ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and Right Heart Failure Assessed by Continuous Long-term Cardiac Monitoring
Conditions: Pulmonary Hypertension, Arrhythmias, Cardiac, Heart Rate Variability, Risk Assessment
Sponsor: Rigshospitalet, Denmark

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
1 
 
 
Trial Protocol  
 
Official title: 
ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and  
right heart failure assessed by continuous  
long-term cardiac monitoring 
 
 ASPIRE 
Date of approval 3th May 2018 Journal-nr.: H-18005164 (from 
Videnskabsetisk komité) 
 
 
 
Jørn Carlsen & Jesper Hastrup Svendsen 
Department of Cardiology 2141 & 2012  
Copenhagen University Hospital, Rigshospitalet 
  
 
Correspondence: 
Jørn Carlsen, MD, DMSc 
Department of Cardiology 2141 
Copenhagen University Hospital, Rigshospitalet 
9- Blegdamsvej 
2100 Copenhagen 
DK-Denmark   
Ph.: (+45) 35458060 
E-mail: joern.carlsen@regionh.dk 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
2 
 
 
Content  
 
Introduction 
3 
Project I: 
Incidence of supraventricular and ventricular arrhythmias in PAH 
4 
 
- 
Reveal LINQ Insertable Cardiac Monitor 
5 
- 
CareLink Remote Monitoring Network 
   
5 
- 
Study synopsis – ASPIRE I 
 
6 
- 
Study chart – ASPIRE I 
7 
Project II 
Predictive value of CMR-Derived RV and LV parameters for  
arrhytmogenesis in PAH  
8 
- 
Study synopsis- ASPIRE II 
9 
- 
MRI protocol  
11 
- 
Study chart – ASPIRE II  
12 
Project III 
Optimization of specific therapy in PAH using continuous long-term 
arrhythmia monitoring 
13 
- 
Study synopsis- ASPIRE III 
15 
- 
Study chart – ASPIRE III   
16 
Limitations  
 
17 
Conclusions and perspectives 
 
17 
Risk and side effects  
Biobank  
Information from the patient’s journal 
18 
Financial conditions 
Recruitment of patients 
Publication of test results  
 
19 
Abbreviations 
 
20 
References 
 
22 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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Introduction 
 
Pulmonary arterial hypertension (PAH) is a progressive disease affecting both the 
pulmonary vasculature and the heart. PAH is characterized by a mean pulmonary artery 
pressure (mPAP) of ≥25 mmHg, pulmonary capillary wedge pressure (PCWP) of ≤15 
mmHg and PVR ≥ 3 WU (1). As a response to the changed vascular conditions, the right 
side of the heart adapts via hypertrophy and increased contractility by an increase in 
cardiomyocyte size and addition of sarcomeres (2). This is referred to as adaptive 
remodeling and compensates for the elevated afterload. However, as the disease 
progresses these compensatory mechanisms are insufficient and a ventriculoarterial 
uncoupling occurs (3;4). With further progression, the remodeling process becomes 
maladaptive leading to eccentric hypertrophy and dysfunction of the RV (fig.1). Ultimately, 
stroke volume declines, RV failure (RVF) develops and subsequent arrhythmias become 
a prominent phenomenon of PAH, which again may reduce right ventricular function 
(5;6). Furthermore, modulation in autonomic activity, delayed cardiac repolarization and 
right ventricular ischemia contributes to the pathobiology of arrhythmias. 
 
 
  
 
 
Figure 1 (3): Pathophysiological mechanisms of right ventricular failure (RVF) in pulmonary 
arterial hypertension (3). RV wall stress induces altered bioenergetics and activates the 
neurohormonal axis and an inflammatory response. These factors contribute to myocardial 
remodeling which is divided into adaptive and maladaptive remodeling. The latter is characterized 
by ventriculoarterial uncoupling and dilatation. 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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The incidence of supraventricular arrhythmias is between 8 - 35% (6-11) and 
considerably lower for ventricular arrhythmias (5;10-14). Cardiac parameters, such as 
right ventricular diameter, right ventricular longitudinal dimension and right atrial length, 
significantly correlate with an increased risk of arrhythmias (7). Supraventricular 
tachycardias (SVT) may compromise cardiac function and worsen the prognosis of 
patients with PAH (6), but information about their incidence and clinical role is based on a 
small number of retrospective studies (5;6;10;11;15). Additionally, permanent atrial 
fibrillation and prolonged QTc interval are associated with the highest mortality (16). The 
goal in management of arrhythmias is to maintain sinus rhythm either by pharmacological 
or device treatment.  
 
This research project is the first study applying continuous long-term monitoring of 
arrhythmias in patients with PAH and right heart failure (RHF). The study specifically 
seeks to investigate following: 
 
• The incidence and type of supraventricular and ventricular arrhythmias in PAH by 
continuous long-term monitoring 
• The predictive value of both right and left ventricular cardiac magnetic resonance 
(CMR) imaging parameters for arrhythmogenesis in PAH.  
• Optimization of specific therapy in PAH using continuous long-term arrhythmia 
monitoring 
 
Project ASPIRE I: 
 
Incidence and characteristics of supraventricular and ventricular 
arrhythmias in PAH 
 
Background 
 
A. Supraventricular arrhythmias 
In a 6-year retrospective analysis of 231 patients with PAH and chronic thromboembolic 
pulmonary hypertension, Tongers et al. noted a cumulative supraventricular arrhythmia 
(SVA) incidence of 11.7% and an annual risk of 2.8% per patient (9). All patients were 
seen regularly at 1 to 6 monthly intervals, or whenever clinically indicated and 12-channel 
electrocardiograms (ECGs) were obtained. None of the patients was carrying any device 
that could record rhythm events continuously. The most common types of arrhythmia 
were atrial flutter (AFL) and atrial fibrillation (AF) diagnosed from standard surface ECG. 
AV nodal re-entry tachycardia (AVNRT) was less common and documented by 
standardized electrophysiologic studies. However, this cohort of PAH patients was not 
entirely homogeneous and the relative incidence of various types of SVA may vary based 
on the etiology of pulmonary hypertension. Other retrospective studies have reported an 
incidence of SVA in PAH of 8.4%, 22% and 35 %, respectively (9;5;10). In prospective 
studies the incidence of SVA in PAH and PH have been described as 15% in IPAH (7) 
and 20% in PAH and CTEPH(8) respectively.  
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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B. Ventricular arrhythmias 
RV failure is reported to account for approximately 38 % of death in a low-risk group and 
up to 63 % in a high-risk group (17), whereas sudden cardiac death accounts for 30%. 
Together, RV failure and sudden cardiac death represent the majority of deaths in 
patients with PAH (18-20). However, in contrast to patients with advanced left heart 
disease, malignant ventricular arrhythmias such as ventricular tachycardia (VT) and 
ventricular fibrillation (VF) are relatively rare in patients with PAH. In patients with PAH, 
pulseless electrical activity is often heralded by bradycardia. Hoeper et al. reported the 
outcome in 132 of 513 patients (26%) after cardiopulmonary resuscitation (12). The initial 
ECGs at the time of cardiopulmonary arrest showed bradycardia in 58 cases (45%), 
electromechanical dissociation in 37 cases (28%), asystole in 19 cases (15%), ventricular 
fibrillation in only 10 cases (8%), and other arrhythmias in 6 cases (4%).  
C. Bradyarrhytmias 
Ventricular tachycardia is less common, and relative bradycardia is an ominous sign, with 
bradyarrhythmias frequently observed in the setting of cardiopulmonary arrest. Clinical 
studies of defibrillator/pacemaker therapy for primary prevention against sudden death in 
PAH patients are lacking.   
 
D. Heart rate variability 
 
As PH progresses, the RV afterload increases, ultimately leading to impaired cardiac 
output and right-side heart failure. Consequently, the sympathetic nervous system activity 
(SNS) increases and the parasympathetic nervous system (PNS) decreases [12, 18]. The 
autonomic nervous system (ANS) regulates the sinus node, and can be assessed by 
heart rate variability (HRV) [19, 20]. The HRV illustrates the autonomic balance between 
the sympathetic and parasympathetic input, and is a noninvasive indicator of the 
autonomic input to the heart [21]. 
 
 
 
Reveal LINQ Insertable Cardiac Monitor 
The Reveal LINQ Insertable Cardiac Monitor is a wireless and the smallest insertable 
cardiac monitor. The Reveal LINQ insertion procedure is minimally invasive, and 
requires short procedure time and clinical resources. It is placed under the skin of the 
chest and automatically detects and records abnormal heart rhythms for up to 3 years.   
 
Figure 2. The Reveal LINQ Insertable Cardiac Monitor is supported by a CareLink Network and a 
patient monitor easy to use that features cellular technology. Alert notifications can result in earlier 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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clinical decisions compared to non-wireless devices (21). The Reveal LINQ is safe for use in an 
MRI setting.  
CareLink® Remote Monitoring Network 
 
The Medtronic CareLink Network ensures timely identification of clinically important 
issues, such as asymptomatic atrial fibrillation or device integrity issues (22). Data are 
automatically sent to the CareLink server from the device. In addition, patients can 
transmit device information from home (Figure 3), and clinicians can review device data 
when and where they choose on the Medtronic CareLink Clinician Website. The 
Medtronic CareLink Network provides comprehensive data comparable to an in-clinic 
device check, including full parameter summary, A-V conduction histograms and 
arrhythmia summary.  
 
 
Figure 3 The Medtronic CareLink Network is fast and easy to use with scheduling flexibility, 
allowing patients to transmit data within a time range rather than at a set time. Clinic staff need not 
be present during transmissions. 
 
Study Synopsis – ASPIRE I 
 
Name of the study  
Incidence and characteristics of supraventricular and ventricular arrhythmias in PAH 
(ASPIRE-I) 
Study design 
Single centre observational study in patients treated with PAH specific medication. 
Patients will be followed for 2 years after inclusion. 
Study objectives 
Primary objective 
To assess the incidence of arrhythmias in prevalent and incident cases of PAH using 
continuous long-term monitoring by Reveal LINQ insertable cardiac monitor.  
 
To assess heart rate variability in correlation to known risk markers in PH. 
Methodology 
The study will be conducted as a single center study at Copenhagen University Hospital, 
Rigshospitalet, DK-Denmark.  
Trial duration 
Enrolment duration: 9 months 
Number of patients  
 
40 patients. WHO Group I PAH: 10 with IPAH, 10 with CTD-aPAH, WHO Group III: 10 
with pulmonary disease related PH and Group IV: 10 with CTEPH.    
Study treatment 
Patients with PAH/PH will be consecutively selected from the cohort of patients being 
treated with PAH specific medication, and incident cases will be enrolled prospectively.  

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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Selection criteria 
Inclusion criteria: 
The following patients will be included in the study: 
- 
Patients >18 years of age  
- 
Patients on current PAH specific medication must be stable for at least 3 months.   
- 
Patients can be included in WHO group 1 only with IPAH or CTD-aPAH and group 
IV, CTEPH 
Exclusion Criteria: 
- 
Patients who are unlikely to comply with the study protocol and procedures required 
by the study protocol. 
- 
Patients with any severe complication or comorbidity other than PAH which might 
determine the prognosis and functional level of the patient.  
- 
Need for escalation of PAH specific therapy  
- 
Patients who are already in specific treatment for arrhythmias.   
 
Concomitant treatments 
- 
Patients can be on the following treatments only if they have been at least treated 
for three months prior to inclusion and are planned to be continued during the whole 
study period: diuretics, digoxin, beta-blockers and amiodarone 
Data collection 
At screening: 
- 
PAH verified with right heart catheterization before start of PAH specific 
medication. 
- 
Basic demographic data including medication. 
- 
Physical examination and vital signs 
- 
6 MWT 
- 
Digital ECG to verify rhythm at baseline 
  
Care Link Network  
- 
Device information send from home  
- 
Clinicians review device data on the Medtronic CareLink Clinician Website 
Visits every 6 months  
- 
6 MWT  
- 
Lab tests, including NT-proBNP  
- 
Record concomitant medications 
Statistical methods  
SPSS/PASW Statistics 19 software (SPSS Inc, Chicago IL), SAS or R are used for all 
statistical analyses.  
In addition, descriptive time serial analysis will be done on heart rate variability and 
heart rate. 
Correlation statistics will be done to assess heart rate variability and heart rate in 
correlation to known risk markers in PH.  
 
Endpoints 
To assess the incidence of arrhythmias in patients with PAH.  
  
 
 
Study Chart - ASPIRE I 
 
 
 
Screening 
Operation  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
 
1 
6 mo 
12 mo 
18 mo 
24 mo  
Informed 
consent 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
RHC`¤ 
X 
 
 
 
 
 
SPECT/CT 
X 
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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LFT 
X 
 
 
 
 
 
ECG 
X 
x 
X 
X 
x 
X 
Echocardiog
raphy 
X 
 
 
x 
 
x 
6 MWT  
X 
X 
X 
X 
x 
X 
Clinical data 
collection 
X 
X 
X 
X 
X 
X 
Blood 
Samples# 
X 
x 
X 
x 
x 
x 
 
¤ RHC;: right heart catheterisation for incident cases only. Prevalent cases have had RHC at the time of 
diagnosis.  *CMR, cardiac index, RV size, stroke volume and pulmonary artery diameter including exercise 
measurements   #Blood samples include haematology, liver chemistry (ALT, AST, LDH bilirubin) renal 
(creatinine, eGFR), and NT-proBNP.  
 
 
 
 
 
Project ASPIRE II 
 
Predictive value of Cardiac Magnetic Resonance, CMR-Derived RV and LV 
parameters for arrhythmogenesis in PAH  
 
Background: 
 
Several factors contribute to the arrhythmogenic shift in the electrophysiology of the heart 
in PAH/RHF. The major four predisposing factors for arrhythmias in PAH are 1. 
modulation in autonomic activity, 2. remodeling of the myocardium 3. delayed cardiac 
repolarization and 4. RV myocardial ischemia.  
 
The function of the RV and the RA decreases when remodeling progresses. Li Wen et al. 
(7) examined the changes in cardiac parameters as measured by echocardiography and 
their associated risk of arrhythmias (Table 1).  
 
 
Variable 
Hazard Ratio [95% CI] 
p Value 
Right atrial diameter 
1.80 [1.40-3.11] 
<0.001 
Right atrial length 
2.08 [1.62-2.69] 
<0.001 
Right atrial area 
1.07 [1.05-1.10] 
<0.001 
Right ventricular diameter 
2.76 [2.07-3.70] 
<0.001 
Right ventricular longitudinal dimension 
2.06 [1.49-2.81] 
<0.001 
mRAP 
1.14 [1.08-1.19] 
<0.001 
PVR 
1.08 [1.03-1.13] 
0.001 
Cardiac output 
0.72 [0.55-0.95] 
0.022 
 
Table 1 Univariate analysis of risk factors for SVA in IPAH, modified after LiWen (7) CI: 
Confidence interval, mRAP: mean Right Atrial Pressure, PVR: Pulmonary Vascular Resistance.   

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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Cardiac parameters measured by cardiac magnetic resonance (CMR) has not been used 
in the assessment and prediction of arrhythmias in PAH/RHF. However, arrhythmias 
often leads to clinical deterioration, right sided cardiac failure and is associated with a 
higher risk of death in patients with PAH (7;9;15).  
 
CMR-derived RVEF is an independent noninvasive imaging predictor of adverse 
outcomes in this patient population (23;24). Van de Veerdonk et al. (25) confirmed that, in 
110 patients with newly diagnosed PAH, CMR-derived RVEF measured at baseline was 
an independent predictor of mortality. In addition, they found that even though pulmonary 
vascular resistance measured at baseline was also predictive of mortality, after a year of 
PAH-targeted therapy, only changes in RVEF were associated with survival. This finding 
suggests that RVEF, as measured by CMR, is a clinically important determinant of 
prognosis. 
 
Several studies have reported that, when using contrast-enhanced CMR in patients with 
PAH, late gadolinium enhancement (LGE) of the RV insertion points strongly correlated 
with multiple indices of RV function (26-30). The presence of late gadolinium 
enhancement of the RV insertion points seems to be a marker for more advanced 
disease and poor prognosis in patients with PH (31). Rydman et al. described that 
systemic RV LGE is strongly associated with adverse clinical outcome especially 
arrhythmia in transposition of the great arteries (32). 
 
More recently, T1-mapping and extracellular volume fraction has emerged as novel 
techniques to assess myocardial involvement prior to overt RV dysfunction in 
experimental pulmonary hypertension (33). ECV was also increased in the RV in patients 
with pulmonary hypertension, even after adjusting for RV volume and ejection fraction 
(34).This has led to requests of further investigation of the roles of T1-mapping and ECV 
as methods of risk assessing patients with pulmonary hypertension (35). 
Myocardial strain is defined as the percentage of change in tissue length. A study of 
strain velocity in the left ventricle in pulmonary hypertension showed that it predicted 
functional capacity and clinical worsening before significant changes in RVEF and SV 
(36). Today, CMR analysis software allow strain assessment using standard steady-state 
free precession cine-imaging of both the left and right ventricle, leading to requests of 
studies investigating the role of RV strain and strain velocities as predictors of adverse 
outcome in pulmonary hypertension (35). 
 
Study Synopsis - ASPIRE II 
 
Title of the study 
Predictive value of CMR-Derived RV and LV parameters for arrhytmogenesis in PAH 
(ASPIRE-II) 
Study design 
Single centre observational study with CMR and insertable cardiac long term 
monitoring in newly referred and PAH patients treated with PAH-specific therapy. 
Patients will be followed for 2 years after inclusion. 
Study objectives 
Primary objective 
To evaluate CMR as a tool for providing noninvasive predictors for arrhythmias in 
patients with PAH.   
Secondary objectives 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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- 
To assess change in 6 MWT 
- 
To assess hemodynamic changes with RHC 
- 
To assess hemodynamic changes in echocardiography 
- 
To assess the number of patients progressing one FC (Modified NYHA class) 
- 
To assess changes in NT-proBNP.  
- 
To assess Hospital admission for any reason 
- 
To assess Death or transplantation 
Methodology 
The study will be conducted as a single center study at Copenhagen University 
Hospital, Rigshospitalet, DK-Denmark.  
Trial duration 
Enrollment duration: 9 months   
Number of patients  
 
40 patients. WHO Group I PAH: 10 with IPAH, 10 with CTD-aPAH, WHO Group III : 10 
with pulmonary disease related PH and Group IV: 10 with CTEPH.    
Selection criteria 
 
 
 
 
 
 
Inclusion criteria: 
The following patients will be included in the study: 
- 
Patients >18 years of age 
- 
Voluntary participation after giving informed verbal and written consent 
- 
Patients untreated with PAH specific therapy   
- 
Patients on current PAH specific medication independent of duration of therapy 
- 
Patients can be in WHO group 1 only with IPAH or CTD-aPAH, and group IV, 
CTEPH  
 
Exclusion Criteria 
- 
Patients who are unlikely to comply with the study protocol and procedures 
required by the study protocol. 
- 
Patients with any severe complication or comorbidity other than PAH which might 
determine the prognosis and functional level of the patient.  
- 
Renal insufficiency (GFR estimated <60 ml/min/ 1.73 m2). 
- 
Implanted ferromagnetic metal parts unsuited for CMR (ICD, cerebral clips) 
- 
Claustrophobia 
- 
Allergy or hypersensitivity to Gadovist 
Concomitant treatments 
- 
Patients can be on the following treatments only if they have been at least treated 
for three months prior to inclusion and are planned to be continued during the 
whole study period: diuretics, digoxin, beta-blockers, amiodarone 
 
 
Data collection 
At screening: 
- 
SPECT/CT will be performed at diagnosis for prevalent cases only and at 
screening for incidents cases to evaluate pulmonary embolism  
- 
LFT to exclude pulmonary disease: COPD and ILD 
- 
Echocardiography to exclude left heart disease  
- 
PAH verified with right heart catheterization before start of PAH specific 
medication 
- 
Basic demographic data including medication. 
- 
Physical examination and vital signs 
- 
6 MWT 
- 
ECG  
- 
Lab tests including liver and renal function tests and NT-pro-BNP  
 
Visits every 6 months or with increased symptomatology 
- 
CMR with measurement of RV/LV volumes, CI (volumetric and flow), RVEF and 
pulmonary artery diameter according to standard criteria. Yearly measurement of 
RV fibrose (LGE, T1 mapping and ECV). The same MR-scanner must be used for 
all measurements.  

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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- 
6 MWT  
- 
Lab tests, including liver and renal function tests including yearly eGFR, 
hematocrit and NT-proBNP  
- 
Echocardiography yearly and at 3 month after inclusion 
- 
Record concomitant medications 
- 
PAH medications 
Endpoints 
Coprimary endpoints 
- 
Change in cardiac index, right atrial size, RV size, fibrosis and stroke volume 
- 
Arrhytmias as assessed by Insertable Cardiac Monitors  
Secondary endpoints 
- 
Modified  NYHA functional class  
- 
Reduction in 6 MWT in the study period. 
- 
NT-proBNP change in study period. 
- 
Change and /or escalation of PAH therapy   
- 
Respiratory hospitalization  
- 
Death or transplantation 
 
Statistical methods  
Repeated measurements of CI, right atrial size, RV size, fibrosis and stroke volume will 
be performed every 6 months.  
Two groups of subjects will be defined: 1. Patients with no change in CI, RV size and 
stroke volume, and 2.A group of patients where one of the measurement change more 
than 2 standard deviations.  
It is group-shift (Y/N) if a subject changes out of the 2 stdv band.   
Time to group shift will be analysed in a subsequent analysis. 
Cox-model analysis will be done on measurements of (1) cardiac index, (2) RV size, 
(3) stroke volume and (4) fibrosis to calculate the correlation with risk of developing 
clinical symptoms and clinical deterioration. In other words, this analysis will establish if 
the MR-measurements predict clinical outcome.  
SPSS/PASW Statistics 19 software (SPSS Inc, Chicago IL), SAS or R is used for all 
statistical analysis. 
 
 
MRI protocol  
 
Every six months, all subjects are scanned according to the protocol below.  The 
scanning will take 60-80 minutes. MRI scans will be carried out on a 1.5 to 3.0 Tesla MRI 
scanner. At visit 1, 3 and 5 a cannula will be placed for contrast administration. 
MRI studies will provide time-volume curves for LV and RVs filling and ejection fraction, 
peak emptying rate, peak filling rate and stroke volume will be calculated.  
The measurements will provide time-flow curves for flow in the pulmonary trunk, 
pulmonary branch arteries and aorta. It will be possible to measure the distribution of flow 
to the right and left lung. Since the pulmonary trunk is often dilated with slow flow, it can 
be more accurately to measure the flow in the smaller branch pulmonary arteries. 
Angiography will also provide the flow distribution in the lungs and the different segments 
of the lungs. 
After baseline scan subjects will be exercised by a MR compatible ergometer with a load 
of 1 watt per kg. Stress test will measure the physiological reserve in terms of changes in 
cardiac index and ventricular volumes. Finally, late enhancement will measure the degree 
of fibrosis in the left and right ventricle. 
 
 
 
Scannings protocol 
Sekvens 
1 
Scout 
SSFP, single shot 
2 
Transverse stack, no gaps – covers the hears 
SSFP, 8 mm, 25 phases 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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3 
LV vertical long axis (VLA) 
SSFP, 8 mm, 25 phases 
4 
Scout LV, short axis 
SSFP, single shot 
5 
The four standard views (4 chamber, 3 chamber, 2 chamber, 
LVOT coronal) 
SSFP, 8 mm, 25 phases 
6 
LV short axis stack, no gaps 
SSFP, 8 mm, 25 phases 
7 
RV long axis 
SSFP, 8 mm, 25 phases 
8 
RV inlet-apex-outlet (3 points) 
SSFP, 8 mm, 25 phases 
9 
RVOT – PA x 2 perpendicular views 
SSFP, 8 mm, 25 phases 
10 
RVOT short axis 
SSFP, 8 mm, 25 phases 
11 
Left pulmonary artery x 2 perpendicular 
SSFP, 8 mm, 25 phases 
12 
Left pulmonary artery short axis 
SSFP, 8 mm, 25 phases 
13 
Right pulmonary artery x 2 perpendicular 
SSFP, 8 mm, 25 phases 
14 
Right pulmonary artery short axis 
SSFP, 8 mm, 25 phases 
15 
Pre-contrast T1-mapping 4ch 
Pre-contrast T1-mapping short-axis 
T2-mapping 4ch  
T2-mapping short-axis 
 
 
*Kontrast injection: Gadovist 1.5 mmol/kg 
 
16 
*Rest myocardial perfusion scan 
 
 
 
 
17 
PA flow  
Velocity encoding, VENC 10 % 
above max velocity 
18 
LPA flow  
Velocity encoding, VENC 10 % 
above max velocity 
19 
RPA flow  
Velocity encoding, VENC 10 % 
above max velocity 
20 
Aorta flow  
Velocity encoding, VENC 10 % 
above max velocity 
 
Post-contrast T1-mapping 4ch 
Post-contrast T1-mapping short-axis 
 
21 
*Late enhancement LV short axis stack 
Inversion recovery, FLASH 
 
 
 
 
Stress 1 watt/kg 
 
 
 
 
22 
Transverse stack, no gaps – cover the heart  
SSFP, 8 mm, 25 phases 
23 
PA flow  
Velocity encoding, VENC 10 % 
above max velocity 
24 
Aorta flow  
Velocity encoding, VENC 10 % 
above max velocity 
25 
LV short axis stack, no gaps 
SSFP, 8 mm, 25 phases 
* Contrast studies will only be performed at visit 1, 3 and 5.   
 
LV: left ventricle, LVOT left ventricular aoutflow tract, RV, right ventricle, PA, pulmonary artery, LPA. Left 
pulmonary artery, RPA, right pulmonary artery.   
 
 
 
 
Study Chart – ASPIRE II  
 
 
 
Screening 
ILR 
implantation   
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
 
1 
6 mo 
12 mo 
18 mo 
24 mo  
Informed 
consent 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
RHC`¤ 
X 
 
 
 
 
 
SPECT/CT 
X 
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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LFT 
X 
 
 
 
 
 
ECG 
X 
x 
X 
X 
x 
X 
Echocardiog
raphy 
X 
 
 
x 
 
x 
6 MWT  
X 
X 
X 
X 
x 
X 
Clinical data 
collection 
x 
X 
X 
X 
X 
X 
CMR 
 
X§ 
x 
X§ 
x 
X§ 
Blood 
Samples# 
X 
x 
X 
x 
x 
x 
 
¤ RHC;: right heart catheterisation for incident cases only. Prevalent cases have had RHC at the time of 
diagnosis.  *CMR, cardiac index, RV size, stroke volume and pulmonary artery diameter including exercise 
measurements   #Blood samples include haematology, liver chemistry (ALT, AST, LDH bilirubin) renal 
(creatinine, eGFR), and NT-proBNP.  
 
Project ASPIRE III 
 
Optimization of specific therapy in PAH using continuous long-term 
arrhythmia monitoring 
 
Background 
In most cases, onset of atrial tachyarrhythmias is related to clinical deterioration, and 
deterioration in exercise capacity by one functional class or more, and development of 
ascites and/or edema refractory to diuretic therapy (37). Restoration of normal sinus 
rhythm is invariably associated with clinical improvement. The onset of these arrhythmias 
could be a warning sign for deteriorating RV function and hence the need for increasing 
specific therapy for PAH. Although prospective and controlled data are lacking, these 
findings suggest that maintenance of sinus rhythm is an important treatment goal in 
patients with PAH, which contrasts with the clinical experience in left heart failure in non-
PAH patients, where the rhythm control strategy seems to offer no mortality benefit 
compared to the rate control and systemic anticoagulation strategy (38). 
 
 
 
Figure 3: Kaplan-Meier estimates of survival in patients with PAH in relation to 
supraventricular arrhythmias (SVA; (7)) 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
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With regard to mortality, while AVNRT and AFL were invariably converted to sinus rhythm 
and were not associated with an increased risk of death (cumulative mortality<6%), the 
presence of persistent atrial fibrillation and failure to restore sinus rhythm were 
associated with a cumulative mortality of > 80% (9). AF may be a particularly malignant 
arrhythmia in patients with chronic PAH and RHF (10). 
 
In terms of ventricular arrhythmias QT prolongation increases the risk for VAs and 
especially for torsades-de-pointes tachycardia. QTc interval in PH patients are generally 
longer compared to controls (454.8±29ms vs. 429.8±18ms, p<0.001) (16). A prolonged 
QTc interval correlated with deterioration of the RV, and when QTc was ≥480ms an 
increased risk of death was observed in a multivariate analysis (HR=3.09 [CI 95%; 1.61-
8.38], p = 0.022). Furthermore, an analysis of CPR outcome in PAH patients showed that 
several arrhythmias are indicative of imminent cardiac arrest. The outcome of CPR in 
PAH-patients was critical, with a survival rate of 6% after 90 days (12).  
With regard to therapies for SVTs in PAH patients, medical treatment with calcium-
channel blockers and beta-blockers is considered to be deleterious due to their negative 
inotropic effects and their role is unfortunately limited. In the acute setting, amiodarone 
has been used for control of hemodynamically significant arrhythmias. The role of 
chronic, prophylactic antiarrhythmic drugs to maintain sinus rhythm remains questionable 
given significant potential side-effects. Nevertheless, the recurrent development of poorly 
tolerated arrhythmias may require its use on a long-term basis. Finally, interactions of 
medications must be carefully considered since for instance amiodarone may increase 
levels of bosentan, requiring close monitoring and adjustment. In a retrospective analysis 
of 22 patients with AFL and PAH due to pulmonary artery hypertension and chronic 
thromboembolic pulmonary hypertension, Showkathali et al. demonstrated that AFL 
cavotricuspid isthmus ablation can be performed successfully and without complications, 
and was accompanied with a statistically significant improvement in functional class after 
ablation (39).  
The role of cardiac resynchronization therapy (CRT) in patients with right heart failure due 
to PAH is currently uncertain. In an experimental model of PAH and right heart failure, 
investigators found that pre-excitation of the RV free wall in the absence of baseline 
conduction disturbances resulted in improved RV systolic function and reduced adverse 
left ventricular diastolic interaction (40).  Another study demonstrated that 
resynchronization therapy acutely reduced ventricular dyssynchrony and enhanced RV 
contractility, left ventricular diastolic filling, and stroke volume in a patient suffering from 
right heart failure and ventricular dyssynchrony secondary to chronic thromboembolic 
pulmonary hypertension (41). In addition, recent analysis notes that pediatric patients 
with PAH manifest abnormal mechanical as well as electrical RV activation when 
compared to patients without PAH. These promising results warrant further investigations 
of CRT as a novel treatment for right heart failure secondary to PAH. However, without 
further data, the relative benefits versus risks of CRT in this setting remain unknown. 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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15 
 
Study Synopsis – ASPIRE III 
 
Title of the study 
Optimization of specific therapy in PAH using continuous long-term arrhythmia 
monitoring (ASPIRE-III). 
Study design 
Single centre observational study with CMR in newly referred and PAH patients treated 
with PAH-specific therapy. Patients will be followed for 2 years after inclusion. 
Study objectives 
Primary objective 
To evaluate long-term monitoring of arrhythmias as a predictor tool for escalation of 
PAH specific therapy and prognosis in patients with PAH.   
Secondary objectives 
- 
To assess change in 6 MWT 
- 
To assess hemodynamic changes with RHC 
- 
To assess hemodynamic changes in echocardiography 
- 
To assess the number of patients progressing one FC (Modified NYHA class) 
- 
To assess changes in NT-proBNP.  
- 
To assess Hospital admission for any reason 
- 
To assess Death or transplantation 
Methodology 
The study will be conducted as a single center study at Copenhagen University 
Hospital, Rigshospitalet, DK-Denmark.  
Trial duration 
Enrollment duration: 9 months 
Number of patients  
 
40 patients. WHO Group I PAH: 10 with IPAH, 10 with CTD-aPAH, WHO Group III : 10 
with pulmonary disease related PH and Group IV: 10 with CTEPH.    
Selection criteria 
Inclusion criteria: 
The following patients will be included in the study: 
- 
Patients >18 years of age 
- 
Voluntary participation after giving informed verbal and written consent 
- 
Patients untreated with PAH specific therapy   
- 
Patients on current PAH specific medication independent of duration of therapy 
- 
Patients can be included irrespective of pre-medication disease (WHO group 1) 
Exclusion Criteria 
- 
Patients who are unlikely to comply with the study protocol and procedures 
required by the study protocol. 
- 
Patients with any severe complication or comorbidity other than PAH which might 
determine the prognosis and functional level of the patient. 
Concomitant treatments 
- 
Patients can be on the following treatments only if they have been at least treated 
for three months prior to inclusion and are planned to be continued during the 
whole study period: diuretics, digoxin, beta-blockers and amiodarone 
Data collection 
At screening: 
- 
SPECT/CT will be performed at diagnosis for prevalent cases only and at 
screening for incidents cases to exclude pulmonary embolism  
- 
LFT to exclude pulmonary disease: COPD and ILD 
- 
Echocardiography to exclude left heart disease  
- 
PAH verified with right heart catheterization before start of PAH specific 
medication 
- 
Basic demographic data including medication. 
- 
Physical examination and vital signs 
- 
6 MWT 
- 
ECG  
- 
Lab tests including liver and renal function tests and NT-pro-BNP  
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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16 
 
Visits every 6 months or with increased symptomatology 
- 
6 MWT  
- 
Lab tests, including liver and renal function tests including yearly eGFR and NT-
proBNP  
- 
Echocardiography yearly and at 3 month after inclusion 
- 
Record concomitant medications 
- 
PAH medications 
Endpoints 
Primary endpoints 
- 
Arrhytmias as assessed by Insertable Cardiac Monitors  
Secondary endpoints  
- 
Modified NYHA functional class  
- 
Reduction in 6 MWT in the study period. 
- 
NT-proBNP change in study period. 
- 
Change and /or escalation of PAH therapy   
- 
Respiratory hospitalization  
- 
Death or transplantation 
 
Statistical methods  
SPSS/PASW Statistics 19 software (SPSS Inc, Chicago IL), SAS or R is used for all 
statistical analysis. 
 
  
 
 
Study Chart – ASPIRE III  
 
 
 
Screening 
Operation  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
 
1 
6 mo 
12 mo 
18 mo 
24 mo  
Informed 
consent 
x 
 
 
 
 
 
Height 
x 
 
 
 
 
 
Weight 
x 
 
 
 
 
 
RHC`¤ 
x 
 
 
 
 
 
SPECT/CT 
x 
 
 
 
 
 
LFT 
x 
 
 
 
 
 
ECG 
x 
X 
X 
X 
x 
X 
Echocardiog
raphy 
x 
 
 
x 
 
x 
6 MWT  
x 
X 
X 
X 
x 
X 
Clinical data 
collection 
x 
X 
X 
X 
X 
X 
Blood 
Samples# 
x 
X 
X 
x 
x 
x 
 
¤ RHC;: right heart catheterisation for incident cases only. Prevalent cases have had RHC at the time of 
diagnosis.  *CMR, cardiac index, RV size, stroke volume and pulmonary artery diameter including exercise 
measurements   #Blood samples include haematology, liver chemistry (ALT, AST, LDH bilirubin) renal 
(creatinine, eGFR), and NT-proBNP.  
 
 
 
 
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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17 
 
Limitations  
Reveal LINQ Insertable Cardiac Monitor, ICM 
The ICM used in this study is wireless and the smallest available device, and the  
insertion procedure is minimally invasive, and requires short procedure time and clinical 
resources. To be able to send device information from home cellular technology is 
required.   
 
Cardiac magnetic resonance imaging, CMR 
CMR has its own limitations. Unlike echocardiography, it is expensive and not widely 
available. Data acquisition and post-processing can be time consuming and the need for 
patients to lie flat in the scanner can be somewhat challenging. However, with improved 
technology, many of the parameters mentioned above can be attained in almost the 
same amount of time as a standard 2-dimensional echocardiography (2DE).  
Conclusions and perspectives  
Arrhythmias in pulmonary arterial hypertension and right heart failure are prominent 
problems with an incidence of up to 35%. Supraventricular arrhythmias are the most 
prevalent in patients with pulmonary arterial hypertension. Permanent atrial fibrillation is 
the most ominous supraventricular arrhythmias and at the same time the most difficult to 
treat, whereas transient episodes of supraventricular arrhythmias seem to have no effect 
on mortality. Right ventricular and atrial parameters correlate with an increased risk of 
supraventricular arrhythmias in idiopathic pulmonary arterial hypertension patients. 
Prolonged QTc is associated with an increased risk of death.   
 
More data is needed to determine the optimal way to restore sinus-rhythm and manage 
arrhythmias in pulmonary arterial hypertension. In cases with atrial flutter, the most 
feasible and the safest therapy is radiofrequency ablation.  
 
This is the first study to assess arrhythmias in a homogeneous patient population 
prospectively, equally distributed among the different subgroups of pulmonary arterial 
hypertension with long-term monitoring.  The implantation of an Insertable Cardiac 
Monitor records the heart rhythm continuously, for up to three years, and saves ECG 
details immediately preceding and during arrhythmia. This approach in combination with 
MR scanning of RV haemodynamic parameters holds the promise for optimizing specific 
therapy in patients with PAH and right heart failure.   
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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18 
 
Risks and side effects  
MR scan: 
Contrast agents will be used in connection with the yearly MR-scan. This can have side 
effects such as nausea, dizziness or a minor impact on the patient’s kidney function. In 
rare cases, MR scans with contrast agents can be associated with more severe side 
effects such as shortness of breath and rashes. If a patient develops reduced kidney 
function, contrast agents will no longer be used in the yearly MR controls.  
The patient may have the same symptoms in connection with the bike test as with 
physical work load outside the scanner. The work load in the bike test will gradually be 
increased but will be stopped in case the patient feels discomfort.  
No radiation will be used in the study.   
 
Blood samples: 
Withdrawal of blood samples entails a minor risk of infection at the place of insertion of 
the needle, and a risk of puncture of an artery or nerve damage. Those complications are 
very rare and will be treated. Nerve damage will often disappear by itself. The most 
common complication in connection with taking blood samples is the occurrence of a 
hematoma, which will gradually disappear. 
 
Side effects of the insertion of a loop recorder: 
Pain may occur in the area around the place where the loop recorder is implanted.  The 
pain can be relieved by using painkillers, such as paracetamol. In very rare cases, the 
loop recorder can displace itself from its start position (1%), or it can cause inflammation 
(1%) or a hematoma under the skin (0.3 %). Finally, there is a risk of erosion in the 
pocket, in which the loop recorder lies (0.2 %) (42).  
 
Biobank: 
A biobank will be established in connection with the study. The biobank will enable the 
investigation of new hypotheses upon renewed authorization by The Danish Scientific 
Ethical Committee and the patient’s renewed consent. In the test, 10 ml blood will be 
withdrawn for every visit (6 visits in total) and the excess amount of blood will be kept in 
the biobank. The material will be kept for up to 25 years after the ending of the study and 
will then be destroyed.   
 
Information from the patient’s journal 
Release of any information from the patient’s journal to the person in charge of the study 
will take place according to section 46, subsection 1 of the Danish Health Act. According 
to this section, information about an individual person’s health, other private conditions 
and confidential information in patient journals etc. may be released to a researcher for 
the use in a concreate biomedical research project. Information about gender distribution, 
population distribution within various age groups, age distribution, blood pressure and 
weight may be obtained from a patient’s journal. In addition, information may be obtained 
about symptoms in relation to PAH, medical treatment and possible concomitant 
diseases. This kind of information may be compared with data appearing from the loop 
recorder and the MR scans. Any information used for publication will be anonymized.  
 
We adhere to the European regulation on protection of personal data. 
The study has been announced to and approved by the Danish Data Protection Agency 
(J.nr.  2018-41-5331<) 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
continuous long-term cardiac monitoring 
 
19 
 
Financial conditions: 
We will apply for funding from external foundations. We will keep The Danish Scientific 
Ethical Committee currently informed about funding and also notify them when the final 
funding has taken place. 
The study has been started by the initiative of consultant Jørn Carlsen 
 
Recruitment of patients 
The patients will be recruited from the cohort already treated at “Kardiologisk Klinik” for 
PAH. In addition, we will prospectively offer new patients participation in the study and 
obtain their acceptance.  
 
Publication of test results: 
We aim at publishing all results, whether positive, inconclusive or negative, in articles in 
international scientific journals. Such articles will be found on the internet at 
www.ncbi.nlm.nih.gov/pubmed by a search on “Carlsen J” and “Hastrup J” and the 
subject “pulmonary arterial hypertension”. If the test results are not accepted by 
international journals publication of the results will be made in national journals and in 
presentations at national and international conferences.  
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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20 
 
 
Abbreviations 
2-DE 
2-dimensional echocardiography  
6 MWT 
6-Minute Walk Test   
AF 
Atrial Fibrillation 
AFL 
Atrial Flutter 
AVNRT 
AtrioVentricular Nodal Reentry Tachycardia 
BNP 
Brain Natriuretic Peptide 
CMR 
Cardiac Magnetic resonance imaging 
CO/CI 
Cardiac Output/Cardiac Index  
CPR 
CardioPulmonary Resuscitation 
CRT 
Cardiac Resynchronization Treatment 
CTEPH 
Chronic ThromboEmbolic Pulmonary Hypertension 
EPS 
Electrophysiological Study 
ECG 
ElectroCardioGraphy 
HR 
Hazard Ratio 
ICM 
Insertable Cardiac Monitor 
IPAH 
Idiopathic Pulmonary Arterial Hypertension 
LV 
Left Ventricle  
LVF 
Left Ventricle Failure 
mPAP 
mean Pulmonary Arterial Pressure 
mRAP 
mean Right Atrial Pressure 
PAH  
Pulmonary Arterial Hypertension 
PAP 
Pulmonary Arterial Pressure 
PH 
Pulmonary Hypertension 
PVR 
Pulmonary Vascular Resistance 
RA  
Right Atrium 
RHF 
Right Heart Failure 
RV 
Right Ventricle 
RVEDV 
Right ventricular end-diastolic volume  
RVESV 
Rright ventricular end-systolic volume 
RVEF 
Right ventricle ejection fraction 
SV  
Stroke Volume  
 
RVF 
Right Ventricle Failure 
SVA 
SupraVentricular arrhythmia 
SVT 
SupraVentricular Tachycardia 
VA 
Ventricular Arrhythmia 
VT 
Ventricular Tachycardia 
RHC: right heart catheterization 
SPECT/CT: Single photon emission computed tomography/ Computed tomography 
 
 
 
 
 
 
 
 

 
ASPIRE: ArrhythmiaS in Pulmonary arterIal hypeRtEnsion and right heart failure assessed by 
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21 
 
 
 
 
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