Effects of sustained-release isradipine on left ventricular anatomy and function in systemic hypertension

SYSTEMIC HYPERTENSION

Effects of Sustained-Release lsradipine on Left Ventricular Anatomy and Fun&ion in Systemic Hypertension Massimo Bignotti, MD, Giovanni Gaudio, MD, Giovanna Gorini, MD, Orlando Rinaldi, MD, Anna M. Grandi, MD, and Achille Venco, MD

Wlth use of digitized lKmode echocardiograms and 244our noninvasive ambulatory blood m sure (BP) monitoring, the effects of chronic treatment with sustaineckelease isradipine on left ventWuiar (LV) morphology and function in hypertensive patii were evaluated. We selected l2 patients with IN hypettrophy and nom~~l LV diiolic diameter. Ecbcardio#amsand24-hour BP monitoring were performed after 2 weeks of placebo and after 6 manths of oral treatment with sustaine&ekase isradipine (5 mg once daily). Therapy sl@flcantiy reduced BP without changes in all patients inheartrate.LVmassm and peak lengthening rate of LV d&meter, index of diastolic function, increased in all, with nom& izatien in 7 of the 9 with basal diastolic impairment. Peak shortening rate of LV diameter, index of systolic function, was normal in all patients at basal evaluation and did not me after therapy. Reduction in LV mass significantly (p ~0.05) car in average -our and NbtdWltiithedecrease daytime systolic and diastolic BP. Sustainecke lease isradlpine administered once daily is an e+ fective antihypertensive agent; the dnrg also irr duces tqpession of LV hypertrophy, with significant improvement in LV diastolic function and no deterioratii in systolic function. (Am J Cardiol1993;72:1201-1304)

From the Department of Internal Medicine and Medical Therapy, University of Pavia, Ospedale di Circolo, Varese, Italy. Manuscript received March 17, 1993; revised manuscript received and accepted July 1, 1993. Address for reprints: Massimo Bignotti, MD, Divisione di Medicina Genemle, Ospedale di Circolo, Viale Borri 57,2 1100 Varese, Italy.

any antihypertensive drugs have proven effective in reversing left ventricular (LV) hypertrophy,l,* which is an independent risk factor for cardiovascular morbidity and mortality.3-5 Both development and regression of LV hypertrophy inlluence LV function, primarily affecting diastolic performance, which is also significantly load-dependent.6,7 Isradipine is a new dihydropyridine calcium antagonist and its effectivenessas an antihypertensivedrug has been demonstratedin many clinical controlled trial~.~-‘* Studies on rats have demonstratedthat the drug is able to reverse LV hypertrophy,‘* but few and controversial data are now available concerning its effectson LV mass and function in hypertensive patients.‘>15These studies have been performed with a twice daily administration of the drug. We have evaluated LV responseto chronic treatment with sustained-releaseisradipine once daily in hypertensive patients with LV hypertrophy.

M

METHODS Study group: From among the patients consecutively evaluated at our hypertension clinic we selected 14 subjects with mild to moderate essential hypertension (stage I or II, World Health Organization) and LV hypertrophy (LV mass index >130 s/m* in men, and >llO g/m* in women and normal LV diastolic diameter). Other selection criteria were: M-mode echocardiogram of good quality and reproducibility; absenceof clinical, radiologic, electrocardiographic or echocardiographic evidence of heart failure, myocardial infarction, angina pectoris, or congenital or valvular heart disease; and absenceof systemic diseasesthat could induce changes in LV structure and function. Patients were judged to have essential hypertension on the basis of history, physical examination and laboratory tindings. The ethical committee of our hospital approved the study and all patients gave informed consent. Protocok Previous treatmentswere discontinued for 23 weeks; patients were then treated with placebo (1 tablet once daily) for 2 weeks. After this period patients underwent 24-hour noninvasive ambulatory blood pressure (BP) monitoring. Only the 12 patients (6 men and 6 women, mean age 46 + 8 years) with daytime BP >140/90 mm Hg were admitted to active treatment with 5 mg of sustained-releaseisradipine once daily in the morning. Ambulatory BP monitoring was repeatedafter 6 months of treatment. Echocardiographic examination was performed before and after placebo and after 6 months.of therapy. SUSTAINED-RELEASEISRADIPINEIN HYPERTENSION 1301

TABLE I Systolic and Diastolic Blood Pressure (mm Hg) and Heart Rate (beats/min) Parameters from 24-Hour Blood Pressure Monitoring After Placebo and Drug Treatment

Systolic BP 24-hour Daytime Nighttime Diastolic BP 24-hour Daytime Nighttime Heart rate 24.hour Daytime Nighttime ‘p <0.005; tp
Values are expressedas mean 2 BP = blwd pressure

Placebo

Treatment

145 + 9 149 t 7 128 -+ 8

132 +- 10t 135 + 12* 115 + lot

97 -t 4 98 2 5 84 f 5

86 + 6t 88 T 7* 76 t 8t

68 f 6 72 r 4 65 + 6

70 f 5 74 2 6 63 f 5

SD.

methods: The M-mode echocardiograms were recorded under 2-dimensional control, at a paper speedof 50 mm/s, with a simultaneouselectrocardiogram; The tracings were evaluated by 1 operator unaware of the patient’s clinical course, who digitized 4 consecutive cardiac cycles of each echocardiogram, as originally described by Gibson and Brown,16 using a Numosonic 2205 graphic tablet. The IBM personalcomputer processeddigitized data, averaging the 4 cardiac cycles, and from tracings obtained using an INTEL processor 80286, we evaluated the following parameters: LV end-diastolic and end-systolic diameters, end-diastolic thickness of interventricular septum and posterior wall, LV mass17and LV mass index, peak shortening rate of LV diameter in systole, peak lengthening rate of LV diameter in diastole, and end-systolic wall stress.18 The parameterswere compared with normal values obtained from 200 normal adults evaluated at our laboratory. The reproducibility of echocardiographic measurementswas tested in our laboratory on 20 normal subjects (each examined 3 times) with the same ultra-

Placebo LV diastolic diameter (mm) LV mass index (g/m*) Peak shortening rate (s-1) Peak lengthenirig rate (s-1) End-systolic wall stress (dynes/cm*)

49 131 2.3 3.2 59

r + f k f

6 15 0.3 0.8 6

Treatment 47 106 2.4 4.8 56

e k k + +

*p <0.005; tp
sonic technique; the sameoperator digitized 4 consecutive cardiac cycles of each echocardiogram.The coefficients of variation were as follows: LV end-diastolic diameter 0.4%; septal thickness 3.2%; posterior wall thickness 3.4%; peak shortening rate 1.1%; and peak lengthening rate 4.7%. Ambulakny blood pressurrt m Ambulatory BP monitoring was performed with a portable automated TakedaTM 2420 and simultaneous24-hour heart rate monitoring was obtained. The unit was set to take readingsevery 15 minutes during the daytime (6:00 A.M. to 11:OOP.M.) and every 30 minutes at night. The following parameterswere evaluated:24-hour, daytime and nighttime systolic and diastolic BP, and heart rate. Statistical analysis: Statistical evaluation of the results was performed using paired Student’s t test and Pearson’slinear correlation coefficients.A p value ~0.05 was considered statistically significant. RESULTS Hemodynami=parametenr (Table I): The treatment significantly (p
60

FlBURE 1. Left venbWult~ mass index In men before (I after treatment (T). Bmken line, upper IimR of normal. VOLUME 72

1

6 19* 0.4 0.9t 6

140

QOk-----T THE AMERICAN JOURNAL OF CARDIOLOGY

Parameters after Placebo and

g/m2

g/m2 I

1302

TABLE II Echocardiographic Drug Treatment

B

T

FmuRE2.Leftv~ mass index in women before aldafterbeatnKd(T).cRoken/ine,upperllmiiofnormd. DECEMBER 1,1993

(B)

treatment, although no information is available on wall thickness before therapy. A reduction in afterload plays an important role in reversing LV hypertrophy. In our study the decreasein LV mass significantly correlated with reduction in 24-hour and daytime systolic and diastolic BP In previous studies15,21-23 no correlation was found between reduction in LV mass and BP decrease, probably becausecasual BP measurementswere used, which are less reliable than ambulatory monitoring in assessingpressureload. In addition to BP decrease,other factors probably contribute to the regression of LV hypertrophy induced by calcium antagonists,namely an anticatecholamineaction, a reduced amount of calcium available for protein synthesis,and an interference with the renin-angiotensin system.24-27 With regard to LV function, peak shortening rate, an index of systolic performance,was normal in all patients at basal evaluation and did not change after regression B of LV hypertrophy,as found by similar studies using dif3. Peak lengthening rate of left ventlicular diameter Flwl ferent kinds of drugs.22~28~29 before (6) and after treatwnt 0. Broken /he, lower limit Peak lengthening rate, index of LV relaxation, inof nomlal. creasedin all patients after treatment.This improvement is probably due both to reduction in afterload and to Baseline B data: As a consequence hypertrophy regression. In fact, increased afterload of the selection criteria, LV diastolic diameter was nor- affectsLV diastolic performance, slowing active relaxamal (~56 mm) and LV mass increasedin all patients; 9 tion.7 Myocardial morphologic changesin hypertensive subjects had asymmetric septal hypertrophy (septal/ hypertrophy negatively inlluence diastolic function30; posterior wall thickness ratio >1.3) without systolic ante- many studies have also found an improvement in LV rior motion of the mitral valve. Peak lengthening rate diastolic function after regressionof hypertrophy due to was reduced (~3.6 s-l) in 9 patients, and peak shorten- an effective antihypertensive treatment.1,22,23,29,31 The beneficial effect of isradipine on LV diastolic ing rate was normal (>1.9 s-i) in all. The echocardiofunction is probably related also to the changesinduced graphic parametersdid not change after placebo. by the drug on myocardia! structure. In fact, in spontaChanges in left venbicukir mass and function after therapy (Table II): After 6 months of treatment neously hypertensive rats, isradipine as well as nifediLV massdecreasedin all patients, with normalization in pine and verapamil induced hypertrophy regression and 10 subjects(Figure 1 and 2). Regressionof LV hypertro- reduction of myocardial collagen content.32-34 In a previous study15with isradipine, a decreasein phy was due to a reduction in septal and posterior wall thickness, without any change in LV diameter. After LV mass was found after 5 months of treatment and therapy,septal/posteriorwall thickness ratio was cl.3 in diastolic improvement only after 9 months, whereas in all the patients. The percent reduction in LV mass sig- our study the 2 events are both detectable after 6 nificantly (p ~0.05) correlated with percent decreasein months. This discrepancy could probably be ascribedto 24-hour (r = 0.60) and daytime systolic BP (r = 0.64) the difference between the diastolic parameters used. and in 24-hour (r = 0.61) and daytime diastolic BP Torok and co-workers15used Doppler-derived indexes, (r = 0.59). Peaklengthening rate increasedin all patients, which mainly reflect ventricular filling and are more senwith normalization in 7 of the 9 subjectswith basal dia- sible to various factors such as heart rate and filling volstolic impairment (Figure 3). End-systolic wall stress ume. Peak lengthening rate precedesearly peak mitral and peak shortening rate did not change after treatment. flow velocity and is more directly related to active processesof relaxation within the myocardial wall.35 DISCUSSION In conclusion, in our patients sustained-releaseisradThe study demonstratesthe efficacy and safety of ipine once daily appearsto be an effective antihypertensustained-releaseisradipine as an antihypertensiveagent. sive agent. The drug, like other calcium antagonists,is With regard to LV morphology, our results demonstrate able to induce regression of LV hypertrophy, with imthat the drug, as well as other calcium antagonists,2~*9~20 provement in diastolic performanceand no deterioration is able to reverseLV hypertrophy without any changein in LV systolic function. LV diameter and with a decrease in septal thickness more pronounced than that in the posterior wall. This may be due to the binding radius of the septum, greater 1. Clementy J, Dulhoste MN, Bordier P, Lartigue MC, Pans N. Traitement antihypettenseur et regression de l’hypatrophie ventriculaire gauche. Etude critique. than that of the LV free wall, which makes the septum Arch Mal Coeur 1990;83:3%43. more sensible to changesin afterload. 2. Dtiof B, Pemwt K, Hansson L. Reversal of left ventricular hypemophy in Our results are in keeping with some previous stud- hypertensive patients. A me&analysis of 109 treatment studies. Am J Hypertens 10. ies with isradipine14J5;however, Mayer et all3 found no 3.19925:95-l Straw RE. Stmchual and functional adaptation of the chronically overloaded changes in posterior wall thickness after 6 months of heart in essential hypertension. Am Heart J 1987; 114948-957. SUSTAINED-RELEASEISRADIPINEIN HYPERTENSION 1303

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