Regression of electrocardiographic left ventricular hypertrophy predicts regression of echocardiographic left ventricular mass: the LIFE study

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1 (2004) 18, & 2004 Nture Pulishing Group All rights reserved /04 $ ORIGINAL ARTICLE Regression of electrocrdiogrphic left ventriculr hypertrophy predicts regression of echocrdiogrphic left ventriculr mss: the LIFE study PM Okin 1, RB Devereux 1, JE Liu 1, L Oikrinen 2, S Jern 3, SE Kjeldsen 4, S Julius 5, K Wchtell 6, MS Nieminen 2 nd B Dhlöf 3 for the LIFE study investigtors 1 Deprtment of Medicine, Division of Crdiology, Weill Medicl College of Cornell University, New York, NY, USA; 2 Division of Crdiology, Deprtment of Medicine, Helsinki University Centrl Hospitl, Helsinki, Finlnd; 3 Shlgrensk University Hospitl/O str, Göteorg, Sweden; 4 Ullevål University Hospitl, Oslo, Norwy; 5 University of Michign Medicl Center, Ann Aror, MI, USA; 6 Glostrup University Hospitl, Glostrup, Denmrk The electrocrdiogrm (ECG) is widely used for detection of left ventriculr hypertrophy (LVH). However, whether chnges in ECG LVH during ntihypertensive therpy predict chnges in LV mss remins uncler. Bseline nd yer-1 ECGs nd echocrdiogrms were ssessed in 584 hypertensive ptients with ECG LVH y Sokolow Lyon or Cornell voltge durtion product criteri t entry into the Losrtn Intervention For Endpoint reduction in hypertension (LIFE) echocrdiogrphic sustudy. A X25% decrese in Cornell product defined regression of ECG LVH; o25% decrese defined no significnt regression; nd n increse defined progression of ECG LVH. Regression of echocrdiogrphic LVH ws defined y X20% reduction in LV mss. After 1 yer of therpy, 155 ptients (27%) hd regression of ECG LVH, 286 (49%) hd no significnt chnge, nd 143 (25%) hd progression of ECG LVH. Compred with ptients with progression of ECG LVH, ptients with no significnt decrese nd ptients with regression of ECG LVH hd stepwise greter solute decreses in LV mss ( vs vs g, Po0.001), greter percent reductions in LV mss ( vs vs %, Po0.001), nd were more likely to decrese LV mss y X20% (11.2 vs 24.8 vs 36.1%, Po0.001), even fter djusting for possile effects of seline nd chnge in systolic nd distolic pressures. Compred with progression of ECG LVH, regression of the Cornell product ECG LVH is ssocited with greter reduction in LV mss nd greter likelihood of regression of ntomic LVH. (2004) 18, doi: /sj.jhh Pulished online 1 April 2004 Keywords: lood pressure; electrocrdiogrphy; hypertrophy Introduction Left ventriculr hypertrophy (LVH) detected y the electrocrdiogrm (ECG) 1 3 nd echocrdiogrm 4 8 re common mnifesttions of preclinicl crdiovsculr disese tht strongly predict crdiovsculr moridity nd mortlity. Antihypertensive therpy cn produce regression of LVH, 3,4,9 13 nd ville dt suggest tht regression of LVH nd prevention of progression to LVH cn decrese crdiovsculr moridity. 2 4,12,13 However, utility of ECG criteri for Correspondence: Dr PM Okin, Weill Medicl College of Cornell University, 525 Est 68th Street, New York, NY 10021, USA. E-mil: pokin@mil.med.cornell.edu Pulished online 1 April 2004 detection of LVH nd for seril evlution of chnges in LV mss hs een limited y the low sensitivity of stndrd voltge criteri for identifiction of ntomic LVH Cornell voltge criteri modestly improve ECG detection of LVH, 15,16 nd the product of Cornell voltge nd QRS durtion (Cornell voltge durtion product), 17,18 s n pproximtion of the true re under the QRS complex, 19 further enhnces sensitivity of the ECG for LVH while mintining high specificity. As consequence, Cornell voltge durtion product criteri were used in comintion with stndrd Sokolow Lyon voltge criteri 14 to identify hypertensive ptients t incresed risk of crdiovsculr moridity nd mortlity in the Losrtn Intervention For Endpoint reduction in

2 404 hypertension (LIFE) study These ECG criteri identified hypertensive ptients with 470% likelihood of hving echocrdiogrphic LVH nd with high-norml indexed LV mss in those ptients not fulfilling strict cutoff criteri for echocrdiogrphic LVH. 24 However, few dt exist on the vlue of seril chnges in ECG voltge for predicting chnges in LV mss, 25,26 nd the ility of chnges in more sensitive voltge durtion product criteri to predict chnges in LV mss during ntihypertensive therpy hs not een exmined. Therefore, the present study exmined the ility of chnges in the Cornell voltge durtion product criteri over the first yer of ntihypertensive therpy in LIFE to predict regression nd progression of echocrdiogrphic LVH. Methods Sujects The doule-lind LIFE tril enrolled hypertensive ptients with ECG LVH y the Cornell voltge durtion product 17,18 nd/or Sokolow Lyon voltge criteri 14 on screening ECG to determine whether greter reduction in mortlity nd moridity is ssocited with the use of losrtn- s opposed to tenolol-sed therpy. 21 The study ws pproved y ll ethics committees concerned. Study inclusion nd exclusion criteri hve een previously pulished A previously descried 24 representtive smple of the whole LIFE study, totling 960 ptients, underwent seline echocrdiogrms, of which 584 hd mesurle echocrdiogrphic LV mss nd complete ECG mesurements t seline nd yer 1 of follow-up. There were 235 women nd 349 men whose men ge ws 6677 yers. ECGs were interpreted t the ECG Core Lortory t Shlgrensk University Hospitl/Östr in Göteorg, Sweden, y experienced investigtors linded to clinicl informtion. The product of QRS durtion times the Cornell voltge comintion (R VL þ S V3, with 8 mm dded in women 17,18 ) ws used with threshold vlue of 2440 mm ms to identify LVH. After the design of the LIFE study, studies were pulished suggesting smller gender djustment, 27,28 nd feedck from LIFE investigtors showed tht otherwise eligile ptients hd ECG LVH y highly specific ut insensitive Sokolow Lyon voltge criteri, 14 ut not y the Cornell product. Accordingly, chnges were mde in ECG entry criteri: the gender djustment of Cornell voltge ws reduced from 8 to 6 mm, nd Sokolow Lyon voltge (S V1 þ RV 5/6 )438 mm ws ccepted for ECG eligiility. 22 For the present study, dditionl ECG mesurements were performed t Helsinki University Centrl Hospitl, s previously descried. 29 QRS durtion ws mesured to the nerest ms, nd QRS mplitudes to the nerest 0.1 mm, y trined technicin unwre of clinicl dt who used digitizer connected to personl computer. Bsed on previous mesures of repet vriility of Cornell voltge nd QRS durtion mesurements nd on the reproduciility of intervl mesurements in Helsinki, 29 X25% decrese in the Cornell product ws used to define regression of ECG LVH, o25% decrese to represent no significnt regression, nd n increse in the Cornell product of ny mgnitude to define progression of ECG LVH. Regression of ECG LVH ws not defined y chnge in ECG sttus from LVH to no LVH y either criterion in order to void misclssifying ptients with only miniml chnges in ECG LVH or erroneously considering regression to the men 33,34 s true regression of LVH. Echocrdiogrphy Studies were performed with commercilly ville phsed-rry echocrdiogrphs using stndrdized recording procedures s previously reported in detil. 24,29,34 LV mss ws clculted 35 nd indexed for ody surfce re, nd LVH ws considered present if LV mss index (LVMI) ws 4104 g/m 2 in women nd 4116 g/m 2 in men. 1,7 Regression of LVH ws defined s X20% decrese in LV mss etween the seline nd yer-1 echocrdiogrm. This provides 495% likelihood of representing true decrese in LV mss sed on ssessment of interstudy vriility nd regression to the men on chnges in LV mss on seril echocrdiogrms, 34 nd pproximtes the upper qurtile of chnge in LV mss in the study popultion. Electrocrdiogrphy Sttisticl nlysis Dt mngement nd nlysis were performed with the SPSS version 10. Dt re presented s men7s.d. for continuous vriles, nd s proportions for ctegoricl vriles. Differences in prevlences etween groups were compred using w 2 -nlyses. Men vlues of continuous vriles were compred using two-wy ANOVA to djust for the possile influence of gender, with post hoc testing of intergroup differences y Scheffe s method. Chnges in LV mss etween seline nd yer 1 were further compred etween groups using AN- COVA to djust for differences etween groups in ge, gender, seline distolic lood pressure (DBP), nd chnge in systolic nd distolic pressures from seline to yer 1. The independent reltion of regression of echocrdiogrphic LVH to chnge in Cornell product ws determined using stepwise logistic regression nlyses. For ll tests, twotiled P-vlue o0.05 ws required for sttisticl significnce.

3 Results Ptient chrcteristics After 1 yer of ntihypertensive therpy in the LIFE study, regression of ECG LVH y the Cornell product ws present in 155 ptients (26.5%); there ws no significnt decrese in the Cornell product in 286 ptients (49.0); nd progression of ECG LVH ws present in 143 ptients (24.5%). The men reduction in the Cornell product fter 1 yer ws mm ms. There were only minor differences in seline demogrphic chrcteristics mong groups defined y the chnge in the Cornell product etween seline nd yer 1 (Tle 1). The reltions of seline BP nd LV mss, nd the chnge in BP nd in ody weight over the 1 yer of therpy, to regression vs progression of ECG LVH re shown in Tle 2. Bseline distolic pressure ws significntly lower in ptients with progression of ECG LVH, nd there ws trend towrds lower seline systolic pressure in this group s well. BP decresed in ll groups, ut ptients with regression of ECG LVH hd the gretest decreses in oth systolic nd distolic pressure; ptients with no significnt decrese in the Cornell product hd intermedite decreses in BP; nd ptients with progression of ECG LVH hd the smllest decreses in systolic nd distolic pressure fter 1 yer of ntihypertensive therpy. There were no differences etween groups in the chnge in ody weight over 1 yer. The men LV mss nd indexed LV mss were elevted in ll three groups t study seline, without significnt differences etween groups. 405 Tle 1 Bseline demogrphic chrcteristics ccording to the presence or sence of regression of electrocrdiogrphic LVH y Cornell voltge durtion product Vrile Chnge in Cornell product Progression (increse, n ¼ 143) No significnt decrese (o25% decrese, n ¼ 286) Regression (X25% decrese, n ¼ 155) Overll P-vlue Age (yers, men7s.d.) c Sex (% mle) Rce (% lck) Dietes (%) Previous MI (%) Previous stroke (%) Angin (%) Peripherl vsculr disese (%) Body mss index (kg/m 2, men7s.d.) Adjusted for the possile influence of gender using two-wy ANOVA for continuous vriles. Po0.05 vs progression group. c Po0.05 vs no significnt decrese group. MI¼ myocrdil infrction. Tle 2 Clinicl nd seline echocrdiogrphic chrcteristics ccording to the presence or sence of regression of electrocrdiogrphic LVH y the Cornell voltge durtion product Vrile Chnge in Cornell product Progression (increse, n ¼ 143) No significnt decrese (o25% decrese, n ¼ 286) Regression (X25% decrese, n ¼ 155) Overll P-vlue Bseline SBP (mmhg) Bseline DBP (mmhg) c DSBP (mmhg) ,c o0.001 DDBP (mmhg) ,c DWeight (kg) Bseline LV mss (g) Bseline LVMI (g/m 2 ) Adjusted for the possile influence of gender using two-wy ANOVA for continuous vriles. Po0.05 vs progression group. c Po0.05 vs no significnt decrese group. DBP ¼ distolic lood pressure, LV ¼ left ventriculr, LVMI ¼ left ventriculr mss index, SBP ¼ systolic lood pressure. Dt re expressed s men7s.d. D ¼ Chnge from seline to yer 1.

4 406 nd chnge in LV mss The reltions of solute nd percent chnges in LV mss to the chnge in the Cornell product re exmined in Tle 3. After djusting for gender, oth the solute nd percent chnge in LV mss were strongly ssocited with the presence of regression of ECG LVH y the Cornell product criteri. Compred to ptients with no significnt decrese in the Cornell product, ptients with progression of ECG LVH hd smller, nd those with regression of ECG LVH hd greter, decreses in LV mss in solute terms or percent chnge. The differences persisted fter djusting for the possile effects of ge, sex, seline distolic pressure, nd chnge in systolic nd distolic pressures (Tle 3). The ility of regression of ECG LVH y the Cornell product to identify ptients most likely to experience regression of echocrdiogrphic LVH s determined y X20% decrese in LV mss is exmined in Figure 1 nd Tle 4. After 1 yer of ntihypertensive therpy, 36.1% of ptients with regression of ECG LVH y the Cornell product hd X20% reduction in LV mss, compred with 24.8% of ptients who hd no significnt decrese in the Cornell product, nd only 11.2% of ptients who hd progression of ECG LVH (Po0.001, Figure 1). Of note, the solute degree of ssocition etween regression of ECG nd echocrdiogrphic LVH ws moderte (gmm ¼ 0.41, Po0.001). Univrite logistic regression nlysis demonstrted tht, compred with ptients who hd no significnt decrese in ECG LVH, ptients with regression of ECG LVH hd nerly 180% greter likelihood of regression of echocrdiogrphic LVH, wheres those with progression of ECG LVH hd 460% lower likelihood of experiencing X20% reduction in LV mss (Tle 4). After djusting for effects of sex, seline LV mss, nd seline nd chnge in systolic nd distolic BP on regression of hypertrophy, regression of ECG LVH y the Cornell product criteri remined strongly ssocited with regression of echocrdiogrphic LVH, with no ttenution of odds rtios (Tle 4). y the Cornell product criteri remined significnt predictor of regression of echocrdiogrphic LVH when chnge in the Cornell product ws considered s continuous vrile (w 2 ¼ 20.48, Po0.001) nd when exmined seprtely in men nd women. Of note, regression of ECG LVH y simpler Cornell voltge criteri ws univrite (P ¼ 0.011) ut not multivrite (P ¼ 0.208) predictor of regression of echocrdiogrphic LVH. y Sokolow Lyon voltge criteri ws not significnt predictor of regression of ntomic LVH (P ¼ 0.068). Discussion This study demonstrtes tht regression of ECG LVH y the Cornell product criteri is n independent Regression of Echocrdiogrphic LVM y 20% (%) Overll χ 2 =25.06 p< Increse <25% Decrese Regression Chnge in Cornell Product Figure 1 Reltion of regression of echocrdiogrphic LVH, defined y X20% decrese in LV mss, to chnge in the Cornell product fter 1 yer of ntihypertensive therpy. Tle 3 Chnge in echocrdiogrphic LV mss from seline to yer-1 ccording to the presence or sence of regression of electrocrdiogrphic LVH y the Cornell voltge durtion product Vrile Chnge in Cornell product Progression (increse, n ¼ 143) No significnt decrese (o25% decrese, n ¼ 286) Regression (X25% decrese, n ¼ 155) Overll P-vlue Gender-djusted LV mss (g) ,c o0.001 LV mss (%) ,c o0.001 Multivrite LV mss (g) ,c LV mss (%) ,c o0.001 Adjusted for ge, sex, seline DBP, nd chnge in SBP nd DBP from seline to yer 1. Po0.05 vs progression group. c Po0.05 vs no significnt decrese group. Dt re expressed s men7s.d.

5 Tle 4 Assocition of the chnge in electrocrdiogrphic LVH y the Cornell voltge durtion product with X20% reduction in echocrdiogrphic LV mss etween seline nd yer 1 in univrite nd multivrite logistic regression nlyses 407 Vrile w 2 P-vlue Coefficient Odds rtio 95% CI Univrite Chnge in Cornell product o0.001 Progression (increse) o No significnt decrese (o25% decrese) 1 Regression (X25% decrese) Multivrite Chnge in Cornell product o0.001 Progression (increse) No significnt decrese (o25% decrese) 1 Regression (X25% decrese) Odds rtio of X20% decrese in echocrdiogrphic left ventriculr mss for regression or progression in Cornell product compred with no significnt decrese (o25% decrese) of Cornell product. Adjusted for ge, sex, seline LV mss, seline DBP, nd chnge in SBP nd DBP from seline to yer 1. predictor of the presence nd degree of regression of echocrdiogrphic LVH fter 1 yer of ntihypertensive therpy in the LIFE study. Compred with ptients with no significnt decrese in ECG LVH, ptients with regression of ECG y the Cornell product criteri hd greter solute nd percent decreses in LV mss, nd were nerly twice s likely to decrese LV mss y X20%, even fter djusting for the greter reductions in systolic lood pressure (SBP) nd DBP in this group. These findings further support the use of voltge durtion product criteri for ECG ssessment of the presence of LVH, nd for identifying significnt seril chnges in LV mss over time. Reltion of chnges in ECG LVH criteri to chnges in LV mss Previous studies hve demonstrted tht ntihypertensive therpy cn produce significnt decreses in LV mss nd regression of LVH; 3,4,9 13 however, there re only limited dt exmining the ility of seril chnges in ECG LVH criteri to predict chnges in LV mss. 25,26 Ditchey et l 25 exmined short-term chnges in ECG nd echocrdiogrphic LVH in 15 norml sujects nd in 18 ptients undergoing ortic or mitrl vlve replcement, nd found tht seril chnges in R-wve mplitude in VL, ut not Sokolow Lyon voltge, prlleled seril chnges in LV mss. However, this study did not quntify the predictive vlue of chnges in ECG voltges for chnges in LV mss, nd ws limited y the smll numer of ptients exmined nd y inclusion of postopertive studies in which other clinicl fctors could hve ffected ECG vriles. Crow et l 26 found poor correltions etween verge chnges in LV mss nd eight ECG LVH criteri, including Sokolow Lyon voltge nd the Cornell product, over 4 yers in 834 prticipnts in the Tretment of Mild Hypertension Study. However, prticipnts hd low prevlence of echocrdiogrphic LVH t seline (15.3%), nd no dt were provided on the degree of chnge in LV mss or ECG criteri. The mild hypertension nd expected smll chnges in LV mss over time could truncte the reltionship etween chnges in LV mss nd ECG LVH criteri, which could hve een further reduced y the use of verge chnges in these mesures compred with seline. In contrst, the present study clerly demonstrtes tht chnges in the Cornell product independently predict significnt chnges in LV mss. nd prognosis A numer of previous studies hve demonstrted tht regression of ECG LVH nd prevention of LVH development re ssocited with reduced risk of crdiovsculr moridity. 2,3,12,13 In 524 prticipnts in the Frminghm Hert Study who hd ECG LVH y vrious criteri t qulifying exmintion, Levy et l 2 found tht significnt decline in Cornell voltge, defined y chnge to lower qurtile, ws ssocited with lower risk for crdiovsculr disese; wheres significnt increse in Cornell voltge, defined y chnge to higher qurtile of voltge, identified sujects t incresed risk. Importntly, these reltionships persisted when chnge in Cornell voltge ws exmined s continuous vrile nd when voltge chnge ws defined y 410% seril increse or decrese. 2 Prines et l 13 demonstrted tht incident LVH nd increses in ECG LVH y the Cornell product nd Novcode criteri were ssocited with incresed risk of mortlity in the usul cre rm of MRFIT. In contrst, increses in Sokolow Lyon voltge were ssocited with decresed risk in MRFIT. 13 However, these investigtors verged chnges in ECG LVH criteri over 6 yers of follow-up, which could underestimte the predictive vlue of seril increses or decreses in ECG mesures over this time period. Furthermore, their findings were limited to

6 408 men. In contrst, recent findings from the HOPE tril using Sokolow Lyon voltge criteri for LVH 3 suggest tht reduced development of ECG LVH nd incresed regression of ECG LVH y these criteri, in response to rmipril therpy re ssocited with reduced risk of deth, myocrdil infrction, stroke, nd congestive hert filure. However, HOPE did not ssess the degree of chnge in Sokolow Lyon voltge, only whether voltge ws less thn or greter thn the threshold vlue of 3.5 mv, nd did not djust for other risk fctors. 3 The present findings tken together with the greter sensitivity of Cornell product criteri for LVH, 17,18 nd the findings of Prines et l, 13 further suggest tht seril chnges in the Cornell product my e useful for strtifying risk in hypertensive ptients. Further nlysis of dt from the LIFE study will llow this issue to e ddressed. Methodologic issues The present study defined significnt chnges in ECG LVH nd LV mss sed on percent chnges expected to exceed chnges due to norml vriility nd regression to the men of these mesures Regression of LVH ws specificlly not defined y either the Cornell product or LV mss mesurements declining elow threshold vlues used to define the presence of LVH y these methods. Use of this pproch would overestimte true regression y including smll chnges in LV mss or the Cornell product in ptients just ove or elow the threshold vlue s reflecting significnt chnges, wheres these chnges re more likely to reflect regression to the men or norml intrinsic vriility in these mesurements At the sme time, this pproch would underestimte regression of LVH in ptients with lrge reductions in LV mss tht fil to fll elow this rtificil threshold for defining hypertrophy. Implictions These findings hve importnt clinicl implictions. The strong reltionship etween chnges in the Cornell voltge durtion product nd significnt chnges in LV mss, tken together with previous studies relting chnges in ECG voltge to prognosis 2,3 nd the greter ccurcy of the Cornell product criteri for detecting LVH, 17,18 suggest tht seril chnges in Cornell product my e le to e used to determine whether ptients re hving n pproprite reduction in LV mss in response to ntihypertensive therpy. As the LIFE study ws restricted to ptients with ECG LVH on screening ECG, dditionl studies in lrge groups of hypertensive ptients without ECG LVH will e required to vlidte these findings in less-selected popultion. Further study will e necessry to elucidte the vlue of chnges in the Cornell product criteri for predicting crdiovsculr moridity nd mortlity in the LIFE study Acknowledgements We thnk Pulette A Lyle for ssistnce with preprtion of the mnuscript. This work is supported in prt y Grnt COZ-368 from Merck & Co., Inc., West Point, PA, USA. References 1 Verdecchi P et l. Prognostic vlue of new electrocrdiogrphic method for dignosis of left ventriculr hypertrophy in essentil hypertension. J Am Coll Crdiol 1998; 31: Levy D et l. Prognostic implictions of seline electrocrdiogrphic fetures nd their seril chnges in sujects with left ventriculr hypertrophy. Circultion 1994; 90: Mthew J et l. Reduction of crdiovsculr risk y regression of electrocrdiogrphic mrkers of left ventriculr hypertrophy y the ngiotensin-converting enzyme inhiitor rmipril. Circultion 2001; 104: Verdecchi P et l. Prognostic significnce of seril chnges in left ventriculr mss in essentil hypertension. Circultion 1998; 97: Koren MJ et l. Reltion of left ventriculr mss nd geometry to moridity nd mortlity in uncomplicted essentil hypertension. Ann Intern Med 1991; 114: Levy D et l. Prognostic implictions of echocrdiogrphiclly determined left ventriculr mss in the Frminghm Hert Study. N Engl J Med 1990; 322: Lio Y et l. The reltive effects of left ventriculr hypertrophy, coronry rtery disese, nd ventriculr dysfunction on survivl mong lck dults. JAMA 1995; 273: Schillci G et l. Continuous reltion etween left ventriculr mss nd crdiovsculr risk in essentil hypertension. Hypertension 2000; 35: Dhlöf B, Pennert K, Hnsson L. Reversl of left ventriculr hypertrophy in hypertensive ptients. A metnlysis of 109 tretment studies. Am J Hypertens 1992; 5: Schlich MP, Schmieder RE. Left ventriculr hypertrophy nd its regression: pthophysiology nd therpeutic pproch: focus on tretment y ntihypertensive gents. Am J Hypertens 1998; 11: Neton JD et l. Tretment of mild hypertension study. Finl results. Tretment of Mild Hypertension Study Reserch Group. JAMA 1993; 270: Five-yer findings of the Hypertension Detection nd Follow-up Progrm. Prevention nd reversl of left ventriculr hypertrophy with ntihypertensive drug therpy. Hypertension Detection nd Follow-up Progrm Coopertive Group. Hypertension 1985; 7: Prines RJ et l. Independent risk for crdiovsculr disese predicted y modified continuous score

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