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Hemodynamic Ranges During Daily Activities and Exercise Testing in Patients With Pulmonary Arterial Hypertension
Accepted Manuscript Hemodynamic ranges during daily activities and exercise testing in patients with pulmonary arterial hypertension Barbro Kjellström, Robert P. Frantz, Raymond L. Benza, Tom Bennett, Robert C. Bourge, Michael D. McGoon PII:
S1071-9164(14)00187-0
DOI:
10.1016/j.cardfail.2014.04.019
Reference:
YJCAF 3295
To appear in:
Journal of Cardiac Failure
Received Date: 14 May 2013 Revised Date:
27 April 2014
Accepted Date: 30 April 2014
Please cite this article as: Kjellström B, Frantz RP, Benza RL, Bennett T, Bourge RC, McGoon MD, Hemodynamic ranges during daily activities and exercise testing in patients with pulmonary arterial hypertension, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT B Kjellström, PAH hemodynamic ranges
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pulmonary arterial hypertension
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Running title: PAH hemodynamic ranges
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Hemodynamic ranges during daily activities and exercise testing in patients with
Barbro Kjellström1, Robert P Frantz2, Raymond L Benza3, Tom Bennett4, Robert C Bourge5, Michael D
1
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McGoon2
Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 2Division of
Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, Minnesota; 3Allegheny General Hospital, Pittsburgh, Pennsylvania; 4NT&D Research, Medtronic Inc, Minneapolis, Minnesota; 5
Department of Medicine, Division of Cardiovascular Diseases, University of Alabama at Birmingham,
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Birmingham, Alabama
The study was supported by Medtronic, Inc, Minneapolis, Minnesota. This manuscript represents results
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from a clinical trial that was begun before July 1, 2005 and therefore is not registered.
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Address correspondence to:
Barbro Kjellstrom
Department of Cardiology Research Karolinska hospital Solna Building N3:06 S-171 76 Stockholm Sweden E-mail: [email protected]
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Abbreviations AMB = ambulatory range
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HR = heart rate IHM = implantable hemodynamic monitor MAXWT = maximal exercise test
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MPAP = mean pulmonary artery pressure
RVSP = right ventricular systolic pressure RVDP = right ventricular diastolic pressure 6MWT = 6-min walk test
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12W = 12-weeks
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PAH = pulmonary arterial hypertension
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Abstract Background: In patients with pulmonary arterial hypertension (PAH) the relation of hemodynamic
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impairment experienced during daily activity and exercise test is not known. Methods and results: Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary artery pressure (MPAP). Before starting a new PAH treatment (baseline) and after 12-weeks on treatment (12W) a 6-min walk test
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(6MWT) and a maximal exercise test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT.
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Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24-hours. One week of ambulatory ranges were averaged for each patient before each exercise test.
Mean age was 54±18 years, 9 were female and all in WHO functional class 3. At baseline RVSP and
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MPAP increased 136±49% and 164±49% during AMB, 63±26% and 79±30% during MAXWT and 59±32% and 69±33% during 6MWT. There was no difference in pressure change at 12W. Conclusions: Changes in RV and PA pressures during exercise tests were relatively small compared to the
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range seen during ambulatory conditions.
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Introduction Patients with pulmonary arterial hypertension (PAH) commonly have limitations attending to daily activities, often appearing early in the course of their disease progression. Symptoms of exercise induced
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dyspnea, fatigue and lightheadedness (1-4) are among the first signs a patient will experience and therefore, exercise testing is important in the patient assessment. Submaximal exercise testing, such as the 6 minute walk test (6MWT), is routinely used to evaluate patients with cardiopulmonary disease and is
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considered to have a close relation to maximal exercise test in patients with reduced functional capacity (5). However, respiratory exchange ratio measured during 6MWT in patients with PAH remained below
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1.0 and the Borg score increased only moderately, confirming the 6MWT as a submaximal test (6). It has been suggested that the workload during submaximal exercise is applicable to everyday activities (7-8). However, the relation between physical stress levels during exercise tests and daily living are not known in patients with PAH, mainly due to lack of available tools for reliable measurements under such
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conditions. An implantable hemodynamic monitor (IHM) allowed for new discoveries in this field (9-12).
Methods
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Study population/study protocol
Twenty-four patients with PAH were implanted with an IHM (Chronicle®1, Model 9520, Medtronic, Inc,
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Minneapolis, USA; 7-9) to evaluate if the measurements could verify treatment responses as a new PAH treatment was initiated. Results from this study have been reported previously (12). Patients enrolled in the study were adult patients diagnosed with idiopathic PAH, PAH related to connective tissue disease or anorexigen drug use and in World Health Organization functional class II-III. In addition, they were either newly diagnosed or on stable PAH therapy for at least 3 months, but clinically indicated for additional PAH therapy. Exclusion criteria included left ventricular dysfunction, obstructive or restrictive
1
The Chronicle® IHM was an investigational device, limited by Unites States law to investigational use.
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lung disease, six minute walk distance <50 or ≥450 m or unable to tolerate a one-week baseline observation period prior to adding new therapy. All centers obtained approval of their institution’s ethics committee prior to the study and all patients provided written informed consent.
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Right ventricular and calculated pulmonary artery mean pressure measurements were obtained via an IHM, similar to a pacemaker in shape and placed subcutaneously in the pectoral area. A pressure sensor lead was placed with the tip in the right ventricle, preferably in a mid to high septal position. The pressure
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monitoring system has been described in detail previously (9-12). Measurement of heart rate (HR), right ventricular systolic (RVSP), diastolic (RVDP) and mean pulmonary artery pressure (MPAP) were derived
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from each cardiac cycle and stored continuously as the median over a preprogrammed storage interval. MPAP was the time weighted average of RVSP and estimated pulmonary artery pressure (ePAD) where ePAD was derived from the RV pressure waveform at maximum, dP/dt corresponding to the time of pulmonary valve opening (13-14)
Activity counts from an internal accelerometer were sampled every 2 seconds and an average of all counts
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over each storage interval was stored. Continuous ambulatory hemodynamic data collection (4-6 minute resolution) was initiated at time of device implant. The IHM data was transmitted via transtelephonic transmission from the patient’s home or current location to a secure website at least once a week (15). At
was started (baseline).
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least seven days had to elapse after the IHM implant until treatment with a new or additional PAH drug
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At baseline and after 12 weeks (12W) the patients performed a scheduled maximal, symptom limited exercise test on a treadmill (MAXWT) and a 6MWT. During the tests hemodynamic data was collected in high resolution (2 second sampling interval) and downloaded to a programmer after each test. Oxygen consumption was measured during MAXWT by a metabolic assessment system (CPX; Medgraphics; St Paul, MN) utilizing breath-by-breath technique. To be included in the analysis presented in this paper two conditions had to be met; 1) high resolution hemodynamic values available from both MAXWT and 6MWT performed at baseline and 12W visits and
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2) AMB hemodynamic data available from 7 consecutive days before each of the tests. Ten patients from the original study cohort met these restrictive criteria. The two most common reasons for exclusion was that exercise tests were not performed due to the patient’s condition or restrictions of time or that the test
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was performed without reprogramming the hemodynamic monitor to high resolution. Thus, only a limited number of complete datasets was available for the present study.
An increase of 30 meters in six minute walked distance between two tests was considered as a meaningful
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change (16). Thus, if walked distance increased 30 meters or more from baseline to 12W it was considered an improvement (Group 1) and no increase or decreased walked distance during the same time period
Data analysis and statistical methods
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were considered no improvement (Group 2).
Ambulatory hemodynamic values (AMB) were collected during seven consecutive days before the
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baseline and the 12W follow-up tests. The day of in-clinic exercise testing was not included in the analysis. The data collection during AMB was programmed to 4-6 minute resolution, a period similar in length to the time the patients exercised. Data was saved as the median and the 6th and 94th percentiles of
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each data collection interval.
For each day of the seven-day ambulatory period, a daily median, a daily minimum (lowest value of the
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low (6th) percentile during that 24-hour period) and a daily maximum (highest value of the high (94th) percentile during that 24-hour period) were determined. The seven daily values were then averaged to represent a baseline and a 12W value respectively. The daily minimum value represents rest and the daily maximum represents the max AMB values. The daily hemodynamic range was calculated as the difference between the daily maximum value and the daily minimum value and averaged over the seven day period. Exercise hemodynamic values were collected continuously during the MAXWT and 6MWT including a rest period prior to exercise, the full exercise period and a post exercise rest period. The data collection
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during exercise tests were set to 2 seconds resolution. Resting hemodynamic values were averaged over a 30 second period with stable hemodynamic values and zero activity counts before the start of exercise. During exercise a running 10 sec average (5 values) was calculated. The highest value during the period
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was used as the maximal hemodynamic value achieved during exercise. The hemodynamic range was calculated as the difference between values at rest before exercise and the maximal value during exercise. Data are reported as mean ± standard deviation (SD) if not indicated otherwise. Student’s paired t-test was
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used to determine differences between measured variables; differences were considered significant if
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p<0.05. Survival was apprehended from hospital records in April 2014 and reported as descriptive data.
Results
Patients
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Ten patients met the inclusion criteria for analysis of exercise data; paired high resolution hemodynamic data collected during the MAXWT and 6MWT at baseline and after 12 weeks and AMB hemodynamic data available from 7 consecutive days before each of the tests. Nine patients were female, mean age was
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54±18 years and all had symptoms corresponding to WHO-class 3 at baseline. RV and PA pressures were consistent with moderate to severe PAH. After baseline testing, eight patients started treatment with oral
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bosentan, one with subcutaneous treprostinil infusion and one with intravenous epoprostenol infusion. Further details of patient characteristics and treatments at time of enrollment can be found in Table 1. During follow-up six patients improved the walked distance from baseline to 12W.
Hemodynamic measurements Baseline ambulatory RV and PA resting pressures were significantly lower than resting values measured before MAXWT and 6MWT. There was no difference between MAXWT and 6MWT rest values (Table
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2). In the daily living conditions, the AMB hemodynamic pressures increased 136±49% and 164±49% for RVSP and MPAP respectively. During MAXWT, RVSP increased 63±26% and MPAP 79±30% while during 6MWT pressure increased 59±32% and 69±33% respectively. Thus, the AMB ranges were
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consistently significantly larger than the range achieved during both type of exercise (Figure 1) and this pattern remained at 12W (Table 2). This was a result of both lower RV and PA pressures at rest and higher maximal values during ambulatory conditions. Max values during MAXWT and 6MWT did not change
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over time.
In patients who improved walked distance (Group 1) resting RVSP and MPAP had decreased significantly
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from baseline to 12W during all three conditions while, despite a significant increase in exercise time and VO2 (Table 3), there was no change in AMB or MAXWT max pressures during the same time period (Figure 2). In contrast, during 6MWT, Group 1 reached lower max pressures at 12W compared to baseline, even though the walked distance was significantly longer at 12W (baseline 320±56 m, 12W 384±41 m, p=0.0185). Group 2 did not change RVSP, MPAP, walked distance (375±72 m vs. 314±60 m,
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NS) or MAXWT related variables from baseline to 12W.
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Survival
In April 2014 four patients in Group 1 where alive, of those one had undergone a heart-and-lung
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transplant in 2013, 9 years after device implant. Two patients died one from lung cancer at age 79, three years after entering the study and one at age 80, five years after device implant (unknown cause of death). In Group 2, one patient was known to be alive and one was lost to follow-up due to a move to another state and clinical cause unknown. Of the remaining two patients one underwent heart-and-lung transplant 2 years after device implant (died 6 months later) and one died at age 88 after nine years in the study (cause unknown).
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Hemodynamic trend in an individual patient The duration and extent of PA pressure increase have been suggested to play an important role in the remodeling of the vessel walls of large pulmonary arteries (17). Thus, hemodynamic responses to
hemodynamic trends, as illustrated in the following case report (Figure 3).
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submaximal and maximal exercise levels could be of interest when contrasted to the ambulatory
A 71 years old female were diagnosed in 1998 with PAH secondary to use of an appetite suppressant. At
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time of this study, treatment included a calcium channel blocker, bosentan, digitalis, angiotensin II receptor blocker, anti-coagulant and diuretics and initiation of subcutaneous treprostinil. Figure 3 shows 8
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months of continuous RVSP in this patient and where treprostinil treatment was initiated at the start of the trend. While the treprostinil dose was uptitrated, the daily median values (solid black line) decreased steadily as did the lower range values (lower gray line), indicating that more time of the day was spent at lower pressure levels. However, the daily upper range values (upper gray line) remained at an elevated level. There was no change in mean activity levels. The marked decrease in daily median and daily
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minimum values indicates overall lower PA pressures and suggests improved vasoreactivity. However, the widening upper pressure range (median to max pressure) shows that over time a smaller proportion of
Discussion
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samples, and thus less time during the day, was spent at this higher end of the range.
This study shows that patients with PAH have dramatically elevated right ventricular and PA pressures in an ambulatory setting as well as in the clinical exercise test environment. The daily pressure range, from rest to maximal pressures, during ambulatory conditions greatly exceeded the range of pressures in the limited setting of clinical exercise testing. Twelve weeks after starting a new treatment six patients had increased their walked distance 30 meters or more (16). In these patients an overall lowering of resting RV and PA pressures were also seen at this time suggesting an improved vasoreactivity. As could be expected, a significantly longer exercise time and
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improvement in VO2 during the MAXWT was associated with a larger pressure increase during the exercise. However, due to the lower resting values similar maximal values as at the baseline tests were observed. In contrast, during the 6MWT performed at 12W and despite a significantly longer walked
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distance, the pressures increased less than at baseline and thus a lower maximal pressure level was reached. The effect of this pattern on pressure response during daily living is illustrated in the case report (Figure 3) where, without change in activity counts, the majority of time during the day is spent at lower
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pressures. This is indicated by a marked decrease in daily minimum and daily median values. However, the daily maximum pressures show a greater variability over time but only a very limited decrease in
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pressure level. Recent cardiac MRI studies have demonstrated that progressive RV enlargement and dysfunction can occur despite seemingly effective PAH therapy (18). Our observation, that in spite of improved exercise tolerance at 12W, the ambulatory hemodynamic burden during stress and during daily living remained unchanged, may help to explain this phenomenon.
The hemodynamic responses seen during exercise in the present study agree with the results from Wonish
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et al. (19) who compared the results from exercise tests performed before and after inhalation of iloprost. Similarly to the study reported here, they found lower RV and PA pressures at rest and at the submaximal exercise level after the iloprost inhalation. As in our tests, similar maximal pressure values were reached
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during exercise before and after iloprost inhalation. The decreased rest and submaximal pressure values after iloprost were most likely due to greater vasodilatation resulting in a decreased afterload. On the other
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hand, one might speculate that the reason for the similar response in maximal RV pressures during maximal exercise before and after the iloprost inhalation could be attributed to a limitation in how high a pressure the RV can sustain during exercise, and this limitation continued to be reached during the MAXWT despite PAH therapy. In the present study, peak VO2 was below normal value in both groups indicating compromised oxygen uptake in the whole study population. The difference between the two groups was not significant, probably due to a high variation in peak response values and the low number of patients.
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The daily hemodynamic range was calculated as the difference between the daily maximum value and the daily minimum value and averaged over the seven day period. This range was considered the maximal range reached over the day as the daily minimum values measured in these 10 patients were significantly
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lower than their night-time minimum values (data not shown). This might indicate that these PAH patients exhibited large RV and PA pressure changes related to orthostatic stresses. This pattern of higher RV and PA pressures at night is also commonly seen in patients with heart failure due to shifts in the blood
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volume to the central circulation that occur when the patient are in the supine position.
Ten years after the study was conducted five of ten patients were still alive and only four reported to have
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died. One patient was lost to follow-up after 3 years and clinical course is unknown. This survival rate is in line, or even somewhat higher, with those has been reported recently (20-21). It has been suggested that the physical stress achieved during clinical exercise testing reflects the stress achieved during daily living (7-8). The data in this report raises questions about this assumption since the ranges in RV and PA pressures recorded during daily living (AMB) were greater than ranges achieved
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during both maximal and submaximal exercise testing. The overall larger range in pressures seen in the ambulatory setting was due to both lower values at rest and somewhat higher pressure values achieved, at least transiently, when patients perform their ordinary daily tasks. In addition, the dramatic rise in RVDP
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during ambulatory conditions has not been shown before. One might speculate that at time of stress during daily activities an oxygen supply/demand imbalance in the myocardium might further compromise
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contractility and dilatation and cause an increase in RVDP and contribute to limitations in patient daily living activities.
Conclusion Changes in RV and PA pressures during submaximal and maximal exercise tests were relatively small compared to those seen during ambulatory conditions. Patients who increased walked distance decreased RV and PA pressures at rest and lowered max pressure during submaximal exercise but the max pressures
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observed during maximal exercise or during daily living was not demonstrably affected.
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Limitations The number of patients in the study is rather small which makes statistical comparison between groups weak. However, the study results provide new and important information about hemodynamic ranges experienced during daily living and exercise in patients with pulmonary arterial hypertension. At the time
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the study was conducted available treatments were CCB, Flolan, Bosentan and Subq Remodulin. Sildenafil was approved in the end of the study period (2005) but no patients were started on it during this
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initial phase of the study. The aim of this study was to compare hemodynamic ranges during different conditions and due to the small study population details of different treatments have not been addressed. Activity counts were not used in the analysis as it was collected in a mode that did not allow for comparison between the different data storage resolutions used at exercise tests compared to ambulatory setting. The study results would have been strengthened if cardiac output derived from the RV waveform
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had been available. A cardiac output algorithm (22) was under development but not incorporated in the device at the time of the presented study. Long-term survival has been reported, however, due to the small
Disclosures
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number of patients in the study, no conclusion about its relation to hemodynamic response could be made.
Barbro Kjellstrom was a Medtronic Inc. employee at the time this study was started but is since 2009 working at the Karolinska Institute, Stockholm, Sweden, with no conflict of interest. Robert C Bourge have received research grant support from Medtronic Inc. Robert P Frantz, Raymond L Benza, Michael McGoon have no conflicts of interest relevant to this paper. Tom Bennett is an employee of Medtronic Inc.
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Acknowledgement The authors thank Cathy Anderson Severson, Louise Durst, LuAnn Koenig and Gina Horton for their
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expert assistance during patient visits and for data collection.
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References 1.
McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE; American College of Chest Physicians. Screening, early detection, and diagnosis of pulmonary arterial hypertension:
2.
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ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S D'Alonzo GE, Gianotti LA, Pohil RL, Reagle RR, DuRee SL, Fuentes F, Dantzker DR. Comparison of progressive exercise performance of normal subjects and patients with primary pulmonary hypertension. Chest. 1987;92:57-62
McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-31
4.
Galie N, Manes A, Branzi A. Evaluation of pulmonary arterial hypertension. Curr Opin Cardiol.
SC
3.
5.
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2004;19:575-81
Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487-92
6.
Deboeck G, Niset G, Vachiery JL, Moraine JJ, Naeije R. Physiological response to the six-minute
7.
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walk test in pulmonary arterial hypertension. Eur Respir J. 2005;26:667-72 Riley MS, Porszasz J, Engelen MP, Shapiro SM, Brundage BH, Wasserman K. Responses to constant work rate bicycle ergometry exercise in primary pulmonary hypertension: the effect of inhaled nitric oxide. J Am Coll Cardiol. 2000;36:547-56
Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson
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8.
VF, Zwicke D, DeMarco T, Schilz R, Rubenfire M, Barst RJ. The 6-min walk test (6MW) as an
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efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol. 2005;43:36-9 9.
Bennett T, Kjellstrom B, Taepke R, Ryden L. Development of implantable devices for continuous ambulatory monitoring of central hemodynamic values in heart failure patients. Pacing Clin Electrophysiol 2005; 28:573-84
10. Magalski A, Adamson P, Gadler F, Boehm M, Steinhaus D, Reynolds D, Vlach K, Linde C, Cremers B, Sparks B, Bennett T. Continuous ambulatory right heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure. J Card Fail 2002; 8:63-70
Page 14 of 23
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Apr 27, 2014
11. Fruhwald FM, Kjellstrom B, Perthold W, Watzinger N, Maier R, Grandjean PA, Klein W. Continuous hemodynamic monitoring in pulmonary hypertensive patients treated with inhaled iloprost. Chest 2003; 124:351-9 12. Frantz RP, Benza RL, Kjellström B, Bourge RC, Barst RJ, Bennett TD, McGoon MD. Continuous
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hemodynamic monitoring in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2008;27:780-8
13. Reynolds DW, Bartelt N, Taepke R, Bennett TD. Measurement of pulmonary artery diastolic pressure from the right ventricle. J Am Coll Cardiol 1995; 25:1176–1182
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14. Ohlsson A, Bennett T, Nordlander R, Rydén J, Aström H, Rydén L. Monitoring of pulmonary arterial diastolic pressure through a right ventricular pressure transducer. J Card Fail 1995;1:161– 8.
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15. Kjellstrom B, Igel D, Abraham J, Bennett T, Bourge R. Trans-telephonic monitoring of continuous haemodynamic measurements in heart failure patients. J Telemed Telecare 2005; 11:240-4 16. Mathai SC, Puhan MA, Lam D, Wise RA. The Minimal Important Difference in the Six Minute Walk Test for Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2012 Jun 21 (PubMed ahead of print)
17. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, Postmus PE,
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Vonk-Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132:1906-12 18. van de Veerdonk, M C, Kind, T, Marcus, JT, Mauritz, GJ, Heymans, MW, Bogaard, H, Boonstra, A, Marques, KMJ. Westerhof, N, Vonk-Noordegraaf, A. Progressive right ventricular dysfunction in
2011;58:2511-19
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patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol.
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19. Wonisch M, Fruhwald F, Maier R, Watzinger N, Hödl R, Kraxner W, Perthold W, Klein W. Continuous hemodynamic monitoring during incremental exercise in patients with pulmonary hypertension treated with inhalative prostanoids. Int J Cardiol 2005; 101:415-20 20. Tiede H, Sommer N, Milger K, Voswinckel R, Bandorski D, Schermuly RT, Weissmann N, Grimminger F, Seeger W, Ghofrani HA. Short-term improvement in pulmonary hemodynamics is strongly predictive of long-term survival in patients with pulmonary arterial hypertension. Pulm Circ. 2013;3:523-32
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21. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448-56 22. Karamanoglu M, Bennett T, Stahlberg M, Splett V, Kjellstrom B, Linde C and Braunschweig F.
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pressure waveforms. BioMedical Engineering OnLine 2011, 10:36
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Estimation of cardiac output in patients with congestive heart failure by analysis of right ventricular
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Group 1
Group 2
10
6
4
54±18
56±18
9/1
5/1
BMI (kg/m2)
33±9
31±5
Time since diagnosis (months)
5±28
20±32
Etiology: IPAH/CTD/Appetite Suppressant agent
6/2/2
4/0/2
Echo LVEF (%)
57±7
61±6
52±6
0.0332
RV Systolic pressure (mmHg)
80±26
84±21
73±35
0.2739
Number of patients Age (years)
RV Diastolic pressure (mmHg) Mean PA pressure (mmHg) Heart rate (bpm) Baseline PAH treatment (n)
CCB
Bosentan
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New PAH treatment (n)
Oxygen Bosentan
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Gender (female/male)
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All
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Table 1. Baseline characteristics (mean ± SD or number) from all patients and divided by group. Group 1 = increased the walk distance > 30 meters from baseline to 12W; Group 2 = did not increase or decreased walked distance. P-values represent differences between Group 1 and 2.
Treprostinil SQ
52±19
p-value
0.3900
4/0
36±11
0.2160
5±3
0.1008
2/2/0
17±6
15±4
19±19
0.1405
58±17
60±13
54±24
0.3137
80±12
81±12
80±15
0.4611
5
3
2
1
1
-
2 8
1 5
1 3
1
1
-
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Epoprostenol IV 1 1 BMI=body mass index, WHO=world health organization, IPAH=idiopathic pulmonary arterial hypertension, CTD=connective tissue disease, LVEF=left ventricular ejection fraction, RV=right ventricular, PA= pulmonary artery, CCB=calcium channel blocker. Heart rate, RV and PA pressure values reported in Table 1 were measured at rest at the time of IHM implant.
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Table 2. Baseline and 12W hemodynamic rest, max and range values (mean±SD) and percent (%) achieved during exercise of AMB max and range values. N=10 AMB MAXWT 6MWT Base 12W
Base 12W
rest
59±10 56±9
81±13† 78±11
80±9† 80±16†
max
131±24 132±26
133±19 136±21
128±24 125±22
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HR (bpm)
Base 12W
% of AMB max
103±11
104±15
98±6
range
†
†
†
73±22 76±25
65±15
44±22†
59±26
53±20 45±15
70±25† 60±18†
72±25† 69±21†
max
117±29 115±27
109±26 111±28
109±29† 103±26†
range % of AMB range
94±15
64±13 71±14
39±8
†
96±8
63±18
†
51±11
73±12
93±10
37±11
†
59±18
89±6
35±11† 50±12
rest
6±6 4±3
14±8† 11±6†
14±7† 15±5†
max
42±14 42±12
27±10† 27±9†
27±11† 24±8†
% of AMB max
36±11 38±12
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range
% of AMB range
68±19
65±12
66±15
59±15
†
†
†
10±4†
37±13
28±12
13±5
38±18
16±5
43±10
13±5
rest
37±13 31±10
51±17† 44±14†
53±17† 51±15†
max
94±23 96±28
87±19 93±28
86±22† 85±26†
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MPAP (mmHg)
48±19
rest
% of AMB max
RVDP (mmHg)
78±21
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RVSP (mmHg)
75±19
57±16
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% of AMB range
52±11
96±14
% of AMB max
range
94±16
57±12 64±19
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% of AMB range
97±8
91±11
88±8
36±6† 49±16†
33±9† 35±14†
67±20
59±17
76±11
53±9
Base=Baseline, 12W=12-week follow-up, 6MWT = 6-minute walk test, HR=heart rate, RVSP=right ventricular systolic pressure, RVDP=right ventricular diastolic pressure, MPAP=mean pulmonary artery pressure. † p<0.05 Exercise pressures vs. ambulatory pressures
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Table 3. Results from the MAXWT at baseline and 12W divided by Groups (Mean±SD) Group 1 (n=6) Group 2 (n=4) Baseline 12W Exercised time (s)
Baseline 12W
288±83 443±103*
VO2 (mL/min)
VO2/kg (mL/min/kg)
VE/VCO2
119±17 109±6
Peak
142±11 143±22
Rest
69±11 67±7
Peak
75±13 66±8
Rest
99±2 97±2
Peak
93±2 92±5
Rest
343±78 293±108
Peak
877±238 1112±266*
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SaO2 (%)
108±15 111±14
144±24 147±11 67±11 69±11 66±12 76±5 97±3 95±3
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Diastolic cuff BP (mmHg)
Rest
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Systolic cuff BP (mmHg)
384±125 435±109
Rest
3.8±0.4 3.1±0.6
Peak
9.9±2.3 12.2±1.4*
86±11 81±6
303±114 382±189
1199±430 1401±452 3.0±0.7 3.8±0.8 12.4±0.8 14.6±1.9
Rest
48±11 43±9
45±7 45±11
Peak
49±12 45±9
46±13 46±20
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MAXWT =maximum walk test, 12W=12-week follow-up, SaO2=arterial oxygen saturation, VO2=oxygen consumption, VO2/kg=oxygen consumption normalized by body weight, VCO2=peak CO2 production, VE BTPS= maximum ventilation measured in body temperature pressure saturated units. *=p<0.05 compared to baseline
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Figure legends Figure 1. Baseline hemodynamic ranges (max – min values) during ambulatory conditions and during exercise tests. HR=heart rate, RVSP=right ventricular systolic pressure, RVDP=right ventricular diastolic
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pressure, ePAD=estimated pulmonary artery diastolic pressure, MPAP=mean pulmonary artery pressure. *=p<0.05
Figure 2. Rest and max right ventricular systolic (RVSP), mean pulmonary artery (MPAP) and right
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ventricular diastolic (RVDP) pressures during ambulatory conditions (AMB), a 6-min walk test (6MWT), and a symptom limited exercise on treadmill (MAXWT). The left hand panels show patients that
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improved walked distance from baseline to 12W (Group 1) and the right hand panel show patients who did not improve or decreased walked distance (Group 2). *=p<0.05
Figure 3. The trend shows continuous right ventricular systolic pressure and activity counts over 8 months in a patient with PAH and an implanted IHM. The black line is the daily median and the gray lines are the upper (94th percentile; UQ) and lower (6th percentile; LQ) daily ranges (rest and max). The patient started
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subcutaneous treprostinil (prostacyclin) treatment in mid-January (beginning of trend). The daily median and lower daily range values decrease indicating a positive treatment response, while the upper daily
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range remain at a similar high pressure level as before start of new treatment.
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S1071-9164(14)00187-0
DOI:
10.1016/j.cardfail.2014.04.019
Reference:
YJCAF 3295
To appear in:
Journal of Cardiac Failure
Received Date: 14 May 2013 Revised Date:
27 April 2014
Accepted Date: 30 April 2014
Please cite this article as: Kjellström B, Frantz RP, Benza RL, Bennett T, Bourge RC, McGoon MD, Hemodynamic ranges during daily activities and exercise testing in patients with pulmonary arterial hypertension, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.04.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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pulmonary arterial hypertension
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Running title: PAH hemodynamic ranges
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Hemodynamic ranges during daily activities and exercise testing in patients with
Barbro Kjellström1, Robert P Frantz2, Raymond L Benza3, Tom Bennett4, Robert C Bourge5, Michael D
1
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McGoon2
Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 2Division of
Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, Minnesota; 3Allegheny General Hospital, Pittsburgh, Pennsylvania; 4NT&D Research, Medtronic Inc, Minneapolis, Minnesota; 5
Department of Medicine, Division of Cardiovascular Diseases, University of Alabama at Birmingham,
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Birmingham, Alabama
The study was supported by Medtronic, Inc, Minneapolis, Minnesota. This manuscript represents results
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from a clinical trial that was begun before July 1, 2005 and therefore is not registered.
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Address correspondence to:
Barbro Kjellstrom
Department of Cardiology Research Karolinska hospital Solna Building N3:06 S-171 76 Stockholm Sweden E-mail: [email protected]
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Abbreviations AMB = ambulatory range
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HR = heart rate IHM = implantable hemodynamic monitor MAXWT = maximal exercise test
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MPAP = mean pulmonary artery pressure
RVSP = right ventricular systolic pressure RVDP = right ventricular diastolic pressure 6MWT = 6-min walk test
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12W = 12-weeks
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PAH = pulmonary arterial hypertension
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Abstract Background: In patients with pulmonary arterial hypertension (PAH) the relation of hemodynamic
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impairment experienced during daily activity and exercise test is not known. Methods and results: Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary artery pressure (MPAP). Before starting a new PAH treatment (baseline) and after 12-weeks on treatment (12W) a 6-min walk test
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(6MWT) and a maximal exercise test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT.
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Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24-hours. One week of ambulatory ranges were averaged for each patient before each exercise test.
Mean age was 54±18 years, 9 were female and all in WHO functional class 3. At baseline RVSP and
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MPAP increased 136±49% and 164±49% during AMB, 63±26% and 79±30% during MAXWT and 59±32% and 69±33% during 6MWT. There was no difference in pressure change at 12W. Conclusions: Changes in RV and PA pressures during exercise tests were relatively small compared to the
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range seen during ambulatory conditions.
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Introduction Patients with pulmonary arterial hypertension (PAH) commonly have limitations attending to daily activities, often appearing early in the course of their disease progression. Symptoms of exercise induced
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dyspnea, fatigue and lightheadedness (1-4) are among the first signs a patient will experience and therefore, exercise testing is important in the patient assessment. Submaximal exercise testing, such as the 6 minute walk test (6MWT), is routinely used to evaluate patients with cardiopulmonary disease and is
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considered to have a close relation to maximal exercise test in patients with reduced functional capacity (5). However, respiratory exchange ratio measured during 6MWT in patients with PAH remained below
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1.0 and the Borg score increased only moderately, confirming the 6MWT as a submaximal test (6). It has been suggested that the workload during submaximal exercise is applicable to everyday activities (7-8). However, the relation between physical stress levels during exercise tests and daily living are not known in patients with PAH, mainly due to lack of available tools for reliable measurements under such
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conditions. An implantable hemodynamic monitor (IHM) allowed for new discoveries in this field (9-12).
Methods
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Study population/study protocol
Twenty-four patients with PAH were implanted with an IHM (Chronicle®1, Model 9520, Medtronic, Inc,
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Minneapolis, USA; 7-9) to evaluate if the measurements could verify treatment responses as a new PAH treatment was initiated. Results from this study have been reported previously (12). Patients enrolled in the study were adult patients diagnosed with idiopathic PAH, PAH related to connective tissue disease or anorexigen drug use and in World Health Organization functional class II-III. In addition, they were either newly diagnosed or on stable PAH therapy for at least 3 months, but clinically indicated for additional PAH therapy. Exclusion criteria included left ventricular dysfunction, obstructive or restrictive
1
The Chronicle® IHM was an investigational device, limited by Unites States law to investigational use.
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lung disease, six minute walk distance <50 or ≥450 m or unable to tolerate a one-week baseline observation period prior to adding new therapy. All centers obtained approval of their institution’s ethics committee prior to the study and all patients provided written informed consent.
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Right ventricular and calculated pulmonary artery mean pressure measurements were obtained via an IHM, similar to a pacemaker in shape and placed subcutaneously in the pectoral area. A pressure sensor lead was placed with the tip in the right ventricle, preferably in a mid to high septal position. The pressure
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monitoring system has been described in detail previously (9-12). Measurement of heart rate (HR), right ventricular systolic (RVSP), diastolic (RVDP) and mean pulmonary artery pressure (MPAP) were derived
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from each cardiac cycle and stored continuously as the median over a preprogrammed storage interval. MPAP was the time weighted average of RVSP and estimated pulmonary artery pressure (ePAD) where ePAD was derived from the RV pressure waveform at maximum, dP/dt corresponding to the time of pulmonary valve opening (13-14)
Activity counts from an internal accelerometer were sampled every 2 seconds and an average of all counts
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over each storage interval was stored. Continuous ambulatory hemodynamic data collection (4-6 minute resolution) was initiated at time of device implant. The IHM data was transmitted via transtelephonic transmission from the patient’s home or current location to a secure website at least once a week (15). At
was started (baseline).
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least seven days had to elapse after the IHM implant until treatment with a new or additional PAH drug
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At baseline and after 12 weeks (12W) the patients performed a scheduled maximal, symptom limited exercise test on a treadmill (MAXWT) and a 6MWT. During the tests hemodynamic data was collected in high resolution (2 second sampling interval) and downloaded to a programmer after each test. Oxygen consumption was measured during MAXWT by a metabolic assessment system (CPX; Medgraphics; St Paul, MN) utilizing breath-by-breath technique. To be included in the analysis presented in this paper two conditions had to be met; 1) high resolution hemodynamic values available from both MAXWT and 6MWT performed at baseline and 12W visits and
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2) AMB hemodynamic data available from 7 consecutive days before each of the tests. Ten patients from the original study cohort met these restrictive criteria. The two most common reasons for exclusion was that exercise tests were not performed due to the patient’s condition or restrictions of time or that the test
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was performed without reprogramming the hemodynamic monitor to high resolution. Thus, only a limited number of complete datasets was available for the present study.
An increase of 30 meters in six minute walked distance between two tests was considered as a meaningful
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change (16). Thus, if walked distance increased 30 meters or more from baseline to 12W it was considered an improvement (Group 1) and no increase or decreased walked distance during the same time period
Data analysis and statistical methods
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were considered no improvement (Group 2).
Ambulatory hemodynamic values (AMB) were collected during seven consecutive days before the
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baseline and the 12W follow-up tests. The day of in-clinic exercise testing was not included in the analysis. The data collection during AMB was programmed to 4-6 minute resolution, a period similar in length to the time the patients exercised. Data was saved as the median and the 6th and 94th percentiles of
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each data collection interval.
For each day of the seven-day ambulatory period, a daily median, a daily minimum (lowest value of the
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low (6th) percentile during that 24-hour period) and a daily maximum (highest value of the high (94th) percentile during that 24-hour period) were determined. The seven daily values were then averaged to represent a baseline and a 12W value respectively. The daily minimum value represents rest and the daily maximum represents the max AMB values. The daily hemodynamic range was calculated as the difference between the daily maximum value and the daily minimum value and averaged over the seven day period. Exercise hemodynamic values were collected continuously during the MAXWT and 6MWT including a rest period prior to exercise, the full exercise period and a post exercise rest period. The data collection
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during exercise tests were set to 2 seconds resolution. Resting hemodynamic values were averaged over a 30 second period with stable hemodynamic values and zero activity counts before the start of exercise. During exercise a running 10 sec average (5 values) was calculated. The highest value during the period
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was used as the maximal hemodynamic value achieved during exercise. The hemodynamic range was calculated as the difference between values at rest before exercise and the maximal value during exercise. Data are reported as mean ± standard deviation (SD) if not indicated otherwise. Student’s paired t-test was
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used to determine differences between measured variables; differences were considered significant if
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p<0.05. Survival was apprehended from hospital records in April 2014 and reported as descriptive data.
Results
Patients
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Ten patients met the inclusion criteria for analysis of exercise data; paired high resolution hemodynamic data collected during the MAXWT and 6MWT at baseline and after 12 weeks and AMB hemodynamic data available from 7 consecutive days before each of the tests. Nine patients were female, mean age was
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54±18 years and all had symptoms corresponding to WHO-class 3 at baseline. RV and PA pressures were consistent with moderate to severe PAH. After baseline testing, eight patients started treatment with oral
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bosentan, one with subcutaneous treprostinil infusion and one with intravenous epoprostenol infusion. Further details of patient characteristics and treatments at time of enrollment can be found in Table 1. During follow-up six patients improved the walked distance from baseline to 12W.
Hemodynamic measurements Baseline ambulatory RV and PA resting pressures were significantly lower than resting values measured before MAXWT and 6MWT. There was no difference between MAXWT and 6MWT rest values (Table
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2). In the daily living conditions, the AMB hemodynamic pressures increased 136±49% and 164±49% for RVSP and MPAP respectively. During MAXWT, RVSP increased 63±26% and MPAP 79±30% while during 6MWT pressure increased 59±32% and 69±33% respectively. Thus, the AMB ranges were
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consistently significantly larger than the range achieved during both type of exercise (Figure 1) and this pattern remained at 12W (Table 2). This was a result of both lower RV and PA pressures at rest and higher maximal values during ambulatory conditions. Max values during MAXWT and 6MWT did not change
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over time.
In patients who improved walked distance (Group 1) resting RVSP and MPAP had decreased significantly
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from baseline to 12W during all three conditions while, despite a significant increase in exercise time and VO2 (Table 3), there was no change in AMB or MAXWT max pressures during the same time period (Figure 2). In contrast, during 6MWT, Group 1 reached lower max pressures at 12W compared to baseline, even though the walked distance was significantly longer at 12W (baseline 320±56 m, 12W 384±41 m, p=0.0185). Group 2 did not change RVSP, MPAP, walked distance (375±72 m vs. 314±60 m,
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NS) or MAXWT related variables from baseline to 12W.
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Survival
In April 2014 four patients in Group 1 where alive, of those one had undergone a heart-and-lung
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transplant in 2013, 9 years after device implant. Two patients died one from lung cancer at age 79, three years after entering the study and one at age 80, five years after device implant (unknown cause of death). In Group 2, one patient was known to be alive and one was lost to follow-up due to a move to another state and clinical cause unknown. Of the remaining two patients one underwent heart-and-lung transplant 2 years after device implant (died 6 months later) and one died at age 88 after nine years in the study (cause unknown).
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Hemodynamic trend in an individual patient The duration and extent of PA pressure increase have been suggested to play an important role in the remodeling of the vessel walls of large pulmonary arteries (17). Thus, hemodynamic responses to
hemodynamic trends, as illustrated in the following case report (Figure 3).
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submaximal and maximal exercise levels could be of interest when contrasted to the ambulatory
A 71 years old female were diagnosed in 1998 with PAH secondary to use of an appetite suppressant. At
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time of this study, treatment included a calcium channel blocker, bosentan, digitalis, angiotensin II receptor blocker, anti-coagulant and diuretics and initiation of subcutaneous treprostinil. Figure 3 shows 8
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months of continuous RVSP in this patient and where treprostinil treatment was initiated at the start of the trend. While the treprostinil dose was uptitrated, the daily median values (solid black line) decreased steadily as did the lower range values (lower gray line), indicating that more time of the day was spent at lower pressure levels. However, the daily upper range values (upper gray line) remained at an elevated level. There was no change in mean activity levels. The marked decrease in daily median and daily
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minimum values indicates overall lower PA pressures and suggests improved vasoreactivity. However, the widening upper pressure range (median to max pressure) shows that over time a smaller proportion of
Discussion
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samples, and thus less time during the day, was spent at this higher end of the range.
This study shows that patients with PAH have dramatically elevated right ventricular and PA pressures in an ambulatory setting as well as in the clinical exercise test environment. The daily pressure range, from rest to maximal pressures, during ambulatory conditions greatly exceeded the range of pressures in the limited setting of clinical exercise testing. Twelve weeks after starting a new treatment six patients had increased their walked distance 30 meters or more (16). In these patients an overall lowering of resting RV and PA pressures were also seen at this time suggesting an improved vasoreactivity. As could be expected, a significantly longer exercise time and
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improvement in VO2 during the MAXWT was associated with a larger pressure increase during the exercise. However, due to the lower resting values similar maximal values as at the baseline tests were observed. In contrast, during the 6MWT performed at 12W and despite a significantly longer walked
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distance, the pressures increased less than at baseline and thus a lower maximal pressure level was reached. The effect of this pattern on pressure response during daily living is illustrated in the case report (Figure 3) where, without change in activity counts, the majority of time during the day is spent at lower
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pressures. This is indicated by a marked decrease in daily minimum and daily median values. However, the daily maximum pressures show a greater variability over time but only a very limited decrease in
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pressure level. Recent cardiac MRI studies have demonstrated that progressive RV enlargement and dysfunction can occur despite seemingly effective PAH therapy (18). Our observation, that in spite of improved exercise tolerance at 12W, the ambulatory hemodynamic burden during stress and during daily living remained unchanged, may help to explain this phenomenon.
The hemodynamic responses seen during exercise in the present study agree with the results from Wonish
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et al. (19) who compared the results from exercise tests performed before and after inhalation of iloprost. Similarly to the study reported here, they found lower RV and PA pressures at rest and at the submaximal exercise level after the iloprost inhalation. As in our tests, similar maximal pressure values were reached
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during exercise before and after iloprost inhalation. The decreased rest and submaximal pressure values after iloprost were most likely due to greater vasodilatation resulting in a decreased afterload. On the other
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hand, one might speculate that the reason for the similar response in maximal RV pressures during maximal exercise before and after the iloprost inhalation could be attributed to a limitation in how high a pressure the RV can sustain during exercise, and this limitation continued to be reached during the MAXWT despite PAH therapy. In the present study, peak VO2 was below normal value in both groups indicating compromised oxygen uptake in the whole study population. The difference between the two groups was not significant, probably due to a high variation in peak response values and the low number of patients.
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The daily hemodynamic range was calculated as the difference between the daily maximum value and the daily minimum value and averaged over the seven day period. This range was considered the maximal range reached over the day as the daily minimum values measured in these 10 patients were significantly
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lower than their night-time minimum values (data not shown). This might indicate that these PAH patients exhibited large RV and PA pressure changes related to orthostatic stresses. This pattern of higher RV and PA pressures at night is also commonly seen in patients with heart failure due to shifts in the blood
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volume to the central circulation that occur when the patient are in the supine position.
Ten years after the study was conducted five of ten patients were still alive and only four reported to have
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died. One patient was lost to follow-up after 3 years and clinical course is unknown. This survival rate is in line, or even somewhat higher, with those has been reported recently (20-21). It has been suggested that the physical stress achieved during clinical exercise testing reflects the stress achieved during daily living (7-8). The data in this report raises questions about this assumption since the ranges in RV and PA pressures recorded during daily living (AMB) were greater than ranges achieved
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during both maximal and submaximal exercise testing. The overall larger range in pressures seen in the ambulatory setting was due to both lower values at rest and somewhat higher pressure values achieved, at least transiently, when patients perform their ordinary daily tasks. In addition, the dramatic rise in RVDP
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during ambulatory conditions has not been shown before. One might speculate that at time of stress during daily activities an oxygen supply/demand imbalance in the myocardium might further compromise
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contractility and dilatation and cause an increase in RVDP and contribute to limitations in patient daily living activities.
Conclusion Changes in RV and PA pressures during submaximal and maximal exercise tests were relatively small compared to those seen during ambulatory conditions. Patients who increased walked distance decreased RV and PA pressures at rest and lowered max pressure during submaximal exercise but the max pressures
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observed during maximal exercise or during daily living was not demonstrably affected.
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Limitations The number of patients in the study is rather small which makes statistical comparison between groups weak. However, the study results provide new and important information about hemodynamic ranges experienced during daily living and exercise in patients with pulmonary arterial hypertension. At the time
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the study was conducted available treatments were CCB, Flolan, Bosentan and Subq Remodulin. Sildenafil was approved in the end of the study period (2005) but no patients were started on it during this
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initial phase of the study. The aim of this study was to compare hemodynamic ranges during different conditions and due to the small study population details of different treatments have not been addressed. Activity counts were not used in the analysis as it was collected in a mode that did not allow for comparison between the different data storage resolutions used at exercise tests compared to ambulatory setting. The study results would have been strengthened if cardiac output derived from the RV waveform
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had been available. A cardiac output algorithm (22) was under development but not incorporated in the device at the time of the presented study. Long-term survival has been reported, however, due to the small
Disclosures
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number of patients in the study, no conclusion about its relation to hemodynamic response could be made.
Barbro Kjellstrom was a Medtronic Inc. employee at the time this study was started but is since 2009 working at the Karolinska Institute, Stockholm, Sweden, with no conflict of interest. Robert C Bourge have received research grant support from Medtronic Inc. Robert P Frantz, Raymond L Benza, Michael McGoon have no conflicts of interest relevant to this paper. Tom Bennett is an employee of Medtronic Inc.
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Acknowledgement The authors thank Cathy Anderson Severson, Louise Durst, LuAnn Koenig and Gina Horton for their
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expert assistance during patient visits and for data collection.
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References 1.
McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE; American College of Chest Physicians. Screening, early detection, and diagnosis of pulmonary arterial hypertension:
2.
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ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S D'Alonzo GE, Gianotti LA, Pohil RL, Reagle RR, DuRee SL, Fuentes F, Dantzker DR. Comparison of progressive exercise performance of normal subjects and patients with primary pulmonary hypertension. Chest. 1987;92:57-62
McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-31
4.
Galie N, Manes A, Branzi A. Evaluation of pulmonary arterial hypertension. Curr Opin Cardiol.
SC
3.
5.
M AN U
2004;19:575-81
Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487-92
6.
Deboeck G, Niset G, Vachiery JL, Moraine JJ, Naeije R. Physiological response to the six-minute
7.
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walk test in pulmonary arterial hypertension. Eur Respir J. 2005;26:667-72 Riley MS, Porszasz J, Engelen MP, Shapiro SM, Brundage BH, Wasserman K. Responses to constant work rate bicycle ergometry exercise in primary pulmonary hypertension: the effect of inhaled nitric oxide. J Am Coll Cardiol. 2000;36:547-56
Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, Robbins IM, Shapiro S, Tapson
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8.
VF, Zwicke D, DeMarco T, Schilz R, Rubenfire M, Barst RJ. The 6-min walk test (6MW) as an
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efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol. 2005;43:36-9 9.
Bennett T, Kjellstrom B, Taepke R, Ryden L. Development of implantable devices for continuous ambulatory monitoring of central hemodynamic values in heart failure patients. Pacing Clin Electrophysiol 2005; 28:573-84
10. Magalski A, Adamson P, Gadler F, Boehm M, Steinhaus D, Reynolds D, Vlach K, Linde C, Cremers B, Sparks B, Bennett T. Continuous ambulatory right heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure. J Card Fail 2002; 8:63-70
Page 14 of 23
ACCEPTED MANUSCRIPT B Kjellström, PAH hemodynamic ranges
Apr 27, 2014
11. Fruhwald FM, Kjellstrom B, Perthold W, Watzinger N, Maier R, Grandjean PA, Klein W. Continuous hemodynamic monitoring in pulmonary hypertensive patients treated with inhaled iloprost. Chest 2003; 124:351-9 12. Frantz RP, Benza RL, Kjellström B, Bourge RC, Barst RJ, Bennett TD, McGoon MD. Continuous
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hemodynamic monitoring in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2008;27:780-8
13. Reynolds DW, Bartelt N, Taepke R, Bennett TD. Measurement of pulmonary artery diastolic pressure from the right ventricle. J Am Coll Cardiol 1995; 25:1176–1182
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14. Ohlsson A, Bennett T, Nordlander R, Rydén J, Aström H, Rydén L. Monitoring of pulmonary arterial diastolic pressure through a right ventricular pressure transducer. J Card Fail 1995;1:161– 8.
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15. Kjellstrom B, Igel D, Abraham J, Bennett T, Bourge R. Trans-telephonic monitoring of continuous haemodynamic measurements in heart failure patients. J Telemed Telecare 2005; 11:240-4 16. Mathai SC, Puhan MA, Lam D, Wise RA. The Minimal Important Difference in the Six Minute Walk Test for Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2012 Jun 21 (PubMed ahead of print)
17. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, Postmus PE,
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Vonk-Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132:1906-12 18. van de Veerdonk, M C, Kind, T, Marcus, JT, Mauritz, GJ, Heymans, MW, Bogaard, H, Boonstra, A, Marques, KMJ. Westerhof, N, Vonk-Noordegraaf, A. Progressive right ventricular dysfunction in
2011;58:2511-19
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patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol.
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19. Wonisch M, Fruhwald F, Maier R, Watzinger N, Hödl R, Kraxner W, Perthold W, Klein W. Continuous hemodynamic monitoring during incremental exercise in patients with pulmonary hypertension treated with inhalative prostanoids. Int J Cardiol 2005; 101:415-20 20. Tiede H, Sommer N, Milger K, Voswinckel R, Bandorski D, Schermuly RT, Weissmann N, Grimminger F, Seeger W, Ghofrani HA. Short-term improvement in pulmonary hemodynamics is strongly predictive of long-term survival in patients with pulmonary arterial hypertension. Pulm Circ. 2013;3:523-32
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21. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448-56 22. Karamanoglu M, Bennett T, Stahlberg M, Splett V, Kjellstrom B, Linde C and Braunschweig F.
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pressure waveforms. BioMedical Engineering OnLine 2011, 10:36
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Estimation of cardiac output in patients with congestive heart failure by analysis of right ventricular
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Group 1
Group 2
10
6
4
54±18
56±18
9/1
5/1
BMI (kg/m2)
33±9
31±5
Time since diagnosis (months)
5±28
20±32
Etiology: IPAH/CTD/Appetite Suppressant agent
6/2/2
4/0/2
Echo LVEF (%)
57±7
61±6
52±6
0.0332
RV Systolic pressure (mmHg)
80±26
84±21
73±35
0.2739
Number of patients Age (years)
RV Diastolic pressure (mmHg) Mean PA pressure (mmHg) Heart rate (bpm) Baseline PAH treatment (n)
CCB
Bosentan
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New PAH treatment (n)
Oxygen Bosentan
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Gender (female/male)
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All
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Table 1. Baseline characteristics (mean ± SD or number) from all patients and divided by group. Group 1 = increased the walk distance > 30 meters from baseline to 12W; Group 2 = did not increase or decreased walked distance. P-values represent differences between Group 1 and 2.
Treprostinil SQ
52±19
p-value
0.3900
4/0
36±11
0.2160
5±3
0.1008
2/2/0
17±6
15±4
19±19
0.1405
58±17
60±13
54±24
0.3137
80±12
81±12
80±15
0.4611
5
3
2
1
1
-
2 8
1 5
1 3
1
1
-
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Epoprostenol IV 1 1 BMI=body mass index, WHO=world health organization, IPAH=idiopathic pulmonary arterial hypertension, CTD=connective tissue disease, LVEF=left ventricular ejection fraction, RV=right ventricular, PA= pulmonary artery, CCB=calcium channel blocker. Heart rate, RV and PA pressure values reported in Table 1 were measured at rest at the time of IHM implant.
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Table 2. Baseline and 12W hemodynamic rest, max and range values (mean±SD) and percent (%) achieved during exercise of AMB max and range values. N=10 AMB MAXWT 6MWT Base 12W
Base 12W
rest
59±10 56±9
81±13† 78±11
80±9† 80±16†
max
131±24 132±26
133±19 136±21
128±24 125±22
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HR (bpm)
Base 12W
% of AMB max
103±11
104±15
98±6
range
†
†
†
73±22 76±25
65±15
44±22†
59±26
53±20 45±15
70±25† 60±18†
72±25† 69±21†
max
117±29 115±27
109±26 111±28
109±29† 103±26†
range % of AMB range
94±15
64±13 71±14
39±8
†
96±8
63±18
†
51±11
73±12
93±10
37±11
†
59±18
89±6
35±11† 50±12
rest
6±6 4±3
14±8† 11±6†
14±7† 15±5†
max
42±14 42±12
27±10† 27±9†
27±11† 24±8†
% of AMB max
36±11 38±12
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range
% of AMB range
68±19
65±12
66±15
59±15
†
†
†
10±4†
37±13
28±12
13±5
38±18
16±5
43±10
13±5
rest
37±13 31±10
51±17† 44±14†
53±17† 51±15†
max
94±23 96±28
87±19 93±28
86±22† 85±26†
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MPAP (mmHg)
48±19
rest
% of AMB max
RVDP (mmHg)
78±21
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RVSP (mmHg)
75±19
57±16
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% of AMB range
52±11
96±14
% of AMB max
range
94±16
57±12 64±19
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% of AMB range
97±8
91±11
88±8
36±6† 49±16†
33±9† 35±14†
67±20
59±17
76±11
53±9
Base=Baseline, 12W=12-week follow-up, 6MWT = 6-minute walk test, HR=heart rate, RVSP=right ventricular systolic pressure, RVDP=right ventricular diastolic pressure, MPAP=mean pulmonary artery pressure. † p<0.05 Exercise pressures vs. ambulatory pressures
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Table 3. Results from the MAXWT at baseline and 12W divided by Groups (Mean±SD) Group 1 (n=6) Group 2 (n=4) Baseline 12W Exercised time (s)
Baseline 12W
288±83 443±103*
VO2 (mL/min)
VO2/kg (mL/min/kg)
VE/VCO2
119±17 109±6
Peak
142±11 143±22
Rest
69±11 67±7
Peak
75±13 66±8
Rest
99±2 97±2
Peak
93±2 92±5
Rest
343±78 293±108
Peak
877±238 1112±266*
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SaO2 (%)
108±15 111±14
144±24 147±11 67±11 69±11 66±12 76±5 97±3 95±3
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Diastolic cuff BP (mmHg)
Rest
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Systolic cuff BP (mmHg)
384±125 435±109
Rest
3.8±0.4 3.1±0.6
Peak
9.9±2.3 12.2±1.4*
86±11 81±6
303±114 382±189
1199±430 1401±452 3.0±0.7 3.8±0.8 12.4±0.8 14.6±1.9
Rest
48±11 43±9
45±7 45±11
Peak
49±12 45±9
46±13 46±20
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MAXWT =maximum walk test, 12W=12-week follow-up, SaO2=arterial oxygen saturation, VO2=oxygen consumption, VO2/kg=oxygen consumption normalized by body weight, VCO2=peak CO2 production, VE BTPS= maximum ventilation measured in body temperature pressure saturated units. *=p<0.05 compared to baseline
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Figure legends Figure 1. Baseline hemodynamic ranges (max – min values) during ambulatory conditions and during exercise tests. HR=heart rate, RVSP=right ventricular systolic pressure, RVDP=right ventricular diastolic
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pressure, ePAD=estimated pulmonary artery diastolic pressure, MPAP=mean pulmonary artery pressure. *=p<0.05
Figure 2. Rest and max right ventricular systolic (RVSP), mean pulmonary artery (MPAP) and right
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ventricular diastolic (RVDP) pressures during ambulatory conditions (AMB), a 6-min walk test (6MWT), and a symptom limited exercise on treadmill (MAXWT). The left hand panels show patients that
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improved walked distance from baseline to 12W (Group 1) and the right hand panel show patients who did not improve or decreased walked distance (Group 2). *=p<0.05
Figure 3. The trend shows continuous right ventricular systolic pressure and activity counts over 8 months in a patient with PAH and an implanted IHM. The black line is the daily median and the gray lines are the upper (94th percentile; UQ) and lower (6th percentile; LQ) daily ranges (rest and max). The patient started
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subcutaneous treprostinil (prostacyclin) treatment in mid-January (beginning of trend). The daily median and lower daily range values decrease indicating a positive treatment response, while the upper daily
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range remain at a similar high pressure level as before start of new treatment.
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Figure 3
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