REVIEW ARTICLES doi: http://dx.doi.org/10.18501/arrhythmia.2016.016 유태양 1, 이대호 2 원광대학교의과대학내과학교실 1, 가천대학교 의과대학내과학교실 2 Tae Yang Yu, MD 1 ; Dae Ho Lee, MD, PhD 2 1Department of Internal Medicine, Wonkwang University School of Medicine & Hospital; 2 Department of Internal Medicine, Gachon University Gil Medical Center Received: March 13, 2016 Revision Received: 18 April. 2016 Accepted: June 29, 2016 Correspondence: Dae Ho Lee, MD, PhD Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Republic of Korea Tel: +82-32-460-3204 Fax: +82-32-899-6033 E-mail: drhormone@naver.com Copyright 2016 The Official Journal of Korean Heart Rhythm Society Editorial Board and MMK Communications Limited Dizziness and Syncope Related with Diabetic Autonomic Neuropathy ABSTRACT Dizziness is a common symptom in patients with diabetes mellitus; it can lead to or may be confused with presyncope or syncope. The causes of these three symptoms include various drugs, metabolic decompensation, cerebrovascular diseases, vestibular diseases, and diabetic autonomic neuropathy. Although cardiac autonomic neuropathy (CAN) in patients with diabetes is associated with increased cardiovascular morbidity and mortality, CAN might exist in a subclinical state before patients develop resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction, and diabetic cardiomyopathy. Thus, it is important to detect CAN in the early phase. This article aimed to review the pathogenesis, manifestations, diagnosis, and treatment of diabetic CAN related to dizziness, presyncope, and syncope. Key Words: Diabetes Mellitus Diabetic Autonomic Neuropathy Dizziness Syncope, Cardiogenic 서론 어지럼증 (dizziness) 은환자가자각하는증상을설명하기위해사용하는비특이적인용어로원인이다양하다. 성인에서어지럼증은흔히경험하게되는증상으로유병률은 20 30% 이다. 1,2 어지럼증의원인은다양하지만크게현훈 (vertigo), 균형장애 (disequilibrium), 실신성어지럼증 (presyncope), 심인성어지럼증 (psychiatric dizziness), 기타어지럼증으로분류할수있다. 3,4 본장에서는어지럼증의여러감별진단중당뇨병환자의자율신경병증과관련되어나타날수있는 실신성어지럼증을이해하기위해서당뇨병성심혈관계자율신경병증에대하여병인, 임상증상, 진단, 예방과치료에대하여체계적으로기술하고자한다. 당뇨병성심혈관계자율신경병증 당뇨병의합병증중당뇨병성신경병증은다양한형태로신경계를침범하는만성합병증이다. 그중발생빈도가높고심각한합병증을야기하는데반하여증상이없는경우가많아간과되는합병증중하나가심혈관계자율신경병증 90
(cardiac autonomic neuropathy, CAN) 이다. 임상경과는안정빈맥, 기립성저혈압, 실신, 운동불응성, 무증상허혈, 당뇨병성심근병증, 급사등으로다양하다. 5 교감신경계의손상보다부교감신경계의손상이선행하게되는데, 이는신경병증이긴신경섬유 (longest nerve fiber) 부터손상시킴으로써미주신경이가장먼저이환되기때문이다. 6 결과적으로상대적인교감신경활성도가상승함으로써안정빈맥을유발하며, 시간의경과에따라교감신경도함께이환된다. 7 신경손상이진행됨에따라운동불응성, 기립성저혈압등의경과로발현되며, 8 심장의감각신경섬유이환으로인하여흉통을감지하지못하고, 무증상허혈이나무증상심근경색증도야기할수있다. 9 병인 당뇨병성심혈관계자율신경병증의병인은복잡하며, 상당부분은불명확하다. 하지만고혈당은병인중가장중요한인자로여겨지는데, 6 고혈당으로인한산화스트레스가미토콘드리아의활성산소생성을증가시키고, 직접적으로신경세포손상과내피기능장애를일으켜신경세포허혈을유발하는것으로생각된다. 10 또한신경세포내 myo-inositol 이감소하고, phosphoinositol 대사가감소하며, Na + /K + ATPase 활성이저하되어신경세포의손상과함께구조적이상이발생한다. 11,12 Diabetes Control and Complications Trial (DCCT) 연구에서평균 6.5년추적하였을때인슐린강화요법을통하여적극적인혈당조절을한군은그렇지않은군에비하여심혈관계자율신경병증의발생률이약 50% 감소하였다고보고하였다. 13 이러한효과는연구종료후 14 년까지지속되어엄격한혈당조절의중요성은더욱강조된다. 14 임상증상 심혈관계자율신경병증의증상은병의경과가상당히진행된후나타나게되는데, 피로, 기립성저혈압, 어지럼증, 전실신, 실신등이다. 15 이중기립성저혈압은진행된당뇨병성자율신경병증의대표적임상양상이며, 심혈관질환과총사망률 (all-cause mortality) 의독립적인 위험인자이다. 16 당뇨병성자율신경병증의진단에서기립성저혈압은앙와위 (supine) 자세에서기립후최대수축기혈압감소가 30 mmhg 초과하거나혹은이완기혈압감소가 10 mmhg 초과하는경우로정의한다. 13,17 기립성저혈압의원인은자세변화에따른교감신경반응의둔화인데, 이는 norepinephrine 반응감소, 압수용체 (baroreceptor) 감수성의감소때문인것으로알려져있으며, 결과적으로심박동수조절능력과말초혈관의수축기능이상실된다. 18,19 또한이뇨제, 혈관확장제, 삼환계항우울제, 인슐린등당뇨병환자에게흔히사용하는약물은기립성저혈압을더욱악화시킬수있으므로세심한관찰과주의를기울여야한다. 20 진단 당뇨병성심혈관계자율신경병증은제2 형당뇨병환자에서심혈관질환관련사망과높은연관성을보이나, 21 초기에는 50% 까지무증상을보일수있으므로 22 조기진단이중요하며, 조기진단을통하여관련된심혈관질환의발생이나사망을줄일수있다. 23 당뇨병성심혈관계자율신경병증의진단은여러방법이있지만 Ewing 및 Clarke가제안한방법 24 이많이사용되며, 주로심장박동수의변화를측정한다 (Table 1). 이는비침습적이며객관적인지표로평가가가능하여널리쓰인다. 부교감신경기능의지표로심호흡시심장박동수변화 (heart rate response to deep breathing), 발살바수기에의한심장박동수반응 (valsalva ratio to valsalva maneuver), 기립시심장박동수변화 (lying to standing heart rate response) 가있다. 25 위의다섯가지검사중한가지라도이상을보이는경우조기심혈관계자율신경병증의진단이가능하며, 두개혹은세개이상의검사에서이상을보이는경우명확한심혈관계자율신경병증으로진단할수있다. 또한기립성저혈압이동반되었을경우에는보다진행된심혈관계자율신경병증으로판단할수있다. 27 치료 식이요법, 유산소운동, 금연, 체중감량이도움이되며, 혈당조절을엄격히함으로써심혈관계자율신경병증의 91
Table 1. The battery of cardiovascular reflex tests Method Parameter Normal value Borderline value Abnormal value Tests to investigate parasympathetic function Heart rate response to deep breathing Beat-to-beat variation (beats/min) 15 11 14 10 Valsalva maneuver Valsalva ratio 1.21 1.11 1.20 1.10 Lying to standing heart rate response 30:15 ratio 1.04 1.01 1.03 1.00 Tests to investigate sympathetic function Lying to standing blood pressure response Decrease in systolic pressure 10 mmhg 11 29 mmhg 30 mmhg Sustained handgrip test Increase in diastolic pressure 16 mmhg 11 15 mmhg 10 mmhg 예방이가능하고, 악화를막을수있다. 14,28,29 기립성저혈압의증상과치료는아래와같은주의가필요하다. 1) 가능하다면원인이될수있는약물을피한다 ( 예 ; 삼환계항우울제, 이뇨제, 알파차단제 ). 2) 식사는조금씩자주하고, 적당한수분과염분을섭취한다. 3) 기립시천천히단계적으로일어설수있도록하며, 갑작스러운기립은피한다. 4) 서있는시간이길어질경우양측발을교차하여힘을주도록한다. 이러한방법을통하여심장박출량을 16% 까지증가시킬수있으며, 수축기혈압은 13% 까지증가시킬수있다. 30 5) 기립전발의배굴 (dorsiflexion) 과악력운동 (handgrip exercise) 을시행한다. 기립성저혈압의약물요법은많이사용되지는않지만증상이심한경우임상가가판단하여시도해볼수있다. 선택성알파효능제 (pripheral selective α 1 -adrenergic agonist; e.g. midodrine) 는말초혈관을수축시킴으로써, 31 합성코르티코이드 (9-α-fluorohydrocortisone) 는나트륨저류와혈류량의유지를통하여 32 기립성저혈압을예방할수있으며, somatostatin과 somatostatin 유사체는위장관에서혈관활성펩타이드의분비를억제함으로써내장혈관을수축시켜증상완화에도움이될수있다. 33 결론 당뇨병환자가어지럼증이나실신전조증상, 혹은실신이있을때다른원인과함께당뇨병성심혈관계자율신경병증과관련된증상을반드시염두에두어야한다. 당뇨병성심혈관계자율신경병증은초기에는 50% 까지무증상을보일수있으며, 심혈관질환과연관된사망과높은연관성을보인다. 그러므로조기진단이중요하며, 적절한생활습관개선이나약물치료로이와관련된심혈관질환의발생이나사망을줄일수있다. Acknowledgments This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2011-0010128). References 1) Neuhauser HK, Radtke A, von Brevern M, Lezius F, Feldmann M, Lempert T. Burden of dizziness and vertigo in the community. Arch Intern Med. 2008;168:2118-2124. 2) Nazareth I, Landau S, Yardley L, Luxon L. Patterns of presentations of dizziness in primary care--a cross-sectional cluster analysis study. J Psychosom Res. 2006;60:395-401. 3) Dieterich M. Dizziness. Neurologist. 2004;10:154-164. 92
4) Chawla N, Olshaker JS. Diagnosis and management of dizziness and vertigo. Med Clin North Am. 2006;90:291-304. 5) Singh JP, Larson MG, Tsuji H, Evans JC, O'Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension. 1998;32:293-297. 6) Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010;33:434-441. 7) Ewing DJ, Campbell IW, Clarke BF. Heart rate changes in diabetes mellitus. Lancet. 1981;1:183-186. 8) Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev. 1994;10:339-383. 9) Jalal S, Alai MS, Khan KA, Jan VM, Rather HA, Iqbal K, Tramboo NA, Lone NA, Dar MA, Hayat A, Abbas SM. Silent myocardial ischemia and cardiac autonomic neuropathy in diabetics. J Assoc Physicians India. 1999;47:767-769. 10) Leinninger GM, Edwards JL, Lipshaw MJ, Feldman EL. Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy. Nat Clin Pract Neurol. 2006;2:620-628. 11) Finegold D, Lattimer SA, Nolle S, Bernstein M, Greene DA. Polyol pathway activity and myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy. Diabetes. 1983;32:988-992. 12) Scarpini E, Bianchi R, Moggio M, Sciacco M, Fiori MG, Scarlato G. Decrease of nerve Na+,K(+)-ATPase activity in the pathogenesis of human diabetic neuropathy. J Neurol Sci. 1993;120:159-167. 13) The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia. 1998;41:416-423. 14) Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, Sommer C, Cleary PA, Lachin JM, Herman WH, Group DER. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/ EDIC). Circulation. 2009;119:2886-2893. 15) Balcioglu AS, Muderrisoglu H. Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. World J Diabetes. 2015;6:80-91. 16) Xin W, Lin Z, Mi S. Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies. Heart. 2014;100:406-413. 17) Vinik AI, Freeman R, Erbas T. Diabetic autonomic neuropathy. Semin Neurol. 2003;23:365-372. 18) Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O'Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27:2942-2947. 19) Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387-397. 20) Kuehl M, Stevens MJ. Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol. 2012;8:405-416. 21) Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003;26:1895-1901. 22) Wheeler SG, Ahroni JH, Boyko EJ. Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes. Diabetes Res Clin Pract. 2002;58:131-138. 23) Gerritsen J, Dekker JM, TenVoorde BJ, Kostense PJ, Heine RJ, Bouter LM, Heethaar RM, Stehouwer CD. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. Diabetes Care. 2001;24:1793-1798. 24) Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med. 1980;92:308-311. 25) Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985;8:491-498. 26) Stranieri A, Abawajy J, Kelarev A, Huda S, Chowdhury M, Jelinek HF. An approach for Ewing test selection to support the clinical assessment of cardiac autonomic neuropathy. Artif Intell Med. 2013;58:185-193. 27) Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop- Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P, Toronto Consensus Panel on Diabetic N. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:639-653. 28) LeRoith D, Fonseca V, Vinik A. Metabolic memory in diabetes-- focus on insulin. Diabetes Metab Res Rev. 2005;21:85-90. 29) Ceriello A, Esposito K, Ihnat M, Thorpe J, Giugliano D. Longterm glycemic control influences the long-lasting effect of hyperglycemia on endothelial function in type 1 diabetes. J Clin Endocrinol Metab. 2009;94:2751-2756. 30) Ten Harkel AD, van Lieshout JJ, Wieling W. Effects of leg muscle pumping and tensing on orthostatic arterial pressure: a study in normal subjects and patients with autonomic failure. Clin Sci (Lond). 1994;87:553-558. 31) Parsaik AK, Singh B, Altayar O, Mascarenhas SS, Singh SK, Erwin PJ, Murad MH. Midodrine for orthostatic hypotension: a 93
systematic review and meta-analysis of clinical trials. J Gen Intern Med. 2013;28:1496-1503. 32) Campbell IW, Ewing DJ, Clarke BF. 9-Alpha-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes. 1975;24:381-384. 33) Hoeldtke RD, O'Dorisio TM, Boden G. Treatment of autonomic neuropathy with a somatostatin analogue SMS-201-995. Lancet. 1986;2:602-605. 94