Cover Page

(1)

Cover Page

The handle

http://hdl.handle.net/1887/136091

holds various files of this Leiden University

dissertation.

Author: Rosendael, P.J. van

Title: Cardiac computed tomography for valvular heart disease and non-coronary

percutaneous interventions

(2)

545024-L-bw-Rosendael 545024-L-bw-Rosendael 545024-L-bw-Rosendael 545024-L-bw-Rosendael Processed on: 22-7-2020 Processed on: 22-7-2020 Processed on: 22-7-2020

Processed on: 22-7-2020 PDF page: 41PDF page: 41PDF page: 41PDF page: 41

Part I

(3)

(4)

2

Calcification of Aortic Valve and Coronary

Atherosclerosis: Age Differences in

Bicuspid and Tricuspid Aortic Valves

Philippe J van Rosendael, MD1_{; Vasileios Kamperidis, MD, PhD}1_{; William KF} Kong, MD1_{; Alexander R van Rosendael, MD}1,2_{; Nina Ajmone Marsan, MD, PhD}1_; Jeroen J Bax, MD, PhD1_{; Victoria Delgado, MD, PhD}1_.

1_{The Department of Cardiology, Leiden University Medical Center, Leiden, the} Netherlands;

2_{The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the} Netherlands;

van Rosendael PJ, Kamperidis V, Kong WK, van Rosendael AR, Marsan NA, Bax JJ, Delgado V.

(5)

44

ABSTRACT

(6)

45 BAV calcification and CAD

INTRODUCTION

Calcific aortic valve stenosis has been associated with the presence of coronary atherosclerosis. Both processes share common pathophysiologic mechanisms: increased mechanical stress and reduced shear stress result in endothelial damage which is the first step of the inflammation, fibrosis and calcification cascade.(1, 2) In the tricuspid aortic valve, the increased mechanical stress is located near to the hinge points of the aortic cusps anchoring into the aortic root wall whereas the non-coronary cusp shows the least shear stress leading to the characteristic distribution of the valve calcifications.(2, 3) However, there are some important pathophysiological differences between calcific aortic stenosis and development of atherosclerosis. These differences may explain why statin therapy effectively slows down the atherosclerosis process and stabilizes the atherosclerotic plaque of coronary arteries but does not affect the progression of calcific aortic valve stenosis.(4-6) Furthermore, in bicuspid aortic valves, the mechanical and shear stress distribution is totally different to that of tricuspid valves, which may explain why aortic valve calcification and stenosis develops at an earlier stage than in patients with tricuspid aortic valve.(1, 2, 7) However, the evidence correlating the aortic valve calcification process in bicuspid aortic valves and the development of coronary artery atherosclerosis in relation to age is scarce. Multi-detector row computed tomography (MDCT) enables accurate quantification of aortic valve calcium (8) and provides a high diagnostic accuracy for coronary artery disease (CAD).(9) In propensity score matched populations, the current study compared the extent of aortic valve calcification and the presence of coronary atherosclerosis, as evaluated with MDCT, in patients with bicuspid versus tricuspid aortic valve across different ages.

METHODS

From an ongoing clinical registry of patients who underwent clinically indicated MDCT at the Leiden University Medical Centre (Leiden, the Netherlands),(9) 85 patients with a bicuspid aortic valve were identified. Additional 713 patients with a tricuspid aortic valve were identified. A propensity score was used to match in a 1:3 fashion patients with a bicuspid aortic valve to patients with a tricuspid aortic valve (see details in the statistical analysis section). The resulting population comprised 70 patients with bicuspid aortic valve and 210 patients with tricuspid aortic valve. MDCT data of aortic valve calcification and presence

(7)

46

of coronary atherosclerosis were evaluated and compared between patients with a bicuspid versus a tricuspid aortic valve. The presence and severity of aortic regurgitation and aortic stenosis were assessed with transthoracic echocardiography according to current recommendations.(10, 11) Data were prospectively collected in the departmental electronic clinical files (EPD vision version 11.3.26.0; Leiden, The Netherlands) and retrospectively analyzed. The Institutional Review Board approved this retrospective analysis of clinically acquired data and waived the need of patient written informed consent.

(8)

47 BAV calcification and CAD applied with the maximal tube currents at 75%, 65-85% or 30-80% of the RR interval in patients whose heart rates were <60 bpm, 60-65 bpm or >65 bpm, respectively.(9) MDCT data were reconstructed initially at 75% of the RR interval with a slice thickness and reconstruction interval of 0.5 mm and 0.25 mm. In the presence of multiple phases, additional phases with the least motion artifacts were reconstructed. Subsequently, for off-line image analysis, the reconstructed datasets were transferred to an external workstation (Vitrea 2, Vital Images, Plymouth, Minnesota).

The non-contrast calcium scans were used to assess the Agatston coronary artery calcium score and the calcium score and calcium volume of the aortic valve (including a volume from the aortic annulus until the level of the coronary ostia).(8, 12) To accurately exclude contiguous calcium located in the coronary arteries and mitral valve annulus from the calcium analysis of the aortic valve, the aortic valve calcifications were also evaluated on the higher-spatial, contrast-enhanced images enabling an accurate delineation of the calcifications by multiplanar reformation planes. On the contrast-enhanced images, the presence of significant CAD was defined as ≥50% stenosis.(9) The location of the aortic valve calcifications was also assessed on the contrast-enhanced MDCT images. In addition, the bicuspid aortic valves were classified based on the number and orientation of the raphe: type 0 for bicuspid aortic valves with no raphe, type 1 for bicuspid aortic valves with a single raphe and type 2 for bicuspid aortic valves with two raphes.(13) Furthermore, bicuspid aortic valve type 1 was further subdivided into left-right coronary, right-non-coronary or left-non-coronary cusps fusion based on the interposition of the single raphe between the cusps.(13)

Continuous data are presented as mean ± standard deviation or as median and interquartile range (or with the minimal and maximal values), as appropriate. Categorical data are displayed as frequencies and percentages. To control the effects of confounding factors, propensity score matching was performed using a multivariate binary logistic regression model with the type of aortic valve (bicuspid or tricuspid) as dependent variable. Cardiovascular risk factors (age, gender, hypertension, hypercholesterolaemia, diabetes and smoking), the presence of chest pain symptoms and the MDCT clinical indication were added as covariates. The Hosmer-Lemeshow goodness-of-fit test was used to check the accuracy of the model. Subsequently, propensity score 1:3 (bicuspid:tricuspid) matching was performed with replacement and a caliper of 0.22 that was twice the standard deviation of the probability.(14) Differences between patients with a bicuspid aortic valve and patients with a tricuspid aortic valve were analyzed

(9)

48

using the unpaired Student t test or the Mann-Whitney U test, as appropriate, for continuous data and with the chi-square test for categorical data. Statistical tests were 2-sided and p-values <0.05 were considered significant. All statistical analyses were performed with the SPSS software (version 20.0, SPSS Inc., Chicago, Illinois).

RESULTS

(10)

(11)

(12)

51 BAV calcification and CAD MDCT data of the aortic valve calcium and coronary atherosclerosis of the patient population are summarized in Table 3. The median Agatston coronary artery score was higher among patients with a tricuspid aortic valve compared with patients with a bicuspid aortic valve (27 [0-563] vs. 0 [0-57], respectively; p=0.003) (Table 3). In contrast, the median Agatston score and calcium volume of the aortic valve were higher in the patients with bicuspid aortic valve compared with patients with tricuspid aortic valve (510 [55-2637] vs. 0 [0-2301] and 391 [43-2028] mm3_{vs. 0 [0-1844] mm}3_{, respectively; p<0.001 for both) (Table} 3). Compared with patients with tricuspid aortic valves, patients with bicuspid aortic valve showed more frequently calcification of the aortic valve (47 [67%] compared with 68 [32%], p<0.001). The most frequent calcified spot in patients with tricuspid valves was the non-coronary cusp (90%) whereas in patients with bicuspid aortic valves, the fusion raphe (60%) was the most frequently calcified component of the valve followed by the cusp located in relation with origin of the left main coronary artery (59%).

The distribution of aortic valve calcium (calcium volume >0 mm3₎_{and Agatston} coronary artery score >0 across the age quintiles in patients with bicuspid versus tricuspid aortic valve is graphically displayed in Figure 1. In patients with bicuspid aortic valve, the calcification process of the aortic valve started at an earlier age (second quintile 35-51 years) compared with patients with tricuspid aortic valve while the coronary atherosclerosis process was similar in both groups.

Table 2. Clinical and echocardiographic characteristics

Variable Bicuspid aortic valve (n = 70)

Tricuspid aortic

valve (n = 210) p-value Systolic blood pressure (mmHg) 130 ± 20 133 ± 22 0.457 Diastolic blood pressure (mmHg) 79 ± 11 79 ± 13 0.915

Echocardiography

Left ventricular ejection fraction (%) 63 ± 15 61 ± 11 0.246 Moderate or severe aortic regurgitation 14 (20%) 10 (5%) <0.001 Moderate or severe aortic stenosis 29 (41%) 53 (28%) 0.035

Medication

β-blockers 26 (37%) 91 (43%) 0.363 Angiotensin-converting enzyme inhibitor 12 (17%) 42 (20%) 0.600 Calcium channel blocker 8 (11%) 22 (11%) 0.823 Diuretics 13 (19%) 50 (24%) 0.363 Statins 12 (17%) 65 (31%) 0.025 Aspirin 15 (21%) 52 (25%) 0.571 Oral anticoagulants 15 (21%) 51 (24%) 0.626

(13)

52

DISCUSSION

In a propensity-score matched population, the present study demonstrated by using MDCT that the aortic valve calcium load was significantly larger in patients with a bicuspid aortic valve than in patients with a tricuspid aortic valve, independently from the extent and severity of coronary artery atherosclerosis. In addition, the calcification process started at an earlier age among patients with bicuspid aortic valves than in patients with tricuspid aortic valves. The present study adds further evidence into the concept of calcific aortic valve process and coronary atherosclerosis as two distinct entities despite sharing some pathophysiological mechanisms.

Table 3. Multi-detector row computed tomography data

Variable Bicuspid aortic valve (n = 70)

Tricuspid aortic

valve (n = 210) p-value

Coronary artery disease

Agatston calcium score 0 (0-57) 27 (0-563) 0.003 Significant stenosis ≥50% 11 (16%) 51 (24%) 0.135

Aortic valve calcification

Calcium volume (mm3_{) (IQR)} _{391 (43-2028)} _{0 (0-1844)} _<0.001

Calcium volume (mm3_{) (min-max)} _{391 (0-8547)} _{0 (0-6952)} _<0.001

Agatston calcium score 510 (55-2637) 0 (0-2301) <0.001

Type of bicuspid valve

Type 0 no raphe 7 (10%) -Type 1 raphe Left-Right coronary cusp 52 (74%) -Type 1 raphe Right-Non-coronary cusp 11 (16%)

(14)

53 BAV calcification and CAD stress causing endothelial damage which enables infiltration of lipids and subsequently triggers inflammation, fibrosis and calcification.(2) However, despite these pathophysiological similarities, there are fundamental differences between the development and progression of calcific aortic valve and coronary atherosclerosis. Combined positron emission tomography and computed tomography (PET-CT) has recently provided novel insights into the exact contribution of inflammation and calcification to the development of atherosclerosis and tricuspid aortic valve stenosis. Two PET radiotracers have been recently used to visualize inflammation and calcification process of the aortic valve in patients with tricuspid aortic valve: the 18F-fluorodeoxyglucose (18F-FDG) is a glucose analogue that is up taken by cells with high metabolic requirements and is used as PET marker of macrophage activity reflecting inflammation, whereas the 18F-sodium fluoride (18F-NaF) is a PET tracer which is incorporated onto the surface of hydroxyapatite crystal, key element in the calcification process. Quantification of 18F-FDG and 18F-NaF uptake using PET-CT has demonstrated to accurately quantify the inflammation and calcification activity in the aortic valve, major vessels and coronary arteries.(18-21) To compare the calcification and inflammation activity in the aortic valve and in regions of atherosclerosis, Dweck et al assessed the calcium scores and the 18F-FDG and 18F-NaF tracer uptake (as a tissue-to-background ratio (TBR)) of the aortic valve and of the coronary arteries in 101 patients with calcific aortic valve disease.(20) Despite that 90% of these patients had coexistent calcium in the coronary arteries (coronary calcium score >0), there was only a weak correlation between the calcium scores of the aortic valve and the coronary arteries (r2_{=0.039, p=0.049). For calcification activity, the maximal 18F-NaF} uptake was higher in the aortic valve than in the coronary arteries (2.68±0.84 TBR vs. 1.68±0.49 TBR) and the correlation between valvular and coronary artery 18F-NaF uptake was weak (r2_{=0174, p<0.001).(20) In contrast, the 18F-FDG uptake} was lower in the aortic valve than in regions of atherosclerosis (1.56±0.21 TBR vs. 1.81±0.24 TBR, p<0.001).(20) These findings suggest that active calcification rather than inflammation is the predominant pathophysiological process in aortic valve calcification whereas inflammation is the more dominant process in regions of atherosclerosis. The present study provides further insights into the pathophysiological differences between aortic valve calcification and coronary atherosclerosis by studying the coronary and aortic valve calcification burden in patients with a bicuspid aortic valve. Bicuspid aortic valves tend to become calcified two decades earlier than tricuspid aortic valves and this process may be independent of the coronary atherosclerotic process. The

(15)

54

current data showed that in patients with a bicuspid aortic valve, the onset and progression of aortic valve calcification occurred earlier and independent from coronary atherosclerosis whereas in patients with tricuspid aortic valves, valvular calcification and coronary atherosclerosis increased along with increasing age.

Aortic valve calcification occurs more rapidly in bicuspid than in tricuspid aortic valves (4, 22) and it has been shown that calcific bicuspid aortic valve stenosis accounts for almost 50% of isolated aortic valve replacement.(23) In a population-based study of 642 patients with a bicuspid aortic valve (mean age 35±16 years), Tzemos et al observed that 22% of the population had at least moderate aortic stenosis at baseline and of these patients, 64% required aortic valve surgery within a mean follow up of 9±5 years.(24) Currently, it is not fully understood why the bicuspid aortic valve becomes earlier calcified than a tricuspid aortic valve.(7) Histopathologically, the calcification process of bicuspid aortic valves appears to be similar to that of tricuspid aortic valves,(25, 26) and it is therefore assumed that especially the altered mechanical and shear stress contribute to the premature calcification in bicuspid aortic valves.(1, 2, 7, 25) Compared to a tricuspid aortic valve, mechanical forces are less efficiently distributed in bicuspid aortic valves and the higher tensile stress may provoke an earlier onset and a more rapid progression of valvular calcification (2, 7, 25) Interestingly, Jermihov et al developed biomechanical models simulating tricuspid and bicuspid aortic valves and evaluated the maximal in-plane stress distribution exposed to the leaflets.(27) These models showed that the maximal computed magnitude of in-plane stress was 61% higher in the bicuspid than in the tricuspid aortic valve model. The results of the present study also point out other factors beyond cardiovascular risk profile that contribute to calcific aortic valve stenosis in patients with bicuspid aortic valve. Correlation of blood flow patterns and shear stress within bicuspid aortic valves, as recently demonstrated by 4-dimensional cardiac magnetic resonance imaging,(28) with the distribution of valvular calcifications on MDCT may provide a better understanding of the pathophysiology of aortic valve calcification in this subgroup of patients.

(16)

55 BAV calcification and CAD if the statistical approach would have led a similar number of patients to that included in the present study

FUNDING

The Department of Cardiology received research grants from Biotronik, Edwards Lifesciences, Medtronic and Boston Scientific. V. Kamperidis received a European Society of Cardiology training grant, a European Association of Cardiovascular Imaging research grant, a Hellenic Cardiological Society training grant and a Hellenic Foundation of Cardiology research grant. Alexander R. van Rosendael is supported by a research grant from the Interuniversity Cardiology Institute of the Netherlands (ICIN, Utrecht, The Netherlands).

DISCLOSURES

V. Delgado received speaking fees from Abbott Vascular. The other authors have no conflicts of interest to declare.

(17)

56

REFERENCES

1. Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373:956-966. 2. Dweck MR, Boon NA, Newby DE.

Calcific aortic stenosis: a disease of the valve and the myocardium. J Am

Coll Cardiol 2012;60:1854-1863.

3. Otto CM, Kuusisto J, Reichenbach DD, et al. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies.

Circulation 1994;90:844-853.

4. Otto CM, Prendergast B. Aortic-valve stenosis--from patients at risk to severe valve obstruction. N Engl J

Med 2014;371:744-756.

5. Chan KL, Teo K, Dumesnil JG, et al. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306-314. 6. Cowell SJ, Newby DE, Prescott RJ, et

al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

N Engl J Med 2005;352:2389-2397.

7. Michelena HI, Prakash SK, Della CA, et al. Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).

Circulation 2014;129:2691-2704.

8. Clavel MA, Messika-Zeitoun D, Pibarot P, et al. The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined Doppler echocardiographic and computed tomographic study. J

Am Coll Cardiol 2013;62:2329-2338.

9. van Velzen JE, Schuijf JD, de Graaf FR, et al. Diagnostic performance of non-invasive multidetector computed tomography coronary angiography to

detect coronary artery disease using different endpoints: detection of significant stenosis vs. detection of atherosclerosis. Eur Heart J 2011;32:637-645.

10. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am

Coll Cardiol 2014;63:2438-2488.

11. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012).

Eur Heart J 2012;33:2451-2496.

12. Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary ar ter y calcium using ultrafast computed tomography. J Am Coll

Cardiol1990;15:827-832.

13. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac

Cardiovasc Surg 2007;133:1226-1233.

14. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate

Behav Res 2011;46:399-424.

15. Paradis JM, Fried J, Nazif T, et al. Aortic stenosis and coronary artery disease: what do we know? What don’t we know? A comprehensive review of the literature with proposed treatment algorithms. Eur Heart J 2014;35:2069-2082.

(18)

17. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients.

N Engl J Med 2011;364:2187-2198.

18. Dweck MR, Jones C, Joshi NV, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation 2012;125:76-86. 19. Dweck MR, Chow MW, Joshi NV, et al.

Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol 2012;59:1539-1548.

20. Dweck MR, Khaw HJ, Sng GK, et al. Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

Eur Heart J 2013;34:1567-1574.

21. Dweck MR, Jenkins WS, Vesey AT, et al. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging 2014;7:371-378.

22. Beppu S, Suzuki S, Matsuda H, et al. Rapidity of progression of aortic stenosis in patients with congenital bicuspid aortic valves. Am J Cardiol 1993;71:322-327.

23. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation.

Circulation 2005;111:920-925.

24. Tzemos N, Therrien J, Yip J, et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008;300:1317-1325. 25. Otto CM. Calcification of bicuspid

aortic valves. Heart 2002;88:321-322. 26. Wallby L, Janerot-Sjoberg B, Steffensen

T, et al. T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves.

Heart 2002;88:348-351.

27. Jermihov PN, Jia L, Sacks MS, et al. Effect of Geometry on the Leaflet Stresses in Simulated Models of Congenital Bicuspid Aortic Valves.

Cardiovasc Eng Technol 2011;2:48-56.

28. Mahadevia R, Barker AJ, Schnell S, et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation 2014;129:673-682.

(19)