Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—The Multi-Ethnic Study of Atherosclerosis (MESA)

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  Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—The Multi-Ethnic Study of Atherosclerosis (MESA)
  Regional diastolic dysfunction in individuals with left ventricularhypertrophymeasuredbytaggedmagneticresonance imaging—The Multi-Ethnic Study of Atherosclerosis (MESA)  Thor Edvardsen, MD, PhD, a  Boaz D. Rosen, MD, a  Li Pan, MS, a  Michael Jerosch-Herold, MD,  b Shenghan Lai, MD, PhD, a   W. Gregory Hundley, MD, c Shantanu Sinha, PhD, d Richard A. Kronmal, PhD, e David A. Bluemke, MD, PhD, a  and Joa ˜o A.C. Lima, MD, FACC a  Baltimore, MD; Minneapolis, MN; Winston-Salem, NC; Los Angeles, CA; and Seattle, WA Background  Impairment of global diastolic function is considered to be the mechanism of congestive heart failure inindividuals with preserved systolic left ventricular (LV) function. Left ventricular hypertrophy (LVH) is known to be a risk factorfor congestive heart failure with preserved systolic function, and this process may begin as a regional process. Weinvestigated whether regional LV diastolic function measured by magnetic resonance tagging is altered in asymptomaticparticipants of the MESA with LVH and preserved systolic LV function. Methods  Regional systolic and diastolic strain rates were calculated from strain data in 218 participants of the MESAstudy. Circumferential strain was calculated from the midwall layer of the septum, anterior, lateral, and inferior walls at mid-LVlevel. Global LV function measures were studied by magnetic resonance imaging in 4291 MESA participants. Left ventricularhypertrophy for men and women was defined from the MESA population using previously established Framingham criteria. Results  Global systolic function was slightly less in the LVH (ejection fraction = 0.66 F 0.10) versus the non-LVH group(ejection fraction = 0.69  F  0.07,  P   b  .001). Stepwise regression analyses showed a direct relationship between regionaldiastolic dysfunction and increasing LV mass. Regional systolic strain and strain rate measures from participants with LVHwere not significantly different from those without LVH. However, regional diastolic strain rate was significantly reduced inparticipants with LVH (1.5 F 1.1 s  1 ) compared with the non-LVH group (2.2 F 1.1 s  1 ,  P   b  .001) regardless of age or sex. Conclusions  Left ventricular hypertrophy is associated with regional diastolic dysfunction in individuals withoutevidence of clinical cardiovascular disease and preserved systolic function. Magnetic resonance imaging tagging providesdetailed quantification of regional diastolic function noninvasively. (Am Heart J 2006;151:109-14.) Left ventricular hypertrophy (LVH) is one of theleading causes of congestive heart failure (CHF) and isalso found to be associated with an increased risk of major cardiovascular events including myocardial in-farction and sudden death. 1-3 However, many patients with CHF have preserved systolic function. Diastolicheart failure has been proposed as the mechanism of congestive symptoms as a separate clinical entity thataccounts for approximately one third of all CHF cases. 4,5 In this regard, impairment of diastolic function issuspected to precede or be independent of reduced left ventricular (LV) systolic function as a mechanism of CHF. 6-9 Moreover, it is intuitive to hypothesize thatdiastolic heart failure, like its systolic counterpart, may begin as a regional process, although its determinantsare not fully understood.So far, most studies on diastolic myocar dial functionhave used echocardiographic techniques. 10,11 However,tagged magnetic resonance imaging (MRI) of the heart iscapable of providing direct measures of myocardialrelaxation. 12 In addition, this technique has superior soft-tissue contrast and is not limited by acoustic windows.Previous clinical studies have studied LV untwistingpatterns from tagged magnetic resonance (MR) data. 13,14 However, more direct information about intrinsicregional diastolic LV function can be acquired fromLagrangian strain data analysis obtained from tagged From the   a  Division of Cardiology, Department of Medicine, Johns Hopkins University,Baltimore, MD,  b  Department of Radiology, University of Minnesota, Minneapolis, MN, c  Department of Cardiology, Wake Forest University School of Medicine, Winston-Salem,NC,  d  Department of Radiology, UCLA School of Medicine, Los Angeles, CA, and  e  Department of Biostatistics, University of Washington, Seattle, WA.The author have no conflicts of interests to disclose.Submitted November 2, 2004; accepted February 15, 2005.Reprint requests: Joa˜o A.C. Lima, MD, FACC, Cardiology Division, Johns HopkinsHospital, 600 N Wolfe Street/Blalock 524, Baltimore, MD 21287-0409.0002-8703/$ - see front matter  n  2005, Mosby, Inc. All rights reserved.doi:10.1016/j.ahj.2005.02.018   MRI. By calculating the first derivative of strain mea-surements with  respect to time, strain rate can becalculated. 15,16 This index represents a direct measure of regional myocardial relaxation as opposed to fillingparameters that are as dependent on volume loading asthey are on ventricular relaxation itself. Accordingly, we used MRI with tissue tagging to study myocardial function in a large epidemiologic study of risk f actors for subclinical cardiovascular disease: theMESA. 17 The MESA is a large observational prospectivestudy of 6814 men and women with no history of symptomatic cardiovascular disease.The present study was designed to investigate whether regional LV diastolic function measured by MRItagging is affected by LVH in a subset of asymptomaticparticipants of the MESA study (n = 218). Methods Study population Briefly, the purpose of the MESA study is to investigate the various mechanisms and risk factors underlying the develop-ment and progression of subclinical cardiovascular disease. 17 Men and women, aged 45 to 85 years, from 4 different ethnicgroups (white, African American, Hispanics, and Chinese), were enrolled from 6 communities. A major exclusion criterionis the presence of clinical cardiovascular disease. Six thousandeight hundred fourteen men and women have been enrolled inthe study. Of those, 4291 (2250 women and 2041 men)underwent MRI studies of the heart at 6 different centers(Wake Forest University, NC; Columbia University, NY; JohnsHopkins University, Md; University of Minnesota, Minn;Northwestern University, Ill; and University of California at Los Angeles, Calif). Participants were randomly selected to undergotagged MRI studies in 6 centers. All 235 participants with MRItagging data that included time information suitable for calculation of myocardial strain were included in the presentstudy. Because of poor tagging quality and strain traces,17 participants had to be excluded from the study. Thus,218 participants (115 men and 103 women) were included andanalyzed in the present study. All the participants gaveinformed consent for the study protocol. The institutionalreview boards in all the centers participating in MESA approvedthis protocol. MRI protocol Images were obtained using 1.5-T MR scanners: Signa LX andCVi (GE Medical Systems, Waukesha, WI) and Symphony andSonata (Siemens Medical Systems, Erlangen, Germany). Images were acquired using a segmented  k -space, electrocardiogram-gated fast spoiled gradient recalled echocardiograph sequencepulse sequence. Torso phase array coils were used for signalreception. After concluding scout images, 1 vertical long-axisand 6 short-axis cine images (from the level of the mitral valveto LV apex) were prescribed. After completing the standardprotocol, 3 tagged short-axis slices were obtained. Striped tags were prescribed separately in 2 orthogonal orientations (0 8  and90 8  ) using spatial modulation of magnetization. Images wereacquired at resting lung volume during approximately 12- to18-second breath-holds. Parameters for tagged MRI imagesinclude field of view 40 cm, slice thickness 8-10 mm, repetitiontime 3.5-7.2 milliseconds, echocardiograph time 2.0-4.2 milli-seconds, flip angle 12 8 , matrix size 256  96-140, 4 to 9 phase-encoding views per segment, bandwidth range 24.9-62.5 kHz,temporal resolution 36.3  F  12.0 milliseconds, and tagspacing 7 mm.  Analysis For each of the 4291 participants, LV mass end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume,and LV ejection fraction (LVEF) were determined usingstandard commercially available software MASS 4.2 (MEDIS,Leiden, The Netherlands). The papillary muscle was includedas a part of the LV cavity volume. Left ventricular ejectionfraction was computed as (EDV     ESV)/EDV.Left ventricular mass index (LVMI) was defined as LV end-diastolic mass divided by body surface area. To find the cutpoints for LVH and LVEF in the MESA population the same Figure 1 200400600800100012000Strain (%)Time (ms) Peak systolic strainrate (SR S ) Strain rate (1/s) E-wave(SR E )A-wave(SR A ) Representative strain rate (upper) and strain (lower) profiles from aperson with normal LVMI. This example demonstrates a typical strainrate pattern with E and A waves and is taken from the anterior midwall segment at mid-LV level. The markers on the strain and strainrate traces represent the time resolution (54 milliseconds). American Heart Journal January 2006 110  Edvardsen et al  analyses were preformed as described in the Framinghamoffspring cohor t. 18 Briefly, participants with a clinical history of hypertension, taking an antihypertensive medication, or those with a resting systolic blood pressure  N 140 mm Hg or diastolicblood pressure  N 90 mm Hg were excluded. Participants with higher LVMI than the 95th percentile were classified as LVH.Peak regional systolic circumferential strains (Ecc) wereanalyzed by harmonic phase imaging 19 in 4 LV segments(anterior, lateral, inferior, and septal) from the midpart of LV and in the midwall layer in each segment. An in-house–developed tool was used for calculating regional strain rates.Strain rates were obtained from the strain measures from each segment in each participant by dividing strain by the timeinformation (  T   ) from each time frame. SR  ¼  Ecc  2   Ecc  1 T  2  T  1 The peak systolic strain rate (SR  S  ) and peak early diastolicstrain rate (SR  E  ) were assessed from the strain rate trace( Figure 1 ). The MRI reading center was the Johns Hopkins University.Individual strain and strain rate reread variabilities were foundto be 4% and 3%, respectively. Statistical analysis Summary data are presented as mean  F  SD for continuous variables and as proportions for categorical variables. Multiplelinear regression analysis was used to determine which regionalmeasures, including average systolic strain, SR  S , or diastolicstrain rate, were independently associated with increasingLV mass. Age, sex, height, and weight were included in theregression models as covariates.Each myocardial segment was analyzed using unpaired  t   testsbetween the LVH group and the non-LVH group regardingpossible differences in myocardial strains and strain rates.Proportions were compared with the use of   m 2 tests. All  P   values are 2-sided, and the  a  level was set at .05. Results Left ventricular hypertrophy  Demographic and hemodynamic data from all partic-ipants with MRI studies are presented in Table I. Participants without history of hypertension, antihyper-tension medications, or current hypertension were1082 men and 1144 women. The cohort’s upper 95th percentile, that is, men with LVMI  N 107.8 g/m 2 and women with LVMI  N 85.3 g/m 2  were considered ashaving LVH. The cohort’s lower 5th percentile for LVEF values was 57.3%. Global LV function Left ventricular hypertrophy was present in 9.8%individuals (n = 422) in the whole MESA population(including those with hypertension). Global systolicfunction was subnormal (LVEF  b 0.573) in 13.9% of individuals with LVH and in 4.3% of individuals withoutLVH (   P   b  .001). In addition, mean LVEF was slightly reduced in the LVH group compared with individuals with normal LVMI (0.67 F 0.10 vs 0.70 F 0.07, respec-tively,  P   b  .001), although in absolute terms those values would be considered well within the reference range. Regional LV systolic and diastolic function Figures 1 and 2 demonstrate the typical strain andstrain rate patterns from a typical participant with normal LV mass and a participant with LVH, respec-tively. Early diastolic strain rate could be assessed in 80%(692/872) of all segmental analyses. The atrial-inducedstrain rate could be assessed in 32% (277/872) of allsegmental analyses. For the remaining studies, MR tagging lines were faded in signal intensity according to Table I.  Demographic and hemodynamic data from all participants Cardiac MRI MRI-tagged studiesGlobal analysis Strain rate analysisNormal (n = 3869) LVH (n = 422) Normal (n = 188) LVH (n = 30) Men (%) 48.1 42.7  T  52.7 53.3 Age (y) 62  F  10 64  F  10 y  64  F  10 65  F  9BSA (m 2 ) 1.8  F  0.2 1.9  F  0.2 y  1.8  F  0.2 1.9  F  0.2LVEDM (g) 140  F  69 199  F  46 z  141  F  34 205  F  50 z LVEDV (cm 3 ) 123  F  29 149  F  39 z  122  F  29 153  F  35 z LVEF 0.70  F  0.07  0.67   F  0.10 z  0.69  F  0.07  0.66  F  0.10 T SV (mL) 85  F  19 97   F  23 z  84  F  18 93  F  21 z SBP (mm Hg) 124  F  20 141  F  26 z  132  F  23 145  F  22 y DPB (mm Hg) 71  F  10 76  F  12 z  72  F  11 80  F  13 y LVMI (g/m 2 ) 75  F  13 106  F  18 z  78  F  13 108  F  21 z Rx (n/%) 1050 (27) 187 (44) z  59 (31) 15 (50) Significance is tested versus the normal individuals in each group. Values are expressed as mean F  SD.  BSA  , Body surface area;  DBP  , diastolic blood pressure;  LVEDM , left  ventricular end-diastolic mass;  LVEDV  , left ventricular end-diastolic volume;  SBP  , systolic blood pressure;  SV  , stroke volume;  Rx  , use of antihypertensive medications. T P   b  .05. y P   b  .01. z P   b  .001. American Heart JournalVolume 151, Number 1  Edvardsen et al  111  the  T  1 relaxation of the heart. Atrial-induced strain ratemeasures were thus less accurate.Regression analysis demonstrated that the magnitudeof early relaxation (mean SR  E  ) is inversely proportionalto LVMI (   P   b  .001), whereas mean SR   A   was not related.Participants were further subdivided into quartiles by LVMI to test a possible threshold effect ( Figure 3 ).To explore regional differences, multiple regressionanalyses were performed in each LV wall comparingLV mass and regional LV diastolic relaxation after adjusting for age, sex, height, and weight. The regionalanalyses showed an association between increasingLV mass and worse diastolic relaxation in the anterior,lateral, and septal walls ( Table II ).Table III demonstrates the decreased regional early diastolic LV function in the LVH group compared with the non-LVH group (1.5  F 1.1 s  1  vs 2.2  F  1.1 s  1 ,  P   b  .001). The A wave was not affected in the LVH group(1.4  F  1.0 s  1  vs 1.7  F  0.9 s  1 ,  P   = .11). Regionalsystolic strain and systolic strain rates for participants with LVH showed no relationships with higher LV mass.Diastolic functional impairment for each segment varied Figure 2 05-5-10-15-20200400600800100012000Time (ms)Strain (%) Peak systolicstrain rate (SR S ) Strain rate (1/s) A-wave (SR A ) E-wave (SR E ) Strain rate (upper) and strain (lower) from a person with LVH. Notethe depressed SR E  lower than 1.0 s  1 and the intact systolic function.The markers on the strain and strain rate traces represent the timeresolution (45 milliseconds). Figure 3 Participants divided into quartiles by level of LVMI. Participants withhigher LVMI demonstrate lower regional diastolic myocardialfunction by strain rates. Values given are mean diastolic strain ratesand black bars indicate SD. Table III.  Circumferential strain and strain rates from 4 midwallsegments of the left ventricle in normal persons and in participantswith LVH Normal LVH  P  SS (%)   17.1  F  2.5   16.9  F  2.6 .66SR S  (s  1 )   1.5  F  0.6   1.3  F  0.4 .10SR E  (s  1 ) 2.2  F  1.1 1.5  F  1.1  b .001SR  A   (s  1 ) 1.7   F  0.9 1.4  F  1.0 .11  Values are expressed as mean  F  SD. SS  , Systolic strain;  SR  E  , early diastolic strain rate;  SR   A  , diastolic atrial-induced strainrate. Table II.  Stepwise (backward) multiple regression betweenregional diastolic relaxation (SR E ) in 4 LV wall segments and LVmass adjusted for height, weight, age, and sex (n = 218)  Anterior wallLateral wallPosterior wallSeptal wall Regression coefficient    4.1   3.3   1.5   4.7  Adjusted  R  2 0.61 0.58 – 0.60 P   .017 .016 .299 .008 American Heart Journal January 2006 112  Edvardsen et al  from 19% to 35%. There were no differences in systolicand diastolic functions in women versus men in the LVHor non-LVH group (ns) when comparing measures fromeach segment. Discussion This report demonstrates for the first time myocardialrelaxation impairment in asymptomatic individuals with LVH, in a large epidemiologic multicenter study.Moreover, we demonstrate that regional diastolicfunction is impaired despite normal systolic function inthese individuals. Finally, this study proposes a novelindex of LV diastolic performance that is based on directmeasurements of myocardial relaxation using MRItissue tagging.Magnetic resonance imaging results presented in thisstudy derive from quantitative data obtained from 4291asymptomatic participants and thus represent the largestMRI study reported to date. Also, the MRI tagging datafrom 218 persons presented in this study provide uniquedetailed insight on myocardial function and relaxation ina large study group. Most MR tagging studies until now have consisted of small numbers of individuals. Thelarge sample size in this study was possible becauseof the harmonic phase imaging software which is anew technique that enables a fast determination of systolic strain. Using the in-house tool for calculation of diastolic strain rates was more time consuming (typically 60 minutes for 1 participant).This study demonstrates that only 13.9% of asymp-tomatic adults with LVH have global LV systolicdysfunction. Our participants were rigorously excludedfrom the MESA study if they had any kind of heartdisease. Therefore, participants in MESA were expectedto have high ejection fraction values. The range of LVEFin our study is comparable to another study of participants free of clinically overt cardiovascular disease. 18 Global systolic function (LVEF) was mildly reduced (0.03) in the LVH group, and this reduction is of uncertain clinical relevance. On the other hand, regionaldiastolic function was clearly reduced by approximately 30% in MESA participants with LVH. This finding is inagreement with previous studies that have demonstratedglobal diastolic dysfunction in small groups of patients with severe LVH. 20,21 Regional systolic functional meas-ures remained unchanged in this asymptomatic LVHpopulation whereas regional diastolic function wasreduced in approximately one third of the group. Thedifferences in regional diastolic function were presentregardless of sex and age. In only 4 participants,decreased regional systolic function occurred with concomitant decreased regional diastolic function.These findings add support to the concept of regionaldiastolic dysfunction as a separate mechanism of heartfailure in patients with LVH.Traditionally, echocardiographic Doppler flow indicesof LV filling and pulmonary venous flow  have been usedin the assessment of LV diastolic function. 4 Theseindices are load dependent and limited to indirectmeasures of LV function whereas the present study usesa direct measure of myocardial relaxation. Recentechocardiographic studies of tissue velocity and straintechniques indicate that regional myocardial measuresare much less dependent on loading conditions. 11,22 Regional diastolic strain rate measures have previously been used in echocardiographic studies. 10,23-25 Structuraland functional myocardial abnormalities have also beenfound in hypertensive patients without LVH. 26 The MRImethod relies on deformation of taglines to assess strain whereas the echocardiographic method is limited to afixed sampling space during the cardiac cycle. 15 Thismakes the MRI method used in our study theoretically superior to the echocardiographic technique. Limitations Because this is a cross-sectional study, inferencesregarding prognosis and outcome in association with regional diastolic dysfunction cannot be made at thepresent time. However, the MESA population will befollowed for 6 years and will likely reveal importantprognostic information regarding the results reported inthis study. Only midwall circumferential strain and strainrate measures were assessed; diastolic features fromother layers of the LV remain to be studied. In anepidemiologic study of this magnitude we thought thatthe midwall strains and strain rates would best representthe regional function of the whole segment whencompared with subendocardial or subepicardial meas-urements. Second, subendocardial and subepicardialmeasurements will result in more noisy data thanmidwall analysis.The lack of relationship between increasing LV massand worse diastolic relaxation in the posterior wallmight be because of a lower number of analyzablesegments in this particular wall. The E wave could only be analyzed in 67% of the posterior wall segmentscompared with 84% in the anterior wall. Conclusions Tagged MRI provides detailed and reliable informationabout LV diastolic function and we demonstrate in thisstudy that it can also be used to assess regional diastolicstudies in population research. Our findings add impor-tant insight on the mechanisms of regional LV functionalimpairment in LVH. They might also aid in the identifi-cation of individuals who are at a higher risk to developCHF with preserved systolic function in the future.The present study demonstrates that regional LV diastolic function is decreased in asymptomatic individ-uals with LVH and preserved systolic function. It alsodemonstrates the ability of tagged MRI to directly  American Heart JournalVolume 151, Number 1  Edvardsen et al  113
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