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

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.

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

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.