대한내과학회지 : 제 78 권제 1 호 2010 특집 (Special Review) - 폐고혈압 폐동맥고혈압의진단과평가 순천향대학교의과대학부천병원내과 서혜선 이내희 Diagnosis and assessment of pulmonary arterial hypertension Hye-Sun Seo, M.D., Ph.D., and Nae-Hee Lee, M.D., Ph.D. Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical College, Bucheon, Korea The diagnosis and assessment of pulmonary arterial hypertension (PAH) is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging and follow-up assessment. After 4 th World Symposium on pulmonary hypertension (PH) which took place in Dana Point in early 2008, the definition of PH has been simplified (mean pulmonary artery pressure 25 mmhg) based on currently available evidences. The diagnosis of PH involves two stages: detection (determining the cause of a patient s symptoms, or to detect the presence of PAH in a high-risk patient) and characterization (determining the specific clinical context of the PH, including causal factors, associated diseases or substrates and hemodynamic perturbations). Echocardiography and right heart catheterization have been main diagnostic method in PAH. Also, there has been progress in imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. Useful tools to predict outcome include functional class, exercise capacity, pulmonary hemodynamics, acute vasoreactivity, right ventricular function, as well as brain natriuretic peptide, endothelin-1, and so on. As new therapies have been developed for PAH, screening, prompt diagnosis, and accurate assessment of disease severity have become increasingly important. A clear definition of PH and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to advance proper treatment of patients. (Korean J Med 78:5-13, 2010) Key Words: Pulmonary arterial hypertension; Pulmonary hypertension; Outcome assessment 폐동맥고혈압 (pulmonary arterial hypertension, PAH) 은폐혈관의저항성이증가되어폐동맥압이높아진질환으로서, 폐고혈압 (pulmonary hypertension, PH) 의한가지타입이고유병률이아주높지는않지만병리기전과치료방법등에대해관심이증대되고있는질환이라고할수있다. 이단원에서는다음과같은네가지내용즉, (1) 폐동맥고혈압의정의 (2) 스크리닝과진단 (3) 폐동맥고혈압환자의예후 (4) 추적관찰시평가방법등을주로보고자한다. 폐동맥고혈압의정의이전에 (2008년이전 ) 폐고혈압은평균폐동맥압 (mean pulmonary artery pressure, mpap) 이휴식시 >25 mmhg 이거나운동시 >30 mmhg 일경우즉, 두가지기준중한가지를만족하면진단되었다 1). 하지만이러한진단기준을적용할때몇가지제한점이논의되었는데, 운동의종류, 정도, 정상적인운동시폐혈압에대한기준이모호하다는것과연령이증가함에따라정상적인폐혈압도증가하므로모든연령에 - 5 -
- The Korean Journal of Medicine: Vol. 78, No. 1, 2010 - Table 1. The changes of mean pulmonary arterial pressure at exercise according to position and age Supine Upright < 30 yrs 30 to 50 yrs > 50 yrs Slight exercise (HR 100~110 bpm) Submaximal exercise (HR 130~135 bpm) Maximal exercise (HR >160 bpm) 32 mmhg 30 mmhg Slight exercise (HR 100~110 bpm) 31 mmhg 35 mmhg Submaximal exercise (HR 130~135 bpm) 37 mmhg 35 mmhg 29 mmhg 30 mmhg 45 mmhg 33 mmhg 36 mmhg 47 mmhg 서이진단기준을적용하기에는무리가있다는점등이었다. 따라서 2008년미국의 Dana 지방에서열렸던네번째폐고혈압세계심포지엄에서는폐고혈압의정의를수정하여운동시폐동맥혈압의기준은빼고, 평균폐동맥압이 25 mmhg 이상일경우로진단기준을간소화하였다 2). 이러한정의의간소화는 2003년의 3번째폐고혈압심포지엄 Evian 모임이후폐혈압에관련된여러문헌들의고찰을통하여이루어졌다. 건강한사람만포함된 72개의집단을대상으로한 47개의연구에서정상적인평균폐동맥압이 14±3.3 mmhg이며정상인의 upper limit 압력은 20.6 mmhg 으로밝혀졌다. 이연구결과에서폐동맥압은안정시와운동시에따라또한운동시누워있느냐서있는냐에따라서도다양하게측정되었고, 또한운동시폐동맥의압력은연령에따라서도다르다는것이입증되었다 3-13). 특히연령이증가함에따라휴식시폐동맥압의차이는별로없었지만운동시압력은 50세이상에서훨씬증가하는것으로나타났다 ( 표 1). 따라서운동시압력은개인의나이나자세등에따라서너무다양하게나타나므로운동할때의폐혈관압력이나폐혈관저항성을사용하는진단기준은빠지게되었고, 정상인의휴식시평균폐동맥압은 8~20 mmhg로생각되므로평 균폐동맥압력이 25 mmhg 로증가된경우폐고혈압으로진단할수있다는것이 Dana point 의핵심내용이라고할수있다. 앞에서언급했듯이폐고혈압 (pulmonary hypertension, PH) 에는여러가지타입이있으며여러타입중에서좌심장쪽문제로인한이차성폐동맥고혈압을배제하고 ( 폐모세혈관쐐기압이 15 mmhg) 폐색전증이나만성적폐질환등을감별하고나면폐동맥고혈압을진단할수있다. 표 2는폐고혈압의분류와그에따르는진단기준을정리한것이다. 앞에서언급한대로폐고혈압은타입에상관없이평균폐동맥압이 25 mmhg 이상일경우로정의할수있고, 폐모세혈관전레벨에서원인이생기는타입 I, III, IV, V와모세혈관후레벨에서원인이생기는즉, 좌측심장의문제로인한타입 II 폐고혈압으로크게나누어진단기준을확립하였고, 다음과같은표로정리하였다 ( 표 2). 폐동맥고혈압의스크리닝과진단폐동맥고혈압의초기증상은대부분경미하고, 다른질병들과겹치는증상들이나타나고, 흔히볼수있는환자가아 Table 2. The types of pulmonary hypertension and diagnostic criteria at each type Definition Characteristics Clinical group (s) Pulmonary hypertension (PH) mean PAP 25 mmhg All Pre-capillary PH mean PAP 25 mmhg PWV 15 mmhg CO normal or reduced 1. PAH 3. PH d/t lung disease 4. CTEPH 5. PT with multifactorial mechanisms Post-capillary PH Passive Reactive (Out of proportion) mean PAP 25 mmhg PWV >15 mmhg CO normal or reduced TPG 12 mmhg TPG >12 mmhg - 6-2. PH deu to Left heart disease CO, cardiac output; CTEPH, chronic thromboembolic pulmonary hypertension; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PWP, pulmonary wedge pressure; TPG, transpulmonary pressure gradient (mean PAP - mean PWP).
- Hye-Sun Seo, et al. Diagnosis and assessment of pulmonary arterial hypertension - Figure 1. The echocardiographic measurement of peak pulmonary artery pressure (PAP). Left: Color Doppler, Right: CW Doppler. Tricuspid insufficiency peak velocity is measured as 2.2 m/sec and peak gradient can be calculated as follows: 4 (2.2) 2 =20 mmhg. Therefore, estimated PAP is about 25mmHg after added 5mmHg of RA pressure. 니기때문에진단이수개월에서수년까지미뤄지는경우가많다. 따라서진단될당시에는병이상당히진행된상태일수있다. 폐동맥고혈압진단을어렵게하는또한가지의이유는다른모든가능한진단들을제외한후에야진단이가능하기때문에진단을내리기가쉽지않다는것이다. 따라서임상적으로의심이되는환자들에게일단폐고혈압검사를시도해보는것이가장중요하고, 폐고혈압이있을경우어떤타입의폐고혈압인지밝히기위해피검사, 방사선검사, 초음파검사, 심도자술등다양한검사를시행하여야한다. 다른원인들이모두배제된후폐동맥고혈압이진단되면어떤원인에의한것인지를잘찾아내서분류하고분류에맞게치료하는것이최선의방법이라고하겠다. 1. 심초음파검사심초음파는폐동맥의압력을안전하고비침습적으로측정할수있어폐고혈압을진단하는데있어가장유용한검사중하나이다. 삼첨판막역류증 (tricuspid regurgitation, TR) 의도플러초음파검사를이용하여최대폐동맥압력을유추할수있다. 두 chamber 간압력의차이는두 chamber를지나는 flow의속도제곱에비례한다는 Modified Bernoilli equation [Pressure gradient (PG) = 4 X V 2 ] 을이용하게된다. 수축기때우심실과우심방의압력차는두 chamber 간혈류인삼첨판막역류증 (TR) 의최고속도제곱에비례하는값을가지게되고, 여기에우심방의압력을 5 mmhg 로가정한후우심방의압력 (5 mmhg) 을더하면우심실의수축기압력이구해진다. 대부분의성인에서는우심실유출로에협착등의이상소 견이없기때문에우심실의수축기압력을폐동맥압력과거의비슷하다고보고폐동맥압력을구하게되는것이다 ( 그림 1). 아주고령이거나비만인사람을제외하고는휴식시에 TR의최고속도가 2.8 m/sec 이상 ( 즉, peak PG >31 mmhg) 이상이면정상보다증가되었다고진단할수있고우심방의압력을 5 mmhg로가정으로더했을때폐동맥의압력이약 36 mmhg 보다증가하면폐고혈압으로진단할수있다 14). 이렇게측정된값은실제심도자술로측정된값과상당히유사하여폐동맥의압력을비침습적으로빠르게측정할수있다는장점이있다. 하지만어떤연구에서는위양성이최대 45% 정도까지도보고되었기때문에보완적인 screening 이필요한상황이다 15,16). 2. Right heart catheterization ( 우심장심도자술 ) Gold standard 검사로써, 이검사를통하여우심방압력, 평균폐동맥혈압, 폐모세혈관쐐기압력, 폐혈관혹은전신혈관저항성, 동맥이나혼합정맥의산소포화도등을검사할수있으며여러가지약제에대한혈관의반응성정도를확인할수있다. 즉, 짧은반감기를가지는혈관확장제들 (ex. IV epoprostenol, inhaled NO, IV adenosine or inhaled iloprost) 을사용하고평균폐동맥압이 10 mmhg 이상감소하며 cardiac output에는변화없이절대수치가 40 mmhg 이하로떨어지면약제에혈관반응이있다고판단되어칼슘길항제등을치료하는근거가된다 17). 하지만이검사는침습적이고약물반응평가시심부전, 쇽등치명적인합병증이올수도 - 7 -
- 대한내과학회지 : 제 78 권제 1 호통권제 593 호 2010 - Figure 2. Diagnostic algorhithm of pulmonary hypertension. ALK-1, activin-receptor-like kinase; ANA, anti-nuclear antibodies; BMPR2, bone morphogenetic protein receptor 2; CHD, congenital heart disease; CMR, cardiac magnetic resonance; CTD, connective tissue disease; HHT, hereditary haemorrhagic telangiectasia; HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography; LFT, liver function tests; mpap, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary haemangiomatosis; PFT, pulmonary function test; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease; PWP, pulmonary wedge pressure; RHC, right heart catheterization; TEE, transoesophageal echocardiography; TTE, transthoracic echocardiography; US, ultrasonography; V/Q scan, ventilation/ perfusion lung scan. 있으므로적응증을잘가려내고숙련된센터에서시행하는것이좋겠다. 3. 기타검사이밖에 MRI도역시정확한수치를제시해줄수있는검사이지만스크리닝하는검사로서시행하기는힘들다. BNP 나 NT-proBNP 도폐동맥고혈압의조기발견에도움이되며특히젊고증상이경미하면서심초음파소견이경계성일경 우 (borderline results) BNP 가증가되어있으면추적관찰하는것이좋겠다 18). 4. 운동검사운동시도플러초음파를이용하여폐혈압이증가하는것을관찰하여폐동맥고혈압을조기에발견할수있는데, 운동시초음파에서측정하는폐동맥압은심도자술로측정한값과상당히유사하여믿을만하며 19), 특히증상이없는폐고 - 8 -
- 서혜선외 1 인. 폐동맥고혈압의진단과평가 - 혈압유전자변이의 carrier들에게서운동시폐동맥압이 >40 mmhg 로증가된경우가유전자가없는정상인의경우보다많이관찰되었다 20). 따라서운동시심초음파를사용하여폐동맥압의증가를관찰하는것은위험인자를가진환자의조기선별에도움이될것으로보인다. 그림 2는진단적알고리듬을표로서정리한것이다. 앞에서언급한대로가장중요한것은임상양상을보고의심을하는과정이다. 모든폐고혈압에서는폐순환의이상으로인하여폐혈관저항성이증가하게되고이러한변화가우심실쪽에변화를일으키게된다. 이렇게만성적으로, 말기로진행될때까지는무증상이거나비특이적증상만호소하게되므로발견이늦게되는경우가많고, 따라서고위험군에서는폐동맥고혈압이의심될때적절한검사를하여조기진단하는것이중요하다고할수있다. 폐동맥고혈압의가장흔한증상은운동시호흡곤란이고병의중등도에따라서실신, 흉통, 전신피로감, 가슴떨림, 기침, 객혈등을호소할수있다. 신체검사상에서도병의초기단계때는정상소견을나타낼수있다. 병이진행되어우심실의비후나심부전이발생하게되면 P2 sound가커지거나 TR murmur 가들리거나경정맥확장, 간비대, 복수, 말초부종등의징후를발견할수있다. 이런증상, 징후가보이면심전도, X-ray, 동맥혈가스검사등의기본적인검사를시행한다. 심전도에서는우심실의비후와 strain pattern이 X-ray에서는심비대와폐동맥확장등이상소견들이나타날수있다. 증상, 징후, 기본검사에서폐혈압이증가된것이임상적으로의심되면다음단계로심초음파를시행해야하고도플러로측정된우심실압, 폐동맥압이높게측정되면 CT, PFT, V/Q scan 등정밀검사를시행해야하며우심실심도자술로폐동맥고혈압을확진해야한다. 폐동맥고혈압이확진되면원인파악을위하여 virus 검사, drug history, abdominal U/S, antoimmune disease 에관련된검사등을시행하여관련된질환들을결정하게된다 ( 그림 2). 폐동맥고혈압환자의예후 미국의 NIH registry 에서 1981년부터 85년까지 32개의센터에등록된 194명의폐동맥고혈압환자를추적관찰했는데 Median survival이 2.8년으로조사되었고, 1년, 3년, 5년각각의 survival rates이 68%, 48%, 34% 로나와상당히나쁜예후를보여주었다 21). 그중에서도 Scleroderma 와연관된폐동맥고혈압환자는더나쁜예후를보여다른원인에의한 idiopathic PAH 환자보다위험률이 2.32~2.9배높다고조사되었다 22-24). 반면선천성심질환과관련된폐동맥고혈압은예후가좋은것으로나왔으며따라서 Eisenmenger syndrome의 survival rates은 1년, 3년, 5년각각 97%, 89%, 77% 로조사되었다 25). 프랑스의폐동맥고혈압등록사업에의한결과도폐동맥고혈압환자의 1년생존율은 88% 로비교적좋지않게나왔다 26). 하지만치료에의한생존율의향상은상당히좋은것으로관찰되었는데, 81명의 idiopathic PAH 환자를대상으로 Open-label randomized controlled trial (RCT) 를시행한결과 12주동안 epoprostenol 치료를한그룹의 1년, 3년, 5년생존율이각각 68%, 48%, 34% 에서각각 80%, 76% and 49% 로증가한것으로관찰되었으며이러한결과는 Sitbon 등의연구에서도비슷하게나왔다 27,28). 또한 Galie 등이 1990년 1월부터 2008년 10월까지등재된 medline database 를이용하여폐동맥고혈압에대한 RCT를메타분석하였는데 29), 적절한약물치료후 3,140명의환자들의평균치사율이 43% 감소한것으로조사되었다. 이렇듯폐동맥고혈압환자의예후는상당히안좋은편이지만약물반응이좋은경우생존율이많게는 40% 가량향상되므로이런환자들에게는정확하게예후를평가하여적극적으로약물치료하는것이중요하다고할수있다. 예후를평가하는방법으로서는다음과같은것들이이용되고있다. 1. 혈역학적인자우심방의압력이증가되어있을경우, cardiac index가감소되어있을경우, 폐혈관의저항성이증가되어있거나폐동맥압력이증가되어있는경우, 혼합정맥의산소포화도가감소되어있을경우나쁜예후를시사하는소견이다 28-30). 2. 칼슘길항제나 nitric oxide 등의혈관확장약물에반응을보이는환자는전체의약 10% 정도를차지하며이중반수정도에서는약물에좋은반응을보이므로이러한반응성을확인하는것도예후평가의한방법이될수있다 31). 3. 심초음파에서심낭삼출의정도가심할수록, 우심방의크기가클수록, 우심실의기능이저하되어있을경우 ( 특히삼첨판의 annular excursion (TAPSE) 정도가 18 mm보다저하되어있을경우 ), 폐혈관의저항성이증가되어있을경우나쁜예후와관련이되어있으나, 폐동맥고혈압의정도자체는예후와직접적인관련은없는것으로되어있다 32-34). - 9 -
- The Korean Journal of Medicine: Vol. 78, No. 1, 2010-4. 6 minutes walk test 는폐동맥고혈압의연구에서많이사용되는방법이다. 6분동안평지를걷는거리를 meter 로표시하는방법으로, 안전하고저렴하며재현성이좋아세계적으로예후를평가하는중요한방법으로알려져있다. 특히 250 m 이하의값을가지거나산소포화도가 10% 이상감소할경우나쁜예후를시사한다고볼수있다 28,35). 5. Cardiopulmonary exercise test 역시예후평가의한가지방법으로써, anaerobic threshold 에서의산소 uptake 정도와 peak exercise, peak work rate, peak heart rate, ventilator efficiency 등을측정할수있으며폐동맥고혈압환자에서는이모든값이감소되어있다. 하지만 RCT에서아직기준화된값이없고많은기관에서의경험이부족한것이단점일수있겠다 36). 6. Functional class 는강력하게생존을예측할수있는인자가될수있으며 I/II인경우평균생존기간이 6년이지만, III인경우 2.5년, IV일경우 6개월정도로 class의정도와생존간에는강력한반비례관계가관찰되며 21,23), 특히나이가많을경우, 실신의과거력이있는경우, 객혈을한경우, 우심실기능부전의증거가있는경우에는나쁜예후가예상된다. 7. 생화학적지표들 BNP나 NT-proBNP 는우심실기능부전정도를나타내주는지표들로이수치가증가되어있을경우예후가안좋은것을예측할수있으며, 치료이후에이러한지표가많이감소할수록약물반응이좋은것으로평가할수있고, 실제로어떠한한연구에서는생존자들의약물치료후 BNP의감소 정도가비생존자에비해더큰것을관찰할수있었다 37). 109 명의전신경화증환자 (systemic sclerosis) 환자를대상으로한연구에서폐동맥고혈압이동반된그룹의평균 NT- probnp 는 1,474 pg/ml인반면고혈압이동반되지않은경우는 139 pg/ml로많은차이를보였으며 NT-proBNP 가높은값을보이면사망률이 4배증가하는것으로나타났다. NT- probnp level 은평균폐동맥압, 폐혈관저항성과는비례관계에 6 minutes walk distance와는반비례관계에있는것이관찰되었다 38). 폐동맥고혈압의질병활동도 (disease activity) 를평가하고예후를예측할수있는여러인자들을소개하였고, 여러가지검사결과들을잘분석하고해석하여환자에게적용하는것이필요하겠다 ( 표 3). 추적관찰시평가항목아직 guideline으로정립화되지는않았지만다음두가지방법들이추적관찰에이용되고있다. 1. 임상양상에근거한방법증상, 징후에중점을두고접근하는방법으로, functional class I/II나우심실기능부전의증거가없는경우에는현치료를유지하고, 이러한평가를내리기위해심전도, X-ray, 심초음파, 6 minute walk test 등의검사를시행한다. 이방법에서는임상적인안정성이나악화를평가할만한목표나검사결과치가정해지지않았다는특징이있다고하겠다 39). 2. 목표중심의평가방법증상보다는목표로하는한가지 parameter 를정해놓고이 Table 3. The prognostic factors in patients with pulmonary arterial hypertension Better prognosis Determinants of prognosis Worse prognosis No Clinical evidence of RV failure Yes Slow Rate of progression of symptoms Rapid No Syncope Yes I, II WHO-FC IV Longer (>500 m) a 6MWT Shorter (<300 m) Pear O 2 consumption >15 ml/min/kg Cardio-pulmonary exercise testing Pear O 2 consumption <12 ml/min/kg Normal or near-normal BNP/NT-proBNP plasma levels Very elevated and rising No pericardial effusion TAPSE b >2.0 cm Echocardiographic findings b Pericardial effusion TAPSE b <1.5 cm RAP <8 mmhg and CI 2.5 L/min/m 2 Haemodynamics RAP >15 mmhg or CI 2.0 L/min/m 2 TAPSE, Tricuspid annular plane systolic excursion; CI, cardiac index; RAP, right atrial pressure. - 10 -
- Hye-Sun Seo, et al. Diagnosis and assessment of pulmonary arterial hypertension - Table 4. Recommended duration, timing and test at follow up of PAH patients Clinical assessment WHO-FC ECH At baseline (prior to therapy) Every 3~6 months a 3~4 months after initiation or changes in therapy In case of clinical worsening 6MWT b Cardio-pulmonary exercise testing b BNP/NT-proBNP Echocardiography RHC c d d PAH, pulmonary arterial hypertension; 6MWT, 6 minutes walk test; RHC, right heart catheterization. 목표수치에도달하기까지치료방법을바꾸거나다른치료방법을추가하는등의목표중심치료라고할수있겠다. 예를들어 6 minutes walk test에서 distance >380 m, 최고산소이용 >10.4 ml/min/kg, 운동시최고수축기혈압 >120 mmhg이라고목표를정했으면이것에도달할때까지약물조절을하면서 3~6개월마다추적관찰을하는치료방법을말한다 40-41). 적극적인약물치료가행해질수있다. 이방법에서추천되는추적관찰을하는방법과기간등을정리하면다음표와같다 ( 표 4). 앞으로의방향진단에있어서앞으로해결해야될몇가지점은 (1) 폐동맥고혈압의약물치료대부분은 RCT에서 6 minutes walk test 를사용하고있지만, 과연임상적인호전이나악화를대표할수있는최소한의거리가어느정도인지그리고관절이나뼈, 근육등운동에영향을줄수있는다른인자들을어떻게고려할것인지 (2) 우심실의기능을정확하게평가하기위해심초음파결과들을어떻게사용할것인지 (3) 우심실심도자에서 pressure-flow 관계를어떻게이용할것인지등에대해논의중이며, 정확한우심실의부피, 기능, mass 등우측심장을정확히평가하기위한다른보완적인검사들 ( 예를들어 cardiac MRI) 의발전도기대해볼수있겠다. 중심단어 : 폐동맥고혈압 ; 폐고혈압 ; 예후평가 REFERENCES 1) Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43(12 Suppl S):5S-12S, 2004 2) Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 54(1 Suppl):S55-56, 2009 3) Yu PN, Murphy GW, Schreiner BF Jr., James DH. Distensibility characteristics of the human pulmonary vascular bed: study of the pressure-volume response to exercise in patients with and without heart disease. Circulation 35:710-723, 1967 4) Harris P, Segel N, Bishop JM. The relation between pressure and flow in the pulmonary circulation in normal subjects and in patients with chronic bronchitis and mitral stenosis. Cardiovasc Res 2:73-83, 1968 5) Emirgil C, Sobol BJ, Campodonico S, Herbert WH, Mechkati R. Pulmonary circulation in the aged. J Appl Physiol 23:631-640, 1967 6) Gurtner HP, Walser P, Fässler B. Normal values for pulmonary hemodynamics at rest and during exercise in man. Prog Resp Res 9:295-315, 1975 7) Kubicek F, Gaul G. Comparison of supine and sitting body position during a triangular exercise test. I. Experiences in healthy subjects. Eur J Appl Physiol Occup Physiol 36:275-283, 1977 8) Thadani U, Parker JO. Hemodynamics at rest and during supine and sitting bicycle exercise in normal subjects. Am J Cardiol 41:52-59, 1978 9) Hossack KF, Bruce RA, Green B, Kusumi F, DeRouen TA, Trimble S. Maximal cardiac output during upright exercise: approximate normal standards and variations with coronary heart disease. Am J Cardiol 46:204-212, 1980-11 -
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