**3. Pathophysiology**

Highlighting the pathophysiology of PH can help us properly manage acute PH in the specific context of cardiac surgery.

The cause of PH in the case of mitral or aortic valve disease, especially when PH is a complication of stenotic valve disease, is quite complex. Increased left arterial pressures result in chronic obstruction to venous drainage in the pulmonary vasculature, causing remodeling of the pulmonary vascular bed and ultimately PH.

The molecular pathophysiological mechanism of PH has been recently reviewed. The PH 'phenotype' is characterized by endothelial dysfunction, a decrease ratio of apoptosis / proliferation in the pulmonary artery muscle cells and a thickened disordered adventitia in which there is excessive activation of adventitial metalloproteases (McLaughlin et al., 2009).

The fundamental functions of the endothelium include: regulating the vascular tone, coordinating vascular cell growth, controlling inflammatory and immunological processes as well as maintaining the balance between thrombotic and fibrotic activities. Each of these functions is controlled by a finely tuned network of activating and inhibiting compounds.

In the case of PH, the endothelium is characterized by increased production of vasoconstrictor / mitogenic mediators, such as endothelin and thromboxane, and deficient

## **1. Pulmonary arterial hypertension (PAH)**

1.1 Idiopathic

110 Perioperative Considerations in Cardiac Surgery

PH MPAP 25 mmHg All

PCWP 15 mmHg CO normal or reduced

MPAP 25 mmHg PCWP 15 mmHg CO normal or reduced TPG 12 mmHg TPG >12 mmHg

*CO, cardiac output; MPAP, mean pulmonary arterial pressure; PH, pulmonary hypertension; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary pressure gradient (MPAP-*

Data from the multinational database EuroSCORE have demonstrated that PH is an independent risk factor for increased morbidity and mortality in patients undergoing heart

Highlighting the pathophysiology of PH can help us properly manage acute PH in the

The cause of PH in the case of mitral or aortic valve disease, especially when PH is a complication of stenotic valve disease, is quite complex. Increased left arterial pressures result in chronic obstruction to venous drainage in the pulmonary vasculature, causing

The molecular pathophysiological mechanism of PH has been recently reviewed. The PH 'phenotype' is characterized by endothelial dysfunction, a decrease ratio of apoptosis / proliferation in the pulmonary artery muscle cells and a thickened disordered adventitia in which there is excessive activation of adventitial metalloproteases (McLaughlin et al.,

The fundamental functions of the endothelium include: regulating the vascular tone, coordinating vascular cell growth, controlling inflammatory and immunological processes as well as maintaining the balance between thrombotic and fibrotic activities. Each of these functions is controlled by a finely tuned network of activating and inhibiting

In the case of PH, the endothelium is characterized by increased production of vasoconstrictor / mitogenic mediators, such as endothelin and thromboxane, and deficient

Table 1. Hemodynamic definition of pulmonary arterial hypertension.

remodeling of the pulmonary vascular bed and ultimately PH.

Pre-capillary PH MPAP 25 mmHg

Post-capillary PH

Reactive (out of proportion)

surgery (Roques et al., 1999).

specific context of cardiac surgery.

**3. Pathophysiology** 

Passive

*PCWP)* 

2009).

compounds.

**Definition Characteristics Clinical group(s)** 

1. Pulmonary arterial hypertension 3. PH due to lung diseases

thromboembolic pulmonary hypertension 5. PH with unclear and-or multifactorial mechanisms

2. PH due to left heart

disease

4. Chronic

	- 1.2.1 BMPR2
	- 1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)
	- 1.2.3 Unknown
	- 1.4.1 Connective tissue diseases
	- 1.4.2 HIV infection
	- 1.4.3 Portal hypertension
	- 1.4.4 Congenital heart disease
	- 1.4.5 Schistosomiasis
	- 1.4.6 Chronic hemolytic anemia

#### **1a. Pulmonary venoocclusive disease and-or pulmonary capillary hemangiomatosis**

#### **2. Pulmonary hypertension due to left heart disease**


#### **3. Pulmonary hypertension due to lung diseases and/or hypoxia**


#### **4. Chronic thromboembolic pulmonary hypertension**

#### **5. Pulmonary hypertension with unclear and-or multifactorial mechanisms**


5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: Tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

Table 2. Updated clinical classification of pulmonary hypertension (Dana Point, 2008). *ALK-1, activin receptor-like kinase 1 gene; BMPR2, bone morphogenetic protein receptor, type 2; HIV, human immunodeficiency virus* 

production of vasodilators, such as prostacyclin (Christman et al., 1992; Giaid et al., 1993; Stewart et al., 1991). Elevated levels of fibrinopeptide A and plasminogen activator inhibitor-1 and reduced levels of tissue plasminogen activator contribute to a procoagulant state. Endothelial injury may also expose the underlying smooth muscle cells to circulating mitogens and growth factors that stimulate cell proliferation.

The so-called endothelium-dependent mechanism is that receptors located on the surface of the endothelial cells react to various stimulators or mediators and subsequently change signals. Via a cascade of reactions, the presence of shearing forces or mediators such as bradykinine and acetylcholine leads to the formation of so-called second messenger substances such as cyclic adenosine monophosphate (cAMP) or guanosine monophosphate (cGMP). These substances exert vasodilator effects and are responsible for smooth muscle relaxation.

**Nitric oxide (NO)** is a vasodilator and inhibitor of platelet activation and vascular smooth muscle proliferation. The effects of NO are mediated by cGMP, which is rapidly inactivated by phosphodiesterase.

Vascular dilatation occurs via the NO-triggered proliferation of endothelial-dependent hyperpolarizing factors which, through the activation of tension dependent potassium channels leads to relaxation of the smooth muscle cell. NO leads to an increase in the production of prostacyclin. Other potassium channels (ATP-dependent, Ca++ - dependent) are also involved in the regulation of the myosin-actin-calcium interaction.

On the contrary, hypoxia or specific mediators (e.g. thrombin, metabolites of arachidonic acid, angiotensin II and endothelin) lead to vasoconstriction. They also function through signal transduction via various receptors on the endothelial cells themselves or on the smooth muscle cells.

**Prostacyclin and thromboxane A2** are major arachidonic acid metabolites. Prostacyclin is a potent vasodilator, inhibits platelet activation and has antiproliferation properties, whereas thromboxane A2 promotes proliferation and platelet activation In PH, the balance between the two molecules is shifted towards thromboxane A2.

**Endothelin-1 (ET-1)** is a potent vasoconstrictor produced by endothelial cells, which exerts potent vasoactive properties by binding to specific receptors (ETA and ETB) on vascular endothelial and smooth muscle cells. Following the bonding of ET-1 to the ETA receptor, phospholipase C is activated which consecutively leads to the accumulation of inositol-triphosphates and intracellular calcium. Through this mechanism, vasoconstriction as well as cell proliferation take place in various tissues. Activation of the ETB receptor upon the endothelial cells not only leads to the release of NO and prostacyclin and consequence vasodilatation, but also inhibits expression of the endothelin converting enzyme upon endothelial cell and apoptosis. Pulmonary clearance of circulating ET-1 as well as its reentrance into the endothelial cells is also regulated via these receptors.

**Serotonin (5-hydroxytryptamine, 5-HT)** (Jain et al., 2007) is a pulmonary vasoconstrictor and promotes pulmonary artery smooth muscle cells hypertrophy and hyperplasia. There is a transporter for 5-HT that controls serotonin uptake and clearance, which is located on the surface of platelets, neurons, and pulmonary endothelial cells. The presence of elevated levels of 5-HT in the blood of patients with PH suggests that this substance also plays a role in the pathogenesis of PH.

In summary, PH can simply be explained as a functional disturbance of the endothelium, caused by an imbalance between the dilative and contractive mechanisms within the vascular resistance of the pulmonary vascular bed. These functional changes occur together with morphological alterations within the pulmonary vasculature.

inhibitor-1 and reduced levels of tissue plasminogen activator contribute to a procoagulant state. Endothelial injury may also expose the underlying smooth muscle cells to circulating

The so-called endothelium-dependent mechanism is that receptors located on the surface of the endothelial cells react to various stimulators or mediators and subsequently change signals. Via a cascade of reactions, the presence of shearing forces or mediators such as bradykinine and acetylcholine leads to the formation of so-called second messenger substances such as cyclic adenosine monophosphate (cAMP) or guanosine monophosphate (cGMP). These substances exert vasodilator effects and are responsible for smooth muscle

**Nitric oxide (NO)** is a vasodilator and inhibitor of platelet activation and vascular smooth muscle proliferation. The effects of NO are mediated by cGMP, which is rapidly inactivated

Vascular dilatation occurs via the NO-triggered proliferation of endothelial-dependent hyperpolarizing factors which, through the activation of tension dependent potassium channels leads to relaxation of the smooth muscle cell. NO leads to an increase in the production of prostacyclin. Other potassium channels (ATP-dependent, Ca++ - dependent)

On the contrary, hypoxia or specific mediators (e.g. thrombin, metabolites of arachidonic acid, angiotensin II and endothelin) lead to vasoconstriction. They also function through signal transduction via various receptors on the endothelial cells themselves or on the

**Prostacyclin and thromboxane A2** are major arachidonic acid metabolites. Prostacyclin is a potent vasodilator, inhibits platelet activation and has antiproliferation properties, whereas thromboxane A2 promotes proliferation and platelet activation In PH, the balance between

**Endothelin-1 (ET-1)** is a potent vasoconstrictor produced by endothelial cells, which exerts potent vasoactive properties by binding to specific receptors (ETA and ETB) on vascular endothelial and smooth muscle cells. Following the bonding of ET-1 to the ETA receptor, phospholipase C is activated which consecutively leads to the accumulation of inositol-triphosphates and intracellular calcium. Through this mechanism, vasoconstriction as well as cell proliferation take place in various tissues. Activation of the ETB receptor upon the endothelial cells not only leads to the release of NO and prostacyclin and consequence vasodilatation, but also inhibits expression of the endothelin converting enzyme upon endothelial cell and apoptosis. Pulmonary clearance of circulating ET-1 as well as its reentrance into the endothelial cells is also regulated via

**Serotonin (5-hydroxytryptamine, 5-HT)** (Jain et al., 2007) is a pulmonary vasoconstrictor and promotes pulmonary artery smooth muscle cells hypertrophy and hyperplasia. There is a transporter for 5-HT that controls serotonin uptake and clearance, which is located on the surface of platelets, neurons, and pulmonary endothelial cells. The presence of elevated levels of 5-HT in the blood of patients with PH suggests that this substance also plays a role

In summary, PH can simply be explained as a functional disturbance of the endothelium, caused by an imbalance between the dilative and contractive mechanisms within the vascular resistance of the pulmonary vascular bed. These functional changes occur together

with morphological alterations within the pulmonary vasculature.

are also involved in the regulation of the myosin-actin-calcium interaction.

the two molecules is shifted towards thromboxane A2.

mitogens and growth factors that stimulate cell proliferation.

relaxation.

by phosphodiesterase.

smooth muscle cells.

these receptors.

in the pathogenesis of PH.

Thus, NO, endothelin and prostacyclin also have a direct influence upon the thrombocytes, the endothelial-leukocyte interaction as well as vascular cell proliferation. This imbalance leads to thrombotic tendency, vasoconstriction and proliferation.
