IV 만성폐쇄성폐질환에서심부전증과관상동맥질환 김유일 전남대학교의과대학내과학교실 Chronic obstructive pulmonary disease (COPD) can have many concomitant cardiovascular diseases (CVD) because COPD and CVD share tobacco abuse as a risk factor. The common cardiovascular comorbidities include heart failure, coronary artery disease, arrhythmias, peripheral vascular disease and hypertension. Among them, coronary artery disease and heart failure were reviewed mainly in this article. CVD are very common in patient with COPD. Patients with COPD and cardiovascular comordidities usually have greater morbidity and mortality. A high index of suspicion for coexisting CVD should be maintained in all patients with COPD. CVD should be treated according to usual guidelines. Key Words: COPD, Cardiovascular disease, Heart failure, Coronary artery disease Corresponding author: Yu-Il Kim, M.D., Ph.D. Division of Pulmonology, Department of Internal Medicine, Chonnam National University Hospital, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6296, Fax: +82-62-225-8578, E-mail: kyionly@chonnam.ac.kr 만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 은다양한질환을동반할수있다. 동반질환중에서특히, 심혈관계질환 (cardiovascular disease, CVD) 은 COPD 의주요사망원인및예후의중요한인자로서허혈성심질환, 심부전증, 심부정맥, 폐혈관질환, 말초동맥질환을포함한다 1,2. 이러한심혈관계질환은 COPD 환자에서흔하게동반되는데, 이는두질환모두흡연이라는공통된위험인자를가지고있기때문으로알려져있다. 여기에서는주로관상동맥질환과심부전증에대한내용위주로기술하였다. 1. COPD 와심혈관계질환의연관성 만성폐쇄성폐질환과심혈관질환은자주동반되어나타난다 3-5. 영국의대규모연구에서 3만명 COPD 환자들은 COPD 가없는환자들보다 5배정도심혈관질환을가질가능성이높다고보고하였다 3. 다른 351명의진행된 COPD 환자에대한연구에서는 60% 환자에서혈관촬영검사에서관상동맥질환이발견되었다 5. 메타분석에서는 COPD 환자에서심혈관계질환을가질위험이 2.5배정도 (OR 2.46; 95% CI 2.02 3.00) 더높다고보고하였다 6. 동반심혈관질환이 COPD 환자의임상경과및사망률등예후와도관련이있다. 특히 COPD 급성악화시에는허혈성심질환발생위험도가상승할수있다 7. Donaldson 등 8 의연구에서도 25,857 명의 COPD 환자를대상으로분석한결과, 급성악화발생후수주이내에심근경색증의위험도는 2.3배, 뇌졸중은 1.3배증가하였다. 다른보고에서는중등도이상의 COPD (FEV 1 <60% predicted) 에서심혈관질환에의한사망원인은 27% 정도를보였다 9. 그리고매 10% FEV 1 감소마다심혈관계사망률은 28% 증가하고, 관상동맥질환은 20% 정도더발생하는것으로알려졌다 10. 반대로, 심혈관계질환을가진환자에서 COPD 의영향 ( 질환발생률및사망률에미치는영향 ) 에대한연구도있다. 급성 STEMI (acute ST-elevation myocardial infarction) 3,249 명환자에관한연구에서, COPD 는사망률및심인성쇼크에영향을미치는 15
중요하고강력한요인중의하나였다 11. PCI를시행받은 14,346 명을대상으로한연구에서는 COPD 는전체사망률, 심장관련사망률, 심근경색증의의미있는위험인자로작용하였다 12. PCI 를시행받은환자들을각각달리조사한연구에의하면, COPD 환자가더낮은 ejection fraction 을나타내었고, 관상동맥의병변장소 ( 수 ) 가더많았다. 또한 COPD 환자가더높은사망률과관상동맥시술을시행다음해에재차시행한경우도더많았다 13. 안정된 COPD 98명환자에대한전향적인연구에서는, 55명에서악화가발생하였는데, 이러한악화가있는환자들은동맥강직도가상승되어있었다. 동맥경화도정도는 COPD 의염증지표자로생각된다 14. 2. COPD 환자에서관상동맥질환과심부전증의평가및진단 1) 관상동맥질환 COPD 와관상동맥질환자에서호흡곤란과가슴답답함증상은흔하게나타난다. 두질환의증상도같은경우가있어서, 이런경우어느질환에증상발현에어느정도관여했는지평가하고치료해야되는지판단하기어려운경우가있다 1,4. 이러한증상은 COPD 가조절되는않은상태이거나관상동맥질환이동반되어있어서나타날수있다. 그러므로관상동맥질환이동반되어있는지추가적인검사를고려해야된다. 만성폐쇄성폐질환과관상동맥질환등호흡기및심혈관계질환의악화는모두호흡곤란증상으로나타날수있으므로 15, 어떤질환의악화를우선의심하고먼저어떤치료를하여야될지찾는것이중요하다. 전형적인 COPD 악화의증상 ( 호흡곤란, 기침, 천명음및가래변화 ) 은폐질환가능성을, 심전도상새로운허혈증관련소견이나타날경우에는심질환을생각할수있다. 그렇지만, 두기관의질환이동시에있을경우에는구분하기어렵다 15. COPD 에서심근허혈증증상을시사하는증상이있는경우에는 EKG, 도부타민스트레영상촬영을한다. 이는일부에서충분한운동부하검사를하기힘들고 ( 폐기능저하등으로 ), 혈관확장제를이용한핵의학심관류스캔을기관지수축때문에하기어려운경우가있기때문이다 16,17. 호흡곤란과흉부불쾌감 ( 답답함. 조이는듯함 ) 이있는환자에서, 종종혈액내 cardiac tropoin 이상승되어있다. 그러나이것은항상관상동맥질환이있음을시사하는것은아니다. COPD 악화로입원한 242명환자에서, 24명에서트로포닌이상승되어있었다 18. 20명은흉통또는 / 그리고심전도추적검사에서변화가관찰되었다. 그러나흉통이나심전도변화는트로포닌상승과관련이없었다. 이는 COPD 악화시트로포닌상승은심근손상의지표를의미하지는않는다고볼수있다. 다른연구에서는 19, highly sensitive cardiac troponin (hs-ctnt) 를 COPD 악화환자 50명에서측정하였고, 안정시환자 124명에서측정하였다. 악화군에서 5.6배정도 hs-ctnt 상승을보였지만, 이러한상승은심혈관질환이나저산소증에의한혈관수축과관련성은관찰되지않았다. 2) 심부전증 (Heart failure) 발견하지못한심부전증은문제가될수있다. 244명의만성폐쇄성폐질환자를대상으로한연구에서 20, 21% 에서심부전증이발견되었고, 심근허혈증이가장많은심부전증의원인이었다. COPD 악화와심부전증악화의증상은서로비슷하게나타날수있다. N-terminal pro-brain natriuretic peptide (NT pro-bnp) 과 troponin T 측정으로심부전증과 COPD 악화를구별하기위한연구에서 21, 31% (46명/148명중 ) 에서 COPD 악화와심부전증을함께갖고있었다. 그러므로 COPD 악화자에서심장초음파나 NT pro-bnp 나 BNP 측정을함께시행을추천하는연구자도있다. 그러나 BNP나 NT pro-bnp 는폐동맥고혈압에의해서도상승될수있다는점, 흉부단순사진에서폐기종이심한경우에는심부전증이심한폐기종으로인한폐팽창소견에가려서비전형적인양상을보일수있으므로이에대한주의가필요하겠다. 3. 비약물적치료 만성폐쇄성폐질환과심혈관계질환을동시에가지고있는자에서심폐재활, 금연, 산소치료등의비약물적치료로증상과삶의질개선효과를볼수있다. 이러한비약물적치료에대한연구는각각질환에대해서는많이있지만, 16
두질환을모두동반한자에대한연구는많지않다. 1) 심폐재활 (Cardiopulmonary rehabilitation) COPD 나심혈관질환자에서운동재활의유익성에대한결과는많다. 그러나두질환이동반되었을때에대한연구는많지않다 22. 호흡재활시동반심혈관질환에대한효과는일부상반된결과의보고들이있다. 그렇기때문에운동검사에서호흡곤란이나심근허혈성흉통등이발생하지않는일부환자에게만재활치료적용을추천하는연구자들도있다. 2) 금연금연약물치료및행동요법은금연성공률을향상시키고, 만성폐쇄성폐질환자및심혈관질환자에서예후개선에중요하게작용한다. 단, 급성심근경색증당시초기입원기간동안에니코틴대체제를사용해서금연성공률을올릴수있다는일부보고가있다 (2017. 금연진료지침. 대한결핵및호흡기학회 ). 그러나급성기심혈관질환자에대한금연약물치료에대한연구는아직까지는많지않으므로주의가필요하다. 3) 저산소증의심장에대한영향및산소치료심장허혈증을초래하는저산소증정도와기간은명확하지않다. 보통산소포화도 85% 정도에 3분정도노출될지라도심장에대한영향은별로중요하지않아보인다 23. 심근허혈증은저산소증이 5분이상지속되거나, 저산소증정도가심한경우 ( 산소포화도가 85% 이하인경우 ) 에는심근허혈증이악화될가능성이있다 24. 저산소증은또한심부정맥의위험인자이다. 심실또는심실상성부정맥발생이만성폐쇄성폐질환자에서흔하다. 이는안정시악화시모두에서관련성이제시되어지고있다 25,26. 산소투여로저산소증을개선하면, 심박출량을낮추어서좌심실부담을줄여줄수있다. 이러한효과는장기산소치료시생존율향상에기여하는이유가될수있다 27,28. 다만, 일부고탄산혈증이있는만성폐쇄성폐질환자에서산소투여는고탄산혈증을악화시킬수있으므로이에대한주의가필요하다. 그러나산소투여는약간의이산화탄소분압상승을약간더초래할수있지만, 대부분허용가능한수준인경우가많다. 오히려산소치료를중단하였을때발생할수있는여러합병증위험도가고탄산혈증에의한위험도보다훨씬중요하다 27-29. 이외에도비약물치료로적용되고있는폐렴이나독감백신접종등으로감염증예방등이있다. 4. 약물치료 1) 흡입항콜린제 (Inhaled anticholinergic medications) 장시간작용항콜린제 (eg, aclidinium, glycopyrronium, tiotropium, umeclidinium) 는기저심혈관계질환유무와상관없이사용이추천되고있다 1. 과거몇연구에서항콜린제의심혈관위험성에대한보고가있었지만, 최근에는별문제없다는보고가되고있다. 특히항콜린제사용으로급성악화를낮추고, 입원횟수감소, 호흡곤란개선등의효과는이러한약제로인한심혈관계위험도를상쇄하는것으로알려지고있다. 대표적인연구로, 티오트로피옴레스피맷에대한심혈관계질환사망률증가가능성에대한이전보고가있었다 30,31. 그러나최근메타분석등연구 (TIOtropium Safety and Performance In Respimat, TIOSPIR trial) 에의하면사망률과안정성에있어서타약제와비교시문제되지는않았다 32. 2) 흡입베타2 항진제 (Beta-2 agonists) 흡입용베타항진제는비교적베타2 선택적항진제 (eg, albuterol, terbutaline, formoterol, indacaterol, olodaterol, salmeterol, vilanterol) 로대부분심혈관질환여부와상관없이사용할수있다. 속효성흡입베터2항진제를사용한 12,090 명을대상으로한연구에서도, 심근경색증등의위험도상승은관찰되지않았다 33. 일부약간의베타1 항진효과로심장부정맥등의원인이될수는있다. 17
3) 장시간작용베타항진제 (Long-acting beta agonists, LABA) 심혈관질환자에서도비교적안전하게사용할수있다. 최근연구에의하면, 살메테롤 50 μg 또는 100 μg 2차례흡입시용량과상관없이모두비교적안전하게 심장박동수증가, 조기수축, 심근허혈증소견없이-사용할수있다고보고하였다 34,35. TORCH 연구에서도, 살메테롤단독군이나살메테롤+플루티카손병합제사용군모두에서심장관련부작용증가는없었다 36. 일부과거연구에서베타2항진제가좌심실기능장애부작용을초래할수있다는보고가있었다 37. 좌심실기능장애를가진 1,529명을분석한결과, 흡입용베타항진제사용량에따라서심부전증으로인한입원위험도가일부상승하였다. 그러나최근 1,294 명의심부전증환자분석연구에서는베타2항진제사용과사망률과의관련성은발견되지않았다 38. 베타2 항진제가일부비선택적베타항진작용으로심장박동수와심부정맥을초래할수있을것으로추정할수있지만, 많은연구에서이러한부작용위험도는상승하지않는것으로보고되고있다. 4) 복합제 ( 기관지확장제+흡입스테로이드 ) 다음와같은연구에서 LABA/ICS 복합제의심혈관질환에대한안정성이보고되었다. 1) SUMMIT 연구에서 fluticasone furoate-vilanterol (100 mcg 25 mcg) 를각각의단일약제및위약군과비교시, 전체사망률이나심혈관계부작용위험도의차이는없었다 39. 2) 메타분석 (10 studies, 10,680 participants) 에서도, 복합제제와단일제제와비교시사망률의차이는보이지않았다 (OR 0.92, 95% CI 0.76 1.11) 40. 723 명만성폐쇄성폐질환자를대상으로한무작위연구에서도복합제제와단일제제와의심전도이상정도의차이는관찰되지않았다. ORCH 연구에서도복합제제의심혈관부작용은위약군과비교시증가하지않았다 36,41. 5) Roflumilast 심혈관계질환관련사망률이나심근경색증의위험은증가시키지않았다 42. 일부심방세동의빈도는올릴수있음을보고가있지만 43, LABA 제제와함께사용하더라도추가적인심혈관계부작용을초래하지는않는것으로주로보고된다 44. 6) Theophylline 일반적으로치료농도범위가좁고, 빈맥증과부정맥이농도의존성으로발생할수있으므로사용을가능한피하거나자제할필요가있다 45,46. 5. COPD 를가지고있는심혈관질환자의약물치료 COPD 가없는환자의치료와다르지않고일반적인치료지침에따라서치료가권고되고있다. 다만, 비선택적베타차단제사용은기관지수축을초래할가능성이있으므로, 가능한베타차단제사용은베타1선택적차단제 (atenolol orr metoprolol etc.) 사용을하는것이좋겠다 47. 베타차단제사용시에는 COPD 환자의새로운증상 ( 호흡곤란, 기침, 운동능력저하등 ) 이나베타2흡입제사용량증가여부등을관찰할필요가있다. 1) 베타차단제 (Beta-blockers) 일반적으로베타차단제는 COPD 를가지고있는심혈관계질환자들의사망률과 COPD 악화위험도를낮출수있다고보고되고있다 48,49. 심혈관계선택적베타차단제는비교적안전하게사용할수있다. 2) 스타틴 (Statins) 계열약물심혈관계질환을가진자들은거의모든환자에서스타틴제제를사용하고있다. 스타틴제제는 COPD 악화를줄일수있는추가적인효과가있을수있다. 그러나 COPD 악화를줄일수있는것에대한연구결과는아직상반된 18
결과를보이는경우도있어서여기에대해서는추가적인연구가필요한상황이다 50,51. 6. 요약 COPD 와심혈관계질환은흡연이라는공통된위험인자로, 비교적흔하게두질환이동반되어나타나고, COPD 환자의주요사망원인및예후의중요한인자로서허혈성심질환, 심부전증, 심부정맥, 폐혈관질환, 말초동맥질환등의심혈관계질환이작용하므로이에대한평가와검사가중요하다. 심혈관질환동반자의치료는 COPD 가없는환자의치료와크게다르지않고일반적인치료지침에따라서치료가권고되고있다. 다만, 심혈관질환치료제로사용되는일부약제, 비선택적베타차단제사용은기관지수축을초래할가능성이있으므로가능한베타차단제사용은베타1 선택적차단제사용을하는것이좋겠다. COPD 치료약제로사용되어지는약제도대부분심혈관질환자에서도안전하게사용할수있으나일부단시간작용기관지확장제, 테오필린제제등은빈맥증과같은심혈관계부작용위험도를일부높일수있으므로주의가필요하겠다. References 1. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD Executive Summary. Am J Respir Crit Care Med 2017;195:557-82. 2. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006;28:1245-57. 3. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 2010;65:956-62. 4. Enriquez JR, de Lemos JA, Parikh SV, Peng SA, Spertus JA, Holper EM, et al. Association of chronic lung disease with treatments and outcomes patients with acute myocardial infarction. Am Heart J 2013;165:43-9. 5. Reed RM, Eberlein M, Girgis RE, Hashmi S, Iacono A, Jones S, et al. Coronary artery disease is under-diagnosed and under-treated in advanced lung disease. Am J Med 2012;125:1228.e13-1228.e22. 6. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015;3:631-9. 7. Høiseth AD, Neukamm A, Karlsson BD, Omland T, Brekke PH, Søyseth V. Elevated high-sensitivity cardiac troponin T is associated with increased mortality after acute exacerbation of chronic obstructive pulmonary disease. Thorax 2011;66:775-81. 8. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010;137:1091-7. 9. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411-5. 10. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2:8-11. 11. Wakabayashi K, Gonzalez MA, Delhaye C, Ben-Dor I, Maluenda G, Collins SD, et al. Impact of chronic obstructive pulmonary disease on acute-phase outcome of myocardial infarction. Am J Cardiol 2010;106:305-9. 12. Konecny T, Somers K, Orban M, Koshino Y, Lennon RJ, Scanlon PD, et al. Interactions between COPD and outcomes after percutaneous coronary intervention. Chest 2010;138:621-7. 13. Enriquez JR, Parikh SV, Selzer F, Jacobs AK, Marroquin O, Mulukutla S, et al. Increased adverse events after percutaneous coronary intervention in patients with COPD: insights from the National Heart, Lung, and Blood Institute dynamic registry. Chest 2011;140:604-10. 14. Patel AR, Kowlessar BS, Donaldson GC, Mackay AJ, Singh R, George SN, et al. Cardiovascular risk, myocardial injury, and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1091-9. 19
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