Author's summary
Mitral annular calcification and aortic arch calcification are more markers of advanced age and comorbidity rather than a direct determinant of post-aortic valve replacement survival. It is therefore essential to optimize overall comorbidity management for this patient subgroup.
Keywords: Aortic stenosis, Mitral valve, Aortic arch, Calcium
Abstract
Background and Objectives
Patients with severe aortic stenosis (AS) often have mitral annular calcification (MAC) and aortic arch calcification (AAC). We investigated the clinical significance of a MAC and extensive AAC in patients with AS requiring aortic valve replacement (AVR).
Methods
We retrospectively analyzed 636 patients with severe AS who underwent AVR (surgical or transcatheter) at our institution. Preoperative echocardiography and computed tomography were used to identify MAC, and chest radiographs were reviewed for AAC.
Results
Of the 636 patients, 133 (20.9%) had MAC, while 156 (24.5%) had extensive AAC (≥180°). Patients with MAC were older and more often female, with higher Society of Thoracic Surgeons scores and greater comorbidities. Over a median follow-up of 5.2 years, 157 patients (24.7%) died. In univariate analysis, the presence of any MAC and extensive AAC was associated with significantly higher mortality. In multivariable analysis, however, neither was an independent predictor of mortality. Instead, age, male sex, diabetes mellitus, chronic kidney disease (eGFR <60 mL/min/1.73 m2), and dialysis emerged as independent risk factors.
Conclusions
MAC and extensive AAC identify a subset of patients with severe AS who are older and have more comorbid disease. Management of such patients should focus on optimizing overall risk factors, and the presence of MAC or AAC alone should not exclude patients from life-saving AVR therapies.
Graphical Abstract
INTRODUCTION
Most studies on intracardiac calcification have focused on aortic valve (AV) calcification, which is known to progress through initiation and propagation phases.1) In contrast, the pathogenesis of mitral annular calcification (MAC) remains unclear. Although MAC was historically considered a passive degenerative process, it is now increasingly recognized as an active, regulated process.2),3) While MAC shares some risk factors with aortic stenosis (AS), including older age, there are notable differences between the two conditions, such as sex.1),4),5) In the general population, the prevalence of MAC ranges from 8% to 15%, but it is found in a higher proportion of patients with severe AS, ranging from 14.8% to 22%.6),7),8) MAC is frequently associated with AV calcification and coronary artery disease,4),9) and has been linked to adverse clinical outcomes.10) Although some data exist regarding the prognostic impact of MAC on mortality after surgical or transcatheter aortic valve replacement (AVR) in patients with severe AS, most studies have had relatively short follow-up durations.11),12) Thoracic aortic calcification shares many risk factors with coronary artery calcification and is commonly observed as an incidental finding on imaging performed for other indications, including the evaluation of severe AS.13),14) Although its role as an independent cardiovascular risk factor remains equivocal, thoracic aortic calcification is generally considered a contributor to increased all-cause mortality.14),15),16),17) Data regarding aortic arch calcification (AAC) in AS patients are even more limited. While the presence of extensive AAC can influence the choice of AVR strategy—favoring TAVR in cases of porcelain aorta—its direct impact on post-AVR long-term survival remains unclear. Given the conflicting evidence and the paucity of data in mixed surgical and transcatheter AVR cohorts, we hypothesized that extensive calcification in these anatomical regions may be associated with worse outcomes, reflecting the higher-risk clinical profile of affected patients. Accordingly, we aimed to investigate the prognostic significance of MAC and AAC in patients with severe AS undergoing AVR.
METHODS
Ethical statement
The study was approved by the Pusan National University Institutional Review Board (number: 55-2025-069), with a waiver of informed consent due to the retrospective design.
Study population
This study retrospectively included patients with severe AS who underwent aortic valve replacement between December 1st, 2008, and July 5th, 2023, at Pusan National University Yangsan Hospital. Severe AS was defined by standard criteria (aortic valve area <1.0 cm2 or indexed AVA <0.6 cm2/m2, and peak transaortic velocity ≥4.0 m/s, or mean transaortic pressure gradient ≥40 mmHg). Both patients who underwent surgical aortic valve replacement (SAVR) and those who underwent transcatheter aortic valve replacement (TAVR) were included. Patients undergoing concomitant other valve surgeries were excluded. Clinical data, including demographics and comorbidities, were obtained from hospital records. Follow-up vital status and clinical events were ascertained from clinic visits and telephone follow-up.
Imaging assessment
All patients underwent comprehensive transthoracic echocardiography before AVR. The severity of AS (peak aortic jet velocity, mean transaortic pressure gradient, and calculated aortic valve area by continuity equation) was documented. Severe AS cases with a low gradient (mean transaortic pressure gradient <40 mmHg) had a stroke volume index <35 mL/m2 and were classified as either paradoxical or classic low flow low gradient according to the 50% left ventricular ejection fraction (LVEF) cutoff. True severe AS in patients with paradoxical low-flow, low-gradient (LFLG) AS was determined by integrating multiple parameters, including the dimensionless index. In classic LFLG AS, true severity was confirmed when dobutamine stress echocardiography demonstrated myocardial contractile reserve and an increase in the mean transaortic pressure gradient. The number of AV cusps was determined by integrating findings from echocardiography and computed tomography (CT). Cases suggestive of congenital bicuspid AV due to raphe fusion, without prior evidence to exclude it, were classified as bicuspid.
The presence of MAC was determined from echocardiography as an echo-dense calcification of the mitral annulus. In patients who MAC was detected on echo, preoperative cardiac CT (maximum intensity projection image) was reviewed to grade the MAC severity on a four-point scale based on the circumferential extent of calcification around the annulus: grade 0 (no MAC), grade 1 (mild MAC involving <180° of the annulus circumference), grade 2 (moderate MAC involving approximately 180–270°), and grade 3 (severe MAC involving ≥270° of the annulus).18)
Chest radiography was reviewed to evaluate AAC. A standard posteroanterior chest X-ray was graded on a 0–4 scale for AAC. Grade 0 indicated no visible calcification in the aortic arch, grade 1 indicated mild calcification occupying <90° of the aortic arch circumference, grade 2 indicated calcific involvement of 90–180° of the arch, grade 3 indicated 180–270°, and grade 4 indicated nearly circumferential calcification of 270–360° of the arch. For analysis, “extensive” AAC was defined as grade 3 or 4 (≥180°), and “encircling” MAC was defined as grade ≥2 (≥180°) (Figure 1).
Figure 1. Grading of MAC and AAC on imaging.
(A) Representative cardiac CT images illustrating MAC grades: Grade 0 = no MAC; Grade 1 = MAC involving <180° of the annular circumference; Grade 2 = MAC involving approximately 180–270°; Grade 3 = MAC involving ≥270° of the annulus. (B) Representative chest X-rays illustrating AAC grades: Grade 0 = none; Grade 1 = calcification spanning 0–90° of the aortic arch; Grade 2 = 90–180°; Grade 3 = 180–270°; Grade 4 = 270–360°. Patients with Grade 3 or 4 AAC were considered to have “extensive” AAC, and those with MAC grade ≥2 were considered to have encircling MAC, for purposes of analysis.
AAC = aortic arch calcification; CT = computed tomography; MAC = mitral annular calcification.
Outcomes
The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, stroke, myocardial infarction, hospitalization for heart failure, new permanent pacemaker (PPM) implantation, and other valve-related events. Causes of death were adjudicated by chart review and death certificates when available and were categorized as cardiovascular, cerebrovascular, septic, malignancy-related, postoperative within 1 month, or unknown.
Statistical analysis
Continuous variables are presented as mean ± standard deviation if normally distributed or median (interquartile range) if non-normal. Categorical variables are presented as counts and percentages. Group comparisons between patients with vs. without MAC, and with vs. without extensive AAC, were performed using the Wilcoxon rank-sum test for continuous variables and Pearson’s χ2 or Fisher’s exact test for categorical variables, as appropriate. Survival and event-free survival curves were constructed with the Kaplan-Meier method and compared by the log-rank test. Patients were censored at the time of last follow-up or at 10 years.
To identify independent predictors of mortality, univariate Cox proportional hazards analyses were first conducted for a range of candidate variables. AS severity measures (gradient and valve area), grades of mitral regurgitation (MR) and tricuspid regurgitation, and major comorbidities, as well as medication use (e.g., aspirin, oral anticoagulants, and diabetes medications such as dipeptidyl peptidase-4 [DPP-4] inhibitors and sodium-glucose cotransporter 2 inhibitors). Variables with a p value <0.1 in the univariate analysis were included in the multivariate analysis. Extensive AACs were included a priori regardless of statistical significance due to their established clinical relevance. A 2-sided p<0.05 was considered statistically significant for all tests. Analyses were performed using R version 4.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Patient characteristics and imaging findings
A total of 636 patients (median age 72 years, 56.6% male) with severe AS underwent AVR during the study period. Of these, 516 patients (81.1%) received SAVR (192 mechanical valves and 324 bioprosthetic valves), and 120 patients (18.9%) received TAVR (57 self-expanding and 63 balloon-expandable transcatheter valves). The prevalence of MAC was 20.9% (133 patients), and 4.7% (30 patients) had encircling circumferential MAC involving ≥180° of the annulus. AAC on chest X-ray was present in 62.3% of patients, with 24.5% (156 patients) classified as extensive. There was considerable overlap between MAC and AAC: patients with MAC were more likely to have advanced AAC and vice versa. For example, among those with any MAC, 40% had an AAC grade ≥3, compared to about 20% of those without MAC (p<0.001).
Table 1 presents baseline clinical characteristics. Patients with MAC were significantly older than those without and more likely to be female. AS etiology differed between groups: nearly all patients (93.2%) with MAC had degenerative tricuspid aortic valve stenosis, whereas very few had functionally bicuspid valves (6.8% in MAC patients vs. 27.2% in no-MAC patients, p<0.001). Severe AS hemodynamic subtypes (high-gradient vs. LFLG) were similarly distributed between groups, with high-gradient AS predominating. The transaortic peak velocity and mean gradient were high in all patients and did not differ significantly by MAC status. Left ventricular (LV) size and wall thickness were similar, although MAC patients had slightly smaller left ventricular end-diastolic diameter (LVEDD) (median 48 vs. 49 mm, p=0.039). There was no significant difference in LVEF between groups. The prevalence of significant aortic regurgitation (AR) or MR was low and comparable between groups.
Table 1. Baseline characteristics of patients with severe AS undergoing AVR.
| Characteristic | Overall (n=636) | MAC | AAC | |||||
|---|---|---|---|---|---|---|---|---|
| No MAC (n=503) | MAC (n=133) | p value | Grade 0–2 (n=480) | Grade 3–4 (n=156) | p value | |||
| Age at AVR | 72 (65–78) | 71 (63–77) | 78 (71–83) | <0.001 | 70 (63–76) | 78 (72–82) | <0.001 | |
| Male | 360 (56.6%) | 305 (60.6%) | 55 (41.4%) | <0.001 | 290 (60.4%) | 70 (44.9%) | <0.001 | |
| BMI (kg/m2) | 24.2 (22.2–26.6) | 24.1 (22.2–26.3) | 24.7 (22.6–27.2) | 0.044 | 24.3 (22.2–26.6) | 23.9 (22.2–26.7) | 0.9 | |
| AS etiology | <0.001 | <0.001 | ||||||
| Tricuspid degenerative | 488 (76.7%) | 364 (72.4%) | 124 (93.2%) | 345 (71.9%) | 143 (91.7%) | |||
| Non-tricuspid degenerative | 147 (23.1%) | 138 (27.4%) | 9 (6.8%) | 134 (27.9%) | 13 (8.3%) | |||
| Rheumatic | 1 (0.2%) | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) | |||
| AS class | 0.4 | 0.8 | ||||||
| High gradient | 620 (97.5%) | 488 (97.0%) | 132 (99.2%) | 468 (97.5%) | 152 (97.4%) | |||
| LFLG with preserved EF | 8 (1.3%) | 8 (1.6%) | 0 (0.0%) | 6 (1.3%) | 2 (1.3%) | |||
| LFLG with reduced EF | 6 (0.9%) | 5 (1.0%) | 1 (0.8%) | 4 (0.8%) | 2 (1.3%) | |||
| AS AVA (cm2) | 0.63 (0.50–0.80) | 0.62 (0.50–0.80) | 0.64 (0.50–0.80) | 0.6 | 0.62 (0.50–0.80) | 0.65 (0.50–0.80) | >0.9 | |
| AS Vmax (m/s) | 4.90 (4.40–5.40) | 4.90 (4.40–5.40) | 5.00 (4.50–5.50) | 0.13 | 4.90 (4.40–5.40) | 4.90 (4.49–5.44) | >0.9 | |
| AS mPG (mmHg) | 56 (44–70) | 56 (44–70) | 57 (47–69) | 0.2 | 56 (44–70) | 56 (46–69) | 0.8 | |
| AV cusps | <0.001 | <0.001 | ||||||
| Tricuspid | 489 (76.9%) | 365 (72.6%) | 124 (93.2%) | 346 (72.1%) | 143 (91.7%) | |||
| Bicuspid | 146 (23.0%) | 137 (27.2%) | 9 (6.8%) | 133 (27.7%) | 13 (8.3%) | |||
| Unicuspid | 1 (0.2%) | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) | |||
| AVR | <0.001 | <0.001 | ||||||
| Mechanical SAVR | 192 (30.2%) | 174 (34.6%) | 18 (13.5%) | 177 (36.9%) | 15 (9.6%) | |||
| Tissue SAVR | 324 (50.9%) | 259 (51.5%) | 65 (48.9%) | 239 (49.8%) | 85 (54.5%) | |||
| SX-TAVR | 57 (9.0%) | 33 (6.6%) | 24 (18.0%) | 34 (7.1%) | 23 (14.7%) | |||
| BX-TAVR | 63 (9.9%) | 37 (7.4%) | 26 (19.5%) | 30 (6.3%) | 33 (21.2%) | |||
| STS mortality | 2.0 (1.1–3.9) | 1.7 (1.0–3.4) | 3.6 (1.8–5.3) | <0.001 | 1.6 (1.0–3.1) | 3.6 (2.0–6.3) | <0.001 | |
| MAC grade | <0.001 | <0.001 | ||||||
| 0 | 503 (79.1%) | 503 (100.0%) | 0 (0.0%) | 405 (84.4%) | 98 (62.8%) | |||
| 1 | 103 (16.2%) | 0 (0.0%) | 103 (77.4%) | 63 (13.1%) | 40 (25.6%) | |||
| 2 | 17 (2.7%) | 0 (0.0%) | 17 (12.8%) | 7 (1.5%) | 10 (6.4%) | |||
| 3 | 13 (2.0%) | 0 (0.0%) | 13 (9.8%) | 5 (1.0%) | 8 (5.1%) | |||
| AAC grade | <0.001 | <0.001 | ||||||
| 0 | 237 (37.3%) | 208 (41.4%) | 29 (21.8%) | 237 (49.4%) | 0 (0.0%) | |||
| 1 | 158 (24.8%) | 131 (26.0%) | 27 (20.3%) | 158 (32.9%) | 0 (0.0%) | |||
| 2 | 85 (13.4%) | 66 (13.1%) | 19 (14.3%) | 85 (17.7%) | 0 (0.0%) | |||
| 3 | 92 (14.5%) | 58 (11.5%) | 34 (25.6%) | 0 (0.0%) | 92 (59.0%) | |||
| 4 | 64 (10.1%) | 40 (8.0%) | 24 (18.0%) | 0 (0.0%) | 64 (41.0%) | |||
| AR grade | 0.8 | 0.13 | ||||||
| 0 | 279 (43.9%) | 225 (44.7%) | 54 (40.6%) | 217 (45.2%) | 62 (39.7%) | |||
| 1 | 250 (39.3%) | 192 (38.2%) | 58 (43.6%) | 177 (36.9%) | 73 (46.8%) | |||
| 2 | 55 (8.6%) | 45 (8.9%) | 10 (7.5%) | 41 (8.5%) | 14 (9.0%) | |||
| 3 | 39 (6.1%) | 31 (6.2%) | 8 (6.0%) | 33 (6.9%) | 6 (3.8%) | |||
| 4 | 13 (2.0%) | 10 (2.0%) | 3 (2.3%) | 12 (2.5%) | 1 (0.6%) | |||
| MR grade | 0.6 | 0.14 | ||||||
| 0 | 465 (73.1%) | 369 (73.4%) | 96 (72.2%) | 362 (75.4%) | 103 (66.0%) | |||
| 1 | 140 (22.0%) | 110 (21.9%) | 30 (22.6%) | 96 (20.0%) | 44 (28.2%) | |||
| 2 | 16 (2.5%) | 14 (2.8%) | 2 (1.5%) | 12 (2.5%) | 4 (2.6%) | |||
| 3 | 14 (2.2%) | 9 (1.8%) | 5 (3.8%) | 9 (1.9%) | 5 (3.2%) | |||
| 4 | 1 (0.2%) | 1 (0.2%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) | |||
| EF (%) | 63 (56–67) | 62 (56–67) | 63 (58–68) | 0.076 | 63 (56–67) | 63 (57–66) | 0.7 | |
| LVEDD (mm) | 49 (44–53) | 49 (44–54) | 48 (44–52) | 0.039 | 49 (44–53) | 49 (44–53) | 0.8 | |
| LV wall thickness (mm) | 12.30 (11.40–13.50) | 12.20 (11.30–13.50) | 12.40 (11.50–13.50) | 0.14 | 12.20 (11.35–13.50) | 12.40 (11.40–13.50) | 0.8 | |
| NYHA | 0.10 | <0.001 | ||||||
| 1 | 113 (17.8%) | 89 (17.7%) | 24 (18.0%) | 81 (16.9%) | 32 (20.5%) | |||
| 2 | 254 (39.9%) | 212 (42.1%) | 42 (31.6%) | 209 (43.5%) | 45 (28.8%) | |||
| 3 | 212 (33.3%) | 157 (31.2%) | 55 (41.4%) | 158 (32.9%) | 54 (34.6%) | |||
| 4 | 57 (9.0%) | 45 (8.9%) | 12 (9.0%) | 32 (6.7%) | 25 (16.0%) | |||
| HTN | 423 (66.5%) | 323 (64.2%) | 100 (75.2%) | 0.017 | 296 (61.7%) | 127 (81.4%) | <0.001 | |
| DM | 215 (33.8%) | 160 (31.8%) | 55 (41.4%) | 0.039 | 157 (32.7%) | 58 (37.2%) | 0.3 | |
| Lipid profile (mg/dL) | ||||||||
| TC | 156 (131–181) | 158 (132–182) | 151 (129–178) | 0.3 | 158 (134–182) | 149 (123–179) | 0.077 | |
| HDL-C | 46 (39–55) | 46 (39–55) | 46 (40–54) | 0.8 | 46 (40–55) | 44 (37–54) | 0.092 | |
| LDL-C | 79 (59–100) | 78 (59–100) | 80 (62–98) | 0.8 | 79 (60–100) | 78 (58–102) | 0.9 | |
| TG | 122 (89–180) | 125 (89–185) | 114 (84–158) | 0.053 | 125 (90–187) | 113 (83–168) | 0.014 | |
| PAOD | 26 (4.1%) | 20 (4.0%) | 6 (4.5%) | 0.8 | 20 (4.2%) | 6 (3.8%) | 0.9 | |
| CVA | 65 (10.2%) | 50 (9.9%) | 15 (11.3%) | 0.7 | 43 (9.0%) | 22 (14.1%) | 0.065 | |
| MI | 7 (1.1%) | 4 (0.8%) | 3 (2.3%) | 0.2 | 4 (0.8%) | 3 (1.9%) | 0.4 | |
| PCI | 51 (8.0%) | 31 (6.2%) | 20 (15%) | <0.001 | 28 (5.8%) | 23 (14.7%) | <0.001 | |
| CABG | 2 (0.3%) | 1 (0.2%) | 1 (0.8%) | 0.4 | 1 (0.2%) | 1 (0.6%) | 0.4 | |
| AF | 52 (8.2%) | 42 (8.3%) | 10 (7.5%) | 0.8 | 37 (7.7%) | 15 (9.6%) | 0.5 | |
| CKD | 0.062 | <0.001 | ||||||
| eGFR ≥60 mL/min/1.73 m2 | 543 (85.4%) | 438 (87.1%) | 105 (78.9%) | 429 (89.4%) | 114 (73.1%) | |||
| eGFR <60 mL/min/1.73 m2 | 66 (10.4%) | 46 (9.1%) | 20 (15.0%) | 37 (7.7%) | 29 (18.6%) | |||
| Dialysis | 27 (4.2%) | 19 (3.8%) | 8 (6.0%) | 14 (2.9%) | 13 (8.3%) | |||
| COPD | 31 (4.9%) | 25 (5.0%) | 6 (4.5%) | 0.8 | 21 (4.4%) | 10 (6.4%) | 0.3 | |
| Aspirin | 137 (21.5%) | 106 (21.1%) | 31 (23.3%) | 0.6 | 97 (20.2%) | 40 (25.6%) | 0.2 | |
| P2Y12 inhibitor | 69 (10.8%) | 51 (10.1%) | 18 (13.5%) | 0.3 | 35 (7.3%) | 34 (21.8%) | <0.001 | |
| Oral anticoagulant | 119 (18.7%) | 79 (15.7%) | 40 (30.1%) | <0.001 | 86 (17.9%) | 33 (21.2%) | 0.4 | |
| Statin | 563 (88.5%) | 453 (90.1%) | 110 (82.7%) | 0.018 | 418 (87.1%) | 145 (92.9%) | 0.13 | |
| Ezetimibe | 27 (4.2%) | 20 (4.0%) | 7 (5.3%) | 0.4 | 21 (4.4%) | 6 (3.8%) | 0.7 | |
| DPP-4 inhibitor | 106 (16.7%) | 72 (14.3%) | 34 (25.6%) | 0.002 | 70 (14.6%) | 36 (23.1%) | 0.013 | |
| SGLT2 inhibitor | 25 (3.9%) | 19 (3.8%) | 6 (4.5%) | 0.7 | 18 (3.8%) | 7 (4.5%) | 0.7 | |
| Hemoglobin (g/dL) | 12.40 (10.90–13.70) | 12.70 (11.20–13.90) | 11.20 (10.30–12.60) | <0.001 | 12.80 (11.30–14.00) | 11.20 (10.10–12.70) | <0.001 | |
| BNP (pg/mL) | 269 (98–779) | 256 (94–738) | 375 (125–995) | 0.017 | 227 (81–611) | 479 (192–1,132) | <0.001 | |
| Concurrent operation | ||||||||
| Maze | 38 (6.0%) | 32 (6.4%) | 6 (4.5%) | 0.4 | 28 (5.8%) | 10 (6.4%) | 0.8 | |
| CABG | 33 (5.2%) | 30 (6.0%) | 3 (2.3%) | 0.086 | 25 (5.2%) | 8 (5.1%) | >0.9 | |
| Aortic graft | 11 (1.7%) | 11 (2.2%) | 0 (0.0%) | 0.13 | 10 (2.1%) | 1 (0.6%) | 0.3 | |
Data are presented as median (Q1, Q3) for continuous variables and number (%) for categorical variables. The p values are from the Wilcoxon rank-sum test for medians and χ2/Fisher’s exact test for proportions. Significant differences (p<0.05) are in bold.
AAC = aortic arch calcification; AF = atrial fibrillation; AR = aortic regurgitation; AS = aortic stenosis; AV = aortic valve; AVA = aortic valve area; AVR = aortic valve replacement; BMI = body mass index; BNP = brain natriuretic peptide; BX = balloon-expandable bioprosthesis; CABG = coronary artery bypass grafting; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CVA = cerebrovascular accident; DM = diabetes mellitus; DPP-4 = dipeptidyl peptidase-4; EF = ejection fraction; eGFR = estimated glomerular filtration rate; HDL-C = high-density lipoprotein cholesterol; HTN = hypertension; LDL-C = low-density lipoprotein cholesterol; LFLG = low-flow, low-gradient; LV = left ventricle (or left ventricular); LVEDD = left ventricular end-diastolic diameter; MAC = mitral annular calcification; MI = myocardial infarction; mPG = mean pressure gradient; MR = mitral regurgitation; NYHA = New York Heart Association; PAOD = peripheral arterial occlusive disease; PCI = percutaneous coronary intervention; SAVR = surgical aortic valve replacement; SGLT2 = sodium-glucose; STS = Society of Thoracic Surgeons; SX = self-expanding bioprosthesis; TAVR = transcatheter aortic valve replacement; TC = total cholesterol; TG = triglycerides; Vmax = maximum uptake velocity.
Comorbidity profiles indicated that MAC patients had a heavier burden of cardiovascular risk factors, including hypertension and diabetes mellitus (DM). The 21% of MAC patients had an estimated glomerular filtration rate <60 mL/min/1.73 m2 or were on dialysis, compared with 13% of no-MAC patients, although this did not reach statistical significance (p=0.06).
DPP-4 inhibitor usage was slightly more common in MAC patients (26% vs 14%, p=0.002). Importantly, the calculated Society of Thoracic Surgeons-predicted 30-day mortality risk was substantially higher in patients with MAC (median 3.6% vs. 1.7%, p<0.001). The type of AVR differed as well: among MAC patients, fewer underwent mechanical SAVR (14% vs. 35% in no-MAC), and more underwent TAVR (38% vs. 14% in no-MAC, p<0.001).
In summary, the presence of MAC identified an older, predominantly female population with a higher comorbidity burden and risk profile. Patients with extensive AAC were, on average, older, had higher rates of hypertension, chronic kidney disease (CKD), higher New York Heart Association class, and higher brain natriuretic peptide levels than those with less arch calcification.
Long-term clinical outcomes
All patients underwent successful AVR, either by surgical or transcatheter approach. Median clinical follow-up was 5.2 years (interquartile range, 3.1–8.4 years).
Over the follow-up period, 157 patients (24.7%) died. Figure 2 shows Kaplan-Meier curves for all-cause mortality stratified by MAC and AAC status. Patients with any MAC had significantly lower survival than those without MAC (log-rank p=0.007; Figure 2A). However, patients with MAC ≥180° had insignificantly lower survival than those with non-encircling or no MAC, with a 10-year mortality of 47.4% in the ≥180° group vs. 40.6% in the <180° group (log-rank p=0.096; Figure 2B).
Figure 2. Cumulative incidence of death of any cause stratified by calcification status.
(A) Any MAC vs. no MAC. (B) By severe MAC extent: patients with circumferential MAC ≥180° vs. those with <180° MAC or none. (C) All-cause mortality curves by AAC grade 0 through 4. (D) Extensive AAC ≥180° vs. none to calcification <180°. (E) Extensive MAC or AAC.
AAC = aortic arch calcification; AVR = aortic valve replacement; MAC = mitral annular calcification.
AAC had an even more pronounced association with mortality. Figure 2C depicts all-cause mortality stratified by AAC grade 0 through 4. There was a stepwise increase in survival with increasing calcification grade (p for trend <0.001). As shown in Figure 2D, the extensive calcification group had significantly higher cumulative mortality than the non-extensive group (p<0.0001). In Figure 2E, simultaneous consideration of both encircling MAC and extensive AAC further illustrates their combined prognostic impact.
We also examined other clinical outcomes (Table 2). There were no statistically significant differences in most secondary outcomes between patients with MAC and those without MAC, except for long-term mortality (p=0.007). When stratified by AAC, mortality remained significantly higher in the AAC ≥180° group (p<0.001).
Table 2. Clinical outcomes at 10 years.
| Characteristic | As per MAC | As per AAC | |||||
|---|---|---|---|---|---|---|---|
| No MAC (n=503) | MAC (n=133) | p value* | None to <180° (n=480) | ≥180° (n=156) | p value* | ||
| Post procedure ≤30 days | |||||||
| Death | 2 (0.7%) | 0 (0%) | >0.99 | 2 (0.7%) | 0 (0%) | >0.99 | |
| PVL ≥ Mild | 3 (0.6%) | 1 (0.8%) | >0.99 | 1 (0.2%) | 3 (1.9%) | 0.048 | |
| PPM | 10 (2.0%) | 6 (4.5%) | 0.12 | 9 (1.9%) | 7 (4.5%) | 0.081 | |
| Long-term (10-year cumulative incidence) | |||||||
| Death | 38.3% | 55.1% | 0.007 | 35.0% | 64.4% | <0.001 | |
| CVA | 6.9% | 30.4% | 0.374 | 9.3% | 2.6% | 0.665 | |
| CVD | 7.0% | 13.9% | 0.931 | 8.0% | 3.4% | 0.657 | |
| Hospitalization for HF | 4.5% | 5.3% | 0.836 | 4.7% | 2.7% | 0.295 | |
| Myocardial infarction | 0.9% | 8.4% | 0.334 | 1.8% | 0.7% | 0.816 | |
| PCI in stable angina | 0.0% | 0.0% | 1.000 | 0.0% | 0.0% | 1.000 | |
| Dialysis | 0.2% | 0.0% | 0.612 | 0.2% | 0.0% | 0.578 | |
| Infective endocarditis | 2.8% | 0.8% | 0.726 | 2.3% | 4.2% | 0.622 | |
| Structural deterioration | 4.8% | 0.0% | 0.437 | 5.0% | 0.0% | 0.378 | |
| PVL ≥ Mild | 1.0% | 1.5% | 0.610 | 0.6% | 2.6% | 0.039 | |
| AV re-intervention | 3.2% | 0.0% | 0.256 | 2.7% | 3.2% | 0.392 | |
| MV intervention | 0.3% | 0.0% | 0.656 | 0.0% | 1.3% | 0.033 | |
| AF | 7.5% | 3.8% | 0.442 | 6.5% | 10.5% | 0.923 | |
| PPM | 5.1% | 5.4% | 0.169 | 4.3% | 9.6% | 0.011 | |
| ICD | 0.4% | 0.0% | 0.466 | 0.2% | 0.6% | 0.400 | |
| CRT | 0.8% | 0.0% | 0.725 | 0.0% | 6.2% | 0.006 | |
Significant differences (p<0.05) are in bold.
AAC = aortic arch calcification; AF = atrial fibrillation; AV = aortic valve; CRT = cardiac resynchronization therapy; CVA = cerebrovascular accident; CVD = cardiovascular disease; HF = heart failure; ICD = implantable cardioverter defibrillator; MAC = mitral annular calcification; MV = mitral valve; PCI = percutaneous coronary intervention; PPM = permanent pacemaker; PVL = paravalvular leakage.
*Pearson’s χ2 test or Fisher’s exact test for post-procedure ≤30 days outcomes; Log-rank test for 10-year cumulative incidence.
Of note, during follow-up, excluding 1 case, 8 of 22 pacemaker implantations in TAVR patients occurred within 1 month after the procedure. For AAC ≥180°, 10 of 156 (6.4%) required PPM implantation, compared with 12 of 480 patients (2.5%) in the <180° group (p=0.011). Additionally, 1 patient required cardiac resynchronization therapy.
When considering the mode of AVR, we found that in patients with MAC or AAC, long-term mortality differed by AVR type (Supplementary Figure 1). Notably, in patients who underwent SAVR, the presence of MAC or AAC was associated with higher mortality, whereas these factors had no discernible impact on mortality in patients who underwent TAVR. Among MAC patients, those treated with balloon-expandable TAVR had the highest mortality. By 5 years, approximately 50% of MAC patients who received a balloon-expandable TAVR had died, compared to ~30% of those with mechanical SAVR. Those who received mechanical valves were significantly younger (mean 61 years) than those who underwent TAVR (mean 80 years).
Regarding causes of death, we were able to ascertain specific causes in 44% of the 157 total deaths. The distribution of causes is shown in Figure 3 and Supplementary Figure 2. The single largest category was “Unknown” (56% of deaths)—many patients died outside the hospital or in other facilities without a definitive cause investigated or recorded. Among known causes, the most common was sepsis or infection-related death (18.5% of all deaths), followed by cardiovascular causes (12.7%), malignancy (8.3%), and stroke (3.2%). In MAC-present patients, a slightly higher proportion of deaths were cardiovascular (15% vs. 12% in MAC-absent) and stroke-related (5% vs. 2%), but numbers were small. Similarly, comparing SAVR vs. TAVR patients (Supplementary Figure 2), the cause-of-death distributions were broadly similar, though TAVR patients had a slightly higher fraction of septic deaths (22% vs. 17%) and early postoperative deaths (2.4% vs. 0.9%), consistent with their higher initial risk. Overall, these data suggest that in this treated severe AS cohort, late mortality was often due to non-cardiac causes and that having MAC did not specifically predispose to more cardiac vs non-cardiac death.
Figure 3. Distribution of causes of death in the cohort.
Left: Overall causes of death among all 157 deaths. Top center: Causes of death in patients without MAC. Top right: Causes of death in patients with MAC. Colors correspond to: green = CV death (12.7% of all deaths); red = cerebrovascular death (stroke-related, 3.2%); purple = septic cause (infection/sepsis, 18.5%); yellow = malignancy (8.3%); blue = postoperative within 1 month (1.3%); brown = unknown cause (56.1%). Unknown indicates deaths for which insufficient information was available to assign a cause (many occurred outside the hospital).
CV = cardiovascular; MAC = mitral annular calcification.
Predictors of mortality–Cox regression analysis
Table 3 displays the results of the univariate and multivariate Cox proportional hazards analysis for all-cause mortality. AAC was retained in the multivariate Cox model due to its clinical importance. The proportional hazards assumption was tested using Schoenfeld residuals (p=0.052). Higher age at AVR, male sex, atrial fibrillation, diabetes mellitus, and chronic kidney disease carried a higher risk of death. Undergoing TAVR (as opposed to SAVR) was associated with higher mortality risk in unadjusted analysis (hazard ratio [HR], 3.090; 95% confidence interval [CI], 2.11–4.51; p<0.001), but did not remain significant after adjustment (adjusted HR, 1.52; 95% CI, 0.96–2.42; p=0.076). Patients with AAC ≥180° were not an independent predictor of mortality in the final model (adjusted HR, 1.24; 95% CI, 0.83–1.86; p=0.30). Higher baseline hemoglobin was protective (HR, 0.83 per 1 g/dL; p<0.001).
Table 3. Risk factors for death in AVR patients.
| Characteristic | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | ||
| Age at AVR | 1.08 (1.06–1.10) | <0.001 | 1.07 (1.04–1.10) | <0.001 | |
| Male | 1.67 (1.18–2.38) | 0.004 | 2.45 (1.62–3.70) | <0.001 | |
| Presence of MAC | 1.53 (1.03–2.26) | 0.034 | 0.92 (0.60–1.43) | 0.72 | |
| AAC ≥180° | 2.48 (1.76–3.50) | <0.001 | 1.24 (0.83–1.86) | 0.30 | |
| Bicuspid AV | 0.25 (0.14–0.44) | <0.001 | 0.58 (0.32–1.06) | 0.078 | |
| AS Vmax | 0.73 (0.58–0.93) | 0.011 | 0.90 (0.69–1.16) | 0.41 | |
| EF | 0.98 (0.97–0.99) | 0.002 | 0.99 (0.98–1.01) | 0.39 | |
| TAVR | 3.09 (2.11–4.51) | <0.001 | 1.52 (0.96–2.42) | 0.076 | |
| LVEDD | 1.03 (1.01–1.05) | 0.008 | 1.01 (0.98–1.04) | 0.42 | |
| MR grade | |||||
| 1 | 1.65 (1.14–2.38) | 0.008 | 1.03 (0.68–1.56) | 0.89 | |
| 2 | 1.52 (0.62–3.73) | 0.36 | 1.27 (0.50–3.24) | 0.62 | |
| 3–4 | 1.96 (0.80–4.83) | 0.14 | 1.71 (0.66–4.46) | 0.27 | |
| LV wall thickness | 0.97 (0.90–1.04) | 0.33 | |||
| MI | 1.20 (0.30–4.85) | 0.80 | |||
| PCI | 1.44 (0.81–2.56) | 0.21 | |||
| CABG | 7.13 (1.76–28.9) | 0.006 | 0.35 (0.07–1.83) | 0.21 | |
| AF | 1.92 (1.23–3.00) | 0.004 | 1.86 (1.14–3.06) | 0.014 | |
| HTN | 1.43 (1.01–2.04) | 0.047 | 0.84 (0.57–1.23) | 0.37 | |
| DM | 1.70 (1.22–2.37) | 0.002 | 2.03 (1.28–3.23) | 0.003 | |
| PAOD | 2.40 (1.36–4.25) | 0.003 | 1.08 (0.57–2.05) | 0.80 | |
| CVA | 1.14 (0.68–1.92) | 0.61 | |||
| CKD | |||||
| eGFR <60 mL/min/1.73 m2 | 3.09 (1.98–4.82) | <0.001 | 1.70 (1.02–2.83) | 0.042 | |
| Dialysis | 8.47 (5.13–14.0) | <0.001 | 4.56 (2.35–8.83) | <0.001 | |
| COPD | 1.37 (0.67–2.80) | 0.39 | |||
| Aspirin | 1.06 (0.70–1.59) | 0.78 | |||
| P2Y12 inhibitor | 2.13 (1.35–3.37) | 0.001 | 1.00 (0.60–1.67) | 0.99 | |
| Oral anticoagulant | 1.73 (1.12–2.67) | 0.013 | 0.85 (0.49–1.48) | 0.56 | |
| DPP-4 inhibitor | 1.57 (1.03–2.38) | 0.035 | 0.56 (0.31–1.04) | 0.065 | |
| SGLT2 inhibitor | 1.21 (0.44–3.28) | 0.71 | |||
| Hemoglobin | 0.72 (0.66–0.79) | <0.001 | 0.83 (0.74–0.92) | <0.001 | |
LVEDD is measured in the parasternal long axis view of a transthoracic echocardiogram. Significant differences (p<0.05) are in bold.
AAC = aortic arch calcification; AF = atrial fibrillation; AS = aortic stenosis; AV = aortic valve; AVR = aortic valve replacement; CABG = coronary artery bypass graft; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CVA = cerebrovascular accident; DM = diabetes mellitus; DPP4 = dipeptidyl peptidase 4; EF = ejection fraction; eGFR = estimated glomerular filtration rate; HR = hazard ratio; HTN = hypertension; LV = left ventricle (or left ventricular); LVEDD = left ventricular end-diastolic diameter; MAC = mitral annular calcification; MI = myocardial infarction; MR = mitral regurgitation; PAOD = peripheral arterial occlusive disease; PCI = percutaneous coronary intervention; SGLT = sodium-glucose linked transporter; TAVR = transcatheter aortic valve replacement; Vmax = maximum uptake velocity.
DISCUSSION
In this study of patients with severe AS undergoing AVR, we examined the clinical relevance of MAC and extensive AAC, two upstream and downstream markers of diffuse calcific degenerative disease. We found that patients with MAC or those with extensive AAC represent a distinct subgroup of AS patients who are older, more comorbid, and at higher operative risk. These patients had worse unadjusted outcomes following AVR, including higher all-cause mortality and a greater need for pacemaker implantation. However, after adjusting for other risk factors in a multivariable model, neither MAC nor extensive AAC emerged as independent predictors of long-term mortality. In other words, the excess risk associated with these calcific features appears to be explained by the patients’ age, sex, and co-existing conditions rather than the presence of the calcifications themselves.
Our findings highlight a nuanced view of MAC in AS. On one hand, MAC was associated with a trend toward more frequent conduction system complications (among patients with MAC ≥180°, 10% eventually required a PPM compared to 3.1% in those without encircling MAC, a considerable numeric difference). This aligns with prior reports in TAVR populations: Abramowitz et al.12) observed that severe MAC was an independent predictor of both all-cause mortality and new pacemaker implantation after TAVR (HR, 1.95 and odds ratio, 2.83, respectively). MAC can impair the flexibility of the mitral annulus and may indicate calcium extending into the LV outflow tract, which can increase the risk of AV node damage, especially during TAVR (when the device expands in a calcified outflow tract).
On the other hand, our multivariable results suggest that MAC itself may not directly worsen outcomes once known risk factors are accounted for. However, a limitation in drawing definitive conclusions about clinical outcomes of encircling MAC is the relatively small sample size, with only 30 patients having encircling MAC. In our survival curve, the difference in cumulative incidence widened substantially during the first three years but gradually diminished over time as the number of patients at risk decreased.
A striking finding was the strong unadjusted association of AAC with mortality, which disappeared after adjustment. Extensive AAC is often referred to as “porcelain aorta” when circumferential.19) Historically, a porcelain aorta has been considered a contraindication or major challenge for surgical AVR due to the inability to safely apply an aortic cross-clamp and the high risk of embolization of plaque during surgery. In such scenarios, alternatives such as off-pump apical aortic conduit or, more recently, TAVR are considered.20),21) In our cohort, 56 out of 156 patients with AAC ≥180° underwent TAVR. However, it is important to note that many patients underwent SAVR before 2015, when TAVR became covered by health insurance, potentially introducing a selection bias. Despite the observed higher 10-year mortality in patients with extensive AAC, it did not emerge as an independent predictor in the multivariate analysis. We interpret our results to mean that in severe AS patients, AAC is a marker of systemic disease severity. Once patients undergo AVR, correcting the valve obstruction, their survival depends on how robust they are and how much other disease they have. The AAC itself likely does not directly contribute to mortality except insofar as it may complicate the procedure or reflect underlying pathologies.
Our findings resonate with the concept that imaging markers of calcification are important for risk stratification but are not necessarily independent “villains” once therapy is appropriately tailored. Severe AS patients with MAC and AAC should be recognized as high-risk—they often require a Heart Team approach to determine the safest AVR strategy (SAVR vs. TAVR) and careful intra-procedural management (e.g., a different access route for TAVR). However, if managed well, these patients can achieve outcomes comparable to other high-risk AS patients. In our data, after multivariable adjustment, the remaining significant predictors are similar to predictors of mortality in SAVR or TAVR populations.22),23)
It is informative to compare our results with previous studies that quantitatively assessed MAC volume by CT in TAVR patients. They found that greater calcium volume was not associated with long-term mortality after TAVR; instead, it was a “marker of late-stage remodeling” but did not independently influence prognosis.24),25) This is in line with our finding that MAC did not independently impact mortality. In TAVR cohorts, the data have been mixed. Besides the Abramowitz study, another analysis found that MAC severity (graded by CT) did not correlate with increased 1-year mortality.12),26) Our mixed cohort results suggest that when both SAVR and TAVR options are available, the net long-term outcome differences attributed to MAC diminish, perhaps because the worst candidates for one approach can be channeled to the alternative. Indeed, we observed that among MAC patients, those who underwent TAVR had worse unadjusted outcomes than those who underwent SAVR (Supplementary Figure 1), but this reflects selection (TAVR was chosen for older, frailer MAC patients).
The high prevalence of non-cardiac deaths, particularly from sepsis, in our cohort (18.5% of all deaths) is noteworthy. This likely reflects the advanced age and comorbidities—such patients are vulnerable to infections and other systemic illnesses after AVR. It underscores that managing severe AS with AVR is only one aspect; comprehensive geriatric and chronic disease management is crucial to improve long-term outcomes. Our data showing over half of deaths were due to non-cardiovascular causes (or unknown) dovetail with other studies in elderly valve patients.27),28) In terms of cardiovascular mortality specifically, we did not find a significant difference by MAC or AAC status.
Our results suggest that when such patients undergo AVR with appropriate technique (SAVR with modified strategy or TAVR), their long-term survival can be acceptable and mainly determined by their general health. Thus, the presence of a heavy MAC or porcelain aorta should prompt a tailored approach. In fact, in the multivariate analysis, a patient’s diabetes status or renal function was far more impactful on survival. This emphasizes treating the whole patient: aggressively manage diabetes, consider strategies to reduce renal injury, etc.
This study is limited by its retrospective, single-center design, which may introduce selection bias regarding who was offered SAVR vs TAVR. The grading of MAC by echocardiography is semi-quantitative; while we validated most cases with CT when available, there is still some subjectivity in classifying 180° vs. 170°, etc. However, our use of broad categories (≥180°) likely captured truly extensive calcification. The grading of AAC on chest X-ray, though based on prior literature, is also an approximation and was not confirmed by CT in all cases; small calcifications might be under-detected on X-ray. Another limitation is that we did not have systematic CT calcium scoring for all patients, which could provide a continuous measure of global calcium burden. Nonetheless, our practical grading approach reflects what is readily available in clinical practice (echo, CT, and chest X-ray). A significant limitation of our study is the imbalance in sample size between patients who underwent SAVR and those who received TAVR. While the overall number of TAVR procedures was lower, the inherent patient characteristics also contributed to this imbalance. Specifically, the TAVR population initially comprised a disproportionate number of high-risk patients. Conversely, TAVR was performed on intermediate- to low-risk patients more recently; although this group is growing, their follow-up period is inherently short. As TAVR was first covered by national insurance for the inoperable/high-risk group in the summer of 2015, with coverage gradually expanding to the across-risk group starting in mid-2022, the longest-observed TAVR cases in our cohort are predominantly from the early high-risk procedures, and the follow-up duration for intermediate/low-risk TAVR patients is shorter. Despite these limitations, we were particularly curious about the general influence of MAC and AAC on resolving AS through the AVR intervention across the entire disease entity of severe AS, leading us to include the combined cohort. The follow-up cause-of-death data had a high proportion of “unknown” causes, making it hard to draw firm conclusions about differences in specific cause distributions; our cause-of-death analysis should be viewed as descriptive. Finally, the outcomes beyond 10 years were not analyzed, and it’s possible that very late consequences of MAC (like progression of mitral valve disease) or AAC could manifest beyond the follow-up of most patients. However, further survival analysis beyond 10 years was considered questionable given the advanced age of the cohort. The relatively small sample size of 30 patients with encircling MAC also limits the statistical power to draw definitive conclusions regarding specific clinical outcomes for this subgroup. While extensive AAC often renders patients inoperable, as observed in trials like PARTNER 1B,21) our study included only patients who were able to undergo AVR. Furthermore, the inclusion of a significant number of SAVR patients from before TAVR became widely covered by health insurance may also have introduced selection bias.
In conclusion, our study demonstrates that in patients with severe AS undergoing AVR, the presence of MAC and extensive AAC is associated with higher unadjusted mortality and highlights a higher-risk patient profile. However, these calcific features are not independent determinants of long-term survival after AVR once age, sex, and comorbid conditions are taken into account. Rather than being direct prognostic factors, MAC and AAC serve as markers of advanced age and comorbidity burden. It is thus deemed necessary to pay close attention to comorbidity management in these patients.
Footnotes
Funding: The study was supported by a 2025 research grant from Pusan National University Yangsan Hospital.
Conflict of Interest: The authors have no financial conflicts of interest.
Data Sharing Statement: The data generated in this study are available from the corresponding author upon reasonable request.
- Conceptualization: Kim SH, Lee SH, Kim JS.
- Data curation: Lee SY, Lim MH, Ju MH.
- Formal analysis: Lee SY, Choi JH, Lim MH.
- Investigation: Lee SY, Lim MH, Lee CH, Je HG, Kim JS, Park YH, Kim JH, Chun KJ.
- Methodology: Lee SY, Je HG, Ju MH.
- Resources: Kim JS, Kim JH, Chun KJ.
- Validation: Hwang KW, Park YH.
- Visualization: Kim SH, Lee SH, Kim JS.
- Writing - original draft: Kim SH.
- Writing - review & editing: Choi JH, Chon MK, Lee SH, Park YH, Lee CH, Ju MH.
SUPPLEMENTARY MATERIALS
All-cause mortality in patients with MAC or AAC, stratified by the type of AVR prosthesis.
Distribution of causes of death according to AVR types and AAC extensiveness.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
All-cause mortality in patients with MAC or AAC, stratified by the type of AVR prosthesis.
Distribution of causes of death according to AVR types and AAC extensiveness.