Prolonged QT period in diabetic autonomic

Transcription

1 Br Hert J 1988;59: Prolonged QT period in dibetic utonomic neuropthy: possible role in sudden crdic deth? F BELLAVERE, M FERR, L GUARN, G BAX, A PCCOL, C CARDONE, D FEDELE From the stituto di Medicin ntern, Cttedr di Ptologi Medic Policlinico, Pdu, tly SUMMARY Twenty four men with insulin dependent dibetes nd different degrees of utonomic neuropthy were studied to estblish the response of the QT intervl to vrious hert rtes. Nine men with utonomic neuropthy hd longer QT intervl thn 13 helthy individuls nd 15 ptients who hd dibetes without, or with only mild, utonomic neuropthy. Those with utono.mic neuropthy lso hd proportionlly greter lengthening of the QT intervl for given increse in RR intervl. The results of this study suggest bsis for the finding tht sudden deth is more common in ptients with dibetic utonomic neuropthy. An ssocition between n bnorml QT intervl nd sudden crdic deth hs been found in vrious diseses.'2 The influence of utonomic tone on the QT period is lso widely ccepted, lthough the mechnisms underlying the shortening or lengthening of this period re still not cler."4 n the lte 197s severl reports noted the high incidence of sudden deth in dibetic ptients who hd severe utonomc neuropthy."6 n some cses deth ws ttributed to crdiorespirtory rrest, but in the overwhelming mjority the cuse of deth ws not identified. This prompted us to investigte chnges in QT intervl during sttic (quiet lying, sitting, nd stnding) nd dynmic (Vlslv mnoeuvre) conditions in groups of dibetic ptients with different degrees of utonomic neuropthy. Ptients nd methods The dibetic ptients (men ged (men (SD)) 42 (12)) were subdivided into three groups: eight without utonomic neuropthy, seven with borderline utonomic neuropthy, nd nine with definite utonomic neuropthy confirmed by their crdiovsculr response to series of utonomic tests (Vlslv mnoeuvre, deep brething, chnge of position from lying to stnding, sustined hnd grip, fll in blood pressure on stnding) recommended by Ewing et l' Requests for reprints to Dr F Bellvere, stituto di Medin ntem, Cttedr di Ptlogi Medic, Vi Giustinini 2, 351 Pdu, tly. Accepted for publiction 22 October 1987 nd scored by specilly devised system.8 All the ptients hd been dmitted to the wrd for tests to evlute metbolic control nd complictions. Their metbolic control ws cceptble (glycosylted hemoglobin men (SD) vlue = 9-2 (1)% nd their electrolyte blnce (sodium, potssium, chloride, clcium, phosphorus, nd mgnesium) ws within the norml rnge. None hd electrocrdiogrphic evidence of, or history of, crdiovsculr disese. The control group consisted of 13 helthy men ged 37 (8) yers. METHODS Electrocrdiogrms were recorded t 25 mm/s. The QT nd RR intervls were mesured on three chnnel ECG trce over rndomly selected segment of ten bets fter three periods of t lest two minutes of lying, sitting, nd stnding. For ech position we took the men of three similr bets in the three recordings s the bseline vlues. QT nd RR intervls were then mesured in ech subject during three Vlslv mnoeuvres t mximum tchycrdi induced on forced expirtion (phse 2) nd mximum brdycrdi fter expirtion (phse 4). We clculted the men of three vlues obtined for ech hert rte. The Vlslv mnoeuvres were performed in stndrdised conditions-tht is by blowing into dynmometer for 15 seconds t 4 mm Hg.9 The Vlslv rtio ws clculted (longest RR in phse 4: shortest RR in phse 2). The QT intervl ws mesured crefully ccording to the guidelines of Simonson et l.' We clculted the corrected QT intervl (QTc) for ech hert rte by Bzett's formul (QTc = QT//RR). 379 Br Hert J: first published s /hrt on 1 Mrch Downloded from on 26 September 218 by guest. Protected by copyright.

2 38 STATSTCAL ANALYSS We used Student's tests for pired nd unpired dt. Anlysis of covrince ws pplied to the regression slopes between QT (dependent vrible) nd RR (covrite) for the four groups studied. We used progrm P1V of the Biomedicl Computer Progrms sttisticl pckge for these clcultions." Results STATC ANALYSS Figure 1 shows tht the QT intervl during quiet sitting, even when uncorrected for hert rte, ws significntly longer in dibetic ptients with utonomic neuropthy thn in helthy individuls (36 (3)) ms vs 34 (1) ms, p < -5 when the RR intervl ws 75 (9) ms vs 824 (8) ms respectively (NS). During quiet stnding the QT intervl ws significntly longer in dibetic ptients with utonomic neuropthy thn in those without utonomic neuropthy (35 (2) ms vs 32 (3) ms (p < -5)) when the RR intervl ws 751 (1) ms vs 712 (78) ms respectively (NS) nd in the controls QT 32 (1) ms (p < -1) when the RR intervl ws 77 (1) ms (NS). Figure 1, however, lso shows tht in ll cses the QTc intervl ws significntly longer in dibetic 36- ā 32-3J 4n E poo5 pc<o5 P.1 E pco5 p-co-ol 1- L p*. } Bellvere, Ferri, Gurini, Bx, Piccoli, Crdone, Fedele ptients with utonomic neuropthy thn in those without nd in controls during lying, sitting, nd stnding. DYNAMC ANALYSS Figure 2 shows the distribution of QT vlues in reltion to RR vlues for ech group exmined t rest, mximl tchycrdi of phse 2, nd mximl brdycrdi of phse 4 during the Vlslv mnoeuvre. Liner regression nlysis of the distribution ofqt nd RR vlues in ll groups gve the regression eqution y = bx +. The regression coefficient for the dibetic ptients with utonomic neuropthy (b = -22, = 193, r = 824) ws significntly different from tht of the dibetic ptients without utonomic neuropthy, with borderline utonomic neuropthy, nd controls (p < -1). Regression coefficients in the lst three groups were not significntly different from one nother (b = -86, = 26,r = 87;b = -17, = 253,r = -881; nd b = -83, = 272, r = -815 respectively). As expected fig 2 shows tht the vrition of RR intervls ws lower in dibetic ptients with utonomic neuropthy (men Vlslv rtio 1-18 ( 1)) (tble). The difference between the slope of the dibetic ptients with utonomic neuropthy ws L Lying ) Controls Dibetes with ntonon* neuroplthy * Dibetes without ntonomic nelropithy * Dibtes with bodleine ntonomic neuropthy Fig Men vlues (ms) for Q T nd Q Tc intervls during quiet stnding, sitting, nd lying in 13 controls, nine dibetic ptients with utonomic neuropthy, seven dibetic ptients with borderline utonomic neuropthy, nd eight dibetic ptients without utonomic neuropthy. Br Hert J: first published s /hrt on 1 Mrch Downloded from on 26 September 218 by guest. Protected by copyright.

3 Prolonged QT period in dibetic utonomic neuropthy: possible role in sudden crdic deth? r_-824 b: *o * n * o RR (ms). -- ' b=.17 j r=-815 * b=.83 r=.87 b=.86 Fig 2 Regression linesfor men individul QT vs RR intervls in phse 2, resting, nd phse 4 of Vlslv mnoeuvre in 13 controls ( ), eight dibetic ptients without utonomic neuropthy (O-- -), seven dibetic ptients with borderline utonomic neuropthy ( nd nine dibetic ptients with utonomic neuropthy (*...). b, regression coefficient; r, correltion coefficient. highly significnt (F = 9-2, p < 1) from the cumultive slope of the other three groups (fig 3)." These three groups my be viewed s hving common regression line (b = -88; = 265, r = -814) becuse there ws no significnt difference (F = 8) between their individul regression lines. Discussion The dt clerly show tht the reltion between QT nd RR intervls is ltered under both sttic nd dynmic conditions in dibetic ptients with overt utonomic neuropthy. The importnce of the utonomic influence in determining the QT intervl is well estblished.34"2 Becuse there ws no other pprent cuse to explin the bnorml lengthening of the QT intervl in our dibetic ptients with utonomic neuropthy, it seems resonble to ttribute this to disturbnce of the utonomic regultion of myocrdil repolristion. The mechnism underlying this ltertion is not esily explined. t is generlly greed tht the prsympthetic system hs little, if ny, direct effect on QT modultion, which is widely ttributed to ible Men group vlues of RR nd relted QT intervls (ms) t mximum tchycrdi (in phse 2) nd t resting nd mximum sdycrdi (in phse 4) mesured during three Vlslv mnoeuvres in 13 controls, eight dibetic ptients without utonomic neuropthy, )en dibetic ptients with borderline utonomic neuropthy, nd nine dibetic ptients with utonomic neuropthy Tchycrdi Resting Brdycrdi No RR QT RR QT RR QT Vlslv rtio Controls (73) 315 (18) 824 (77) 344 (12) 1119 (132) 364 (18) 2-6 (-37) Dibetes without utonomic neuropthy (44) 35 (13) 812 (111) 337 (16) 19 (115) 344 (18) 1-8 (-28) Dibetes with borderline utonomic (11) 318 (14) 793 (137) 34 (19) 91 (139) 349 (18) 1-47 ( 3) neuropthy Dibetes with utonomic neuropthy 9 66 (84) 347 (31) 75 (97) 358 (29) 779 (121) 365 (3) 1-18 (-1) Significnce testing vs b NS - NS - NS - NS vs c NS - NS - < (5 - < 5 vs d <1 - NS - <1 - <1 b vs c NS - NS - NS - NS b vs d <1 - NS - <5 - <1 c vs d NS - NS - NS - < Br Hert J: first published s /hrt on 1 Mrch Downloded from on 26 September 218 by guest. Protected by copyright.

4 382 Bellvere, Ferri, Gurini, Bx, Piccoli, Crdone, Fedele r=.824 Anlysis of our dt on QT dpttion to RR b= -22 vrition during dynmic conditions (fig 2) shows tht the QT intervl ws similr in ll dibetic 4 ptients nd controls t the lowest vlues of RR r=.814 (induced tchycrdi) but tht s the RR intervl 38 b=*88 lengthened, the QT intervl tended to increse 36 proportionlly more in ptients with utonomic neuropthy until highly bnorml vlues of > 4 ms %E34- were reched when the RR intervl ws 1 ms 32- (hert rte = 6 bets/min). There ws tendency towrds tchycrdi in the 3- ptients with dibetic utonomic neuropthy nd none hd resting hert rte s low s 6 bets/min. 28- But even in ptients with utonomic neuropthy some interventions, such s drug tretment nd 26J RR (ms) Fig 3 Regression lines nd confidence intervls for Q T vs RR intervls during the Vlslv mnoeuvre in nine dibetic ptients with utonomic neuropthy (...) nd in ll the remining subjects ( ). b, regression coefficient; r, correltion coefficient. sympthetic influence"4 nd recent evidence suggests tht the left efferent crdic sympthetic fibres my influence QT intervl.2 n our ptients it is difficult to propose sound hypothesis for the effective mechnism underlying lengthening of the QT intervl becuse dibetic ptients with utonomic neuropthy show pttern of overriding prsympthetic withdrwl followed by sympthetic deficiency which t present is difficult to evlute in clinicl prctice. Becuse the prsympthetic pthwy does not pper to operte in these ptients, we gree with recent reports tht some non-quntifible sympthetic imblnce is responsible for the bnorml lengthening of the QT intervl in our ptients. Evidence suggests tht in dibetic ptients with utonomic neuropthy the prolonged men vlues for QT intervl resemble (for exmple QT = 362 ms for n RR = 75 ms, tht is QTc = 413 ms during quiet sitting) those found in ptients with the so-clled "long QT syndrome", condition in which there is high risk of sudden crdic deth.2 n the lte 197s there were severl reports tht unexpected sudden deth ws common in dibetic ptients with utonomic neuropthy.67 n some cses this ws ttributed to respirtory rrest. But this ws confirmed s the cuse of deth in only two cses nd no explntion could be found for the remining cses. Since then evidence hs tended to rgue ginst the hypothesis of simple respirtory rrest s the cuse of deth, becuse no ltertion in the response to hypoxi or hypercpni hs been found in ptients with utonomic neuropthy." 14 nesthesi, cn lower the hert rte. Most sudden deths in such ptients occur during the induction of nesthesi, which commonly provokes pronounced brdycrdi, condition which gretly increses the risk of crdic rrest even in helthy subjects."5 n 1984 we suggested tht the increse in QT intervl tht we found in dibetic ptients with utonomic neuropthy might explin their high risk for sudden deth.'6 The current study nd nother'7 support this view. Should utonomic dibetic crdic neuropthy be included mong the long QT syndromes nd could the ltered reltion between QT intervl nd RR intervl in such ptients explin the high incidence of sudden unexpected deth in these ptients? We hope tht studies such s ours will led to n nswer. References 1 Vly SC, Mllis G, Brown EJ, Cohn PF. Documented sudden crdic deth in prolonged Q-T syndrome. Arch ntern Med 1984;144: Schwrtz PJ. diopthic long Q-T syndrome: progress nd questions. Am Hert J 1985;19: Browne KF, Prystowsky E, Heger JJ, Chilson DA, Zipes DP. Prolongtion of the Q-T intervl in mn during sleep. Am J Crdiol 1983;52: Ahnve S, Vllin H. nfluence of hert rte nd inhibition of utonomic tone on the Q-T intervl. Circultion 1981;65: Pge M, Wtkins PJ. Crdiorespirtory rrest nd dibetic neuropthy. Lncet 1978;i: Pont A, Rushing JL, Kelsy T, Jcobs L. Crdiorespirtory rrest nd dibetic utonomic neuropthy. Lncet 1978;i: Ewing DJ, Cmpbell W, Clrke BF. The nturl history of dibetic utonomic neuropthy. Q J Med 198;49: Bellvere F, Bosello G, Fedele D, Crdone C, Ferri M. Dignosis nd mngement of dibetic utonomic neuropthy. Br Med J 1983;287:61. 9 Ewing DJ. Crdiovsculr reflexes nd utonomic Br Hert J: first published s /hrt on 1 Mrch Downloded from on 26 September 218 by guest. Protected by copyright.

5 Prolonged QT period in dibetic utonomic neuropthy: possible role in sudden crdic deth? 383 neuropthy. Clin Sci 1978;55: dibetic utonomic neuropthy. Dibetes 1984;33: 1 Simonson E, Cdy LD, Woodbury M. The norml Q-T intervl. Am Hert J 1962;63: Keenn RL, Boyn P. Crdic rrest due to nesthesi. 11 Dixon WJ, Brown MB, Engelmn L, et l. BMDP JAMA 1985;253: sttisticl softwre. Berkeley: UCLA, Bellvere F, Ferri M, Crdone C, Gurini L, Bosello G, 12 Bexton RS, Vllin HO, Cmm AJ. Diurnl vrition of Fedele D. The nlysis of QT versus RR ECG the QT intervl-influence of the utonomic nervous intervl vritions in dibetic ptients shows longer system. Br Hert J 1986;55: QT period in subjects with utonomic neuropthy. 13 Rees PJ, Prior JG, Cochrne JM, Clrk TJH. Sleep XX EASD Annul Meeting, September 1984, pnoe in dibetic ptients with utonomic London. Dibetologi 1984;27:255A. neuropthy. JR Soc Med 1981;74: Khn K, Sisson JC, Vinik A. QT intervl prolongtion 14 Ctterl JR, Clverley PMA, Ewing DJ, Shpiro CM, nd sudden crdic deth in dibetic utonomic Clrke BF, Dougls NJ. Brething, sleep, nd neuropthy. J Clin Endocrinol Metb 1987;64: Br Hert J: first published s /hrt on 1 Mrch Downloded from on 26 September 218 by guest. Protected by copyright.