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1 대한내과학회지 : 제 82 권제 6 호 특집 (Special Review) - 심부전의최신지견 말기심부전의비약물적치료 성균관대학교의과대학삼성서울병원순환기내과 최진오 Treatment of Advanced Heart Failure: Beyond Medical Treatment Jin-Oh Choi Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea During last 2 decades, advance in the mechanical circulatory support has altered the management of end-stage heart failure and cardiogenic shock. This includes percutaneous mechanical support devices such as extracorporeal membrane oxygenator (ECMO) and implantable left ventricular assist devices (LVAD). Percutaneous devices may provide prompt circulatory support and save lives of the patients with cardiogenic shock. But for a prolonged support, long-term devices such as implantable LVAD are mandatory. LVAD is useful for both bridge-to-transplantation strategy and destination therapy for the patients with end-stage heart failure. Newer LVAD using continuous flow pump has several advantages over those with pulsatile flow pump, which includes smaller size and durability and showed better outcome in recent studies. In this manuscript, brief reviews of percutaneous and implantable devices for the management of advanced heart failure will be provided. (Korean J Med 2012;82: ) Keywords: Mechanical circulatory support; Heart failure; Ventricular assist device 서론인구의고령화및급성심장질환후의생존확률증가로인하여심부전의발생이증가하여, 이로인한사회경제적손실은지속적으로증가되고있다. 최근신경호르몬계활성이심부전의발생및진행과정의병태생리에중요하다는것이알려지고, 이를조절하는약물치료가만성심부전환자의재입원및사망률을감소시킬수있음이밝혀짐에따라, 만성심부전환자의치료성적은지속적으로향상되었다 [1-10]. 급성으로악화된심부전환자들을대상으로한여러가지약물에대한임상연구들도시행되었으나, 만성심부전에서와는달리장기적인예후를호전시키지는못하였다 [11-14]. 따라서, 불응성혹은말기심부전환자들에게는강심제의지속적정맥투여나기계적순환보조장치를사용하여심실기능을보조해주는치료가필요하며, 궁극적으로는심장이식이나임종환자에대한호스피스치료가시행되어야한다. 지난 10여년간심실보조장치 (ventricular assist device, VAD) 가불응성심부전환자의치료에도움이된다는것이확인 Correspondence to Jin-Oh Choi, M.D. Division of Cardiology, Cardiac and Vascular Center, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , choijean5@gmail.com

2 - Jin-Oh Choi. Mechanical Tx of advanced HF - 되어말기심부전환자의치료방침에도커다란변화가있었다. 본종설에서는약물치료에반응하지않는불응성심부전혹은급성심부전의치료에사용되고있는기계적순환보조장치들에대하여기술하고자한다. 본론진행성심부전환자의치료전략현재미국심장학회의심부전치료지침의분류에따르면약물치료에잘반응하지않는불응성심부전혹은말기심부전환자는 D 단계로, 강심제의지속적정맥투여나기계적순환보조장치를사용하여심실기능을보조해주어야하며궁극적인호전을위해서는심장이식이필요하다 [15]. 일반적인경우심장이식대상자보다공여자의수가부족하므로, 이식대기시간이길어져강심제의지속적인투여만으로는적절한공여자가나타날때까지환자상태를유지할수없는경우가많다. 이러한경우심장이식을위한가교치료 (bridge to transplantation) 의목적으로기계적순환보조장치를사용할수있다 [16]. 최근에는심장이식의대상이되지않는말기심부전환자에게기계적순환보조장치를사용하면약물치료보다생존율이현저하게호전된다는것이알려져, 말기심부전환자의궁극적인치료 (destination therapy, DT) 로서기계적순환보조장치가사용되고있다. 또한심근경색후심인성쇽이나전격성심근염과같은급성심부전환자에게기계적순환보조장치가혈역학적으로불안정한시기에심근이회복될때까지 (bridge to recovery) 일시적으로도움을줄수있고, 악화된심실기능에의한다장기손상등으로그시점에는심장이식대상자가되지못하더라도환자상태가심장이식을받을수있는상태로호전될때까지순환보조장치를가교치료 (bridge to candidacy) 로사용하는경우도있다 [17]. 또한갑자기발생한심인성쇽으로혈역학적상태가매우불안정하거나심부전이급성악화되어강심제의정맥투여로도활력증후를유지할수없는경우에는경피적체외심폐보조장치 (percutaneous cardiopulmonary support device, PCPS) 와같은경피적순환보조장치 (percutaneous mechanical support device) 를사용하여, 장기적으로사용할수있는삽입형심실보조장치를시술하기전까지 (bridge to bridge) 혹은이후의장기치료결정시점까지환자상태를유지하기위한가교치료 (bridge to decision) 의목적 으로순환보조장치를사용할수있다 [16]. 이러한경피적순환보조장치들은비교적간단하게중환자실침상에서도응급으로시행할수있어급성기에환자의생명을유지시킬수있는중요한수단으로사용되지만, 사지허혈및출혈등의합병증이흔하고장기적으로사용할수없어, 장기간의심실보조를위하여는보다안정적인삽입형심실보조장치를사용하여야한다. 대동맥내풍선펌프 (intra-aortic balloon pump, IABP) 1968년 Kantrowitz 등이 2 심인성쇽환자 2명에게 IABP 를시행하여전신혈압과중심정맥압및소변량이호전됨을보고하였다 [18]. IABP 는이완기에하행대동맥내에위치한풍선을확장시켜관상동맥혈류를증가시키고, 수축기에풍선을감압시켜후부하를감소시키는기전으로좌심실을보조하여심박출량을약 0.5 L/min 가량증가시킬수있다. 이후심인성쇽을동반한심근경색환자에게혈전용해술시행시에 IABP 를같이시행하면병원내사망을줄일수있다고알려져심인성쇽환자의치료의중요수단으로사용되어왔다 [19]. 이후 23,180명의심근경색환자를대상으로한후향적연구에서심인성쇽환자중 7,268명에게 IABP 가시행되었고, 혈전용해술을받은경우 IABP 를사용한환자들의병원내사망률은 49% 로그렇지않은환자들의 67% 에비하여유의하게낮았다 [20]. 하지만일차적관상동맥중재시술을받은경우에는 IABP 의시행이병원내사망률에큰영향을주지못하였다. 최근시행된전향적연구에서도심인성쇽을동반한급성심근경색으로관상동맥중재시술을시행한경우 IABP 가혈역학적지표들을호전시키지못하였으며, 이후시행된메타분석에서도사망률이나좌심실구혈률에차이가없었고, 오히려뇌졸중이나출혈등의합병증만증가하였다고보고되어, 심인성쇽환자에게 IABP 가유용하다는증거를제시하지는못하였다 [21,22]. 즉, 실제임상에서는급성심근경색에의한심인성쇽에서 IABP 가혈역학적상태를호전시키는경우가종종있지만, IABP 가심인성쇽환자에서관상동맥중재시술에추가적으로사망률및이환율을감소시킨다는증거는충분하지못하다고할수있다. IABP 는관상동맥협착을동반하지않은심부전환자에서도전신혈압즉후부하를감소시켜좌심실심근에가해지는장력을낮추고산소요구량과좌심실확장기말압을감소시키며, 이에따라심박출량도증가시켜심부전의급성악화

3 - 대한내과학회지 : 제 82 권제 6 호통권제 622 호 에도움이될수있다 [23]. 이외에도심실중격파열이나유두근손상에의한심인성쇽, 약물치료에반응하지않는심실부정맥및불안정성협심증등에도도움이된다고알려져있다 [20,24,25]. 관상동맥우회수술을시행받는환자들중지속되는허혈증상및비대상성심부전으로인한혈역학적이상이동반되어응급수술을시행하는경우에는수술전 IABP 가수술에의한사망률을감소시키는것으로알려졌다 [26,27]. 하지만지속되는심근허혈이나, 심부전의동반없이단지심실기능이저하된이유만으로수술전 IABP 를일괄적으로시행하는것은바람직하지않다. 체외순환펌프를이용한순환보조장치 (Mechanical circulatory support with extracorporeal pumps) IABP 가심인성쇽환자에게어느정도의심실기능을보조할수는있으나심실기능을전적으로대치할수없어환자고유의심실기능에전적으로의존하는것과는달리심실보조장치는심실수축이없어도전신혈액순환에필요한심박출량을제공할수있어심인성쇽환자의치료에더욱 효과적일수있다. 1990년공기압축식체외펌프를사용하는 Abiomed BVS System 5000 (Abiomed, Inc, Danvers, MA) 이개발되어좌심방에서혈액을흡인하여흉부대동맥으로밀어주는수술적심실보조장치가시술되어말기심부전환자의약 2/3가심실기능의호전이나심장이식까지가교치료이후생존할수있었다고보고되었다 [28,29]. 이후 CentriMag VAD (Levitronix, Waltham, MA) 등의원심성펌프를이용한연속파형펌프가개심술후의심인성쇽에일시적인순환보조장치로사용되었다 [30]. 하지만, 이와같은수술적으로사입하는체외순환보조장치들은개흉술및이를위한전신마취가필요하여혈역학적으로불안정한심인성쇽환자에게응급으로시행하기에는제한이많아, 급성악화된심인성쇽의응급치료에는경피적으로시술하는경피적순환보조장치가우선적으로시행된다. 현재전세계적으로사용가능한경피적순환보조장치에는 TandemHeart, Impella Recover 2.5 및경피적막성체외순환보조장치 (extracorporeal membrane oxygenator, ECMO) 등이있으나국내에는 ECMO 를사용하는경피적심폐보조장치 (percutaneous cardiopulmonary support device, PCPS) 만이사용되고있다 (Table 1). Table 1. Comparison of percutaneous ventricular assist devices IABP TandemHeart Impella Recover System ECMO Pump mechanism Pneumatic Centrifugal Axial Centrifugal Insertion Retrograde 7-9F balloon catheter into the descending aorta via the femoral artery 12F catheter (13F sheath) retrograde across the aortic valve via the femoral artery 21F inflow cannula into the left atrium via the femoral vein and transseptal puncture and 15/17F outflow cannula into the femoral artery Difficulty of insertion Degree of circulatory support (with ideal SVR) + (Increased CO by 0.5 L/min) +++ (Increased CO by L/min) (Increased CO by 2.5 L/min) 18-31F inflow cannula into the right atrium via the femoral vein and 15-22F outflow cannula into the descending aorta via the femoral artery ++++ (Increased CO to 4.5 L/min) Implantation time, min Limb ischemia risk Hemolysis Bleeding risk Evidence of efficacy Increased CO and coronary and peripheral perfusion; deceased afterload Increased CO, MAP, MVO2, and urine output; decreased lactic acid, creatinine, and PCWP Increased CO and MAP; decreased lactic acid and PCWP Increased CO, MAP, and oxygenation Adopted and modified from Kar et al. [17]. SVR, systemic vascular resistance; CO, cardiac output; MAP, mean arterial pressure; MVO2, mixed venous oxygen saturation; and PCWP, pulmonary capillary wedge pressure.

4 - 최진오. 말기심부전의비약물적치료 - 막성체외순환보조장치 (ECMO) 를사용하는경피적심폐보조장치 (PCPS) ECMO 는 1960년대부터개발되어호흡부전의치료에사용되었으나, 최근 ECMO 관련기술이급속도로발전하여급성심부전및심인성쇽환자에서그사용이증가하였다. 즉, ECMO 장비가소형화되어이동이좋으며, 삽입하기까지준비시간이매우단축되어응급상황에서시술이가능해졌고, 정맥-동맥간체외순환 (venous-arterial ECMO) 뿐만아니라정맥-정맥간체외순환 (venous-venous ECMO) 의방식으로도사용되어급성호흡부전이동반된환자에서도사용이가능하다. ECMO 의가장큰장점은뒤에설명할 TandemHeart 와달리심방중격을천자할필요가없어침상에서도간단히대퇴정맥과대퇴동맥을통하여경피적으로시술할수있다는것이다. 심장수술후에발생한심인성쇽이나급성전격성심근염과같은가역적심부전환자에게심실기능이회복될때까지가교치료 (bridge to recovery) 로사용할수있고급성심근경색에동반된심인성쇽에서일차적관상동맥중재시술에혈역학적보조장치로사용하여생존율을호전시켰다는보고가있다 [31-34]. 최근에는더욱소형화되어이동성이향상된장비들이개발되어, 2차병원에내원한 38명의심인성쇽환자에게 ECMO 를시행한후 3차병원으로이송하여그중 21명이성공적으로회복되거나심장이식을받을수있었다는보고가있었다 [35-37]. ECMO 를이용한심폐보조장치의최대단점은좌심실의기능저하로인한확장기말압의증가를효과적으로해결할수가없어폐부종등이지속될수있다는점이다. 이를위하여추가적인심방중격천자를시행하여좌심방압을낮출수있었다는보고가있으나, 추가시술에따른합병증이발생할수있어, 장기적인순환보조를위해서는좌심실보조장치로변경하는것이필요하다 [38]. 또한대퇴정맥및대퇴동맥을통하여도관이이루어지므로하지혈관에심각한허혈을초래할수있고, 막성산소화기 (membrane oxygenator) 가일정시간이상사용하면혈장누출로인하여산소교환율이저하되어빈번하게교체해야하는단점등으로장기간사용할수없다 [39]. 따라서 ECMO를사용한경피적심폐보조장치는일시적인심실보조를위해응급상황에서단기적으로사용할수는있으나장기간의심실보조를위해서는적합하지않다. 경피적좌심실보조장치 (percutaneous left ventricular assist devices, percutaneous LVAD) 경피적좌심실보조장치는현재국내에서는사용되고있지는않으나전세계적으로는장기적인심실보조장치를시술하기전까지일시적으로사용되고있다. 여기에는 TandemHeart (CardiacAssist, Inc, Pittsburgh, PA) 와 Impella Recover 2.5 (Abiomed, Inc) 등의경피적좌심실보조장치가있다. TandemHeart는대퇴정맥- 우심방경로를통하여심방중격천자를시행하여좌심방의혈류를흡인하여체외원심성펌프로대퇴동맥으로혈액을밀어주어 L/min 의심박출량을보조할수있다. 초기보고에서는심인성쇽환자에게 IABP 에비하여월등한혈역학적인개선효과를보일수있으나시술에인한합병증은비슷하다고알려졌다 [40]. 하지만 30 일사망률은 IABP 와큰차이없고출혈이나하지허혈등의합병증은오히려증가했다는보고도있어각각의환자상태에따른치료방침결정이필요하다 [41]. 이외에도급성심부전환자에서심장이식, 치료결정, 혹은심실기능회복까지의일시적가교치료로 TandemHeart 를사용할수있으며, 급성이식심장거부반응과같이심한혈역학적이상이동반되는경우에도일시적으로사용될수있다 [42-45]. Impella Recover 2.5는 2.5 L/min 가량의심박출량을보조할수있어부분적인순환보조가가능하다 [17]. 급성심근경색후에발생한심인성쇽환자에게 IABP 에추가적으로사용하여 30분후혈역학적지표들을호전시킬수는있었으나, 용혈현상이증가하였고 30일생존율을증가시키지는못하였다 [46]. 하지만 TandemHeart 및 IABP 등과함께사용하여심한심실기능저하에일시적으로도움이된다는보고들이있어, 급성심부전의효과적인일시적치료로사용할수는있겠다 [47,48]. 삽입형심실보조장치삽입형심실보조장치는 1984년 Novacor 심실보조장치를시술받은환자가성공적으로심장이식을받을수있었다는보고이후, 1990년대중반에는여러가지삽입형심실보조장치들이심장이식까지의가교치료로미국식약청의허가를받아사용되었다 [16,49]. 이후삽입형심실보조장치의사용에획기적인계기를마련한대표적인연구인 REMATCH 연구가 2001년에발표되었다 [50]. 즉, 심장이식의대상이되

5 - The Korean Journal of Medicine: Vol. 82, No. 6, 지않는말기심부전환자들에게궁극적인치료 (destination therapy) 로박동형펌프 (pulsatile flow pump) 를사용하는 Heart- Mate XVE가약물치료보다생존율을호전시킨다는것이확인되어, 이후좌심실보조장치가말기심부전치료의중요수단으로자리잡는계기가되었다. 하지만박동형펌프의내구성이좋지않아대부분의경우 2년이내에펌프이상이발생하여, 1년생존율이 50%, 2년생존율이 25% 이하의기대에못미치는성적으인하여좌심실보조장치가말기심부전의보편적인치료수단이사용되지는못하였다. 이후연속파형펌프 (continuous flow pump) 인 HeartMate II가개발되어심장이식대기환자에게성공적으로사용되었고, 2009년에는전향적무작위연구인 HeartMate II DT 연구에서말기심부전환자의궁극적치료에 HeartMate II가박동형심실보조장치인 HeartMate XVE 보다장기생존율을호전시킨다는것이알려졌다 [51,52]. 이러한 HeartMate II의월등한성적은연속파형펌프가박동형펌프에비하여구조가간단하고내구성이좋은점에기인한다. 이후심장이식의대상이되지못하는말기심부전환자에게연속파형좌심실보조장치를사용하는빈도가 10배이상증가하는등좌심실보조장치는말기심부전치료의효과적인치료법으로받아들여지고있다 [53,54]. 이후로도 INTERMACS 등록사업에서도연속파형심실보조장치의 1년및 2년생존율이각각 68%, 55% 로박동형좌심실보조장치 (1년생존율 55%, 2년생존율 24%) 에비하여월등한성적을보인다는것이확인되었다 [55]. 한가지특이할만한점은 REMATCH 연구이후박동형심실보조장치의성적은 HeartMate II DT 연구에서도 1년생존율 이 50-60% 정도로 10년가량축적된임상경험에도불구하고의미있는성적의향상이없었으나, 연속파형심실보조장치는초기연구에서 1년생존율이 68% 였던것에비하여, 후속연구에서는임상경험이축적됨에따라 1년생존율이 74-85% 까지증가되었으며, 이러한성적향상에는대상환자의선택, 심장외과의의수술경험및수술후관리의개선등이중요하게작용한것으로생각된다 [56-58]. 이외에도연속파형좌심실보조장치는크기가작아체구가작은여성이나청소년에게도시술하기쉽고, 소음이크지않아환자및환자가족에게도편리하며, 현재개발되어임상시험중인장치들은심낭내에설치할수있을정도로소형화되었다 (Table 2) [59,60]. 초기연구에서는심장이식을위한가교치료로심실보조장치를시행받은환자들이그렇지않은환자들에비하여심장이식후성적이좋지않다는보고들이있었으나, 연속파형심실보조장치가사용된이후로는가교치료로시술받은경우의심장이식성적이이식후 30일생존율이 97%, 1년생존율이 87% 로가교치료를받지경우와차이가없었다 [61,62]. 심실보조장치가내구성이향상되고소형화되어기기작동이상과같은문제들은상당부분해결되었으나, 출혈, 뇌졸중혹은감염등의합병증에대한위험은아직도해결되어야할문제로남아있다. 연속파형심실보조장치를사용하고심장이식을기다리는환자 100명당매년 8명에서장애를동반하는뇌졸중이생기는것으로보고되어박동형심실보조장치의성적과 (11 stroke events per 100 person-year, p = Table 2. Implantable left ventricular assist devices HeartMate XVE Thoratec IVAD a HeartMate II HeartWare HVAD Jarvik 2000 Manufacturer Thoratec Thoratec Thoratec HeartWare Jarvik Heart Flow profile Pulsatile Pulsatile Continuous (axial) Continuous (centrifugal) Continuous (axial) Implant site Abdomen Abdomen Abdomen Pericardium Pericardium Driver Electric Pneumatic Electric Electric Electric Weight 1150 g 339 g 290 g 160 g 90 g Displacement 400 ml 252 ml 63 ml 50 ml 25 ml FDA approval BTT, DT BTT BTT, DT IDE IDE Adopted and modified from Stewart et al. [16] BTT indicates bridge to transplant; DT, destination therapy; FDA, Food and Drug Administration; HVAD, HeartWare ventricular assist device; IDE, investigational device exemption; and IVAD, implantable ventricular assist device. a Thoratec PVAD is the same pump placed in a paracorporeal position

6 - Jin-Oh Choi. Mechanical Tx of advanced HF ) 차이가없었고, 심장이식의대상이되지않는환자를대상으로한연구에서도매년 11% 의뇌졸중이발생하여박동형심실보조장치 (12%, p = 0.56) 와차이가없었다 [51,57]. 심실보조장치와관련된감염은아직도드물지않으며, 주로보조장치삽입부와경피연결부위에발생하는것으로알려져있다 [63,64]. 다행히도펌프내의혈류에직접노출되는부위의감염으로인한감염성심내막염은드물다고알려져있다. 일단감염이발생하면치료가매우어려워장치의제거및조속한심장이식이필요하며, 심장이식을받을수없는경우치명적인경우가많다. 연속파형심실보조장치는심한혈관내용혈을일으키지는않지만, 위장관혹은대뇌혈관의동정맥기형 (arteriovenous malformation) 의발생과관련이있고, 후천성 von Willebrand 인자결핍에의한혈소판기능이상이비교적흔하게동반될수있으며, 항응고요법과관련하여위장관이나비강등의점막출혈혹은뇌출혈등과관련이있다 [65-68]. 향후전망 1999년이후심장이식대기환자의 30% 이상이삽입형심실보조장치의도움을받았고, 특히응급도가높은 UNOS (United Network for Organ Sharing status) IA 등급환자들의경우에는 75% 가심실보조장치를시행받았다 [69]. 이는말기심부전으로심실보조장치를시술받고퇴원이가능하며, 심장이식을받을때까지일상생활에지장이없을정도로삶의질이향상된다는것을의미한다 [70]. 최근에는심부전치료성적이향상되어비교적응급도가낮은 UNOS II 등급환자들의 1년생존율이 81%, 2년생존율이 74% 정도로향상되어순환보조장치를시행한환자의예후와비슷해졌으나, 이러한환자들에게도심실보조장치가활동능력을높여삶의질을향상시킬수있을것으로기대되고있다.[16] 이차성폐동맥고혈압으로심장이식의상대적인금기에해당하는환자에게도심실보조장치를시행하여폐동맥압을낮추어성공적으로심장이식을시행하였다는보고도있어, 심장이식의대상자가되기위한심실보조장치의역할 (bridge to candidacy) 도기대되고있다 [71]. 연속파형심실보조장치의성적이향상됨에따라말기심부전환자에게주요장기부전이나이와관련된합병증이발생하기전에심실보조장치를시행하는것이필요하다는의견이일반적으로받아들여지고있다. 이러한견해를뒷받 침하기위해강심제의정맥주입이필요하지않은진행된심부전환자들을대상으로소형순환보조장치인 HeartWare HVAD를심낭내에삽입하는치료의유용성을확인하기위한연구인 REVIVE-IT (Randomized Evaluation of VAD intervention before Inotropic Therapy) 연구가시행되고있고, 이와비슷한대상환자들에게 HeartMate II를사용한궁극적치료를일반적인약물치료와비교하는전향적연구인 ROADMAP (Risk Assessment and Comparative Effectiveness of LVAD and Medical Management in Ambulatory Heart Failure Patients) 연구도시행될예정으로, 말기심부전으로진행하지않은환자에게심실보조장치가과연유용한가에대한관심이높아지고있다 [16,72]. 결 기계적순환보조장치가최근 10여년간말기혹은급성심부전환자의치료에도움이된다는것이확인되어, 말기심부전의치료방침에많은변화가진행되고있다. 국내에서는경피적순환보조장치인 IABP 와 ECMO 를사용한 PCPS 를시행할수있어심인성쇽이나급성심부전환자의일시적인치료에도움을받고있지만, 장기적으로사용할수있는삽입형심실보조장치에대한경험은아직전무한실정이다. 향후국내에서도삽입형심실보조장치에대한임상시험이시행될예정으로조만간국내에도입되어말기심부전환자의치료에효과적으로사용될수있는중요한치료수단이될것으로기대된다. 론 중심단어 : 기계순환보조 ; 심부전 ; 심실보조장치 REFERENCES 1. Fonarow GC, Albert NM, Curtis AB, et al. Associations between outpatient heart failure process-of-care measures and mortality. Circulation 2011;123: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS): the CONSENSUS Trial Study Group. N Engl J Med 1987;316: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure: the SOLVD Investigators. N Engl J Med 1991;325: Effect of enalapril on mortality and the development of

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