although the 6 minute walk test is simple and widely employed to assess submaximal exercise capacity and response to therapy in pulmonary arterial hypertension ( pah ) , it provides limited information.1 maximal cardiopulmonary exercise testing ( cpet ) can provide more comprehensive physiologic information , but is less widely available , is subject to varying interpretation across centers , and may be inconvenient for patients to perform .
submaximal exercise gas exchange measurement , using simplified technology ( ie ,  plug and play systems),2 may be a simple alternative to formal cpet that could provide information beyond that available from a 6 minute walk .
each patient was seen twice in the ph clinic , with the visits separated by approximately 35 months . as part of their assessments standard clinical tests
were performed , which included a transthoracic echo and 6 minute walk test , at both visits .
in addition , submaximal exercise step tests were performed in conjunction with clinical tests , which consisted of 2 minutes rest , 3 minutes exercise and 1 minute recovery .
gas exchange was measured throughout using a shape gas analysis system ( shape medical systems inc , st .
the shape system is a newly designed , small and portable gas analysis system that is self calibrating , containing built - in automated temperature , barometric pressure and humidity corrections .
the interface is simplified and the software designed so that extensive understanding of the methodology and equipment is not required ( fig .
a 29 year old female evaluated for syncope was diagnosed with idiopathic pah following right heart catheterization in december 2009 .
the pulmonary artery pressure at catheterization was 69/29 with a mean pulmonary arterial pressure ( papm ) of 45 mmhg , right atrial pressure ( rap ) 5 mmhg , pulmonary wedge pressure ( pcw ) 5 mmhg , cardiac output ( q ) 4.0 l / min , cardiac index ( qi ) 2.52 l / min / m and pulmonary vascular resistance ( pvr ) 10.0 wood units . the patient was subsequently started on combination therapy , consisting of sildenafil ( revatio ) 20 mg tid and inhaled trepostinil sodium ( tyvaso ) titrated to 9 breaths qid , and re - assessed approximately 3 months later .
a 56 year old female who was first diagnosed with idiopathic pah in september 2004 .
it is possible she may have hereditary hemorrhagic telangiectasia based upon frequent nosebleeds but without other diagnostic features .
most recent right heart catheterization from june 2009 demonstrated a pulmonary artery pressure of 133/40 with a papm 78 mmhg , rap 11 mmhg , pcw 10 mmhg , cardiac output 3.5 l / min with qi 2.09 l / min / m and pvr 19.6 wood units . the patient had been on various therapeutic regimes but when seen in the ph clinic in february 2010 was functional class iii on combination therapy , consisting of bosentan ( tracleer ) 125 mg tid and iloprost ( ventavis ) solution for nebulization 10 ug/1 ml by inhalation 67 times daily , and had been on this medication for approximately 2 years .
the patient remained on the same therapy and returned for re - assessment 5 months later .
a 56 year old male was first diagnosed with pah in 2005 in the context of prior splenectomy and was subsequently started on sildenafil ( revatio ) 20 mg tid in march 2006 .
the patient remained on this therapy until his visit to the ph clinic in march 2010 , when the dose of sildenafil ( revatio ) was increased to 40 mg tid because the patient still had exercise limitations that impaired quality of life .
prior to the dose increase the patient had a right heart catheterization and had a pulmonary artery pressure of 78/21 with a papm 42 mmhg , rap 8 mmhg , pcw 10 mmhg , q 6.0 l / min , qi 2.7 l / min / m and pvr 5.3 wood units . the patient was seen back , and re - tested , approximately 4 months later .
these cases are part of an on going study investigating gas exchange in pah patients that has been reviewed and approved by the mayo institutional review board .
a 29 year old female evaluated for syncope was diagnosed with idiopathic pah following right heart catheterization in december 2009 .
the pulmonary artery pressure at catheterization was 69/29 with a mean pulmonary arterial pressure ( papm ) of 45 mmhg , right atrial pressure ( rap ) 5 mmhg , pulmonary wedge pressure ( pcw ) 5 mmhg , cardiac output ( q ) 4.0 l / min , cardiac index ( qi ) 2.52 l / min / m and pulmonary vascular resistance ( pvr ) 10.0 wood units . the patient was subsequently started on combination therapy , consisting of sildenafil ( revatio ) 20 mg tid and inhaled trepostinil sodium ( tyvaso ) titrated to 9 breaths qid , and re - assessed approximately 3 months later .
a 56 year old female who was first diagnosed with idiopathic pah in september 2004 .
it is possible she may have hereditary hemorrhagic telangiectasia based upon frequent nosebleeds but without other diagnostic features .
most recent right heart catheterization from june 2009 demonstrated a pulmonary artery pressure of 133/40 with a papm 78 mmhg , rap 11 mmhg , pcw 10 mmhg , cardiac output 3.5 l / min with qi 2.09 l / min / m and pvr 19.6 wood units . the patient had been on various therapeutic regimes but when seen in the ph clinic in february 2010 was functional class iii on combination therapy , consisting of bosentan ( tracleer ) 125 mg tid and iloprost ( ventavis ) solution for nebulization 10 ug/1 ml by inhalation 67 times daily , and had been on this medication for approximately 2 years .
the patient remained on the same therapy and returned for re - assessment 5 months later .
a 56 year old male was first diagnosed with pah in 2005 in the context of prior splenectomy and was subsequently started on sildenafil ( revatio ) 20 mg tid in march 2006 .
the patient remained on this therapy until his visit to the ph clinic in march 2010 , when the dose of sildenafil ( revatio ) was increased to 40 mg tid because the patient still had exercise limitations that impaired quality of life .
prior to the dose increase the patient had a right heart catheterization and had a pulmonary artery pressure of 78/21 with a papm 42 mmhg , rap 8 mmhg , pcw 10 mmhg , q 6.0 l / min , qi 2.7 l / min / m and pvr 5.3 wood units . the patient was seen back , and re - tested , approximately 4 months later .
these cases are part of an on going study investigating gas exchange in pah patients that has been reviewed and approved by the mayo institutional review board .
patient a was free of recurrent syncope and was functional class iii at follow up .
echocardiographic estimates of pulmonary artery pressure suggested improvement but were felt to be potentially unreliable due to minimal tricuspid regurgitation .
there did appear to be improvement in right heart function as the tricuspid annular plane systolic excursion by m - mode [ tapse ] improved from 17 to 19 mm at 3 months .
right ventricular index of myocardial performance ( rimp ) improved from 0.88 to 0.54 at 3 months , while there was no significant change in tricuspid lateral annulus systolic velocity ( 0.12 vs 0.11 m / sec ) .
the 6-minute walk distance decreased slightly from 450 m to 436 m. estimates of right ventricular pressure by echocardiography were felt to be potentially spuriously low due to trivial tricuspid regurgitation but was estimated at 65 and then 69 mmhg .
echocardiographic assessments of right ventricular function were equivocal , with tricuspid lateral annulus systolic velocity changing from 0.11 m / sec to 0.08 m / sec , rimp 0.55 to 0.50 , and tapse 10 mm to 12 mm .
patient c symptomatically felt improved but had very little change in rvsp or lateral annulus systolic velocity , which was within the normal range at baseline and follow up .
there was however a large change in tapse , which increased from 21 to a supranormal value of 31 mm following 4 months of increased sildenafil treatment .
six - minute walk distance was decreased by 60 metres however despite this decrease the patient still achieved over 100% of age predicted distance ( 595 m ) .
nbnp level was not available at the baseline assessment but was 100 pg / ml at time of followup , compatible with preserved right ventricular function .
patient a was free of recurrent syncope and was functional class iii at follow up .
echocardiographic estimates of pulmonary artery pressure suggested improvement but were felt to be potentially unreliable due to minimal tricuspid regurgitation .
there did appear to be improvement in right heart function as the tricuspid annular plane systolic excursion by m - mode [ tapse ] improved from 17 to 19 mm at 3 months .
right ventricular index of myocardial performance ( rimp ) improved from 0.88 to 0.54 at 3 months , while there was no significant change in tricuspid lateral annulus systolic velocity ( 0.12 vs 0.11 m / sec ) .
the 6-minute walk distance decreased slightly from 450 m to 436 m. estimates of right ventricular pressure by echocardiography were felt to be potentially spuriously low due to trivial tricuspid regurgitation but was estimated at 65 and then 69 mmhg .
echocardiographic assessments of right ventricular function were equivocal , with tricuspid lateral annulus systolic velocity changing from 0.11 m / sec to 0.08 m / sec , rimp 0.55 to 0.50 , and tapse 10 mm to 12 mm .
patient c symptomatically felt improved but had very little change in rvsp or lateral annulus systolic velocity , which was within the normal range at baseline and follow up .
there was however a large change in tapse , which increased from 21 to a supranormal value of 31 mm following 4 months of increased sildenafil treatment .
six - minute walk distance was decreased by 60 metres however despite this decrease the patient still achieved over 100% of age predicted distance ( 595 m ) .
nbnp level was not available at the baseline assessment but was 100 pg / ml at time of followup , compatible with preserved right ventricular function .
patient a had an improved end - tidal co2 ( petco2 ) and breathing efficiency ( ve / vco2 slope / ratio ) , in accordance with improved heart function and walk distance , after 3-months treatment ( fig .
2 ) . end - tidal co2 was higher at rest and throughout exercise following treatment ( fig .
a similar pattern was evident for breathing efficiency where the ve / vco2 ratio was lower at rest and all points during exercise ( fig .
in addition , the ve / vco2 slope decreased favorably from 49 , at baseline , to 43 ( fig . 2c ) .
patient b had a reduced petco2 and breathing efficiency at the time of 5 month follow up .
ve / vco2 slope was therefore elevated from 37 at baseline to 45 ( fig .
this was despite an actual decrease in walk distance which may reflect the nonspecific nature of moderate changes in walk distance within this well preserved range .
end tidal co2 was similar at rest between the two conditions but differed during exercise ( fig .
4a ) . whilst petco2 remained constant at 28 mmhg during exercise at baseline , after 4 months of treatment petco2 increased to 34 mmhg .
multiple parameters are currently utilized in an effort to track progress of patients with pulmonary arterial hypertension , and each of them has their strengths and weaknesses . following a major shift in therapeutic approach such as occurred in patient a , we saw substantial improvement in multiple parameters including gas exchange variables .
patient b , with no fundamental change in treatment plan , had multiple parameters that were persistently abnormal but without consistent or major changes in direction . worsening of submaximal gas exchange variables , petco2 and ve / vco2 , was of concern but the significance of such changes needs to be further elucidated by serial follow up .
patient c was in a category of quite well preserved 6 minute walk distance and rv function where sensitivity of such methods for improvement in condition is limited .
in fact he had little change in his right heart function / pressure by echo estimates aside from the increase in tapse , and a decrease in 6 minute walk distance .
gas exchange variables suggested there was an improved function following 4 months of therapy and appeared consistent with his impression of clinical improvement .
it is possible that gas exchange variables , such as ve / vco2 , are more sensitive measures than other clinical measures and are able to better detect smaller changes earlier following treatment .
gas exchange data during submaximal exercise could , therefore , be a useful tool to track disease severity in pah patients . reduced pulmonary perfusion and v / q ( ventilatory / perfusion ) mismatch
is thought to be the most likely cause of alterations in breathing efficiency and endtidal co2 levels in pah .
traditional clinical measures used to determine pah severity and track patient responses to treatment are expensive , time consuming and require technical expertise ( echocardiography ) or lack sensitivity and ignore important aspects of disease ( 6 minute walk test).1 there is currently a need for more sophisticated endpoints that can be simply and inexpensively obtained .
recently it has been suggested that measuring gas exchange during exercise may be the answer , considering that one of the main symptoms of pah is dyspnea .
submaximal cpet may be a more meaningful and specific endpoint measure that allows for the measurement of key variables ( ie , physiological dead space , breathing efficiency and end - tidal co2 ) that are likely to be affected by pah .
recent research has described characteristic gas exchange abnormalities in pah patients , including a high ve / vco2 slope / ratio,3 a low resting petco2 and decreased petco2 during exercise.4 it has been suggested that these gas exchange variables track physiological changes in response to therapy.5 there is potential for developing algorithms , using multiple gas exchange variables ( ie , ve / vco2 , petco2 and other parameters ) , that may allow a more sophisticated and sensitive , yet simple , way to track disease status .
more work is clearly required in this area to determine which parameters should be used and also to standardize testing so that there is uniformity in clinical practice .
these cases demonstrate the potential utility of measuring submaximal exercise gas exchange to track responses to therapies in pah patients .
this will need to be evaluated and validated in a study of multiple pah patients before its potential role in a clinical setting and as an endpoint measure can be fully understood .
 introduction : submaximal exercise gas exchange may be a useful tool to track responses to therapy in pulmonary arterial hypertension ( pah ) patients.methods:three patients diagnosed with idiopathic pah , on differing therapies , were included . 
 standard clinical tests ( echocardiography ; 6 minute walk ) were performed pre and 35 months after treatment . 
 gas exchange was measured during 3 minutes of step exercise at both time points.results:gas exchange variables , end tidal co2 ( petco2 ) and the ratio of ventilation to co2 production ( ve / vco2 ) , during submaximal exercise were able to track patient responses to therapy over a 35 month period . 
 two patients demonstrated positive improvements , with an increased petco2 and decreased ve / vco2 during light exercise , in response to an altered therapeutic regime . 
 the third patient had a worsening of gas exchange ( decreased petco2 and increased ve / vco2 ) following no changes in the medical regime from the baseline visit.conclusion:gas exchange variables measured during light submaximal exercise , such as petco2 and ve / vco2 , may be able to better detect small changes in functional status following treatment and could , therefore , be a useful tool to track disease severity in pah patients . 
 further study is required to determine the clinical usefulness of these gas exchange variables . 
Introduction
Methods
Case Descriptions
Patient A
Patient B
Patient C
Results
Traditional clinical tests
Submaximal Exercise Gas Exchange
Discussion
Conclusion