Impact of left ventricular hypertrophy on survival in end-stage renal disease

Transcription

1 Kidney Interntionl, Vol. 36 (1989), pp Impct of left ventriculr hypertrophy on survivl in end-stge renl disese JONATHAN S. SILBERBERG, PAUL E. BARRE, SARAH S. PRICHARD, nd ALLAN D. SNIDERMAN Divisions of Crdiology & Nephrology, Royl Victori Hospitl nd McGill University, Montrel, Quebec, Cnd Impct of left ventriculr hypertrophy on survivl in end-stge renl disese. We exmined the prognostic significnce of left ventriculr hypertrophy determined by echocrdiogrphy in cohort beginning renl replcement therpy. No ptient hd hemodynmiclly significnt vlvulr disese or echocrdiogrphic signs of obstructive crdiomyopthy. Using the Cox proportionl hzrds model, left ventriculr hypertrophy ws significntly ssocited with survivl. The reltive risk, bsed on comprison of upper nd lower quintiles of left ventriculr mss index, ws 3.7 (95% confidence s, 1.6 to 8.3) for ll-cuse mortlity nd 3.7 (95% confidence s, 1.2 to 11.1) for crdic mortlity. The independent risk, djusted for ge, known coronry rtery disese, dibetes, level of systolic blood pressure, nd tretment (dilysis or trnsplnttion), ws 2.9 (95% confidence s, 1.3 to 6.9) for ll-cuse mortlity nd 2.7 (95% confidence s, 0.9 to 8.2) for crdic mortlity. Therefore, left ventriculr hypertrophy ppers to be n importnt, independent, determinnt of survivl in ptients receiving therpy for end-stge renl filure. Left ventriculr hypertrophy is n importnt mrker of risk for deth nd other dverse events in ptients with hypertension [1, 2] s well s in otherwise norml people [3 5]. Although the mechnisms hve not been estblished definitively, symptomtic ventriculr rrhythmis re prevlent [6, 7], s re bnormlities of vsodiltor reserve [8, 91 nd bnormlities of the coronry microcircultion [10]. Crdiovsculr events remin the mjor cuse of mortlity nd morbidity in ptients with end-stge renl disese [11]. We hve reported high prevlence of left ventriculr hypertrophy determined by echocrdiogrphy in ptients treted by chronic mbultory peritonel dilysis; in tht study, left ventriculr hypertrophy seemed to be strongly ssocited with mortlity during short follow-up period [121. The present study ws thus designed to evlute the independent prognostic significnce of left ventriculr hypertrophy in lrger popultion with endstge renl disese treted by ll modlities (hemodilysis, intermittent nd continuous peritonel dilysis, nd trnsplnttion). Methods The Royl Victori Hospitl is tertiry referrl institution ffilited with McGill University which offers ll forms of renl Received for publiction September 14, 1988 nd in revised form Februry 6, 1989 Accepted for publiction Mrch 29, by the Interntionl Society of Nephrology replcement therpy with the exception of home hemodilysis. Since 1983 prospective protocol hs existed to determine the chrcteristics of ptients receiving tretment for end-stge renl disese. All ptients beginning therpy between Jnury 1983 nd August 1987 were screened for inclusion in the study. Ptients were excluded if they hd hemodynmiclly significnt vlvulr disese, if they hd begun dilysis t nother institution, if they were restrting fter filed trnsplnttion, if they hd known pre-existing mlignnt disese, or if they hd cute renl filure nd either died or recovered renl function. Ptients with cute renl filure who did not recover renl function but survived nd required mintennce replcement therpy were included. Ptients beginning tretment here who trnsferred to other institutions were followed s to vitl sttus. Aside from left ventriculr hypertrophy, other potentilly importnt prognostic vribles studied were ge, sex, type nd durtion of underlying kidney disese, durtion of hypertension or dibetes mellitus, level of systolic nd distolic blood pressure, definite nd suspected coronry rtery disese, smoking history, nd serum clcium, phosphte, nd prthyroid hormone levels. Myocrdil infrction ws considered 'Definite' if the electrocrdiogrm reveled bnorml Q-wves or if there ws regionl wll motion bnormlity on the two-dimensionl echocrdiogrm with pproprite electrocrdiogrphic chnges. Electrocrdiogrphic left ventriculr hypertrophy ws bsed on Romhilt-Estes Criteri [13]. Echocrdiogrphy All studies were performed using n ATL-600 pprtus (Advnced Technology Lbortories, Bothell, Wshington, USA), Two-dimensionl imging ws used to guide the M-mode bem. Evlution of vlves included pulsed nd continuous wve Doppler. All studies were reported by one of two observers ccording to Americn Society for Echocrdiogrphy criteri [14]. Left Ventriculr Mss Index (LVMI) ws determined ccording to the method of Devereux nd Reichek [15]. Outcome Vitl sttus ws estblished by physicin for ll subjects. Crdic deth ws defined ccording to criteri bsed on those used in the Lipid Reserch Clinics tril [16] s sudden (unexpected) deth, deth ssocited with definite myocrdil ischemic event, or deth in hert filure (refrctory to ultrfiltrtion). 286

2 390 Screened > (I, Tble 1. Cohort selection 271 Excluded Ill Acute renl filure 100 Begn pre Prior trnsplnttion 28 Begn elsewhere 17 Pre-existing mlignncy 4 Vlve disese: 1 Mixed mitrl vlve disese 1 Mitrl vlve replcement 2 Aortic stenosis 1 Chrt not vilble Sttistics Anlysis ws performed using SAS (SAS Institute Inc., Cry, North Crolin, USA, 1985) nd BMDP (University of Cliforni, 1983) sttisticl softwre. The Cox proportionl hzrds model ws used to estimte the survivl function, with trnsplnttion s time-dependent covrite [17]. Confidence s for rte rtios were test-bsed [181. Survivl curves were constructed ccording the method of Kpln nd Meier [191. Silberberg et l: Left ventriculr hypertrophy nd survivl 287 Tble 2. Clinicl chrcteristics (ll vlues re expressed s men sn) No. ptients Age: men rnge Sex M/F (% Mle) Kidney disese Glomerulonephritis Dibetes Nephrosclerosis Pyelonephritis Results / (27%) 21(23%) 15 (16%) 13 (14%) 119 Eligible Other 17 (18%) 91 Erly echocrdiogrphy 22 Lte echocrdiogrphy only Definite myocrdil infrction 10 (11%) No echocrdiogrphy Angin Hypertension Systolic blood pressure mm Hg Distolic blood pressure mm Hg Ure mmol//iter Hemoglobin gluier Trnsplnted during follow-up Echocrdiogrphy LVMI g/m2 LV End-systole mm LV End-distole mm LV Posterior wll mm Time, yers Fig. 1. Cumultive survivl ccording to echocrdiogrphic left ventriculr hypertrophy defined s LVMI > 125 glm2. This cutpoint corresponds to the 95th centile of 2 norml popultions reported by Csle et l [ (30%) 67 (73%) (20%) Nephrosclerosis includes hypertension but not dibetes; Pyelone- 125 gim2 phritis includes nlgesic nephropthy. Abbrevitions re: LVMI, left ventriculr mss index; LV, left ventricle. Of 390 ptients receiving renl replcement therpy during the study period, 119 met the entry criteri. The resons for exclusion of the remining ptients re shown in Tble 1. Of those eligible, 91 ptients (77%) underwent the intended echocrdiogrphic study either prior to or within the first two months of beginning replcement therpy (medin: 51 dys pre-strting). Twenty-two ptients (19%) were studied for the first time lter in the course of dilysis while six ptients (4%) died within two months of beginning therpy without hving n echocrdiogrphic study. The 91 ptients who hd n erly echocrdiogrphic exmintion were studied in the survivl nlysis (Fig. 1). Their clinicl chrcteristics re given in Tble 2. All ptients with prior definite myocrdil infrction or coronry bypss grfting hd subsequent ngin. No ptient hd symmetric septl hypertrophy, systolic nterior motion of the mitrl vlve, or midsystolic ortic vlve closure t echocrdiogrphy. Medin follow-up ws 576 dys (rnge: 2 to 1839) from the commencement of replcement therpy. Determinnts of mortlity: Crude ssocitions Bsed on comprison of uppermost (>166 gim2) nd lowermost (<83 g/m2) quintiles of left ventriculr mss index, the risk rtio (reltive risk) for left ventriculr hypertrophy ws 3.7 for both ll-cuse mortlity nd crdic mortlity (Tbles 3 nd 4). The risk rtio for end-systolic dimension for ll-cuse

3 288 Silberberg et!: Left ventriculr hyperirophy nd survivl Tble 3. Crude ssocitions: All-cuse mortlity Vrible Coefficient P. riskb 95% Confidence Age yers 0,0785 < Mle sex LVMI g/m ESD mm Syst BP mm Hg Hypertension Angin < Definite MI Dibetes Trnsplnt Abbrevitions re: LVMI, left ventriculr mss index; ESD, endsystolic dimension; Syst BP, systolic blood pressure; MI, myocrdil infrction. pvlues re two sided b For continuous vribles, reltive risk estimtes re bsed on Tble 4. Crude ssocitions: Crdic mortlity Vrible Coefficient P riskb Age yers Mle sex LVMI g/m ESDmm Syst BP mm Hg Hypertension Dibetes Angin < Definite MI TrnsplnP Abbrevitions re: LVMI, left ventriculr mss index; ESD, endsystolic dimension; Syst BP, systolic blood pressure; ML, myocrdil infrction. pvlues re two-sided b For continuous vribles, reltive risk estimtes re bsed on No trnsplnted ptient suffered crdic deth. The coefficient is thus inestimble. mortlity ws 2.6 (one-sided P 0.07), nd for crdic mortlity, 3.8 (one-sided P = 0.04). Age (uppermost quintile: >76 yers; lowermost quintile: <35 yers) ws very powerful predictor, with n estimted reltive risk of 26 for ll-cuse nd 15 for crdic mortlity. The reltive risk ssocited with ngin ws 4.9 for ll-cuse nd 9.2 for crdic mortlity, nd with definite myocrdil infrction 3.2 (ll-cuse) nd 5.6 (crdic). Dibetes ws more strongly ssocited with crdic (reltive risk 3.6) thn with ll-cuse mortlity (reltive risk 2.3). Neither the dignosis of hypertension nor the ctul level of systolic blood pressure were ssocited with ll-cuse mortlity, lthough there ws trend to greter crdic mortlity in hypertensives (reltive risk 5.1, one-sided P = 0.07). Neither cuse (other thn dibetes) nor durtion of known kidney disese were significntly ssocited with mortlity, nor were blood ure, hemoglobin, clcium, phosphte, lkline phosphtse, prthyroid hormone levels, or smoking sttus. Only Tble 5. Adjusted ssocitions: All-cuse mortlity Vrible Coefficient P riskb Age LVMI Hypertension Angin Dibetes Trnsplnt Abbrevition is: LVMI, left ventriculr mss index. pvlues re two-sided For continuous vribles, reltive risk estimtes re bsed on Tble 6. Adjusted ssocitions: Crdic mortlity Vrible Coefficient P risk1' Age LVMI Hypertension Angin Dibetes Abbrevition is: LVMI, left ventriculr mss index. pvlues re two sided b For continuous vribles, reltive risk estimtes re bsed on one of 18 ptients trnsplnted during the follow-up period died, the cuse being noncrdic. The reltive risk with trnsplnttion ws thus inestimble for crdic mortlity, while for ll-cuse mortlity it ws 0.08 (12 to 1 ginst). Multivrite nlysis The reltionship between left ventriculr mss index nd ll-cuse mortlity persisted fter djustment for ge, hypertension, ngin, dibetes nd trnsplnttion (djusted reltive risk: 2.9, Tbles 5 nd 6). Trnsplnttion ws not included in the nlysis of crdic mortlity, where the djusted reltive risk for left ventriculr mss index ws 2.7 (one-sided P = 0.04). Components of left ventriculr mss index The prognostic effects of wll thickness nd end-distolic cvity dimension were exmined in limited model djusting for the other. For both ll-cuse mortlity nd crdic mortlity, the risk ssocited with posterior wll thickness ws independent of cvity dimension (Tble 7). Thickness versus end-systolic dilttion A further model exmined the djusted effects of posterior wll thickness nd end-systolic cvity dimension. Both wll thickness (risk rtio for ll-cuse mortlity 2.6, P =0.0037) nd cvity dilttion t end-systole (risk rtio for ll-cuse mortlity 3.2, P = 0.012) exerted importnt prognostic effects independent of ech other.

4 Silberberg et!: Left ventriculr hypertrophy nd survivl 289 Tble 7. Components of LVMI Vrible Coefficient p. risk" 95% Confidence All-cuse mortlity PW thickness LV distole Crdic mortlity PW thickness LV distole Abbrevitions re: PW, posterior wll; LV left ventricle. P vlues re two-sided b risk estimtes re bsed on comprison of top nd bottom quintiles. Ptients who did not hve erly echocrdiogrphy The 22 ptients who were studied for the first time lter in the course of replcement therpy were of similr clinicl chrcteristics t entry to those who were included in the min survivl nlysis. These 22 ptients were exmined seprtely in n nlysis of survivl from the time of echocrdiogrphy. In this smll popultion the reltive risk of mortlity ssocited with left ventriculr mss index (uppermost vs. lowermost quintile) ws 2.5 (one-sided P = 0.11). Four of the six ptients who died before echocrdiogrphy could be performed hd electrocrdiogrphic left ventriculr hypertrophy. Discussion We hve found left ventriculr hypertrophy, quntitted by echocrdiogrphy nd expressed s left ventriculr mss index, to be n importnt determinnt of outcome in ptients with end-stge renl disese. The effect ws strong nd persisted fter djustment for ssocited known prognostic fctors. The prognostic importnce of left ventriculr hypertrophy evident in the present study is consistent with findings in ptients with hypertension [1, 2], in pprently norml persons [3 5], nd in trined thletes [20]. Ventriculr rrhythmis, probbly reflecting subendocrdil ischemi due to bnorml vsodiltor reserve [8, 9] or structurl chnges in the coronry microcircultion [10] pper to be the most likely mechnism of incresed risk for deth, both unexpected nd ssocited with intercurrent cute illness. The fctors for which we djusted included ge, dibetes mellitus, blood pressure, nd coronry disese. Since coronry ngiogrphy ws not prt of our routine evlution, we will necessrily hve misclssified some ptients. We chose to use ngin rther thn definite myocrdil infrction s our mrker for coronry disese in order to mximize sensitivity. Angin my occur in left ventriculr hypertrophy without coronry rtery disese, but the effect of this would be to reduce rther thn enhnce the pprent hypertrophy/survivl reltionship. Given the reported high prevlence of coronry disese in ptients with end-stge renl disese [21] nd the possibly ccelerted therosclerosis in ptients mintined on hemodilysis [22], we believe coronry rtery disese to be the most importnt fctor in determining survivl in these ptients. However, exmining the effect of left ventriculr hypertrophy while djusting for suspected coronry rtery disese, we found importnt independent effects. Indeed, it is likely tht hypertrophy mgnifies the impct of ssocited coronry rtery disese in these ptients. The importnce of 'prllel' or 'concentric' hypertrophy mnifest s wll thickening [23] versus tht secondry to cvity dilttion (mesured t both enddistole nd end-systole) ws evident when the reduced models were exmined. Posterior wll thickness nd end-systolic dimension, djusted for the other, predicted outcome eqully well, with similr reltive risks. Of interest, end-systolic volume, which reflects ventriculr systolic performnce, hs recently been suggested s the best predictor of outcome following myocrdil infrction [24]. A strength of our study is tht we identified ll ptients receiving dilysis during the study period, nd follow-up ws complete for ll ptients meeting the entry criteri. We were less successful in chieving echocrdiogrphic studies t the intended time since only 77% of our ptients were studied t the initition of dilysis. The findings in the remining ptients, however, supported the importnce of left ventriculr hypertrophy in determining outcome. While echocrdiogrphy is unquestionbly the best clinicl method vilble to estimte left ventriculr mss, its limits must not be overlooked. The method requires ccurte mesurement of the thickness of the left ventriculr wll nd the dimeter of the left ventriculr cvity. From this left ventriculr volume is clculted nd the estimte of left ventriculr mss depends on geometric ssumptions involved in these clcultions nd the ssumption of uniform wll thickness. Thus left ventriculr mss is function of left ventriculr thickness nd left ventriculr volume, nd mesurement of wll thickness lone would incompletely represent left ventriculr mss. It must lso be pprecited tht left ventriculr mss is composite of ll the tissue elements within the hert. Thus Mll et l [25] hve demonstrted tht the increse in left ventriculr mss documented in hypertensive uremic nimls correlted, in fct, better with incresed interstitil tissue thn with chnges in myocyte size. The results of this study estblish the need to understnd more precisely the determinnts of left ventriculr hypertrophy in end-stge renl disese. Hypertension, the presence of n rteriovenous fistul nd nemi must ll be considered s potentilly importnt contributors. Anemi my be of prticulr importnce since this compliction of end-stge renl disese cn now be treted with recombinnt erythropoietin. However, whether left ventriculr hypertrophy will regress with such therpy nd whether regression of left ventriculr hypertrophy would improve outcome in end-stge renl disese remins to be estblished. Reprint requests to Dr. A.D. Snidermn, Crdiology Division, M4.76, Royl Victori Hospitl, Montrel, Quebec, Cnd H3A IAI. References 1. CASALE P, DEvEREUX R, M1LNER M, ZULLO G, HARSHFIELD G, PICKERING T, LARAGH J: Vlue of echocrdiogrphic mesurement of left ventriculr mss in predicting crdiovsculr morbid events in hypertensive men. Ann mt Med 105: , FROHLICH E: Left ventriculr hypertrophy s risk fctor. Crdiol Clin 4: , 1986

5 290 Silberberg et!: Left ventriculr hypertrophy nd survivl 3. KANNEL WB, ABBOTT R: A prognostic comprison of symptomtic left ventriculr hypertrophy nd unrecognised myocrdil infrction: The Frminghm study. Am Hert J 111: , LEVY D, GARRISON Ri, SAVAGE DD, KANNEL WB, CASTELLI WP: Left ventriculr mss predicts coronry disese events independent of the stndrd risk fctors. Circultion 76(4);IV: ANDERSON K: Sudden deth, hypertension nd hypertrophy. J. Crdiovsc Phrmcol 6 (Supp. 3) S498 S503, MCLENACHAN JM, HENDERSON E, MORRIS K, DARGIE H: Ventriculr rrhythmis in ptients with hypertensive left ventriculr hypertrophy, N Engi J Med 317: , , ARONOW W, EPSTEIN S, SCHEARTZ K, KOENIGSBERG M: Correltion of complex ventriculr rrhythmis detected by mbultory ECG monitoring with echocrdiogrphic left ventriculr hypertrophy in persons older thn 62 yers in long-term helth cre fcility. Am J Crdiol 60: , MARCUS M, DOTY D, HIRATZKA L, WRIGHT C, EASTHAM C: Decresed coronry reserve: A mechnism for ngin pectoris in ptients with ortic Stenosis nd norml coronry rteries. N Engi J Med 307: , CANNON R, SCHENKE W, MARON B, TRACY C, LEON M, BRUSH J, ROSING D, EPSTEIN S: Differences in coronry flow nd myocrdil metbolism t rest nd during pcing between ptients with obstructive nd ptients with non-obstructive crdiomyopthy. JAm Coil Crdiol 10:53 65, TANAKA M, FUJIWARA H, ONODERA T, Wu D-J, MATSUDA M, HAMASHIMA Y, KAWAI C: Quntittive nlysis of nrrowings of intrmyocrdil smll rteries in norml herts, hypertensive herts, nd herts with hypertrophic crdiomyopthy. Circultion 75: , KIDNEY FOUNDATION OF CANADA: Cndin Renl Filure Registry, December EISENBERG M, PRICHARD S, BARRE P. PATTON R, HUTCHINSON T, SNIDERMAN A: Left ventriculr hypertrophy in end-stge renl disese on peritonel dilysis. Am J Crdiol 60: , ROMHILT DW, ESTES EN: A point-score system for the ECG dignosis of left ventriculr hypertrophy. Am Hert J 75:752, FEIGENBAUM H: Echocrdiogrphy. 4th ed, Phildelphi, Lee & Febiger, 1986, p DEVEREUX R, REICHEK N: Echocrdiogrphic determintion of Left ventriculr mss in mn: Antomic vlidtion of the method. Circultion 55: , LIPID RESEARCH CLINICS PROGRAM: The Lipid Reserch Clinics Coronry Primry Prevention Tril Results: I. Reduction in the incidence of coronry hert disese. JAMA 251: , MANTEL N, BYAR DP: Evlution of response-time dt involving trnsient sttes: An illustrtion using hert-trnsplnt dt. J Am Stt Assoc 69:81 86, MIETTINEN 0: Estimbility nd estimtion in cse-referent studies. Am J Epidemiol 103: , KAPLAN EL, MEIER P: Non-prmetric estimtion from incomplete observtions, JAm Stt Assoc 53: , HUSTON TP, PUFFER JC, RODNEY WM: The thletic hert syndrome. NEnglJMed3l3:24 32, IKRAM H, LYNN KL, BAILEY RR, LITTLE PJ: Crdiovsculr chnges in chronic hemodilysis ptients. Kidney mt 24: , LINDNER A, CHARRA B, SHERRARD D, SCRIBNER B: Accelerted therosclerosis in prolonged mintennce hemodilysis. N EngI J Med 290: , GROSSMAN W: Crdic Hypertrophy: Useful dpttion or pthologic process? Am J Med 69: , WHITE HD, NORRIS RM, BROWN MA, BRANDT PW, WHITLOCK RM, WILD Ci: Left ventriculr end-systolic volume s the mjor determinnt of survivl fter recovery from myocrdil infrction. Circultion 76:44 51, MALL G, RAMBAUSEK M, NEUMEISTER A, KOLLMAR S, VETTER- LEIN F, RiTz E: Myocrdil interstitil fibrosis in experimentl uremi: Implictions for crdic complince. Kidney list 33: , 1988