complications, including dissection, perforation, slow flow or no-reflow and the need for adjunctive calcium-modification techniques such as cutting or scoring balloons, atherectomy, or intravascular lithotripsy (IVL). Therefore, the clinical consequences of CAC include both prognostic implications at the patient level and technical challenges that directly influence PCI strategy and outcomes.

OUTCOMES OF PCI IN THE CALCIFIED CAD

Heavily calcified CAD has consistently been linked to poorer outcomes following revascularisation procedures. Numerous PCI trials have highlighted a pattern of incomplete revascularisation in patients with calcified lesions, suggesting possible hesitation in fully treating these complex cases[51]. Among patients undergoing PCI for various indications, ranging from stable angina to ACSs, the prevalence of angiographically evident moderate-to-severe CAC is approximately 25%-30%[8,25].

Patients with calcified lesions visible on angiography tend to have worse clinical outcomes, regardless of whether they undergo PCI or coronary artery bypass grafting (CABG)[52,53]. Although CABG has long been considered a more favorable option in these patients, avoiding the technical limitations posed by PCI in calcified vessels, this assumption has been challenged by long-term data[52]. The indicated finding is particularly noteworthy, considering that plenty individuals are directed to CABG precisely due to concerns about poor PCI outcomes in the presence of severe calcification. One explanation for these results is that extensive CAC may serve as a surrogate for overall disease severity and plaque burden, both of which are associated with unfavorable long-term outcomes. Therefore, CAC itself is likely an indicator of advanced atherosclerosis, often coexisting with high-risk comorbidities like DM and CKD, which further contribute to poor prognosis.

Performing PCI in calcified vessels remains technically demanding, with a number of studies reporting suboptimal clinical outcomes. At 12 months, target lesion revascularisation (TLR) rates vary from 6% to 8%, increasing to as much as 12%-14% by two years (Table 2)[7,51]. Additional evidence comes from the MATRIX trial, where a sub-analysis showed that patients with severely calcified lesions experienced nearly double the TLR rate compared to those without calcified lesions[9,51].

Table 2 Calcium classification by morphology and dimension.

Calcium type	Description
Microcalcification	Calcium deposits greater than 0.5 μm but smaller than 15 μm
Punctate calcification	Deposits larger than 15 μm but under 1 mm in diameter
Calcium fragment	Deposits exceeding 1 mm in size
Calcium sheet	Extending over more than one quadrant of the vessel circumference or > 3 mm wide
Nodular calcification	Resulting from calcium sheet fracture while the fibrous cap remains intact
Calcified nodule	Occurs when the fibrous cap ruptures and is accompanied by luminal thrombus

Advances in PCI and stent strategies for calcified CAD

Drug-coated balloon (DCB) utilization is emerging as an alternative for de novo lesions, leveraging a “leave nothing behind” strategy that avoids the challenges of stent under-expansion associated with calcium. Initially limited to small-vessel disease, DCBs have shown similar findings to drug-eluting stent in the aforementioned subgroup[54,55]. Nevertheless, outcomes with DCBs in calcified lesions have been less favorable. A retrospective optical coherence tomography (OCT)-guided study involving 328 Lesions found that calcium significantly predicted DCB failure, with each 90° arc of calcium increasing target lesion failure (TLF) risk[56]. More prospective trials are needed to validate DCB efficacy in heavily calcified arteries[8,19].

Beyond disease weight, several procedural challenges also contribute to worse PCI outcomes in calcified lesions. Stents may be physically damaged during delivery, polymer coatings can be compromised and drug release kinetics may be altered[57]. These complications underscore the necessity for effective plaque modification before the PCI. However, aggressive lesion preparation carries its own risks, including flow-limiting dissections and vessel perforations[58]. Additionally, procedural complications may extend into the early post-PCI period. Patients with calcified lesions have shown a higher risk of bleeding within 30 days of intervention[59-61].

Optimizing PCI outcomes in calcified CAD

Intracoronary imaging-guided calcium modification is currently the most promising approach for improving PCI outcomes in calcified vessels. Unrecognized or underestimated calcium, especially in procedures guided by angiography alone, can lead to inadequate lesion preparation. The agreement between angiographic interpretation by operators and core lab calcium assessment is known to be poor. Angiography is also significantly less sensitive than imaging techniques like IVUS and OCT[62]. Recent software innovations using artificial intelligence (AI) have enhanced the ability of these imaging modalities to identify and quantify coronary calcium, including its arc and depth.

Evidence supports the benefit of imaging-guided PCI, even in complex lesions. Studies have consistently shown that intracoronary imaging reduces adverse events, including TLR, across broad patient populations and in calcified lesions[63-72]. Best practice involves the use of imaging at multiple stages of PCI in calcified vessels, initial assessment, post-modification and after stent deployment, to ensure optimal results[73]. Whether IVUS or OCT is the superior modality remains a matter of ongoing debate. In a trial by Wang et al[74], IVUS was slightly extra effective in detecting coronary calcium compared to OCT. Among 440 lesions evaluated with angiography, OCT and IVUS, less than 14% of calcium found on IVUS was missed or overlooked by OCT, mainly due to limited penetration caused by overlying tissue. Nevertheless, IVUS has limitations too. In another trial by Pu et al[18], IVUS didn’t succeed to identify calcium in almost 15% of histologically confirmed cases, one-third due to acoustic shadowing from necrotic cores and two-thirds involving microcalcifications that were below its resolution.

Despite these limitations, OCT offers key advantages for assessing calcium characteristics, including precise measurement of arc, thickness and volume. In contrast, IVUS often cannot determine calcium thickness due to acoustic shadowing, as sound waves are absorbed by calcified tissue[75].

Predicting and managing stent under-expansion with intracoronary imaging

Additional insights from intracoronary imaging can help identify lesions at high risk for stent under-expansion if calcification isn’t adequately treated beforehand. Fujino et al[76] proposed the “rule of 5s”, an OCT-based calcium scoring method allocating two points for calcium arc > 180°, and one point each for calcium depth > 0.5 mm and length > 5 mm. A total sum of 4 correlated with a stent expansion of less than 80%[76,77]. These tools are primarily used to emphasize the necessity of preparing calcified lesions before stent deployment. Current expert recommendations suggest aiming for > 80% stent expansion, though achieving this remains challenging despite available modification tools[73]. Minimum stent area (MSA) targets have been established based on outcomes: 5.5 mm² by IVUS and 4.5 mm² by OCT. Larger targets apply to LM stenting, with one IVUS sub-analysis from the NOBEL trial showing no TLR at 5 years for LM MSA ≥ 13.4 mm². Importantly, these thresholds are derived primarily from observational and post hoc analyses rather than prospective randomized validation. Nevertheless, achieving adequate MSA has consistently been associated with lower rates of restenosis and TLR, supporting their practical use during imaging-guided PCI[78].

Calcium modification tools

Calcified lesions can generally be classified based on whether the lesion is crossable by an apparatus. For uncrossable lesions, rotational atherectomy (RA) and excimer laser atherectomy persist as primary options[19]. Crossable lesions offer more flexibility and can be treated using balloon-based approaches. These include high-pressure non-compliant balloons (NCBs), cutting balloons (CBs) and scoring balloons. Balloon-based methods remain usually used in the beginning to assess lesion tolerance. The lately conducted COPS trial included 87 individuals to receive NCB or CB intervention. Those treated with CBs had significantly larger final MSAs at the calcified segment[79,80].

RA and orbital atherectomy (OA) remain cutting-edge options typically employed when balloon-based therapies fail. In the ROTAXUS trial, RA showed better immediate procedural results and luminal gain than standard therapy but was associated with more late lumen loss at 9 months[81]. No significant difference in long-term clinical outcomes at 2 years was found[82,83]. In the more recent PREPARE-CALC trial, RA was compared to other techniques showing higher procedural success in the RA group[82,83]. The efficacy of OA has been supported by several single-arm studies[84,85]. In the DIRO trial, RA and OA were directly compared in lesions with > 180° calcification by OCT or moderate-to-severe calcification on angiography. RA produced superior outcomes in either percentage luminal gain and stent expansion[86].

IVL, a newer technology, uses acoustic energy to fracture calcium deposits. Available evidence confirms its safety and therapeutic effectiveness in the DISRUPT CAD trials[67,68,87]. Our group recently demonstrated IVL’s effectiveness in treating both concentric and eccentric calcium, without significant differences in MSA or expansion metrics between morphologies. Despite more frequent fractures in concentric lesions, final stent expansion remained similar. While nodular fractures weren’t common, mean expansion at nodule sites approached 100%[69,88,89]. In a RCT of 70 individuals who received RA or IVL, final MSA did not differ significantly, though values were numerically higher with RA[90]. IVL is emerging as a versatile treatment for various calcium morphologies. A recent meta-analysis further supports the role of IVL as an effective and safe lesion-preparation strategy in severely calcified coronary stenoses. In this analysis of 38 studies including 2977 patients, IVL was associated with high clinical and procedural success rates of 93% and 97%, respectively. The reported in-hospital and 30-day rates of major adverse cardiovascular events, MI and death were 8%, 5%, and 2%, respectively. These findings reinforce the utility of IVL for calcium modification before stent implantation, particularly in lesions where both superficial and deep calcium may contribute to inadequate stent expansion[67,68,87].

Multiple techniques are sometimes needed. The PREPARE-CALC-COMBO trial contrasted a strategy of RA accompanied by CB to historical controls treated with either solitary, describing improved luminal gain and MSA using both treatments[91]. Nevertheless, the ROTA-CUT RCT originated no significant MSA difference among combined rotational atherectomy followed by cutting balloon angioplasty and rotational atherectomy followed by non-compliant balloon angioplasty strategies[92]. IVL has also been used in combination protocols, though most data remain limited to small case series[93] (Table 3). When using sequential strategies, imaging between device applications is recommended to assess for calcium fractures or residual deposits before proceeding to the next modification step. Additionally, addressing systemic comorbidities such as CKD and DM is vital for long-term success after PCI.

Table 3 Summary of major clinical studies, imaging studies and calcium-modification trials in coronary artery calcification.

Ref.	Category	Study type	Main focus	Key message
[1]	Plaque vulnerability and calcified lesion phenotype	Serial CCTA registry	Calcified plaque volume and events	Total calcified plaque volume was associated with events, while higher percentage calcified plaque was inversely associated with event risk
[2]		Prospective cohort	Calcium density and cardiovascular risk	Higher calcium density was inversely associated with cardiovascular events, suggesting a more stable plaque phenotype
[3]		Prospective OCT substudy	Calcified nodules and outcomes	Eruptive calcified nodules were associated with worse outcomes than non-eruptive nodules
[4]	Epidemiology, prevalence, and cardiovascular risk stratification	Population-based cohort	CAC and risk prediction	CAC improved cardiovascular risk stratification and reclassification
[5]		Population-based cohort	CAC and CHD risk classification	CAC improved CHD risk classification in elderly individuals
[6]		Prospective cohort	CAC distribution and CHD events	CAC distribution independently predicted major coronary events
[29]		Observational cohort	CAC plus Framingham risk score	CAC improved risk prediction beyond traditional risk assessment
[31]	Diabetes, CKD, ESRD, and metabolic determinants	Observational prognostic study	CAC and mortality in diabetes	Diabetic patients had higher mortality than non-diabetic patients at any given CAC score
[9]		Prospective cohort	HbA1c and CAC progression	Higher HbA1c was associated with incident CAC and CAC progression
[10]		Prospective cohort	CKD and CAC progression	Reduced eGFR was independently associated with CAC presence and progression
[44]	Statins, supplementation, and medical modifiers	Post hoc pooled IVUS analysis	Statins and coronary calcification	High-intensity statins were associated with plaque regression and increased calcification, suggesting stabilization
[12]		Randomized IVUS trial	Intensive statin therapy after ACS	Statin therapy reduced plaque volume while increasing calcification
[46]		Randomized trial	Intensive atorvastatin vs rosuvastatin	Intensive statin therapy slowed coronary disease progression
[14]		Observational cohort	Dietary calcium/phosphorus and calcification	No clear association was found between dietary calcium intake and vascular calcification
[25,74]	Detection of coronary calcium by imaging	Comparative imaging study	Angiography vs OCT vs IVUS	IVUS and OCT detected coronary calcium more sensitively than angiography
[75]		IVUS/angiography study	Patterns of coronary calcification	Demonstrated limited angiographic sensitivity compared with IVUS
[17]	Clinical outcomes in calcified lesions undergoing PCI or revascularization	Pooled analysis of RCTs	ACS patients undergoing PCI	Moderate/severe calcification was associated with higher mortality, MACE, TLR, TVR, and stent thrombosis
[18]		Patient-level pooled analysis	Stable angina patients treated with DES	Severe calcification was associated with higher TVF, cardiac death, TV-MI, and stent thrombosis
[19]		Pooled trial analysis	Newer-generation DES in all-comer PCI	Moderate/severe calcification was associated with higher TLF, TV-MI, and ischemia-driven TLR
[20]		Trial subgroup analysis	ACS patients	Severe calcification was associated with higher 1-year MACE and composite ischemic outcomes
[21]		10-year trial substudy	Multivessel CAD treated with PCI or CABG	Heavy calcification was associated with increased 10-year all-cause mortality after both PCI and CABG
[55]	Drug-coated balloons and alternative strategies	Meta-analysis of RCTs	DCBs for de novo coronary lesions	DCBs showed comparable results to DES in selected de novo lesions, especially small-vessel disease
[22]		Complex PCI imaging study	Imaging-guided vs angiography-guided PCI	Supported the value of intravascular imaging in complex PCI
[33]	Imaging-guided PCI and optimization	Randomized trial	IVUS-guided vs angiography-guided DES implantation	IVUS-guided PCI reduced adverse clinical events compared with angiography guidance
[34]		Randomized trial	IVUS-guided PCI in long lesions	IVUS guidance improved outcomes after everolimus-eluting stent implantation
[35]		Observational study	IVUS in complex PCI	IVUS guidance was associated with improved outcomes in complex lesions
[66]		Randomized trial	OCT vs angiography guidance in bifurcation PCI	OCT guidance improved procedural assessment in complex bifurcation PCI
[70]		Network meta-analysis	IVUS/OCT-guided DES implantation	Imaging-guided PCI reduced TLF, TV-MI, TLR, stent thrombosis, and mortality
[76]	Prediction of stent under-expansion	OCT-based scoring study	OCT calcium score	Proposed the OCT “rule of 5s” to predict stent under-expansion
[63,77]		IVUS-derived scoring study	IVUS calcium score	Developed an IVUS calcium score to predict inadequate stent expansion
[40]		IVUS substudy	Left main PCI and MSA	Suggested left main MSA thresholds associated with reduced TLR
[41]	Balloon-based calcium modification	Randomized trial	Cutting balloon vs non-compliant balloon	Cutting balloon predilatation produced larger final MSA than non-compliant balloon predilatation
[80]		Retrospective comparative study	Cutting balloon vs scoring balloon	Cutting balloons were associated with greater lumen gain, larger final MSA, and better stent symmetry
[43]	Rotational atherectomy	Randomized trial	RA before DES implantation	RA improved acute procedural success but did not improve long-term clinical outcomes
[44]		Two-year follow-up	Long-term outcomes after RA	No significant difference in 2-year clinical outcomes between RA and standard therapy
[45]		Randomized trial	RA vs modified balloons	RA achieved higher procedural success, largely due to crossover from the balloon arm
[46]	Orbital atherectomy	Prospective single-arm study	Orbital atherectomy	Demonstrated feasibility and acceptable safety of OA in calcified coronary lesions
[48]		Prospective single-arm study	Micro-crown OA	Supported safety and feasibility of OA in severely calcified lesions
[62]		Comparative OCT-guided study	RA vs OA	RA achieved greater lumen gain and better stent expansion than OA
[63]	Intravascular lithotripsy	Patient-level pooled analysis	IVL in severely calcified coronary lesions	IVL showed high procedural success and favorable safety
[21]		Clinical report/study	IVL for calcified nodules	Suggested IVL may be safe and effective for selected calcified nodules
[65]		Randomized trial	IVL vs RA	Final MSA did not differ significantly between IVL and RA, although values were numerically higher with RA
[66]	Combination calcium-modification strategies	Comparative study with historical controls	RA followed by cutting balloon	Combination therapy improved luminal gain and MSA compared with either strategy alone
[67]		Randomized trial	RA plus cutting balloon vs RA plus non-compliant balloon	No significant MSA difference between RA-CB and RA-NCB strategies
[68-93]		Multicenter registry	RA followed by IVL	Planned or bailout RA-IVL showed favorable in-hospital outcomes

ACS: Acute coronary syndrome; CABG: Coronary artery bypass grafting; CAC: Coronary artery calcification; CAD: Coronary artery disease; CCTA: Coronary computed tomography angiography; CHD: Coronary heart disease; CKD: Chronic kidney disease; DCB: Drug-coated balloon; DES: Drug-eluting stent; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease; IVL: Intravascular lithotripsy; IVUS: Intravascular ultrasound; MACE: Major adverse cardiovascular events; MSA: Minimum stent area; OA: Orbital atherectomy; OCT: Optical coherence tomography; PCI: Percutaneous coronary intervention; RA: Rotational atherectomy; RCT: Randomized controlled trial; TLF: Target lesion failure; TLR: Target lesion revascularization; TV-MI: Target vessel myocardial infarction; TVF: Target vessel failure; TVR: Target vessel revascularization.

CONCLUSION

CAC represents a complex and dynamic component of atherosclerotic disease, reflecting both cumulative plaque burden and distinct biological processes that influence plaque stability and clinical outcomes. While extensive calcification is generally associated with more stable plaque phenotypes, specific patterns such as spotty calcification and CN remain strongly linked to plaque vulnerability and thrombotic events.

Beyond its biological significance, coronary calcium poses a major challenge during PCI, contributing to suboptimal lesion preparation, stent under-expansion and increased rates of adverse clinical outcomes. In this context, intracoronary imaging has emerged as an essential tool, enabling detailed characterization of calcium morphology and facilitating tailored interventional strategies. A paradigm shift toward imaging-guided, phenotype-driven management is critical for improving procedural success in calcified CAD. Integrating calcium characteristics with dedicated modification techniques, including atherectomy, cutting and scoring balloons, and IVL, allows for more precise and effective lesion preparation. Such an approach not only enhances stent expansion but also has the potential to translate into improved long-term outcomes.

Future advances will likely focus on the integration of AI in calcium assessment, refinement of calcium modification technologies and the development of standardized, prospectively validated treatment algorithms. Emerging AI-based applications may enable automated or semi-automated calcium quantification from coronary angiography, OCT, IVUS and CT, including assessment of calcium arc, thickness, length and volume. These tools may also support real-time procedural decision-making by identifying lesions at high risk of stent under-expansion and recommending appropriate calcium modification strategies before stent implantation. Future studies should aim to validate standardized, imaging-guided and AI-assisted algorithms in order to establish a unified approach for the management of calcified coronary lesions.