Exercise Facilitates Early Detection of Cardiac and Vascular Remodelling During Development of Chronic Thrombo‐Embolic Pulmonary Hypertension in a Novel Swine Model
Authors: Hoogesteijn‐Stam Kelly , van Duin Richard Willem Benjamin , Duncker Dirk Jan , Merkus Daphne 
Published: November 2023

BackgroundPulmonary hypertension (PH) is a chronic disease of the pulmonary vasculature characterized by impaired pulmonary hemodynamics and vascular remodeling which often progresses to right heart failure with high mortality. One subform of PH is chronic thrombo‐embolic pulmonary hypertension (CTEPH) which develops in 4% of patients after a pulmonary embolism and is characterized by remodeling of the distal, unobstructed pulmonary vasculature.PurposeHere we studied the progression of pulmonary vascular disease as well as the adaptation of the right ventricle to the increased after load, by repeated measurement of hemodynamics at rest and during graded treadmill exercise in a novel swine model of CTEPH.MethodsSwine (n=16) of either sex (23±1kg) were chronically instrumented with catheters (right ventricle (RV), pulmonary artery, left atrium and aorta) for hemodynamic measurements and blood sampling. Additionally, a flow probe was placed around the ascending aorta to measure cardiac output. CTEPH was induced in 8 swine by up to 4 weekly infusions of microspheres (Ø700μm, total ~40,000.‐spheres) into the pulmonary circulation, followed by 4–6 weeks of follow‐up without embolisations. In addition, the CTEPH animals received daily L‐NG‐Nitroarginine methyl ester (L‐NAME) i.v. (30mg·kg−1·day−1, week 1–7), During total follow‐up (7–10 weeks), hemodynamics at rest and during exercise were obtained. RV dimensions were weekly assessed using echocardiography.ResultsRepeated embolisation of the pulmonary vasculature resulted in a progressive increase in mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance index (tPVRi, Table). tPVRi did not change during exercise in either the control or CTEPH swine. At the end of the embolisation period at 4 weeks, the increase in MPAP during exercise was maintained in CTEPH swine while the increase in cardiac index (CI) was attenuated. Despite a lower arterial oxygen content (CaO2) in CTEPH swine, body oxygen consumption (BVO2) was maintained at rest and during exercise by an increase in oxygen extraction resulting in a decreased mixed venous oxygen content (CVO2). After 8 weeks of follow‐up, the increase of MPAP and tPVRi and decrease of CI were sustained at rest, while oxygen extraction in CTEPH swine had returned towards control levels. However, although CI did increase during exercise, the exercise‐induced increase in BVO2 was attenuated due to arterial desaturation.The sustained increase in after load resulted in RV dilation (RV end‐diastolic area index increased from 27±2mm2·kg−1 to 35±3mm2·kg−1 in control vs CTEPH, week 8, P=0.03) and RV hypertrophy (Fulton index increased from 0.44±0.01 to 0.52±0.03, P=0.02).ConclusionsRepeated embolization results in CTEPH in swine, with a progressive increase in tPVRi. The early phase of CTEPH is characterized by RV dilation and dysfunction, as evidenced by the inability of the RV to increase CI commensurate with the increase in body oxygen consumption. When PH is sustained, RV hypertrophy occurs, which, together with an increase in heart rate is able to increase CI during exercise.Support or Funding InformationCVON2012‐08‐PHAEDRA

Effect of exercise and time on hemodynamic and oxygenation status in CTEPH development.

Variable
Follow‐up (wk)
CON rest
CON ex
CTEPH rest
CTEPH ex

MPAP (mmHg)
0
19 ± 1
33 ± 2*
22 ± 1#
33 ± 3*

4
19 ± 1
34 ± 2*
32 ± 4^#
56 ± 8*#

8
21 ± 1
38 ± 5*
41 ± 8^#
68 ± 10*#

tPVRi (mmHg·L−1·kg−1)
0
106 ± 7
121 ± 11
92 ± 6
97 ± 11

4
118 ± 8
124 ± 9
151 ± 29^
216 ± 39#

8
120 ± 10
159 ± 20
374 ± 147^#
323 ± 51#

Cl (L·kg−1)
0
0.18 ± 0.01
0.28 ± 0.03*
0.25 ± 0.03#
0.35 ± 0.03*

4
0.17 ± 0.01
0.28 ± 0.02*
0.21 ± 0.06^
0.27 ± 0.03

8
0.16 ± 0.01
0.25 ± 0.02*
0.14 ± 0.02^$
0.22 ± 0.02*

BVO2i (mmol·min−1·kg−1)
0
0.45 ± 0.02
1.09 ± 0.08*
0.58 ± 0.08^
1.36 ± 0.16*#

4
0.43 ± 0.03
1.18 ± 0.10*
0.64 ± 0.16
1.05 ± 0.12*

8
0.45 ± 0.03
1.25 ± 0.09*
0.31 ± 0.06$
0.85 ± 0.08*#

CaO2 (mL O2·dL−1)
0
5.75 ± 0.22
5.53 ± 0.23
5.53 ± 0.22
5.69 ± 0.12

4
5.89 ± 0.21
6.52 ± 0.31*
5.45 ± 0.18$
5.99 ± 0.29*#

8
6.03 ± 0.25
6.90 ± 0.25*
5.86 ± 0.26
6.14 ± 0.21$

CvO2 (mL O2·dL−1)
0
3.34 ± 0.20
1.87 ± 0.16*
3.40 ± 0.10
2.03 ± 0.17*

4
3.32 ± 0.16
2.41 ± 0.23*
2.90 ± 0.29$
1.99 ± 0.38*$

8
3.32 ± 0.18
2.06 ± 0.30*
3.16 ± 0.21
1.58 ± 0.39*

p<0.05 effect of exercise;
p<0.05 compared to week 0 all at rest;
p<0.05,
p<0.1 CTEPH vs Control same week and exercise level;
con, control animals; ex, exercise.