Pulmonary Hypertension

Question 1

Definition of PH.

Answer 1

Mean PAP >25 mmHg at rest.

Question 2

Definition of post-PH.

Answer 2

Increased PAP associated with increased PAWP (>15 mmHg in humans), a surrogate for LA/LV filling pressure.

Question 3

Definition of pre-PH.

Answer 3

Increased PAP associated with increased PVR in the absence of increased LA pressure.

Question 4

Pathophysiology of PH (main groups).

Answer 4

-increased pulmonary blood flow
-increased pulmonary vascular resistance (PVR)
-increased pulmonary venous pressure

Question 5

Increased pulmonary blood flow.

Answer 5

Congenital L-R shunt
-PDA
-ASD
-VSD
-aortopulmonary window

Question 6

Increased PVR.

Answer 6

-Pulmonary endothelial dysfunction (vasoconstriction, alteration of NO - prostacyclin pathways)
-Pulmonary vascular remodelling
-Perivascular inflammation
-Vascular luminal obstruction
-Increased blood viscosity
-Arterial wall stiffness
-Lung parenchymal destruction

Question 7

Increased pulmonary venous pressure.

Answer 7

-Left heart disease (LV systolic/diastolic dysfunction, inflow obstruction, valvular disease)
-Compression of a large pulmonary vein

Question 8

Common clinical findings.

Answer 8

Syncope (especially exertional)
Dyspnoea (especially at rest)
R-CHF (ascites)
Cyanosis/pallor

Question 9

High echocardiographic probability of PH in dogs.

Answer 9

-TR Vmax >3.4 m/s, echo signs of PH at 1 anatomical site
-TR Vmax 3.0-3.4 m/s, echo signs of PH at 2 anatomical sites
-TR Vmax <30. m/s, echo signs of PH at 3 anatomical sites

Question 10

How to estimate systolic PAP using TRV.

Answer 10

-Measure peak tricuspid regurgitation velocity
-Derive RV-RA pressure gradient using the simplified Bernoulli Equation (PG = 4 × velocity [m/s]2)
-Add estimated RA pressure
Assumes the absence of RV outflow tract obstruction

Question 11

Use of TRV vs estimated systolic PAP to quantify PH.

Answer 11

Systolic PAP may be underestimated when presence of RA hypertension

Question 12

Factors affecting measured peak TRV.

Answer 12

RV function
Pericardial restraint
Patient cooperation
Labored respiration

Question 13

What information does peak PR velocity provide?

Answer 13

-Estimated mean PAP.
-Estimated diastolic PAP (once estimated RA pressure added).

Question 14

Anatomic sites of echo signs of PH.

Answer 14

-Ventricles (flattening of IVS, underfilled LV, RV hypertrophy, RV systolic dysfunction)
-PA (PA dilatation, peak PR velocity >2.5, RPAD index <30%, RV outflow acceleration time <52-58 ms or acceleration time to ejection <0.30, systolic notching of RV outflow profile)
-RA/CauVC (RA or CauVC dilatation)

Question 15

Common physical exam findings.

Answer 15

-Murmur
-Split/loud S2
-Abdominal distension
-Jugular distension/pulsation
-Cyanosis
-Abnormal breathing pattern (insp effort, exp effort, paradoxical)
-Abnormal lung sounds (muffled, crackles, wheezes, bronchovesicular sounds)

Question 16

Proposed classification of pulmonary hypertension in the dog.

Answer 16

1) Pulmonary arterial hypertension (including pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis)
2) Left-heart disease
3) Respiratory disease, hypoxia, or both
4) Pulmonary emboli, thrombi, thromboemboli
5) Parasitic disease
6) Multifactorial or unclear

Question 17

Differentials for PA hypertension.

Answer 17

-idiopathic
-heritable
-drugs/toxins
-congenital cardiac shunts
-pulmonary vasculitis
-pulmonary vascular amyloid deposition

Question 18

Differentials for left-heart disease causing PH.

Answer 18

-LV dysfunction (DCM, myocarditis)
-acquired valvular disease (DMVD, valvular endocarditis)
-congenital heart disease (MVD, mitral stenosis, aortic stenosis)

Question 19

Differentials for respiratory disease or hypoxia causing PH.

Answer 19

-chronic obstructive airway disorders (tracheal or mainstem bronchial collapse, bronchomalacia)
-primary pulmonary parenchymal disease (interstitial lung disease, infectious pneumonia, diffuse pulmonary neoplasia)
-obstructive sleep apnoea
-chronic altitude exposure
-developmental lung disease
-miscellaneous (bronchiolar disorders, bronchiectasis, emphysema, pneumonectomy)

Question 20

Differentials for parasitic causes for PH.

Answer 20

-Angiostrongylus
-Dirofilaria

Question 21

Multifactorial/unclear differentials PH causes.

Answer 21

-clear evidence of 2 or more underlying groups
-masses compressing the pulmonary arteries (neoplasia, granuloma)
-unknown

Question 22

Strategies to decrease the risk of progression or complications of PH.

Answer 22

-exercise restriction
-prophylaxis (respiratory pathogens, parasitic disease)
-avoid pregnancy
-avoid altitude
-avoid elective procedures/anaesthetics

Question 23

Treatment of PH (Group 1).

Answer 23

-closure/occlusion of L-R shunts (or shunts that become L-R with vasodilators)
-periodic phlebotomy or hydroxyurea treatment in R-L shunting cases

Question 24

Treatment of PH (Group 2).

Answer 24

-manage left-heart disease
-PDE5i not indicated as first-line treatment (due to post-PH)

Question 25

Treatment of PH (Group 3).

Answer 25

-treat underlying respiratory disease (cough suppression, sedation, oxygen, control of infection and inflammation; BOAS management)
-general strategies (environmental modification, weight management, avoid triggers)

Question 26

Treatment of PH (Group 4).

Answer 26

-prompt use of antithrombotics (LMWH/riveroxaban preferred over PO antiplatelet medications)
-plasminogen activators (in systemic hypotension/collapse)

Question 27

Action of PDE5i.

Answer 27

-Augment the vascular NO pathway
-Targets pre-PH by reducing PVR

Question 28

Clinical findings vs echo findings with sildenfil treatment.

Answer 28

-improvement of clinical signs, QOL, exercise capacity, and decreased estimated PAP compared with baseline
-TRV might not decrease despite observed clinical benefits (possibly because pulmonary blood flow might increase as PVR decreases, thus resulting in little change in PAP)

Question 29

Sildenafil dosing.

Answer 29

-short half-life (q8 hour dosing)
-rectal administration can be considered

Question 30

Alternatives to sildenafil, compared.

Answer 30

Tadalafil:
-longer half-life (q24h dosing)
-improved compliance
-lower cost?
-equivalent effect based on a randomized double-blinded study

Question 31

Pimobendan for PH in dogs.

Answer 31

Pimobendan
-oral PDE3i
-positive inotropic and systemic vasodilatory properties
- shown to improve RV systolic function following a single oral dose in healthy dogs
-no clear evidence of benefit for pre-PH

Question 32

Milrinone for PH in dogs.

Answer 32

Milrinone
-IV PDE3i
-PA vasodilating and positive inotropic properties
-improved RV function and decreased mea PAP in experimental canine PH

Question 33

TKI for PH in dogs.

Answer 33

Toceranib, Imatinib
-Tyrosine kinase inhibitors
-PA vasodilation (inhibits activation of platelet-derived growth factor by impeding phosphorylation of the platelet-derived growth factor receptor tyrosine kinase)
-in people, specific TKI are effective at improving refractory PH but serious adverse events are common. Paradoxically, some TKI can induce PH in humans
-in dogs, a single study demonstrated imatinib reduced PAP in dogs diagnosed with PH secondary to LHD

Question 34

L-arginine for PH in dogs.

Answer 34

L-arginine
-amino acid
-essential (in conjunction with oxygen) to NO production
-oral administration increases surrogate markers of NO in healthy dogs
-1 study in experimental canine acute PTE showed L-arginine and sildenafil together were not more beneficial than sildenafil aloneC