Age Dependency of Left Ventricular Diastolic Function in Pressure Overload Hypertrophy

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1 JACC Vol. 29, No. 1 January 1997: Age Deendency of Left Ventricular Diastolic Function in Pressure Overload Hyertrohy BRUNO VILLARI, MD, PHD, GIUSEPPE VASSALLI, MD,* JAKOB SCHNEIDER, MD,* MASSIMO CHIARIELLO, MD, OTTO M. HESS, MD* Nales, Italy and Zurich, Switzerland Objectives. We sought to evaluate whether age is a determinant of left ventricular (LV) ressure overload hyertrohy and whether diastolic function influenced the aging rocess. Background. The adatation of the left ventricle to chronic ressure overload is a comlex rocess of hormonal, structural and hemodynamic factors. Different resonses in the elderly atients have been described. Methods. LV bilane cineangiograhy, micromanometry and endomyocardial biosies were carried out in 57 atients with ure or redominant aortic stenosis. Patients were classified into a senior (<60 years, mean age SD years, n 35) and an elderly (>65 years; mean age 70 4 years, n 22) study grou. LV systolic function was evaluated from bilane ejection fraction and midwall fractional shortening, whereas diastolic function was assessed from the time constant of LV ressure decay, eak filling rate and the constant of myocardial stiffness. Biosy samles were examined morhometrically for interstitial fibrosis, fibrous content, muscle fiber diameter and volume fraction of myofibrils. Results. Gender distribution and the severity of aortic stenosis were comarable in the two atient grous. LV eak systolic and end-diastolic ressures were significantly higher in the elderly than in the senior grou. LV ejection fraction and midwall fractional shortening were comarable in the two grous. The time constant of relaxation and the myocardial stiffness constant were greater in the elderly than in the senior grou whereas the early eak filling rate was significantly reduced in the elderly grou. Interstitial fibrosis was increased, although not significantly ( < 0.06), and fibrous content was enhanced ( < 0.001) in elderly atients with resect to the senior grou. There was a linear correlation between age and myocardial stiffness (r 0.55, < ) and an inverse relation between age and early eak filling rate (r 0.52, < ). Conclusions. In the resence of a comarable degree of aortic valve stenosis, elderly atients (>65 years) resent with more severe LV hyertrohy than do senior atients (<60 years). Therefore elderly atients have a more ronounced imairment of LV diastolic function, whereas systolic function is reserved. Thus, there is an age deendency of LV ressure overload hyertrohy that can be exlained by the longer duration of ressure overload or an exhaustion of the adatation rocess in the elderly. (J Am Coll Cardiol 1997;29:181 6) 1997 by the American College of Cardiology The adatation of the left ventricle to chronic ressure overload is a comlex rocess of hormonal, structural and hemodynamic factors (1 3). Recently, we (1) and others (2) have shown that gender is an imortant determinant in the adatation of the left ventricle to aortic stenosis. Moreover, several studies have emhasized the imortance of structural and hemodynamic factors in the adatation of the left ventricle to chronic ressure overload (1 6). Whether age is also a determinant of left ventricular (LV) ressure overload hyertrohy is less clear. It is well known that LV function and structure are influenced by age in healthy subjects (7,8). Aging itself results in an increase in heart weight and myocyte size (9,10) as well as in an increase in the collagen content of the heart (8 11). From the Division of Cardiology, Federico II University, Nales, Italy; and *Deartment of Internal Medicine, Cardiology, Institute of Pathology, University Hosital, Zurich, Switzerland. Manuscrit received February 2, 1996; revised manuscrit received June 27, 1996, acceted Setember 23, Address for corresondence: Dr. Otto M. Hess, Division of Cardiology, University Hosital, Inselsital, 3010 Bern, Switzerland. Aging has been shown to reserve systolic function (12,13), whereas an alteration of filling atterns with a reduced early and an increased late filling rate has been reorted (7,8,14 16). Exerimental studies have documented an increased myocardial stiffness in the aging heart (16,17). These changes were similar to those induced by ressure overload hyertrohy (6,8,18 20). Thus, the urose of the resent study was to evaluate the influence of age on the adatation of the left ventricle to chronic ressure overload hyertrohy in atients with aortic stenosis. Methods Study atients. This retrosective study included 57 consecutive atients with ure or redominant aortic stenosis. Patients were classified into two grous according to their age at the time of reoerative catheterization. Grou 1 consisted of 35 senior atients ( 60 years, mean age SD 46 10) and grou 2 of 22 elderly atients ( 65 years, mean age 70 4). Patients with significant ( 30%) aortic regurgitation or with 1997 by the American College of Cardiology /97/$17.00 Published by Elsevier Science Inc. PII S (96)

2 182 VILLARI ET AL. JACC Vol. 29, No. 1 AGE AND LV PRESSURE OVERLOAD HYPERTROPHY January 1997:181 6 Abbreviations and Acronyms dp/dt first derivative of left ventricular high fidelity ressure ECG electrocardiogram LV left ventricular coronary artery disease ( 50% coronary artery narrowing) were excluded from the resent analysis. Patient characteristics and baseline hemodynamic data are summarized in Table 1. The etiology of aortic stenosis was assessed from reoerative echocardiograhy and was found to be congenital (bicusid valve) in 16 of 35 senior atients and in 11 of 22 elderly atients. A tricusid valve ( degenerative tye of aortic stenosis) was found in 19 of the 35 senior atients and in 11 of the 22 elderly atients ( NS). Cardiac catheterization. Informed consent was obtained from all atients. No differences in theraeutic regimens existed between the two grous of atients; however, all cardiovascular medication was withheld 12 to 24 h before cardiac catheterization to minimize the effect on LV hemodynamics. Premedication consisted of chlordiazeoxide, 10 mg orally, 1 h before catheterization. Right and left heart catheterization was carried out in all atients. Bilane left ventriculograhy was erformed in the right anterior oblique (30 ) and left anterior oblique (60 ) rojection at a filming rate of 50 frames/s. LV ressure was measured simultaneously with ventriculograhy by means of a Millar 7F micromanometercatheter introduced transsetally into the left ventricle by way of an 11.5F Brockenbrough guiding catheter. Central aortic ressure was measured through a fluid-filled 8F igtail catheter. All ressures were recorded at a aer seed of 250 mm/s with a standard lead of the electrocardiogram (ECG), the first derivative of LV high fidelity ressure (dp/dt) and the time markers corresonding with the digital numbers on the angiograhic images (1,4 6,20). Cardiac index was measured by the Fick method. LV angiograhic silhouettes were drawn manually from an Table 1. Patient Characteristics ( 60 years) Elderly Grou Patients (no.) NS Age (yr) Gender 21M/14F 15M/7F NS AVA (cm 2 /m 2 ) NS P (mm Hg) NS FAO (%) NS CI (liters/min er m 2 ) NS NYHA class Symtom duration (mo) NS Data resented are number of atients or mean value SD. AVA aortic valve area; CI cardiac index; P mean aortic gradient; F female; FAO aortic regurgitant fraction; M male; NYHA class New York Heart Association functional class. adequately oacified sinus beat, excluding extrasystolic and ostextrasystolic beats. All atients included in the resent analysis had sinus rhythm. LV volumes were determined on a frame by frame basis using the area-length method (21). Dimensional and volume data were filtered with use of the moving average technique (1,4 6,20). The LV ressure tracing was digitized for one cardiac cycle by an electronic digitizer, interfaced to a comuter. Pressure and volume data were analyzed every 20 ms for one cardiac cycle. End-diastole was defined as the time that corresonded to the beginning of the raid ustroke of dp/dt. LV mass was determined according to the method of Rackley et al. (22). Circumferential wall stress was calculated from a simlified version of Mirsky s thick wall model (23). Mean systolic circumferential wall stress was defined as mean stress occurring during systolic ejection. The end-diastolic short axis/wall thickness ratio was calculated and was used as a variable for assessing the tye of chamber hyertrohy (1,4 6). Assessment of LV function. Systolic function was assessed from LV bilane ejection fraction and its relation to mean systolic circumferential wall stress (1,4,5), as well as midwall fractional shortening (24). Diastolic function was evaluated from isovolumetric relaxation, eak diastolic filling rates and assive elastic roerties. LV relaxation was assessed from the time constant of isovolumetric ressure decline, which was calculated as the negative recirocal of the sloe of the linear relation between LV ressure and negative dp/dt. The isovolumetric relaxation eriod was defined as the time interval beginning immediately after maximal negative dp/dt and ending when ressure had decreased to 5 mm Hg above LV end-diastolic ressure (1,4,5,20). From this time interval, 7 to 14 oints were available for calculation of the time constant of isovolumetric ressure decline. Peak diastolic filling rate was defined as the largest value of diastolic inflow (ml/m 2 er s) during the first half (early) and the second half (late eak filling rate) of diastole. The filling hase was considered to begin 20 ms before the first frame showing the entry of unoacified blood into the left ventricle and to end at end-diastole. Instantaneous diastolic filling rates were calculated every 20 ms after mitral valve oening. To minimize error due to random noise, raw data were filtered using the fifth-grade moving average (1,4,5,20). Diastolic assive elastic roerties were determined during the eriod from minimal ventricular ressure to end-diastole. LV myocardial roerties were evaluated from the diastolic stress strain relation by using an elastic model with shifting asymtote: S ae b c or ds/d b(s c), where S LV circumferential wall stress (kdyne/cm 2 ); a elastic constant (kdyne/cm 2 ); b constant of myocardial stiffness; c asymtote of the stress-strain relation (kdyne/cm 2 ); LaGrangian strain; ds/d instantaneous myocardial stiffness (kdyne/ cm 2 ). The three constants a, b and c were determined by an iteration rocedure. The constant of myocardial stiffness is mathematically reresented by the sloe of the stress-strain

3 JACC Vol. 29, No. 1 January 1997:181 6 VILLARI ET AL. AGE AND LV PRESSURE OVERLOAD HYPERTROPHY 183 curve, and the tangent to this function is defined as the oerative instantaneous myocardial stiffness ds/d (1,4 6,20). Endomyocardial biosies. LV endomyocardial biosies were erformed with the King s College biotome, which was introduced into the left ventricle through the 11.5F Brockenbrough catheter (1,4,6,20). In each atient, two to four biosy samles were obtained from the anterolateral wall of the left ventricle. Immediately after biosy the secimens were fixed in glutaraldehyde, embedded in eon, cut in semithin sections and evaluated as reviously described (1,4,6,20). Assessment of cellular hyertrohy and interstitial nonmuscular tissue. Morhometric analyses were carried out in glutaraldehyde-fixed secimens (1,4 6,20). The following arameters were determined: 1) Muscle fiber diameter. The average fiber diameter of 100 measurements was determined at the level of the nucleus from several randomly chosen cross sections with the use of a mechanical-otical en (Kontron, Zurich, Switzerland). 2) Volume fraction of myofibrils. The myofibrils were evaluated at a magnification of 1000:1 with oil immersion and hase contrast microscoy. From four randomly chosen sections from each atient and at least three random test areas from each section, the intramyocyte volume fraction of myofibrils was determined with a counting grid with 36 intersection oints. 3) Interstitial nonmuscular tissue. Interstitial nonmuscular tissue was determined with the oint-counting system excluding areas with arterioles and erivascular tissue by using a secial ocular grid roviding 100 intersection oints, as reviously described (1,4,6,20). The term interstitial fibrosis was used for this tissue because fibrous tissue is the redominant comonent of the interstitial sace (1,4,6,20). 4) Fibrous content. Fibrous content of the left ventricle was calculated as Fibrous content LV muscle mass interstitial nonmuscular tissue divided by 100 and exressed in g/m 2. Statistics. Comarisons between the two grous were erformed by a one-way analysis of variance. If the analysis was significant, the Scheffé rocedure was alied. In all tables mean values 1 SD are given. Results Gender distribution and severity of aortic valve stenosis (aortic valve area and mean aortic ressure gradient) were comarable in senior and elderly atients. Cardiac index and the duration of symtoms were also similar in the two grous; however, functional classification according to the New York Heart Association was significantly higher in the elderly than in the senior study grou (Table 1). Hemodynamic data. Hemodynamic data are summarized in Table 2; LV eak systolic and end-diastolic ressures were higher in the elderly than in the senior grou. LV muscle mass was higher and the end-diastolic volume-mass ratio lower in the elderly. Systolic function data (Table 2). Ejection fraction and midwall fractional shortening were comarable in the elderly Table 2. Systolic Function Variables in the Two Patient Grous ( 60 year) (n 35) Elderly Grou (n 22) Heart rate (beats/min) NS LVSP (mm Hg) LVEDP (mm Hg) EDVI (ml/m 2 ) NS ESVI (ml/m 2 ) NS EF (%) NS mfs (%) NS Wth (cm) NS LMMI (g/m 2 ) EDS (kdyne/cm 2 ) NS MS (kdyne/cm 2 ) NS EDVI/LMMI EDS end-diastolic circumferential wall stress; EDVI end-diastolic volume; EF ejection fraction; ESVI end-systolic volume; LMMI left ventricular mass; LVEDP left ventricular end-diastolic ressure; LVSP left ventricular eak systolic ressure; mfs midwall fractional shortening; MS mean systolic circumferential wall stress; Wth end-diastolic wall thickness. and senior grous. The sloe and the intercet of the LV ejection fraction mean systolic wall stress relation was similar in the two grous (Fig. 1). Diastolic function data. Diastolic function data are listed in Table 3. The elderly atients with aortic stenosis had a significant rolongation of relaxation rate with a reduction in early eak filling rate and an increase in myocardial stiffness constant comared with findings in the senior atients. Structural data. Structural data are included in Table 4. Interstitial fibrosis was slightly ( 0.06) increased in the elderly atients, whereas muscle fiber diameter and volume fraction of myofibrils were of similar magnitude in the two atient grous. Fibrous content and the fibrous content enddiastolic volume ratio were both increased in the elderly with resect to the senior atients. Correlations. There was a linear relation between age and LV end-diastolic ressure (r 0.28, 0.05; Fig. 2). There was a linear relation between age and the time constant of LV Figure 1. Left ventricular ejection fraction mean systolic wall stress relation in senior (solid circles) and elderly (oen squares) atients with aortic stenosis. No differences were observed between the sloes and the intercets of the two regression lines.

4 184 VILLARI ET AL. JACC Vol. 29, No. 1 AGE AND LV PRESSURE OVERLOAD HYPERTROPHY January 1997:181 6 Table 3. Diastolic Function Variables in the Two Patient Grous ( 60 years) (n 35) Elderly Grou (n 22) Relaxation (ms) Filling PFR1 (ml/m 2 er s) PFR2 (ml/m 2 er s) NS Passive elastic roerties b Data resented are mean value SD. b constant of myocardial stiffness; PFR1 and PFR2 eak filling rate during the first and the second half, resectively, of diastole; time constant of left ventricular ressure decay. Figure 2. Regression line and 95% confidence limits of the relation between age and left ventricular (LV) end-diastolic ressure in atients with aortic stenosis. ressure decay (r 0.27, 0.05), the early eak filling rate (r 0.52, 0.001), the late eak filling rate (r 0.28, 0.05) and the constant of myocardial stiffness (r 0.55, 0.001) (Fig. 3). Discussion The major finding of the resent study is that there is an age deendency of LV diastolic function in ressure overload hyertrohy, whereas systolic function is not affected by aging. These alterations in diastolic function can be exlained by changes in LV structure. Age and LV structure in aortic stenosis. Myocyte hyerlasia and hyertrohy have been observed in the senescent heart in resonse to various hemodynamic overloads (25,26). Furthermore, Olivetti et al. (25) noted in human hearts at autosy that cardiac hyertrohy in the elderly heart is characterized at the cellular level by a marked increase in both muscular and interstitial tissue. However, they observed that the exansion of the myocyte and nonmyocyte comartments of the myocardium occurs in such a way so that the roortions between these two structural constituents remain essentially unchanged (hysiologic hyertrohy) (27). In the resent study, we comared two age grous of atients with aortic stenosis and similar degree of ressure overload and we observed a significant increase of fibrous tissue in the elderly grou together with a slight increase in interstitial fibrosis and Table 4. Morhometric Data in the Two Patient Grous ( 60 years) (n 35) Elderly Grou (n 22) IF (%) FC (g/m 2 ) MFD ( ) NS VFM (%) NS FC/EDVI Data resented are mean value SD. EDVI end-diastolic volume index; FC fibrous content; IF interstitial nonmuscular sace; MFD muscle fiber diameter; VFM volume fraction of myofibrils. muscle fiber diameter. At the macroscoic level, Olivetti et al. (25) reorted that the aging heart is characterized by the resence of ventricular dilation and normal wall thickness. However, chamber size was only indirectly measured from ventricular wall area (25,28). Olivetti et al. (25) included in their study (autosy data) hyertrohic hearts of different etiology (only 3 of 15 hearts had senile aortic calcifications). In the resent study, elderly atients with aortic stenosis had more severe and more concentric LV hyertrohy with resect to that of atients in the senior grou with the same degree of aortic stenosis. Thus, it is ossible that elderly atients with aortic stenosis have a larger increase of LV mass in the resence of similar degree of cellular hyertrohy (25,26,28). Age and LV function in aortic stenosis. The Baltimore Longitudinal Study on Aging (12,13) has demonstrated that systolic ejection erformance in healthy elderly atients is reserved at rest and during exercise by use of the Frank Starling mechanism. In the resent study a similar observation was made because LV end-diastolic ressure was also higher in the older age grou. However, LV systolic ejection erformance was maintained (ejection fraction and its relation to mean systolic stress (Fig. 1) as well as midwall fractional shortening were similar in the senior and elderly atients with aortic stenosis). Functional class was significantly higher in the elderly than in the younger atients. Several studies (28 32) have demonstrated that the aging heart is comarable to a state of normotensive overload with structural alterations of the ventricular wall. However, we cannot comletely rule out that the effect of aortic stenosis on systolic function is suerimosed on the effect of aging on diastolic function and left ventricular mass (5,8). Moreover, Lakatta and coworkers (8,30) have comared the aging heart and the hyertensive heart. It is well known that the aging heart has a rolonged relaxation and a reduced early diastolic filling in the resence of increased stiffness (7 9,30,31). However, age itself does not affect LV systolic erformance excet in the resence of suerimosed stress (32). Similar to findings in hysiologic diastolic dysfunction, we observed a rolongation of relaxation, a decrease in early eak diastolic filling and an increase in myocardial stiffness (Table 3). The occurrence of diastolic

5 JACC Vol. 29, No. 1 January 1997:181 6 VILLARI ET AL. AGE AND LV PRESSURE OVERLOAD HYPERTROPHY 185 dysfunction is exlained by LV hyertrohy ( rolongation of relaxation) and alteration of the collagen network. In fact, the increase in LV mass is resonsible for the rolongation of relaxation (4,5). The rolonged relaxation and the increased nonuniformity (4,5,7) observed in atients with aortic stenosis (33) aears to be resonsible for the reduction of early diastolic filling as seen in the resent study. Finally, the increased fibrous content and fibrous content/end-diastolic volume ratio are resonsible for the increase in myocardial stiffness observed in the elderly atient grou (4,6,20). As a consequence of the increased myocardial stiffness, LV enddiastolic ressure was increased desite a similar end-diastolic volume in the senior and elderly grous (Table 2). This finding is in agreement with data from Downes (34), who noted an increase in end-diastolic ressure in the resence of a normal end-diastolic volume in a grou of elderly healthy subjects. Clinical imlications. It was recently shown (35) that the revalence of critical aortic stenosis in an unselected elderly oulation is 3%. Because the life exectancy of the general oulation will increase significantly in the next 20 years, the number of atients with aortic stenosis will increase as well (36). Thus, a clear definition of the structure-function interlay in elderly atients with aortic stenosis reresents an imortant issue. Moreover, it is well established that aortic valve relacement is ossible with good results even in the elderly (37). There are two ossible exlanations for the adatation of the left ventricle to aortic stenosis in the elderly. The first mechanism may be the duration of the ressure overload, Figure 3. Physiologic diastolic dysfunction. A close relation between age and the time constant of relaxation, early and late eak filling rate as well as the constant of myocardial stiffness was found in atients with aortic stenosis. LV left ventricular. which is longer in the elderly grou. However, the similar symtom duration (Table 1) in the two grous of atients seems to contradict this hyothesis. The second mechanism may be an exhaustion of the adatation rocess in elderly atients. Because of the adative nature of the aging heart there is a suerimosition of the ressure overload hyertrohy and the hysiologically occurring diastolic dysfunction observed in elderly atients. However, we cannot rule out that the age-associated increase in the imedance of the left ventricle to ejection fraction (38) may have layed some role in the develoment of diastolic dysfunction in the elderly atients with aortic stenosis. Conclusions. In the resence of a similar degree of aortic stenosis, elderly atients have more severe LV hyertrohy than do senior atients ( 60 years). This effect on LV hyertrohy causes the occurrence of diastolic dysfunction, whereas systolic function is reserved in both senior and elderly atients. Thus, an age deendency of LV ressure overload hyertrohy can be observed that is exlained by the longer duration of the ressure overload or the exhaustion of the adatation rocess of the left ventricle, or both, in the elderly.

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