**3. Epidemiology of pulmonary hypertension**

A review of a large U.S. database by Memtsoudis *et al* was undertaken to identify mortality in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA).[7] The authors studied 1359 THA and 2184 TKA patients who also carried the diagnosis of PH. In comparison to a demographically-matched group of patients without PH, the THA patients demonstrated a 4-fold increased adjusted risk of in-hospital mortality and the TKA patients demonstrated a 4.5-fold increase (p<.001) [7]. Lai *et al* analyzed 62 patients with PH who underwent non-cardiac, non-local anesthetic surgery; they found that PH is an important predictor of adverse cardiopulmonary outcome in non-cardiac surgery as reflected by markedly increased postoperative complications, especially in patients with coexistent highrisk clinical and surgical characteristics [8]. Their results are listed in Table-3.

sickle cell disease. The predictive value of echocardiography to detect PH in this patient population is low (25-32%) when the threshold of tricuspid regurgitation velocity of 2.5m/s is used. At present, no specific treatment is currently approved for the treatment of PH associat‐

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PH frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific therapies for PH prompted formation of a national Australia and New Zealand registry in 2010 to record the incidence, demographics, presentation and outcomes for these patients. They established a multicenter, prospective, web-based registry which enrolls patients with CHD-associated PH who are being followed at a tertiary medical center. The inclusion criteria stipulate patient age >16 years, a measured mPAP >25mmHg at rest or echocardiographic evidence of PH or a diagnosis of Eisenmenger's syndrome, and these patients have been followed since 1/1/2000. The investigators obtained the following results: of the first 50 patients enrolled, 30 (60%) are female, the mean age [Standard Deviation (SD)] at the time of PH diagnosis or confirmation in an adult center was 27.23 years (SD=10.07) and 32 patients (64%) are currently aged >30 years. Fourteen (28%) patients were in WHO func‐ tional Class (Table-4) II and 36 (72%) in Class III at the time of diagnosis. Forty-seven of 50 (94%) had congenital systemic-pulmonary shunts and 36 (72%) never underwent intervention. 13 (26%) had Down's syndrome. Confirmation of PH by recent cardiac catheterization was available in 30 (60%) subjects. During follow-up a total of 32 (64%) patients received a PH specific therapy. They concluded that CHD-associated PH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical courses and

I Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical

II Patients with pulmonary hypertension resulting in slight limitation of physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain or near

III Patients with pulmonary hypertension resulting in marked limitation of physical activity. These patients are

IV Patients with pulmonary hypertension resulting in inability to perform any physical activity without

comfortable at rest, but less than ordinary physical activity causes undue dyspnea or fatigue, chest pain or

symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at

\*--Modified from the New York Heart Association classification of patients with cardiac disease. Adapted with permission from Rich S., ed. Executive summary from the World symposium on Primary Pulmonary Hypertension 1998, Evian, France, September 6-10, 1998, cosponsored by the World health Organization. Retrieved April 14, 2000, from the World Wide

activity does not cause undue dyspnea or fatigue, chest pain or near syncope.

ed with sickle cell disease due to lack of data in this specific population [10].

long-term outcomes for these patients [11].

syncope.

near syncope.

Web: http://www.who.int/ncd/cvd/pph.html.

**Class Functional status of patients with pulmonary hypertension**

rest, and discomfort is increased by any physical activity.

**Table 4.** WHO Functional Assessment of Patients with Pulmonary Hypertension\*


**Table 3.** Postoperative morbidity in patients with Pulmonary Hypertension [8]

Strange*etal*estimatedcommunity-basedprevalenceofPHinadistrictinAustralia.Theystudied 10,314 individuals (6.2% of the surrounding Armadale community population) between 2003 and 2009 and they had 15,633 echocardiographic studies performed, 3,320 patients (32%) had insufficient tricuspid regurgitant (TR) or echocardiographic pulmonary artery systolic pres‐ sure (ePASP, echocardiographical calculation of PASP requires the measurement of regurgi‐ tant flow's Doppler velocity) and 936 individuals (9.1%) identified having PH regardless of etiology (defined as ePASP > 40 mmHg). Their minimum 'indicative' prevalence for all forms of PHis 326 cases/100,000 inhabitantsofthe localpopulation,withleftheartdisease-associatedPH beingthemost commoncause (250 cases/100,000);thesepatientswithPHsecondaryto leftheart disease also had the worst prognosis. They identified 15 cases of pulmonary arterial hyperten‐ sion/100,000 inhabitants andan additional 144 individuals (15% of allpatients withPH) with no identifiable cause for their PH. The mean time to death for those with ePASP >40 mmHg (calculated from the first recorded ePASP) was 4.1 years. PH increased mortality regardless of the underlying causes, with those with idiopathic pulmonary arterial hypertension (IPAH) receivingdisease-specific treatmenthaving the bestprognoses.Risk ofdeathincreased withPH severity: severe PH shortened the lifespan by an average of 1.1 years compared with mild PH [9]. Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell diseasehave estimatedtheprevalence ofPH inthisdisease groupto be about 6 to 10% [10].Over half of these patients have postcapillary PH. Precapilliary arterial PH seems to be a relatively infrequent complication of sickle cell disease. It is characterized by a different hemodynamic profile from IPAH with lower levels of PAP and PVR. However, pulmonary vascular disease appears to have a significantimpact on the functional status andvitalprognosis ofpatients with sickle cell disease. The predictive value of echocardiography to detect PH in this patient population is low (25-32%) when the threshold of tricuspid regurgitation velocity of 2.5m/s is used. At present, no specific treatment is currently approved for the treatment of PH associat‐ ed with sickle cell disease due to lack of data in this specific population [10].

comparison to a demographically-matched group of patients without PH, the THA patients demonstrated a 4-fold increased adjusted risk of in-hospital mortality and the TKA patients demonstrated a 4.5-fold increase (p<.001) [7]. Lai *et al* analyzed 62 patients with PH who underwent non-cardiac, non-local anesthetic surgery; they found that PH is an important predictor of adverse cardiopulmonary outcome in non-cardiac surgery as reflected by markedly increased postoperative complications, especially in patients with coexistent high-

**Control (N=62) PH (N=62) P value**

15 (24.2) 6 (9.7) 13(21) 1(1.6) 1(1.6) 2(3.2)

0.002 0.028 0.004 NS NS NS

risk clinical and surgical characteristics [8]. Their results are listed in Table-3.

Mortality(in hospital death %) 0(0) 6(9.7) 0.028

Strange*etal*estimatedcommunity-basedprevalenceofPHinadistrictinAustralia.Theystudied 10,314 individuals (6.2% of the surrounding Armadale community population) between 2003 and 2009 and they had 15,633 echocardiographic studies performed, 3,320 patients (32%) had insufficient tricuspid regurgitant (TR) or echocardiographic pulmonary artery systolic pres‐ sure (ePASP, echocardiographical calculation of PASP requires the measurement of regurgi‐ tant flow's Doppler velocity) and 936 individuals (9.1%) identified having PH regardless of etiology (defined as ePASP > 40 mmHg). Their minimum 'indicative' prevalence for all forms of PHis 326 cases/100,000 inhabitantsofthe localpopulation,withleftheartdisease-associatedPH beingthemost commoncause (250 cases/100,000);thesepatientswithPHsecondaryto leftheart disease also had the worst prognosis. They identified 15 cases of pulmonary arterial hyperten‐ sion/100,000 inhabitants andan additional 144 individuals (15% of allpatients withPH) with no identifiable cause for their PH. The mean time to death for those with ePASP >40 mmHg (calculated from the first recorded ePASP) was 4.1 years. PH increased mortality regardless of the underlying causes, with those with idiopathic pulmonary arterial hypertension (IPAH) receivingdisease-specific treatmenthaving the bestprognoses.Risk ofdeathincreased withPH severity: severe PH shortened the lifespan by an average of 1.1 years compared with mild PH [9]. Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell diseasehave estimatedtheprevalence ofPH inthisdisease groupto be about 6 to 10% [10].Over half of these patients have postcapillary PH. Precapilliary arterial PH seems to be a relatively infrequent complication of sickle cell disease. It is characterized by a different hemodynamic profile from IPAH with lower levels of PAP and PVR. However, pulmonary vascular disease appears to have a significantimpact on the functional status andvitalprognosis ofpatients with

2 (3.2) 0(0) 2(3.2) 0(0) 0(0) 0(0)

**Table 3.** Postoperative morbidity in patients with Pulmonary Hypertension [8]

Morbidity % Heart failure %

198 Pulmonary Hypertension

Stroke %

Delayed extubation"/>24 hours %

Myocardial ischemia/infarct %

PH= Pulmonary Hypertension

Major dysrhythmia %

PH frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific therapies for PH prompted formation of a national Australia and New Zealand registry in 2010 to record the incidence, demographics, presentation and outcomes for these patients. They established a multicenter, prospective, web-based registry which enrolls patients with CHD-associated PH who are being followed at a tertiary medical center. The inclusion criteria stipulate patient age >16 years, a measured mPAP >25mmHg at rest or echocardiographic evidence of PH or a diagnosis of Eisenmenger's syndrome, and these patients have been followed since 1/1/2000. The investigators obtained the following results: of the first 50 patients enrolled, 30 (60%) are female, the mean age [Standard Deviation (SD)] at the time of PH diagnosis or confirmation in an adult center was 27.23 years (SD=10.07) and 32 patients (64%) are currently aged >30 years. Fourteen (28%) patients were in WHO func‐ tional Class (Table-4) II and 36 (72%) in Class III at the time of diagnosis. Forty-seven of 50 (94%) had congenital systemic-pulmonary shunts and 36 (72%) never underwent intervention. 13 (26%) had Down's syndrome. Confirmation of PH by recent cardiac catheterization was available in 30 (60%) subjects. During follow-up a total of 32 (64%) patients received a PH specific therapy. They concluded that CHD-associated PH in adult life has resulted in a new population with unique needs. This registry will allow documentation of clinical courses and long-term outcomes for these patients [11].


\*--Modified from the New York Heart Association classification of patients with cardiac disease. Adapted with permission from Rich S., ed. Executive summary from the World symposium on Primary Pulmonary Hypertension 1998, Evian, France, September 6-10, 1998, cosponsored by the World health Organization. Retrieved April 14, 2000, from the World Wide Web: http://www.who.int/ncd/cvd/pph.html.

**Table 4.** WHO Functional Assessment of Patients with Pulmonary Hypertension\*

PH can complicate interstitial lung disease (ILD). Anderson *et al* evaluated 212 ILD patients and found that PH occurred in 14% of a cohort of patients with ILD and was associated with lower lung function parameters. Mortality was markedly higher in ILD patients with PH, and the presence of PH reduced 6 Minutes Walk Test (MWT) independently of lung function. The present results emphasize the need for intensified treatment of patients with ILD and PH [12].

**5.** Miscellaneous: sarcoidosis, histocytosis X, lymphangiomatosis, pulmonary vascular

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Though a small percentage of patients have idiopathic PH [14], most perioperative patients with PH acquired PH secondary to either cardiac or pulmonary disease processes or both. Left sided ventricular or atrial disease and left sided valvular heart disease are common causes of PH. Both of these conditions increase left atrial pressure and elevate pulmonary venous pressure (PVP) and lead subsequently to increased PAP. Multiple respiratory diseases can lead to the development of PH via hypoxia-induced pulmonary vasoconstriction (HPV) or elevated PVR due to pulmonary fibrosis [15]. Regardless of the cause, all pathways may lead to an altered vascular endothelium and smooth muscle function through cellular remodeling and growth [16] [17]. This results in increased vascular contractility or lack of vascular relaxation in response to various endogenous vasodilator substances. Morphological abnormalities of the vascular wall are present in all three layers of the pulmonary arteries of patients with PH, and medial hypertrophy due to overproliferation of smooth muscle cells is a constant feature of all forms of PH. The classical mechanical concepts of pressure, flow, shear stress, RV wall stress and impedance have been gradually complemented with the new concepts of cell injury, repair/remodeling and interactions of complex multi-cellular systems [17]. Integrating these recent concepts will become critically important in completely understanding the mechanisms of PH, as we develop new interventions in order to change the prognosis of the patients with this devastating condition. Since PH can develop in association with many different diseases and with multiple risk factors, it is believed that the multi-factorial interplay may very likely be responsible for the pathogenesis of PH. The right ventricle (RV) is a crescent shaped, thin walled and compliant muscle chamber intended for volume work, not pressure work. Chronic PH leads to right ventricular hypertrophy (RVH) as a compensatory mechanism. However, the ability of the RV to adapt is finite and may eventually lead to RV failure. Unlike the muscular left ventricular chamber, a hypertrophied RV may not tolerate the acute rises in PVR that are associated with pain, surgical stimulation and positive pressure ventilation. RV failure and dilatation can lead to left ventricular compression and diminished cardiac output. This in turn leads to decreased coronary blood flow and perfusion pressure and can become a viscous cycle that can be difficult for the patient to overcome. The mechanisms for the pathogenesis of PH can be simply outlined as one or more of the following aspects: vascular remodeling with narrowness of vascular lumen and increased resistance, abnormal vascular reactivity leading to persistent vasoconstriction and loss of relaxation, left-side cardiac diseases impeding pulmonary venous return and various lung diseases compromising the pulmonary vascular bed leading to increased PVR. Here we discuss the pathophysiological changes of PH:

compression by various pathologies.

**5. Pathophysiology of pulmonary hypertension**

**5.1. Pulmonary vascular inflammation and immune responses**

The presence of antinuclear and antiphospholipid antibodies in the serum of patients with PH has been documented for many years [18]. There is more evidence that lymphoid neogenesis
