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  • Slowing of Mitral Valve Annular Calcium in Systemic Hypertension by Nifedipine and Comparisons with Enalapril and Atenolol

    Federico Cacciapuoti, MD, Nicolb Perrone, MD, Rosalba Diaspro, MD, Domenico Galzerano, MD, Salvatore Gentile, MD, and Bartolomeo Lapiello, MD

    Mitral annular calcium (MAC) is a condition that often occurs in patients with systemic hyperteu sion. To evaluate the effectiveness of nifedipine in preventing MAC, 223 patients with systemic hy- pertension of recent onset and without MAC were selected and randomly enrolled in 3 groups: group l(76 patients) received nifedipine; group 2 (72 patients) received enalapril; and group 3 (75 pa tients) received atenolol. After 5 years, these treatments significantly reduced systolic (p ~0.001) and diastolic (p ~0.05) blood pressure (BP) in 3 treated groups. M-mode echocardiom phy revealed MAC only in 2 patients in the nifedi- pine group (2.6%), in 13 in the enalapril group (Is%) and in 15 in the atenolol group (20%). The degree of MAC was mild (

  • M-mode, 2-dimensional, Doppler and color Doppler echocardiography. For color Doppler, a commercially available instrument by Advanced Technology Labora- tories (Ultramark 9), with a phased-array 3 MHz trans- ducer was used.

    Echocardiographic examination: Two-dimensional echocardiographic examination was performed as de- scribed.8 Parasternal short-axis view at the midventricu- lar level was used to derive the M-mode measurements of left ventricular end-systolic and end-diastolic dimen- sions. Ventricular septum and free left ventricular wall thicknesses were also measured by this approach. Mean left ventricular wall thickness was calculated as half the sum of the septal and free wall thickness. Left ventricu- lar hypertrophy was diagnosed when this mean value was Zl3 mm. The parastemal long-axis approach, at the aortic root level, was used to obtain M-mode left atrial dimensions. Left atria1 enlargement was defmed as left

    atria1 size of >4.0 cm, as measured from the leading edge of the posterior aortic wall to the leading edge of the posterior left atrial wal1.9

    Detedonofmi&alamu&calcification:Mitralvalve apparatus was examined by M-mode, 2-dimensional and color techniques. For the latter, parastemal long-axis and apical 4-chamber views were used. MAC was defined by the M-mode technique as dense echoes behind the posterior leaflet of the mitral valve, moving parallel and anterior to the endocardium of the posterior left ven- tricular wall, and best detected with a sweep horn the aortic root to the left ventricular cavity (Figure 1). The degree of MAC was measured in millimeters at its widest point behind the echoes originating from the mi- tral valve and was defined as mild when 5 nnn10 Finally, to detine the characteris- tics of diastolic mitral flow and to evaluate the presence of mitral valve regurgitation, Doppler and color Doppler

    FlGURE 1. W?, bode echocardii performed at level of the mitral leaflets; rim, 2dimeasional echocardiography by apical 4-chamber approach. An increased bri&tness and thickness of the mitral amudus (ANN.) due to calcinosis (CALC) is evident. AML q atrial mitral leaflet: ANNULD q annulus; IVS = interventricular septum; LA q Left atrium; LV = Left ventikle; M q mitral valve; RV = fight veatrike.

    FlGURE 2. Mean values r 1 SD and statisti- cal significance of the systolic and diastolic -presoure reamled in basal condictioes and in 3 treated groups at final evaluation. ATEN. = atenolol group; BASAL = basal vaC ues; ENAL = enalapril group; NIF. q nifedi- pine WP.


    x p(e.65 m p ( e&31

    WR NlF. EtR. ATEN.


  • transmitral flow velocities during systole and diastole were recorded from the apical 4-chamber approach, with the sample volume placed at level of the mitral leaflets.

    Patient mbmbation: After basal examination, se- lected patients were randomly enrolled in 3 groups: group 1 (82 patients) received nifedipine orally (20 mg twice daily); group 2 (76 patients) was treated with the angiotensin-converting enzyme inhibitor enalapril (20 mg once daily); and group 3 (79 patients) was treated with the P-blocker atenolol(lO0 mg once daily). The di- uretic chlorthalidone (12.5 mg/day) was added when the single antihypertensive drug was inadequate in reducing high systemic BP levels. This drug was necessary in 8 patients in group 1, in 7 in group 2 and in 6 in group 3. All patients underwent the same biochemical, elec- trocardiographic and echocardiographic examinations at each return visit, performed every 6 months and lasting 5 years. During the study, 5 patients in group 1 (6%), 3

    in group 2 (3.9%) and 4 in group 3 (3.8%) withdrew because of adverse effects. In addition, 1 patient in the nifedipine group and 1 in the enalapril group died from unrelated disease. . . Stab&cd analysis: Values in systemic BP, left ven- tricular dimensions, left ventricular wall thickness, left atrial size and biochemical data were expressed as mean I!I 1 SD. These means were compared with those of bas- al measurements, using the Students t test for unpaired data. MAC was identified and its percent incidence was calculated in 3 groups. Results obtained were compared using the &i-square test and differences were considered significant at p

  • RESULTS Two hundred twenty-three patients completed the

    study: 76 from the nifedipine group, 72 from the enala- pril group and 75 from the atenolol group.

    Hemodynamk and biochemical data: Three differ- ent treatments significantly reduced (p 5 mm) in the re- maining 8 patients in the enalapril group and in the other 9 in the atenolol group (Table I).

    Con@kalions induced by mitral znsudw cakinosis: Pulsed and color Doppler echocardiography revealed a diastolic mitral flow turbulence in all 30 patients with MAC (Figure 1). Left atria1 dimensions (Table I) in- creased along with the degree of MAC. In fact, at the end of trial, the mean value of left atrial size in patients without MAC was 3.67 f 0.34 cm; in those with mild MAC this value was 4.77 k 0.33 cm (p

  • oventricular block in 2 patients with severe MAC in the enalapril group, and atrial fibrillation in 3 of those with this degree of MAC in the atenolol group.

    DISCUSSION The significant reduction in high systemic BP in-

    duced by. 3 treatments and lasting for 5 years certainly reduced the theoretical incidence of MAC, which one would expect if patients were untreated. Nevertheless, the smaller incidence of MAC recorded in the nifedi- pine group compared with those recorded in the other 2 groups may be dependent on the specific action mecha- nism of the nifedipine. Currently, no peculiar protective effect of the calcium antagonists on the mitral annulus is known. However, MAC is a degenerative lesion simi- lar to the age-dependent arterial calcinosis described by Fleckenstein et al.11-13 These investigators demonstrated that the calcium antagonist verapamil was able to pro- vide long-term protection of the arterial wall against age-induced calcium overload. Furthermore, Lichtlen14 and Knorr and Kazda,r5 reported similar results with nifedipine. We agree that the calcium antagonist nifedi- pine may interfere with the pathogenetic process induc- ing MAC by means of a specific anticalcinotic mecha- nism, different from its antihypertensive effect.

    Acknowledgment: We are grateful to Eduardo Pel- legrino for technical assistance.

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    general population-based sample (the Framingham Study). Am J Cardiol 1983;51: 1375-1378. 2. Rob&s WC, Perloff JK. Mitral valvulx disease: a clinic-pathological survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972;71:939T-915. 3. Cacciapuoti F, D&pro R, DAvino M, Lama D, Coppola F, Bianchi U, Var- ricchio M. Calcifications of the mitral annulus as a marker of atherosclerosis in the elderly. Arch Gerontol Geriafr 1991;(suppl 2):339-344. 4. Roberts WC, Dangel JC, Bulkley BH. Non-rheumatic valvular cardiac disease: A clinicopathologic survey of 27 different condictions causing valwlar dysfunctions. In: Brest AM, ed. Cardiovascular Clinics. vol 5. No. 2. Philadelphia: FA Davis, 1973:333446. 5. Wailer BF, Roberts WC. Cardiovascular disease in the elderly. An analysis of 40 necmscopy patients aged 90 years or over. Am J Cardiol 1983;51:4031121. 6. Fleckenstein A, Frey M, Fleckenstein-Gmn G. Antihypertensive and arterial an- ticalcinotic effects of calcium antagonist. Am .I Cardiol 1986;57:1D-1OD. 7. Murphy MV, &riven AJ, Dollcry CT. Role. of n&=&pine in the treatment of hypertension. Br Med J 1983;287:257-262. 8. Tajik AJ, Seward JB, Hagler DJ, Mair DD, Lie JT. Twc-dimensional real time ultrasonic imaging of the heart and great vessels: technique, image orientation, stmc- ture, identification and validation. Mayo Clin Proc 1978;53:271-303. 9. Feigenbaum H. Echocardiography. 3rd ed. Philadelphia: Lea & Febiger, 1981:173. 10. Mellino M, Salcedo E, Lewer HM, Vasudevan G, Kramer JR. Echccardio- graphic-quantified severity of mitral ammlus calcification: prognostic correlation to related hemcdynamic, valvular, rhythm, and conduction abnormalities. Am Heart J 1982;103:322-325. 11. Fleckenstein A, Frey M, Fleckenstein-Gmn G. Protection by calcium antago- nists against experimental arterial calcinosis. Ix Pyorala K, eds. Secondary Pre- vention of Coronary Heart Disease. Workshop of the Internat Society and Fe&a- tion of Cardiology, Titisee, Oct. 1983. Stuttgart: G Thieme Verlag, 1983:1l%122. 12. Fleckenstein A, Fleckenstein-Gmn G, Frey M, Zom J. Future directions in the use of calcium antagonists. Am J Cardiol 1987;59:177B-187B.


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