E xperimental1,2 and autoptical 3 data support the hypothesis

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1 Incremental Value of Ultrasonic Tissue Characterization (Backscatter) in the Evaluation of Left Ventricular Myocardial Structure and Mechanics in Essential Arterial Hypertension Vitantonio Di Bello, MD; Davide Giorgi, MD; Enrica Talini, MD; Giulia Dell Omo, MD; Caterina Palagi, MD; Maria Francesca Romano, PhD; Roberto Pedrinelli, MD; Mario Mariani, MD Background Ultrasonic backscatter parameters were analyzed in hypertensive patients and divided into groups according to both severity of left ventricular hypertrophy (LVH) (group A: no LVH [n 52]; B: mild to moderate LVH [n 55]; and C: severe LVH [n 10]) and left ventricular geometry (normal geometry [n 44]; concentric remodeling [n 8]; concentric hypertrophy [n 25]; and eccentric hypertrophy [n 40]). Methods and Results We studied 117 male, essential hypertensive patients and 19 normotensive, age-matched (40 5 years), healthy subjects who served as controls. Ambulatory and office blood pressure measurements were taken and 2-dimensional Doppler echocardiography and ultrasonic myocardial integrated backscatter (IBS) were performed. A group from the hypertensive study population (n 16) was observed after a period of pharmacological antihypertensive treatment to determine the behavior of backscatter parameters in relation to eventual regression of left ventricular mass (LVM). The cyclic variation index (CVIs) of the backscatter signal at the septum level was grouped according to each LVM level and was (controls), (group A), (group B), and (group C) (P 0.001). CVI septum values grouped according to left ventricular geometry were (normal geometry), 12 7 (concentric remodeling), 7 11 (concentric hypertrophy), and (eccentric hypertrophy) (P 0.01). Follow-up data demonstrate a significant reduction of LVM after therapy, as well as a significant increase in CVIs toward normal values. Conclusions Hypertensive patients with higher LVM had the worst prognosis; in fact, those patients had the most significant CVI alterations. Regression of LVM subsequent to chronic pharmacological therapy induces a normalization of ultrasonic backscatter parameters. Ultrasonic tissue characterization (backscatter) analysis could allow early identification of patients at risk of developing complications of hypertensive cardiopathy. (Circulation. 2003;107:74-80.) Key Words: ultrasonics hypertension hypertrophy echocardiography E xperimental1,2 and autoptical 3 data support the hypothesis that the pressure-volume overload that characterizes essential arterial hypertension, by itself or via interaction of complex humoral factors such as the renin-angiotensin-aldosterone system, could cause an increase in intramyocardial fibrosis with alteration of collagen/myocytic content ratio. 4 Systemic arterial hypertension represents a major cause of cardiovascular morbidity and mortality; the predictive value of echocardiographic 5 evidence of left ventricular hypertrophy (LVH) for subsequent cardiovascular morbidity and mortality is well established. Abnormalities of left ventricular diastolic function have been found in patients affected by arterial hypertension and LVH. 6 In the present study, we evaluated 1) the capability of integrated backscatter (IBS) to detect alterations in myocardial structure in both static and dynamic modality; 2) the incremental diagnostic and prognostic value of IBS in comparison with conventional echocardiography; and 3) the potential parallel effects of a chronic antihypertensive therapy on left ventricular mass (LVM) and tissue characterization parameters. Methods Study Population Exclusion criteria were malignant hypertension, heart failure, cardiomyopathy or valvular heart disease, diabetes and/or obesity, coronary artery disease, and renal and connective tissue disease. Furthermore, after repeated casual blood pressure measurements and 24-hour blood pressure monitoring, patients were selected on the basis of their LVM as shown by echocardiography. On the basis of these criteria, 117 male, never-treated, essential hypertensive patients with good hemodynamic compensation and absent to severe LVH were recruited. This group of patients was compared with a group of 19 carefully age- and sex-matched normotensive subjects. Received July 19, 2002; revision received September 17, 2002; accepted September 23, From the Cardiac and Thoracic Department, University of Pisa (V.D.B., D.G., E.T., G.D.O., C.P., R.P., M.M.), and Sant Anna School of Advanced Studies (M.F.R.), Pisa, Italy. Correspondence to Vitantonio Di Bello, MD, Cardiac and Thoracic Department, University of Pisa, Via Paradisa 2, Pisa, Italy. dibellov@ifc.cnr.it or vdibello@med.unipi.it 2002 American Heart Association, Inc. Circulation is available at DOI: /01.CIR C 74

2 DiBello et al Value of Ultrasonic Tissue Catheterization 75 The study was approved by the Ethical Committee of the University of Pisa. Conventional Doppler-Echocardiography Conventional echocardiographic studies were performed with a digital Philips Sonos 5500 echograph (S4 fusion imaging probe, 2 to 4 MHz) in a fundamental imaging mode. Left ventricular diameter and septum and posterior wall thickness were measured according to the procedures of the American Society of Echocardiography. 7 LVM was calculated with Devereux s formula (Penn convention) and normalized for body surface area (LVM bs ) and height 2,7 (LVM h ). Relative wall thickness was also measured according to standard formula. Midwall fractional shortening of the left ventricle was calculated according to Shimuzu s model. 8 Meridional end-systolic stress was calculated using the standard formula. After pulsed Doppler, transmitral flow velocity parameters were evaluated, including peak E, peak A, E/A ratio, mitral acceleration time, mitral deceleration time, and isovolumic relaxation time. All heart rates were corrected by Bazett s formula. Subgroups Analysis Hypertensive patients were distributed into 3 balanced subgroups. Group A comprised patients with LVM bs values within the normal ranges of our laboratory (LVM bs 124 g/m 2 ) (n 52), group B comprised patients with LVM bs values between 125 and 174 g/m 2 (n 55), and group C comprised patients with LVM values 175 g/m 2 (n 10) (Table 2). On the basis of the relationship between relative wall thickness and LVM, 9 the total patient population (n 117) was then divided into 4 different groups (Table 3). The groups consisted of hypertensive patients with normal relative wall thickness and LVM (normal geometry; n 44; 37%); patients with concentric remodeling (n 8; 7%); patients with concentric hypertrophy (n 25; 21%); and patients with eccentric hypertrophy (n 40; 35%). A group of 16 hypertensive subjects selected from the hypertensive study population, all of whom had a high degree of LVH, underwent a new echocardiographic examination after 1 year of chronic homogeneous pharmacological therapy (angiotensinconverting enzyme inhibitors plus Ca 2 antagonist). All patients have achieved good blood pressure level control during this period. Acoustic Densitometry A commercially available Acoustic Densitometry software package (Philips) was used on a Sonos 5500 (Philips) for the quantitative analysis of integrated backscatter. A detailed methodology for IBS analysis has been described previously. 10,11 Statistical Analysis Continuous variables were expressed as mean SD. Intra-group differences were evaluated using an unpaired Student s t test. Upper and lower 95% confidence limits for each variable were calculated with the use of a 2-tailed Student s t test distribution using the formulas mean (2.042 SD) and mean (2.042 SD), respectively. Relations between IBS and 2-dimensional echocardiographic measurements were expressed in terms of linear multiple regression analysis. A paired t test was applied to compare the same patients before and after therapy. A probability value 0.05 was considered significant. Results Age ( versus years) and body mass index ( versus kg/m 2 ) were similar in hypertensive and normotensive patients. Average daytime ambulatory blood pressure was 145 7/93 4 versus 118 6/76 5 mmhg (P ) for hypertensive and normotensive patients, respectively, and casual blood pressure averaged /99 6 versus /79 6 mmhg(p ). Average heart rate was comparable in the 2 groups ( in hypertensive versus in normotensive subjects). Septum and posterior wall TABLE 1. Conventional Echo-Doppler Parameters Hypertensive Normotensive Parameters Mean SD Mean SD P EDD, mm NS FS, % DS th,mm DPW th,mm RWT MFS, % LVM bs, g/m LVM h, g/m Peak E, m/sec NS Peak A, m/sec E/A ratio VTI E, cm NS VTI A, cm VTI E/VTI A macctc NS mdectc IVRTc NS EDD indicates end-diastolic diameter; FS, fractional shortening; DS th, diastolic interventricular septum thickness; DPW th, diastolic posterior wall thickness; RWT, relative wall thickness; MFS, midwall fractional shortening; VTI E, velocity time integral of E; VTI A, velocity time integral of A; macctc; mitral acceleration time corrected for heart rate; mdectc, mitral deceleration time corrected for heart rate; IVRTc, isovolumic relaxation time corrected for heart rate; and NS, not significant. thickness were greater in hypertensive subjects, whereas the end-diastolic diameters were comparable between groups. LVM bs was significantly higher in the hypertensive group (Table 1). Left ventricular end-diastolic diameter and relative fractional shortening overlapped in the 2 groups (Table 1) and were in the normal range. Midwall fractional shortening was significantly lower in hypertensive patients, whereas meridional end-systolic stress was significantly higher (Table 2). The E/A ratio was significantly higher in normotensive subjects (Table 1). The A velocity time integral was significantly higher in hypertensive patients than in controls; as a result, the E/A velocity time integral ratio was significantly lower in hypertensive patients than in controls (Table 1). Subgroups Analysis In the subgroup with no LVH, the cyclic variation indexes (CVIs) of both the septum and posterior wall at the medium and proximal levels were significantly lower than in controls. The E/A ratio, however, did not differentiate between hypertensive subjects and controls (Figure 1). In presence of a moderate degree of LVH, the CVIs for both the septum and posterior wall were significantly lower in comparison with both hypertensive patients with no LVH and controls. An increase in LVM bs produced a decrease in CVI values in the group of hypertensive subjects with severe LVH (Table 2). CVI results for both the septum and the posterior wall, segregated by LVM bs level and left-ventricular geometry, are given in Table 2 and Table 3, respectively.

3 76 Circulation January 7/14, 2003 TABLE 2. Subgroup Analysis by LVM Values Controls (n 19) Hypertensive With LVM 124 g/m 2 (n 52) Hypertensive With LVM between 125 and 174 g/m 2 (n 55) Hypertensive With LVM 175 g/m 2 (n 10) Parameters Mean SD Mean SD Mean SD Mean SD P by ANOVA SAP, mm Hg 123.3* DAP, mm Hg 78.2* MAP, mm Hg 93.8* MFS, % * mess, 10 2 dynes/cm * LVM bs, g/m Peak E, m/sec Peak A, m/sec * E/A ratio * IBI MSi,% IBI PSi,% IBI MPWi,% NS IBI PPWi,% CVI MS,% * CVI PS,% * CVI MPW,% * CVI PPW,% * SAP indicates systolic blood pressure; DAP, diastolic blood pressure; MAP, mean arterial pressure; mess, meridional end-systolic stress; IBI MSi, diastolic backscatter value at mid-septum (expressed as percent of pericardial interface IBS value, assigned 100%, to normalize myocardial signal in each patient by pericardium ); IBI Psi, diastolic backscatter at proximal septum (by pericardium); IBI MPWi, diastolic backscatter value at medium posterior wall (by pericardium); IBI PPWi, diastolic backscatter at proximal posterior wall (by pericardium); CVI MS, cyclic variation index at mid-septum level; CVI PS, cyclic variation index at proximal septum level; CVI MPW, cyclic variation index at medium posterior wall thickness; and CVI PPW, cyclic variation index at proximal posterior wall thickness. Other abbreviations as in Table 1. *Significant comparison between 1 and 2. Significant comparison between 1 and 3. Significant comparison between 1 and 4. Significant comparison between 2 and 3. Significant comparison between 2 and 4. Significant comparison between 3 and 4. The diastolic values of IBS at both the septum and posterior wall levels, indexed for pericardial reflection, showed a significant increase only in patients with the severe form of LVH (Table 2, Figure 2). Midwall fractional shortening was significantly lower in patients with severe LVH or in those with concentric and eccentric LVH (Table 3). Meridional end-systolic stress showed a significant increase in patients with severe LVH, including subjects with concentric and eccentric LVH (Table 2 and Table 3). When considering the sensitivity of the 2 tests in discriminating hypertensive patients from control subjects through individual analysis, we found that the E/A ratio was only able to discriminate 34% (40/117) of hypertensive patients from controls, whereas individual analysis for CVI at both the septum and posterior wall levels was able to discriminate 70% (80/117; P 0.01) of hypertensive patients from controls (Figure 1). Figure 1. Individual plots of CVI at mid-septum (A) and of E/A ratio (B) for controls (contr.) and hypertensive subjects (hypert.). Follow-Up Results LVM was significantly lower after 1 year of treatment because of a significant reduction of septum and parietal thickness. Fractional shortening remained unchanged after 1 year, but midwall fractional shortening significantly increased. Left ventricular diastolic function demonstrated by transmitral flow analysis showed a slight but significant

4 DiBello et al Value of Ultrasonic Tissue Catheterization 77 TABLE 3. Subgroup Analysis by Ganau s Method Controls (n 19) Hypertensive With Normal LVM (n 44) Concentric Remodeling (n 8) Concentric Hypertrophy (n 25) Eccentric Hypertrophy (n 40) Parameters Mean SD Mean SD Mean SD Mean SD Mean SD P by ANOVA SAP, mm Hg 123.3* DAP, mm Hg 78.2* MAP, mm Hg 93.8* * MFS, % * # # mess, 10 2 dynes/cm ** # LVM bs, g/m ** # Peak E, m/sec Peak A, m/sec * E/A ratio * IBI MSi,% NS IBI PSi,% NS IBI MPWi,% NS IBI PPWi,% NS CVI MS,% * CVI PS,% * CVI MPW,% * CVI PPW,% * Abbreviations as in Table 1 and Table 2. *Significant comparison between 1 and 2. Significant comparison between 1 and 3. Significant comparison between 1 and 4. Significant comparison between 1 and 5. Significant comparison between 2 and 3. Significant comparison between 2 and 4. #Significant comparison between 2 and 5. **Significant comparison between 3 and 4. Significant comparison between 3 and 5. Figure 2. Histograms of IBS value at the proximal septum level for the hypertensive patients grouped according to LVM values compared with controls (for statistical significance see text). IBI psi indicates IBS diastolic value at the proximal septum level (indexed by pericardium); LVM i, left ventricular mass indexed by body surface area. improvement. Importantly, after 1 year, we observed a trend toward normalization in IBS parameters, in particular in the CVIs at all sampled levels (Table 4, Figure 3). Relationship Between the Quantitative Backscatter Analysis Data, the Echocardiographic Parameters, and Blood Pressure CVIs at both medium and proximal levels of the septum and posterior wall were unrelated to the left ventricular fractional shortening and diastolic functional parameters. Systolic arterial pressure values were closely linked to both CVIs (mid-septum: r 0.44, P 0.003; midposterior wall: r 0.58, P 0.005). CVIs at both the septum and posterior wall levels showed an inverse, significant correlation with LVM bs (septum: r 0.50, P 0.005; posterior wall: r 0.53, P 0.004) and with meridional end-systolic stress (septum: r 0.51, P 0.005; posterior wall: r 0.52, P 0.004). Furthermore, CVIs at both the septum and posterior wall levels showed a significant correlation with midwall fractional shortening (septum: r 0.46, P 0.005; posterior wall: r 0.53, P 0.001) (Table 5). A stepwise multivariate regression analysis has shown a significant relationship (multiple r 0.79; r ; P 0.02) between the CVI at

5 78 Circulation January 7/14, 2003 TABLE 4. Follow-Up Parameters Hypertensive Before Treatment (n 16) Hypertensive After 1 Year of Pharmacological Treatment (n 16) Parameters Mean SD Mean SD Paired t Test (P) SAP, mm Hg DAP, mm Hg MAP, mm Hg MFS, % mess, 10 2 dynes/cm LVM bs, g/m Peak E, m/sec Peak A, m/sec E/A ratio CVI MS,% CVI PS,% CVI MPW,% CVI PPW,% IBI MSi,% IBI PSi,% IBI MPWi,% NS IBI PPWi,% NS Abbreviations as in Table 1 and Table 2. the mid-septum level after 1 year of therapy subtracted from its basal value (dependent variable) and the values of systolic arterial pressure (P 0.05), LVM (P 0.05), meridional end-systolic stress (P 0.05), and midwall fractional shortening (P 0.06) after 1 year year subtracted from their basal values (independent variables). Discussion Left ventricular hypertrophy has been divided arbitrarily into 3 phases: an adaptive phase and a compensatory phase, in both of which relief of increased load is associated with reversal of contractile dysfunction, and a pathological phase, in which contractile function is abnormal and removal of excessive load is not accompanied by return to normal contractile function. A recent autopsy study in human hearts 12 showed that collagen volume fraction increases in parallel with the severity of LVH. The most important pathological findings were LVH (cardiac myocyte hypertrophy) and interstitial, perivascular, and replacement fibrosis (myocardial apoptosis), the interaction of which play an important role in the determination of left ventricular systolic-diastolic performance. End-diastolic IBS values indexed for IBS value of pericardium at both the septum and posterior wall levels are significantly higher than controls only in severe form of LVH, which suggests the presence of inappropriate hypertrophy with disproportionate connective tissue growth. CVI, which is the expression of the intrinsic myocardial contractility, is also altered when the LVM is in a normal range or when there are initial alteration of left ventricular geometry (geometric remodeling) present. This parameter shows a progressive alteration with the increase of LVM and with concentric or eccentric LVH. The fact that there is no correlation with fractional shortening but there is a correlation with meridional end-systolic stress and with midwall fractional shortening is an expression of the intrinsic functional correlates of CVI with both afterload parameters and with indexes of midwall function. CVI reduction observed in hypertensive patients with a normal fractional shortening could be considered an early, independent index of abnormal intrinsic contractility. Figure 3. Plots of values for left ventricular mass, IBS value at mid-septum indexed for pericardium, and CVI at midseptum before (LVMBS, IBIMSI, and CVISM, respectively) and after 1 year of antihypertensive therapy (LVMBS1, IBIMSI1, and CVISM1, respectively) measured from individual patients.

6 DiBello et al Value of Ultrasonic Tissue Catheterization 79 TABLE 5. Correlation Matrix by Pearson s Method LVM bs DS th DPW th SAP MAP mess MFS CVI PS (P 0.005) (P 0.01) (P 0.001) (P 0.001) (P 0.005) (P 0.005) CVI MS (P 0.003) (P 0.02) (P 0.003) (P 0.001) (P 0.001) (P 0.001) CVI PPW (P 0.001) (P 0.01) (P 0.001) (P 0.001) (P 0.001) (P 0.001) CVI MPW (P 0.004) (P 0.01) (P 0.005) (P 0.001) (P 0.004) (P 0.001) MFS, % (P ) (P 0.001) (P 0.002) (P 0.001) (P 0.001) (P ) LVM bs (P 0.001) (P 0.001) (P 0.001) (P 0.001) (P 0.001) (P ) R and P values are showed for each correlation. Abbreviations as in Table 1 and Table 2. Methodological Considerations about Ultrasonic Backscatter Analysis We acknowledge that the CVI formula, which involves dividing a quantity expressed in a logarithm domain by another logarithm, could present some mathematical problems, but its intuitive approach has induced us to utilize it. The measurements of cyclic variation IBS based on the difference between average peak and average nadir value are more robust, 13 and it is likely that this approach will improve our results when applied in our laboratory. Several authors have demonstrated the potential inaccuracy of a peak-to-peak measurements, which are applied in the present study, and of the magnitude of cyclic variation, not taking in account the dependence of the apparent magnitude on the time delay of cyclic variation of myocardial backscatter. 14 In our echocardiographic images, the examined structures (septum and posterior wall) were nearly perpendicular to the insonifying ultrasonic beam, and thus we obtained a good signal-to-noise ratio and minimized problems associated with tissue anisotropy Collagen and Acoustic Myocardial Properties Different structural components of the myocardium can influence its acoustic properties under different physiological and pathological conditions. Collagen is the primary determinant of both scattering and attenuation of myocardial tissue; a linear relationship was found between IBS and hydroxyproline content in autopsied human hearts, with fibrotic changes associated with remote myocardial infarction. 18 Furthermore, a significant direct correlation was found between collagen content analyzed by myocardial biopsy and regional echo amplitude. 19 Myocardial scattering intensity depends directly on myocyte cellular size; the microstructural arrangement of myocardial cells embedded in a collagen matrix may provide a sufficient local acoustic impedance mismatch to account for the scattering from normal myocardium. 11 Alterations of Ultrasonic Backscatter Parameters in Essential Hypertension Despite the lack of histopathological (endobyopsy) data, which is not ethically acceptable in this type of subject, some hypotheses could be made to explain the alterations in the acoustic properties of the myocardium in hypertension. The increase of the myocardial collagenic network that is realized in hypertension (interstitial, perivascular, and replacement fibrosis) could determine, in systole, an increase in scattering, thereby causing a reduction of its normal cyclic variation. Moreover, the pressure-volume overload in hypertension, which causes a stimulus on the myocardium, could determine a change in the orientation, structure, or geometry of both the muscle fibers and the collagen network, thus influencing the acoustic properties of the tissue. Comparison of Ultrasonic Backscatter Parameters With Transmitral Doppler Echocardiography The analysis of the transmitral flow velocity is largely used in the evaluation of global diastolic function. In the pressurevolume overload of hypertensive patients, an alteration of the passive end-diastolic phase (increased stiffness) was observed. The E/A ratio is inversely related to LVM, and it is lower in the concentric hypertrophy group, thereby selecting the patients with the worst cardiovascular prognosis. Our study, which confirms a previous videodensitometric observation, demonstrated that CVI is better able to differentiate between normal and hypertensive patients than is the E/A ratio. 20 Myocardial Midwall Mechanics and Ultrasonic Backscatter Parameters The significant relationships between midwall fractional shortening, meridional end-systolic stress, and CVI lends credence to the hypothesis that the CVI data could be considered as an index of intrinsic myocardial contractility that is relatively insensitive to the afterload conditions. In this respect, we note that concentric LVH shows a higher impairment of myocardial intrinsic function, both with a lower CVI at septum and posterior wall levels and with a lower midwall fractional shortening, in comparison with other geometric subgroups. What Really Adds the Ultrasonic Tissue Characterization to the Analysis of Hypertensive Heart? After 1 year of appropriate and homogeneous antihypertensive therapy, we observe a significant reduction in LVM (mainly an expression of myocytic compartment) and a decrease of IBS at septum level (mainly an expression of myocardial collagen volume resetting), whereas CVI shows a significant increase in comparison with basal values (expression of intrinsic contractility improvement). These preliminary follow-up data clearly show that ultrasonic tissue characterization is able to detect both the changes of myocardial collagen volume and the reversal of intrinsic contractile dysfunction under the influence of effective antihypertensive

7 80 Circulation January 7/14, 2003 therapy. Interestingly, all patients received angiotensinconverting enzyme inhibitors, which partially block the production of angiotensin, a key regulatory factor in collagen synthesis in the extracellular matrix. An indirect confirmation of the link between backscatter parameters and cardiac fibrosis (serum type I procollagen level) in hypertension is documented by a recent article. 21 Conclusion Ultrasonic backscatter analysis could allow physicians to assess if a patient is still in an adaptive or compensatory phase before irreversible damage (pathological phase) occurs. More extensive, randomized backscatter studies are needed to evaluate the effect of different pharmacological treatments (Ca 2 antagonist, -blockers, or angiotensin-converting enzyme inhibitors) on CVI and IBS indexed values. Acknowledgments The authors thank Dr Roberto Farina, Philips Medical System (Milano, Italy), and EMAC (Genova, Italy) for their technological support. References 1. Doering CW, Jalil JE, Janicki JS, et al. Collagen network remodelling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res. 1988;22: Jalil J,E, Doering CW, Janicki JS, et al. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989;64: Pearlman ES, Weber KT, Janicki JS, et al. Muscle fiber orientation and connective tissue content in the hypertrophied human heart. Lab Invest. 1982;46: Weber KT, Pick R, Jalil JE, et al. Patterns of myocardial fibrosis. J Mol Cell Cardiol. 1989;21: Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in subjects in the Framingham Heart Study. N Engl J Med. 1990;322: Douglas PS, Berko B, Lesh M, et al. Alterations in diastolic function in response to progressive left ventricular hypertrophy. J Am Coll Cardiol. 1989;13: Sahn DJ, DeMaria A, Kisslo J, et al. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58: Shimizu G, Hirota Y, Kawamura K, et al. Left ventricular midwall mechanics in systemic arterial hypertension: myocardial function is depressed in pressure-overload hypertrophy. Circulation. 1991;83: Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometry remodeling in essential hypertension. JAm Coll Cardiol. 1992;19: Di Bello V, Pedrinelli R, Bertini A, et al. Cyclic variation of the myocardial integrated backscatter signal in hypertensive cardiopathy: a preliminary study. Coron Arter Dis. 2001;12: Wickline SA, Thomas LJ III, Miller JG, et al. A relationship between ultrasonic integrated backscatter and myocardial contractile function. J Clin Invest. 1985;76: Rossi MA. Pathological fibrosis and connective tissue matrix in left ventricular hypertrophy due to chronic arterial hypertension in humans. J Hypertens. 1998;16: Finch-Johnston AE, Gussak HM, Mobley J, et al. Dependence of apparent magnitude on the time delay of cyclic variation of myocardial backscatter. Ultrasound Med Biol. 1999;25: Finch-Johnston AE, Gussak HM, Mobley J, et al. Cyclic variation of integrated backscatter: dependence of time delay on the echocardiographic view used and the myocardial segments analyzed. J Am Soc Echocardiogr. 2000;13: Aygen M, Popp RL. Influence on the orientation of myocardial fibers on echocardiographic images. Am J Cardiol. 1987;60: Recchia D, Miller JG, Wickline SA. Quantification of ultrasonic anisotropy in normal myocardium with lateral gain compensation of two-dimensional integrated backscatter images. Ultrasound Med Biol. 1993; Holland MR, Wilkenshoff UM, Finch-Johnston AE, et al. Effects of myocardial fiber orientation in echocardiography: quantitative measurements and computer simulation of the regional dependence of backscatter ultrasound in parasternal short-axis view. J Am Soc Echocardiogr. 1998;11: Hoyt RH, Collins SL, Skorton DJ, et al. Assessment of fibrosis in infarcted human hearts by analysis of ultrasonic backscatter. Circulation. 1985;71: Lythall DA, Bishop J, Greenbaum RA, et al. Relationship between myocardial collagen and echo amplitude in non fibrotic hearts. Eur Heart J. 1993;14: Di Bello V, R Pedrinelli, D Giorgi, et al. Ultrasonic myocardial texture versus doppler analysis in hypertensive heart: a preliminary study. Hypertension. 1999;33: Maceira AM; Barba J, Varo et al. Ultrasonic backscatter and serum marker of cardiac fibrosis in hypertensives. Hypertension. 2002;39: