THE ANALYSIS OF ATHEROSCLEROTIC CAROTID INVOLVEMENT IN SYMPTOMATIC CORONARY PATIENTS WITH MITRAL/AORTIC ANNULUS CALCIFICATION

ORIGINAL ARTICLES THE ANALYSIS OF ATHEROSCLEROTIC CAROTID INVOLVEMENT IN SYMPTOMATIC CORONARY PATIENTS WITH MITRAL/AORTIC ANNULUS CALCIFICATION Silvia Georgiana Ionescu, Irina Popescu 2, Adina Ionac, Sorin Pescariu, Stefan Iosif Dragulescu REZUMAT Introducere: Markerii preclinici de ateroscleroza sunt considerati a fi implicati si in calcificarea de inel mitral/aortic, caracterizata prin depunere de calciu si lipide la nivelul scheletului fibros. Scop: Sa determinam daca prezenta calcificarii de inel mitral/aortic (studiu ecocardiografic) se asociaza cu boala coronariana (studiu angiografic) si/sau boala carotidiana (studiu ecografic). Material si metode: Am inclus 2 pacienti coronarieni (66,20 ± 8, ani) cu indicatie de evaluare angiocoronarografica (angina, modificari ECG sau test de stres pozitiv), care au fost evaluati ecocardiografic si eco carotidian. Cuantificarea leziunilor coronariene s-a facut prin scorul Gensini, a leziunilor caortidiene folosind un scor de placa, iar pentru calcificarile de inel valvular s-au utilizat definitiile din guideline. Rezultate: Intregul lot analizat se caracterizeaza printr-un profil de risc cardiometabolic ridicat. Prevalenta bolii coronariene a fost de 2,4%, cu o mediana a scorului Gensini de 26. Pacientii cu stenoza carotidiana semnificativa (peste 50%) si calcificare de inel mitral/aortic au avut scoruri Gensini mai mari decat cei fara calcificare: 4, ±,96 vs. 26,62 ± 8,06, p < 0,05; respectiv 4,08 ± 8,04 vs. 26.69 ± 2,, p < 0.0. Pacientii cu ocluzie carotidiana, indiferent de localizarea calcificarii inelului valvular, au avut un scor Gensini mai mic decat cei cu stenoza carotidiana severa, p < 0,0. In randul subiectilor cu ocluzie carotidiana, numai cei cu calcificare de inel aortic au avut valori crescute ale presiunii pulsate: 85,6 ±,6 mmhg vs. 62,50 ±,5 mmhg, p < 0,0. Nu am gasit corelatii semnificative statistic intre scorul de carotida-scorul Gensini-calcificarile de inel, in functie de prezenta sindromului metabolic sau a factorilor de risc cardiometabolic. Concluzii: Studiul nostru dovedeste asocierea intre calcificarea de inel mitral/aortic cu leziunile aterosclerotice coronariene si carotidiene, in randul unei populatii selectate. Identificarea stenozei carotidiene la pacientii coronarieni cu calcificare de inel mitral/aortic ar putea sa ofere o mai buna stratificare a riscului, si implicit o mai buna conduita terapeutica. Cuvinte cheie: calcificare de inel mitral/aortic, boala coronariana, ateroscleroza carotidiana ABSTRACT Introduction: Preclinical atherosclerotic markers are also risk factors for mitral/aortic annulus calcification, characterized by lipid and calcium deposits within its fibrous skeleton. Aims: To determine if the presence of mitral/aortic annulus calcification (echocardiographic study) is associated with significant coronary artery disease (angiographic study) and/or carotid artery disease (echographic study). Material and methods: We included 2 coronary patients (66.20 ± 8. years) with indication for angiography (angina pectoris or ECG changes or positive stress testing) that were also evaluated by using echocardiography and carotid ultrasonography. The quantification of coronary lesions was made using the Gensini score, for the carotid lesions we used a plaque score and the calcific annulus lesions were defined according to the Guidelines. Results: The entire population analyzed was characterized by the presence of pro-atherogenic cardio metabolic profile. The prevalence of coronary artery disease was 2.4%, with a median of the Gensini Score of 26. Patients with significant carotid stenosis (>50%) and mitral/aortic annulus calcification had higher Gensini scores vs those without annulus lesions: 4. ±.96 vs. 26.62 ± 8.06, p < 0.05; respectively 4.08 ± 8.04 vs 26.69 ± 2., p < 0.0. Subjects with carotid occlusion, mo matter the site of annulus calcification, had a Gensini score lower than those with significant carotid stenosis: p < 0.0. Among people with carotid occlusion, only those with aortic annulus calcification had high value of the pulsed pressure: 85.6 ±.6mmHg vs. 62.50 ±.5 mmhg, p < 0.0. There were no significant correlations between the carotid score-the Gensini score and annulus calcification based on the metabolic syndrome or on the cardiometabolic risk components. Conclusions: our study proves the association between mitral/aortic annulus calcification with atherosclerotic lesions at the coronary and carotid site, in a group of selected patients. Identification of carotid stenosis among coronary patients with annulus calcification might allow a more accurate risk stratification with better therapeutical decisions. Key Words: mitral/aortic annulus calcification, coronary artery disease, carotid atherosclerosis Department of Cardiology, Victor Babes University of Medicine and Pharmacy, Timisoara, 2 Institute of Cardiovascular Disease, Timisoara Correspondence to: Silvia Georgiana Ionescu, Department of Cardiology, Victor Babes University of Medicine and Pharmacy, 2 E. Murgu Sq., Timisoara, Tel. +40-29-09565 Email: m_horheta@yahoo.com Received for publication: Mar., 20. Revised: Jun. 4, 20. INTRODUCTION Preclinical atherosclerotic markers are also risk factors for mitral/aortic annulus calcification, characterized by lipid and calcium deposits within its fibrous skeleton. Framingham Heart Study has proven that those with echocardiografic evidence of mitral annulus calcification have had higher Odds ratio for cerebral stroke (2.0), cardiovascular event- 4 TMJ 20, Vol. 6, No. - 4

fatal coronary event, non fatal coronary event requiring hospitalization or revascularization procedure (.5), overall cardiac death after 6 years follow up (.6). The nature of these vascular events has proven to be embolic. A question arises: could mitral annulus calcification be a direct source of embolism or is it a marker of a clinical status associated with thrombembolism: age, arterial hypertension, hypercholesterolemia, diabetes mellitus, chronic peripheral arterial disease, atrial fibrillation and heart failure? Cardiovascular Health Study showed that the severity of annulus calcification had a direct correlation with the presence of cerebral infarction (MRI study): OR=.24. 2 Future studies will have to clarify the underlying mechanisms and, if we can slow the process of annulus calcification, would we be able to reduce the incidence of stroke? In the ARIC (Atherosclerosis Risk in Communities Study) cohort, carotid atherosclerotic plaque detection was a marker of advanced atherosclerosis and had a strong predictive value for cerebral stroke. In light of this evidence, we made the following hypothesis: the presence of mitral annulus calcification could be a sign of high susceptibility for the development of atherogenic vascular processes, due to similar aggregation of cardiovascular risk factors. AIM Our study aims to determine whether the presence of mitral/aortic annulus calcification is associated with significant coronary or carotid artery disease. MATERIAL AND METHODS Patient selection: we enrolled 92 patients at high cardiovascular risk, which were evaluated using the echographic method, prior to angiography. The inclusion criteria were as follows: all patients were admitted to the Institute of Cardiovascular Disease, Timisoara, with indication of angiography for signs and symptoms suggestive for coronary artery disease; coronary artery disease diagnosed by ECG changes or positive exercise stress testing; preserved left ventricular ejection fraction; sinus rhythm. Exclusion criteria: acute myocardial infarction (defined by creatin-kinase and troponin elevation), congenital heart disease, heart failure NYHA III, IV. We thus included 2 coronary patients with indication for angiography. All patients have signed the informed consent. The study was approved by the Ethic Committee at The Institute of Cardiovascular Disease Timisoara. Data collection: we have used the clinical charts for data collection: demographic data, anthropometric data, anamnesis, clinical examination and paraclinical data: metabolic profile, hemodynamic profile: systolic and diastolic blood pressure, pulsed pressure. The echocardiographic evaluation was made using a General Electrics Vingmed Ultrasound System, a Vivid and a Vivid 9 machine, with MS4 and MS5 transducers. Annulus calcifications were analyzed by 2D transthoracic echo, parasternal long axis and short axis view and apical views. They were defined according to the ACC/AHA guidelines 2006 and EAE/ASE guidelines. 4,5 In view of the recommendations of The American Society of Echocardiography 2006, we performed the measurements for the evaluation of the carotid intimae-media thickness and we defined carotid atherosclerosis through the plaque score: 0=no calcific lesions; = calcific. atherosclerotic plaques, no stenosis; 2 = stenosis < 50%; = stenosis > 50%; 4 = carotid occlusion. 6 The angiography was done using a Siemens Coroskop standard machine, in order to detect coronary atherosclerotic lesions. We calculated the Gensini Score for each enrolled patient, and we applied this score in relationship with the coronary lumen narrowing, according to the reference. Statistical analysis The data were collected and electronically depositated using The Epiinfo Program, 200, version 6. The statistical analysis was done with The SPSS program, 200, version 8. Results were considered statistically significant for p < 0.05; strong statistical significance was considered for a p < 0.0. For parametric data we applied the t student test; for the non-parametrical data we applied the Mann-Whitney test and the Kruskal-Wallis test; and for the categorical data we used the chi squared test. RESULTS Mitral annulus calcification was detected in cases out of the 2. The proportion of aortic annulus calcification was 56.%. (Table ) The prevalence of mitral and aortic annulus calcification was maximum, 0% respectively 80% among patients with carotid score of 4. Carotid stenosis higher than 50% was present in 25 patients out of 50 with annular calcification (50%). 5 out of 20 patients with annulus calcification had a carotid score of 4 (25%). The variation of the Gensini score in the presence of aortic or mitral annulus calcification in patients with a carotid score of and 4: the prevalence of coronary artery disease defined by the angiographic criteria was Silvia Georgiana Ionescu et al 5

Table. The frequency of annulus calcification and the carotid plaque score. Carotid score Annulus calcification Total 0 2 4 Total Absent Present Ao Mi Ao Mi 5 8 60 24 2 5 9 9 2 2 6 48 0 2.4%. The Gensini score had a median of 26. Relation between the Gensini score and the carotid score The mean Gensini Score was significantly higher among those with carotid artery occlusion (score 4) compared to those without carotid lesions (score 0): 6. ±. vs 9. ± 2., p < 0.0. (Fig. ) Figure. The Gensini score and carotid plaque score. 28 44 50 20 245 Relation between the Gensini score - the carotid score - aortic and mitral annulus calcification In subjects with carotid stenosis higher than 50%, the mean Gensini score was significantly higher in those with mitral annulus calcification (4.08 ± 8.04 vs 26.29 ± 2., p < 0.0) or aortic annulus calcification (4. ±.96 vs 26.62 ± 6.08, p < 0.05) compared to those without degenerative annular lesions. (Fig. 2) No matter the site of the annulus calcification (aortic or mitral), subjects with carotid occlusion (score 4) have had a significantly lower Gensini score compared to those with carotid score of : 6. ±.4 vs. 4. ±.96, p < 0.0; 6.4 ± 2.85 vs. 4.08 ± 8.04, p < 0.05. The cardiovascular profile in the presence of carotid occlusion and annulus calcification a. Metabolic profile: the entire population analyzed was characterized by the presence of proatherogenic cardio metabolic profile: total cholesterol= 209.5 ± 5.9 mg/dl, LDLc =.5 ± 55. 56 mg/dl, triglycerides = 4.88 ± 4.9 mg/dl, HDLc =.00 ± 9.20 mg/dl, fasting plasma glucose = 59.8 ± 4.58 mg/dl. We found no statisticaly significant diferences between those with carotid score 4 and 0, p > 0.05. furthermore, there was no significant relationship between the metabolic syndrome and aortic or mitral annulus calcification, p>0.05. b. Hemodynamic profile: the subjects with carotid occlusion had a hypertensive profile characterized by a mean SBP of 5 mm Hg ± 22.6 mmhg, and a mean DBP of 89.8 mm Hg ± 5.22 mmhg. The entire group was characterized by a mean value of the pulsed pressure of 68.8 ± 9. mm Hg. The histogram of frequency distribution showed a high prevalence of the pulsed pressure above 60mm Hg: 90 out of 2 cases. The behaviour of mean pulsed pressure among the subgroups of subjects with degenerative annulus lesons was higher among those with aortic annulus calcification: - aortic valve sclerosis: mean PP = 5.2 ±.9 mm Hg; - mitral valve fibrosis: mean PP = 6.2 ±.5 mm Hg; - mitral annulus calcification: mean PP = 56.5 ± 20.4 mm Hg; - aortic annulus calcification: mean PP = 66.6 ± 5.0 mm Hg; - atherosclerotic plaques on the ascending aorta mean PP = 49.2 ± 8.68 mm Hg. The variation analysis of the mean PP value in patients with annulus calcification and carotid lesions has found statistically signifficant differences only in the group with carotid score of 4 and aortic annulus calcification: 85.6 ±.6 mm Hg vs. 62.50 ±.5 mm Hg, p < 0.0. (Tables 2,) DISCUSSION Our study clearly proves the association between vascular atherosclerosis and degenerative lesions found at the mitral/aortic annulus site. The prevalence of annulus calcification was maxim among patients with more severe coronary lesions. Furthermore, in the presence of significant carotid artery stenosis, the coronary lesions were more severe in patients with annulus calcification vs those without. An interesting observation refers to the quantitative analysis of the coronary lesions, expressed as the Gensini score: in patients with carotid stenosis higher than 50% and annulus calcification, the coronary lesions were more severe than in patients with carotid stenosis only. 6 TMJ 20, Vol. 6, No. - 4

Table 2. The behaviour of pulsed pressure in the presence of mitral annulus calciciation Carotid Score PP (M+/-DS) Mitral annulus calcification + Mitral annulus calcification - p 0 62.4+/-9.94 6.86+/-2.8 >0.05 66.52+/-8.98 66.88+/-.05 >0.05 2 0+/-0 55.00+/-2.2 >0.05.6+/-2.5 0.+/-2.9 >0.05 4 8.4+/-20.4 80.00+/-.2 >0.05 Table. The behaviour of pulsed pressure in the presence of aortic annulus calciciation Carotid score PP (M+/-DS) Ao annulus calcification + Ao annulus calcification - p 0 0.00 +/- 5.00 56.00+/-20.4 >0.05 65.+/-29.69 6.6+/-5.0 >0.05 2 40.,00+/- 0 0.00+/-0 >0.05 0.42+/-.8.92+/-29.4 >0.05 4 85.6+/-.6 62.50+/-.5 <0.0 First of all, the coexistence of carotid atherosclerosis and mitral annulus calcification could bring to light new information in regard to the incidence and severity of coronary artery disease. 8 Second of all, atherosclerosis is a systemic disease: the distribution of the atherosclerotic lesions is most defiantly heterogeneous. A question arises at this point: which site is more protected from atherosclerosis? The brain or the myocardium? Rosengarten B. et al, by corelating the stenosis of each coronary artery (as a uni-/bi-/tri- vessel disease) with carotid artery stenosis, found no association whatsoever. 9 Only the severity of coronary artery disease assese as the Gensini score has been proven to correlate with cerebravascular disease. Third of all, the patients with mitral annulus calcification are at high risk for arterial calciffications in other vascular teritories, and are therefore at high risk for fatal/nonfatal cardiovascular event. 0, Further research in the field of calcification, both vascular and valvular, could offer new solutions for cardiovascular risk stratification and management. Roger J.M.Rennenberg consider vascular calcification as the result of a complex interaction between stimulating proteins-bmp-2, RANKL and inhibiting ones-matrixglc proteins, BMP-, A-fetuin, thus launching new therapeutic insights. 2 Fourth of all, the relation between valvular annulus calcification and atherothrombotic cardiovascular disease has not been well established. In MESA Study, mitral annulus calcification was statistically significant associated with atherosclerosis risk factors: age, diabetes mellitus, body mass index, especially in women and independently of etnic origins. It seems of intrest the fact that we found a signifficant association between pulsed pressure and aortic annulus calcification. It is well known and proven the value of pulsed pressure as a marker of cardiovascular risk, along with aortic annulus calcification. 4-6 As cerebral hemoragy represents 5% of the total number of cerebral strokes in Europa, Safar s conclusion remains valid: independently of systolic blood pressure, diastolic blood pressure and mean blood pressure, pulsed pressure is an important cardiovascular risk factor needed to be taken into account especially in hypertensive patients undegoing treatment. Agmon et colab. underline the pathognetic similarities between atherosclerosis and pulsed pressure; he is also the one to issue the hypothesys that aortic valve sclerosis and annulus calcification are atherosclerotic-like processes. 8,9 Althoug our study can not prove the implication of traditional cardiovascular risk factors in the genesis of mitral/aortic annulus calcification, the metabolic and hemodynamic profile of the patients justifies an agressive management of modifiable risk factors, in order to reduce the global cardiovascular risk and, obviously, the number of cardiovascular events. Silvia Georgiana Ionescu et al

CONCLUSIONS Our study proves the association between mitral/ aortic annulus calcification with atherosclerotic lesions at the coronary and carotid site, in a group of selected patients. The echografic detection of annulus calcification might improve the algorhythm for the evaluation of the arterial function and therefore, the management of the cardiovascular risk. Identification of carotid stenosi among coronary patients with annulus calcification might allow a more accurate risk stratification with better therapeutical decisions. The limitations of our study regard the selection criteria. Our results should be interpreted in a given context: we included in our study only high risk patients, that were evaluated ECHO before the angiography. It s highly possible for the prevalence data to be overestimated; but our proven associations reflect once again the natural history of atherosclerosis. REFERENCES. Singh JP, Evans GC, Levy D et al. Prevalence and clinical determinants of mitral, tricuspid and aortic regurgitation (the Framingham Heart Study). Am J Cardiol 999;8(6):89-902. 2. Rodriguez CJ, Bartz TM, Longstreth WT et al. Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults. The Cardiovascular Health Study. J Am Coll Cardiol 20;5:22-280.. Burke GL, Evans GW, Riley WA et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 995;26:86-9 4. Bonow RO, Carabello BA, Chatterjee K et al. ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48;e-e48. 5. Baumgartner H, Hung J, Bermejo J et al. EAE/ASE RECOMMENDATIONS Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;0,-25. 6. Roman MJ, Naqvi TZ, Gardin JM et al. American Society Echocardiography Report. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology. Vasc Med 2006;():20-.. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 98;5():606-0. 8. Amasyali B, Kose S, Aytemir K et al. Is carotid atherosclerosis more important in patients with mitral annular calcification than in those without? Jpn Heart J 2004; 45(4):60-6. 9. Rosengarten B, Grebe M, Muller A et al. Severity of coronary artery disease but not degree of coronary stenosis is correlated to cerebrovascular reactivity. Cerebrovasc Dis 2009;28():290-29. 0. Movahed MR, Saito Y, Ahmadi-Kashani M et al. Mitral annulus calcification is associated with valvular and cardiac structural anormalities. Cardiovasc Ultrasound 200;5:4-26. Jassal DS, Tam JW, Bhagirath KM et al. Association of mitral annular calcification and aortic valve morphology: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study. Europ Heart J 2008; 29(2):542-54. 2. Rennenberg JM, Schurgers LJ, Kroon AA et al. Arterial calcifications. J Cell Mol Med 200; 4(9):220-220.. Kanjanauthai S, Nasir K, Katz R et al. Relationship of mitral annular calcification to cardovascular risk factors: the Multi-Ethnic Study of Atherosclerosis(MESA). Atherosclerosis 200;2(2):558-62. 4. Darne B, Girerd X, Safar M et al. Pulsatile versus steady component of blood pressure:a cross-sectional analysis and a prospective analysis on cardiovascular mortality. Hypertension 989;(4):92-400. 5. Benetos A, Safar M, Rudnichi A et al. Pulse pressure: a predictor of long term cardiovascular mortality in a French male population. Hypertension 99;0(6):40-5. 6. Millar JA, Lever AF, Burke V et al. Pulse pressure as a risk factor for cardiovascular events in the MRC mild hypertension trial. J Hypertens 999,(8):065-2.. Safar ME. The arterial system in human hypertension. In: Swales JD Editor. Textbook of hypertension 994. London: Wiley-Blackwell Scientific, 85-02. 8. Agmon Y, Khandheria BK, Meissner I et al. Independent association of high blood pressure and aortic atherosclerosis: a population based study. Circulation 2000,02():208-9 9. Agmon y, Khandheria BK, Meissner I et al. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol 200;8():82-4. 8 TMJ 20, Vol. 6, No. - 4