Overlapping Genetic Background of Coronary Artery and Carotid/Femoral Atherosclerotic Calcification
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Coronary Artery Calcification—Cardiac Non-Contrast Computed Tomography
2.3. Vascular Ultrasound
2.4. Statistics
3. Results
3.1. Descriptive Statistics
3.2. Plaque Localization
3.3. Phenotypic Correlation
3.4. Univariate Analyses
3.5. Bivariate Analysis
4. Discussion
- Coronary artery calcification’s co-occurrence with atherosclerosis in other arterial sites is less investigated. The PESA study found among 849 asymptomatic individuals that CAC co-occurred with atherosclerosis at other sites (carotid, aorta, and/or iliofemoral regions) in 89% on average [9]. Among our study participants, coronary calcification co-occurred with atherosclerotic plaques in the carotid and/or femoral arteries in 87.8% in close agreement with the previous result. About more generalized arterial calcification one study found that calcification of the superior mesenteric artery was significantly associated with the calcification of five other arterial territories (celiac trunk, coronaries, thoracic aorta, abdominal aorta, and iliac arteries) on CT [35]. Another study found that more than two-thirds of patients over 70 years old showed generalized arterial calcification in all investigated arteries (carotid, coronary, aorta, iliac arteries) and calcified atherosclerotic plaques significantly correlated in different vascular beds [36]. One-by-one carotid-coronary, femoral-coronary, and carotid-femoral atherosclerosis correlations were found to be weaker [37].
- Despite the above considerations, our study results strongly support that atherosclerotic calcification is not a passive degeneration that occurs with aging as thought earlier. It is rather an actively regulated process that also might be non-site specific (explaining why intraindividual phenotypic resemblance is high) and highly influenced by genetic predisposition. Generally, there is a growing body of evidence that microcalcification originates from extracellular vesicles released by macrophages and vascular smooth muscle cells within the plaque, which in a collagen-poor environment grow more easily into macrocalcification [50,51,52,53]. Metalloprotease enzymes, developmental, inflammatory, and metabolic factors are thought to regulate the process of atherosclerotic calcification, which in 15–20% can also turn into complex trabecular bone formation due to the plasticity of mesenchymal cells [54,55]. Calcium-phosphate imbalance is also thought to play a role, which contributes to the insufficiency of proposed calcification inhibiting pathways or manifests with the imbalance of positive and negative modulators [56,57]. However, the mechanism of atherosclerotic calcification is still not fully understood—some researchers even suggest that atheroma formation and extensive calcification might be two distinct conditions with some possible overlap [58]. Sage et al. propound that calcification might have an evolutionary explanation: it may be an ultimate immune response mechanism that develops a mechanical barrier [55].
- Screening patients with combined carotid and femoral ultrasound, detection of atherosclerotic calcification could be a cost-effective pre-selecting modality to perform cardiac CT in search for further coronary calcification similarly to the proposal of the PCV METRA group [59]. The common or overlapping genetic background of the calcification process and the hypothesized genetic predilection of plaque locations supports this idea and should generate further prospective research. Although calcified plaques are late, complicated phenotypes, nowadays a wide range of treatment options for heavily calcified plaques are already available such as the double-wire technique and rotational and orbital atherectomy [60]. Also, oral medications are being proposed to treat vascular calcification (primarily in chronic kidney disease)– however, the safety of most of these drugs needs to be addressed, especially in regard of the unwanted parallel inhibition of calcification in bones [61]. Principally, carotid-femoral ultrasound or coronary calcification assessment could help regroup patients regarding their cardiovascular risk better than traditional risk factors do alone. Our study might encourage future investigations about the genetic background of plaque dissemination “route” longitudinally and seek common genetic mechanisms that promote or reduce calcification at these localizations. We believe that a better understanding of the genetic background of atherosclerotic calcification will also lead to better therapeutic options in the future.
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
CAC Severity | ||||
---|---|---|---|---|
0 (n = 116) | 1–100 (Mild) (n = 36) | 100–400 (Moderate) (n = 22) | >400 (Severe) (n = 16) | |
Localization of plaques on ultrasound: | ||||
No plaque/4S_PL = 0/(n, %) | 62 (87.32) | 7 (9.86) | 2 (2.82) | 0 (0.00) |
Unilateral Carotid/4S_PL = 1/(n, %) | 20 (68.97) | 7 (24.14) | 1 (3.45) | 1 (3.45) |
Unilateral Femoral/4S_PL = 1/(n, %) | 6 (50.00) | 5 (41.67) | 1 (8.33) | 0 (0.00) |
Unilateral Carotid and Femoral/4S_PL = 2/(n, %) | 5 (62.50) | 2 (25.00) | 1 (12.50) | 0 (0.00) |
Bilateral Carotid/4S_PL = 2/(n, %) | 9 (42.86) | 5 (23.81) | 4 (19.05) | 3 (14.29) |
Bilateral Femoral /4S_PL = 2/(n, %) | 1 (20.00) | 1 (20.00) | 1 (20.00) | 2 (40.00) |
Bilateral Carotid and unilateral Femoral/4S_PL = 3/(n, %) | 6 (46.15) | 2 (15.38) | 2 (15.38) | 3 (23.08) |
Bilateral Femoral and unilateral Carotid/4S_PL = 3/(n, %) | 6 (42.86) | 2 (14.29) | 4 (28.57) | 2 (14.29) |
Bilateral Carotid and bilateral Femoral/4S_PL = 4/(n, %) | 1 (0.06) | 5 (29.41) | 6 (35.29) | 5 (29.41) |
Generalized state according to ultrasound findings: | ||||
Total plaque number (Mean Rank) | 73.03 | 111.00 | 136.95 | 163.22 |
Total plaque number > Median (n, %) | 33 (38.37) | 20 (23.26) | 17 (19.77) | 16 (18.60) |
Total plaque number ≤ Median (n, %) | 83 (80.58) | 16 (15.53) | 4 (3.88) | 0 (0.00) |
4S_PL > Median (n, %) | 27 (35.06) | 17 (22.08) | 18 (23.38) | 15 (19.48) |
4S_PL ≤ Median (n, %) | 89 (78.76) | 19 (16.81) | 4 (3.54) | 1 (0.88) |
4S_hypo > Median (n, %) | 35 (49.30) | 14 (19.72) | 10 (14.08) | 12 (16.90) |
4S_hypo ≤ Median (n, %) | 81 (68.07) | 22 (18.49) | 12 (10.08) | 4 (3.36) |
4S_mixed > Median (n, %) | 19 (31.15) | 16 (26.23) | 13 (21.31) | 13 (21.31) |
4S_mixed ≤ Median (n, %) | 97 (75.19) | 20 (15.50) | 9 (6.98) | 3 (2.32) |
4S_hyper > Median (n, %) | 24 (32.88) | 18 (24.66) | 16 (21.92) | 15 (20.55) |
4S_hyper(≤ Median (n, %) | 92 (78.63) | 18 (15.38) | 6 (5.13) | 1 (0.85) |
MZ | CAC Concordants: | CAC Discordants: | ||
---|---|---|---|---|
MZ Twin 1+ (More Severe) | MZ Twin 2+ | MZ Twin1+ | MZ Twin 2− | |
Mean CACS: 728.65 | CAR.bil.o. | CAR.bil.o. | CAR.bil + FEM.bil. | - |
CACS: 1233 | CACS: 224.3 | CACS: 195.8 | - | |
Mean CACS: 726.25 | CAR.bil.o. | CAR.bil. + FEM.uni | CAR.uni.o. | CAR.uni.o. |
CACS: 971 | CACS: 481.5 | CACS: 19.71 | - | |
Mean CACS: 556.86 | CAR.bil. + FEM.uni | FEM.bil. + CAR.uni | - | CAR.uni.o. |
CACS: 822.86 | CACS: 290.87 | CACS: 10 | - | |
Mean CACS: 533.02 | FEM.bil.o. | FEM.bil. + CAR.uni | FEM.bil. + CAR.uni | FEM.uni.o. |
CACS: 675.83 | CACS: 390.21 | CACS: 7 | - | |
Mean CACS: 499.885 | CAR.bil + FEM.bil. | CAR.bil.o. | CAR.bil.o. | CAR.uni + FEM.uni |
CACS: 525.64 | CACS: 474.13 | CACS: 5.1 | - | |
Mean CACS: 356.04 | CAR.uni.o. | CAR.bil.o. | - | - |
CACS: 407.54 | CACS: 304.54 | CACS: 3.5 | - | |
Mean CACS: 330.28 | CAR.bil. + FEM.uni | CAR.bil. + FEM.uni | - | CAR.Bil.o. |
CACS: 466.98 | CACS: 193.59 | CACS: 2.5 | - | |
Mean CACS: 319.5 | CAR.bil. + FEM.uni | CAR.bil. + FEM.bil. | CAR.bil.o. | CAR.uni. + FEM.uni |
CACS: 360 | CACS: 279 | CACS: 2.23 | - | |
Mean CACS: 254.95 | CAR.bil. + FEM.bil. | CAR.uni. | - | FEM.uni.o. |
CACS: 413.58 | CACS: 96.32 | CACS: 2 | - | |
Mean CACS: 193.35 | CAR.uni.o. | FEM.bil. + CAR.uni | - | - |
CACS: 262.2 | CACS: 124.5 | CACS: 1.11 | - | |
Mean CACS: 138.5 | CAR.bil. + FEM.bil. | CAR.bil. + FEM.bil. | FEM.uni.o. | - |
CACS: 195 | CACS: 82 | CACS: 0.64 | - | |
Mean CACS: 134.225 | CAR.bil.o. | CAR.bil.o. | ||
CACS: 259.54 | CACS: 8.91 | |||
Mean CACS: 124.1 | FEM.bil.o. | FEM.bil. + CAR.uni | ||
CACS: 209 | CACS: 39.2 | |||
Mean CACS: 71.85 | CAR.uni.o. | CAR.uni.o. | ||
CACS: 91.88 | CACS: 51.82 | |||
Mean CACS: 68.465 | CAR.bil.o. | CAR.uni. | ||
CACS: 80.7 | CACS: 56.23 | |||
Mean CACS: 39.5 | FEM.uni.o. | FEM.uni.o. | ||
CACS: 78 | CACS: 1 | |||
Mean CACS: 36 | CAR.Bil. + FEM.bil. | FEM.uni. | ||
CACS: 68.19 | CACS: 3.81 |
MZ | 0 CAC Concordants | 0 CAC Concordants | ||
---|---|---|---|---|
0 US Concordants | ||||
MZ twin 1 (+) | MZ twin 2 (+/−) | MZ twin 1 (−) | MZ twin 2 (−) | |
CAR.uni | - | - | - | |
CAR.uni. + FEM.uni | - | - | - | |
CAR.uni | CAR.uni | - | - | |
CAR.uni | - | - | - | |
CAR.bil.+ FEM.uni. | FEM.uni.o. | - | - | |
CAR.bil.o. | CAR.uni. | - | - | |
CAR.uni. | - | - | - | |
CAR.bil.o. | CAR.bil.o. | - | - | |
CAR.uni. | CAR.uni. | - | - | |
FEM.Bil. | FEM.uni. | - | - | |
CAR.uni | - | - | - | |
CAR.bil. | CAR.uni. | - | - | |
CAR.bil. | CAR.uni. | - | - | |
CAR.bil. | - | - | - | |
CAR.uni. | - | |||
CAR.bil. + FEM.uni. | CAR.uni. + FEM.uni. | |||
CAR.uni. | - | |||
CAR.bil. + FEM.uni. | - | |||
CAR.uni | CAR.uni | |||
CAR.bilat.fem.uni. | - | |||
FEM.uni. | - |
DZ | CAC Concordants: | CAC Discordants: | ||
---|---|---|---|---|
DZ Twin 1+ (More Severe) | DZ Twin 2+ | DZ Twin 1+ | DZ Twin 2− | |
Mean CACS: 990.3 | CAR.bil. + FEM.bil. | FEM.bil. + CAR.uni | FEM.bil. + CAR.uni | CAR.uni + FEM.uni |
CACS: 1248 | CACS: 732.6 | CACS: 728.44 | - | |
Mean CACS: 877.5 | CAR.bil. + FEM.bil | CAR.uni + FEM.uni | CAR.bil. + FEM.bil. | FEM.bil. + CAR.uni |
CACS: 1467 | CACS: 288 | CACS: 334.4 | - | |
Mean CACS: 252.85 | FEM.bil.o. | CAR.bil. + FEM.bil. | CAR.bil. + FEM.bil. | CAR.uni |
CACS: 413.4 | CACS: 92.3 | CACS: 202 | - | |
Mean CACS: 221.65 | CAR.bil + FEM.bil. | CAR.uni + FEM.uni | CAR.bil.o. | - |
CACS: 438.21 | CACS: 5.09 | CACS: 196 | - | |
Mean CACS: 170.1 | CAR.bil + FEM.bil. | CAR.bil. + FEM.bil. | - | - |
CACS: 256.92 | CACS: 83.25 | CACS: 189.3 | - | |
Mean CACS: 86.46 | FEM.uni | CAR.uni | - | CAR.uni |
CACS: 149.25 | CACS: 23.68 | CACS: 145.6 | - | |
Mean CACS: 73.2 | CAR.bil. + FEM.bil. | CAR.bil. + FEM.uni. | FEM.bil.o. | FEM.bil. + CAR.uni |
CACS: 79.63 | CACS: 66.76 | CACS: 62.69 | - | |
Mean CACS: 68.74 | FEM.bil. + CAR.uni. | CAR.bil. + FEM.uni | CAR.uni. | CAR.bilat + FEM.uni |
CACS: 114.91 | CACS: 22.57 | CACS: 61 | - | |
CAR.uni + FEM.uni | - | |||
CACS: 14.34 | - | |||
- | - | |||
CACS: 14 | - | |||
FEM.uni | - | |||
CACS: 11 | - | |||
CAR.bil.o. | FEM.bil. + CAR.uni | |||
CACS: 6.36 | - | |||
- | CAR.bil. + FEM.uni | |||
CACS: 3.02 | - |
DZ | 0 CAC Concordants | 0 CAC Concordants | ||
---|---|---|---|---|
0 US Concordants | ||||
DZ Twin 1 | DZ Twin 2 | DZ Twin 1 | DZ Twin 2 | |
CAR.bil.o. | - | - | - | |
CAR.uni. | - | - | - | |
FEM.bil. + CAR.uni | CAR.bil. + FEM.bil. | - | - | |
FEM.uni | - | - | - | |
FEM.bil. + CAR.uni | - | - | - | |
FEM.bil.o. | CAR.uni. + FEM. Uni | - | - |
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Total | MZ | DZ | P | |
---|---|---|---|---|
Zygosity | 190 | 120 | 70 | |
Male (n, %) | 72 (37.89) | 48 (40) | 24 (34.29) | 0.43 |
Age (mean, SD) | 56.84 ± 9.33 | 55.46 ± 9.75 | 59.16 ± 8.11 | 0.01 |
BMI (kg/m2) (mean, SD) | 27.57 ± 4.65 | 27.85 ± 4.46 | 27.08 ± 4.95 | 0.27 |
Hypertension (n, %) | 79 (41.58) | 50 (41.67) | 29 (41.43) | 0.96 |
Diabetes (n, %) | 14 (7.37) | 10 (8.33) | 4 (5.71) | 0.52 |
Dyslipidaemia (n, %) | 83 (43.68) | 49 (40.83) | 34 (48.57) | 0.26 |
Smoking (n, %) | 70 (36.84) | 44 (36.67) | 26 (37.14) | 0.89 |
Coronary plaque occurrence (CACS > 0) (n, %) | 74 (38.95) | 44 (36.67) | 30 (42.86) | 0.39 |
Carotid plaque occurrence (n, %) | 89 (46.84) | 54 (45.00) | 35 (50.00) | 0.51 |
Femoral plaque occurrence (n, %) | 71 (37.37) | 38 (31.67) | 33 (47.14) | 0.03 |
Carotid/femoral and coronary plaque co-occurrence (n, %) | 65 (34.21) | 39 (32.50) | 26 (37.14) | 0.51 |
Carotid + femoral + coronary plaque co-occurrence (all 3) (n, %) | 32 (16.84) | 16 (13.33) | 16 (22.86) | 0.09 |
4S_PL > 1 (n, %) 1 | 119 (62.63) | 76 (63.33) | 43 (61.43) | 0.79 |
4S_hypo > 1 (n, %) 2 | 71 (37.37) | 46 (38.33) | 25 (35.71) | 0.72 |
4S_mixed > 1 (n, %) 2 | 61 (34.21) | 39 (32.5) | 22 (31.43) | 0.88 |
4S_hyper > 1 (n, %) 2 | 75 (37.5) | 44 (34.9) | 31 (41.9) | 0.36 |
4S_mixed/hyper > 1 (n, %) 2 | 98 (51.58) | 58 (48.33) | 40 (57.14) | 0.38 |
N = 190 | CACS | p |
---|---|---|
4S_PL | 0.557 | <0.01 |
4S_hypo | 0.289 | <0.01 |
4S_mixed | 0.444 | <0.01 |
4S_hyper | 0.551 | <0.01 |
4S_mixed/hyper | 0.604 | <0.01 |
Trait | Model | Goodness-of-Fit Indices | Parameter Estimates (95% CI) | ||||||
---|---|---|---|---|---|---|---|---|---|
Trait | Model | AIC | −2LL | df | DiffLL | p-Value | A | C | E |
CAC | ACE | 337.2 | 311.9 | 11 | Ref. | Ref. | 0.67 (0.16, 1) | 0 (0, 0.38) | 0.33 (0, 0.67) |
AE * | 334.6 | 311.9 | 10 | 0 | 1 | 0.67 (0.35, 1) | - | 0.33 (0, 0.65) | |
CE | 340.1 | 317.5 | 10 | −5.5 | .02 | - | 0.43 (0.15, 0.66) | 0.57 (0.35, 0.85) | |
E | 346.2 | 326.1 | 9 | −14.1 | .00 | - | - | 1 | |
Sat. | 346.9 | ||||||||
4S_hypo | ACE | 408.7 | 378.2 | 13 | Ref. | Ref. | 0 (0, 0.41) | 0.18 (0, 0.45) | 0.82 (0.55, 1) |
AE | 406.9 | 379.2 | 12 | −0.9 | 0.13 (0, 0.45) | - | 0.87 (0.56, 1) | ||
CE | 406.0 | 378.2 | 12 | 0 | 1 | - | 0.18 (0, 0.45) | 0.82 (0.55, 1) | |
E * | 404.9 | 379.7 | 11 | −1.5 | 0.47 | - | - | 1 | |
Sat. | 419.7 | ||||||||
4S_mixed | ACE | 342.7 | 312.2 | 13 | Ref. | Ref. | 0.49 (0, 0.76) | 0 (0, 0.49) | 0.50 (0.24, 1) |
AE * | 340.0 | 312.2 | 12 | 0 | 1 | 0.50 (0, 0.76) | - | 0.50 (0.24,1) | |
CE | 342.4 | 314.6 | 12 | −2.4 | 0.13 | - | 0.32 (0.02, 0.57) | 0.68 (0.43, 0.98) | |
E | 344.2 | 319.0 | 11 | −6.8 | 0.03 | - | - | 1 | |
Sat. | 355.0 | ||||||||
4S_hyper | ACE | 363.4 | 332.9 | 13 | Ref. | Ref. | 0.69 (0.19, 1) | 0 (0.38, 1) | 0.31 (0, 0.63) |
AE * | 360.7 | 332.9 | 12 | 0 | 1 | 0.69 (0.38, 1) | - | 0.31 (0, 0.63) | |
CE | 366.6 | 338.8 | 12 | −5.8 | 0.02 | - | 0.41 (0.13, 0.63) | 0.59 (0.37, 0.87) | |
E | 371.9 | 346.8 | 11 | −13.9 | 0.00 | - | - | 1 | |
Sat. | 371.9 |
Traits | Adjust | Model | Model Fit (p) | Model Fit (AIC) | A | C | E |
---|---|---|---|---|---|---|---|
CAC and 4S_hyper | Age and sex | ACE | - | −81.9 | 0.99 | 0 | 0.01 |
AE * | 0.98 | −87.8 | 0.86 (0.42, 1) | - | 0.14 (0, 0.58) | ||
CE | 0.01 | −77.4 | - | 0.42 | 0.58 | ||
E | 0 | −67.1 | - | - | 1 | ||
Phenotypic correlation | |||||||
All (95% CI) | MZ (95% CI) | DZ (95% CI) | |||||
CAC and 4S_hyper | Age and sex | 0.48 (0.30, 0.63) | 0.54 (0.31, 0.72) | 0.44 (0.14, 0.68) |
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Hernyes, A.; Piroska, M.; Fejer, B.; Szalontai, L.; Szabo, H.; Forgo, B.; Jermendy, A.L.; Molnar, A.A.; Maurovich-Horvat, P.; Jermendy, G.; et al. Overlapping Genetic Background of Coronary Artery and Carotid/Femoral Atherosclerotic Calcification. Medicina 2021, 57, 252. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina57030252
Hernyes A, Piroska M, Fejer B, Szalontai L, Szabo H, Forgo B, Jermendy AL, Molnar AA, Maurovich-Horvat P, Jermendy G, et al. Overlapping Genetic Background of Coronary Artery and Carotid/Femoral Atherosclerotic Calcification. Medicina. 2021; 57(3):252. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina57030252
Chicago/Turabian StyleHernyes, Anita, Marton Piroska, Bence Fejer, Laszlo Szalontai, Helga Szabo, Bianka Forgo, Adam L. Jermendy, Andrea A. Molnar, Pal Maurovich-Horvat, Gyorgy Jermendy, and et al. 2021. "Overlapping Genetic Background of Coronary Artery and Carotid/Femoral Atherosclerotic Calcification" Medicina 57, no. 3: 252. https://0-doi-org.brum.beds.ac.uk/10.3390/medicina57030252