Diagnostic Assessment and Confirmation of PAH

Diagnostic Assessment and Confirmation of PAH

Learning Objectives Screen high-risk patients for the hemodynamic and clinical features associated with PAH. Refer patients for right heart catheterization for diagnostic confirmation. Follow current guidelines and specifications in order to classify patients with the proper type of pulmonary hypertension. Use diagnostic tests to assess baseline right ventricular morphology and function. The learning objectives for this program are as follows: Screen high-risk patients for the hemodynamic and clinical features associated with PAH; Refer patients for right heart catheterization for diagnostic confirmation; Follow current guidelines and specifications in order to classify patients with the proper type of pulmonary hypertension; Use diagnostic tests to assess baseline right ventricular morphology and function. 3

Lecture Outline Epidemiology Pathology and genetics
Diagnostic algorithm for PAH Clinical classification The right ventricle (RV) in PAH Screening high-risk patients This lecture begins with an overview of the epidemiology of PAH, and include clinical information from PAH patient registries. Then, the current understanding of the pathophysiology of PAH, with an emphasis on the mechanisms of pathology and the relevant genetic mutations will be described. A diagnostic algorithm will be detailed, and the components and steps will be explained. The current clinical classification for pulmonary hypertension and the definition of PAH will be reviewed as well as right ventricular adaptation and maladaptation in patients with PAH. Finally, patients at high risk for developing PAH will be identified. 4

Epidemiology of PAH Prevalence in the U.S. ≈ 50,000 to 100,000
15,000 to 25,000 diagnosed and treated Historically: Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” Modern day: Patient survival has dramatically improved as treatment options for PAH have increased Robin ED. The kingdom of the near-dead: the shortened unnatural life history of primary pulmonary hypertension. Chest. 1987;92:330-4. The prevalence of PAH is estimated at nearly 50,000 to 100,000, with only 15,000 to 25,000 patients diagnosed and treated. The disease course and prognosis for patients with PAH has dramatically improved over the last several decades. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 5

The Expansion of Treatment Options for PAH
18 years ago No treatments for PAH 12 years ago 1 treatment for PAH Today 12 treatment options for PAH Given that PAH is a rare disease, it is remarkable the progress that has been made in the availability of treatment options for patients with PAH. Nearly two decades ago, no treatment options were available for patients. This contrasts greatly with the dozen treatment options that are currently FDA approved for patients. Pulmonary Hypertension Association, January 2014. 6

Patient Registries for PAH
Registry Time Period N NIH 1981 – 1985 187 French 2002 – 2003 674 U.S. Reveal 2006 – 2009 3515 U.S. PHC 1982 – 2006 578 Scottish-SMR 1986 – 2001 374 Chinese 1999 – 2004 72 Spanish 1998 – 2008 866 U.K. 2001 – 2009 482 New Chinese Registry 2008 – 2011 956 Mayo 1995 – 2004 484 Compera 2007 – 2011 587 NIH = National Institutes of Health; PHC = pulmonary hypertension connection; SMR = Scottish morbidity record PAH patient registries are listed in the table. The three major registries are: NIH, French, and U.S. Reveal. The NIH registry took place in the early 1980s and followed 187 patients. The French registry took place in the early 2000s and followed 674 patients. The largest of the registries would be the U.S. REVEAL, which followed over 3500 patients from 2006 to 2009. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 7

Observations from Patient Registries for PAH
Older age at diagnosis NIH registry: 36 (± 15 years) REVEAL: 50 to 65 (± 15 years) Population cohorts at greater risk Patient demographic – advanced age, male gender Etiology – heritable PAH, PAH associated with connective tissue disease or portal hypertension Patient registries give researchers and clinicians insight into the nuances of a disease, and help describe the patients affected by the disease. An observation from the patient registries for PAH is an older age at diagnosis. The registries have also specified patient cohorts with reduced rates of survival. Patients at greater risk include those at an advanced age, men, and those with either heritable PAH, connective tissue disease-associated PAH, or portopulmonary hypertension. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 8

Patient Registries for PAH: Outcome Predictors
High Risk Low Risk Patient demographics Male gender, advanced age Etiology – heritable, associated with CTD or portal hypertension Functional capacity Higher functional class Shorter 6-MWD Lower functional class Longer 6-MWD Laboratory / Biomarkers Higher BNP, NT-proBNP Higher creatinine Lower BNP, NT-proBNP Imaging Echo – pericardial effusion Lung function studies Lower predicted DLCO Higher predicted DLCO Hemodynamics Higher mRAP or PVR Lower CO or CI Higher CO or CI CTD = connective tissue disease; BNP = B-type natriuretic peptide ; NT-proBNP = N-terminal pro-B-type natriuretic peptide; DLCO = diffusing capacity of the lung for carbon monoxide; mRAP = mean right atrial pressure; PVR = pulmonary vascular resistance; CO = cardiac output; CI = cardiac index The patient registries for PAH have yielded useful information regarding predictors of clinical outcomes in patients. The table lists the areas where patients are at an increased risk of poor outcomes, and the areas where patients are at a decreased risk of poor outcomes. Under patient demographics an increased risk would be: male gender, advanced age (over 65 years old), type of PAH – heritable, or associated with CTD or portal hypertension. Under functional capacity an increased risk would be: higher functional class and a shorter 6-MWD. Patients with higher BNP / NT-proBNP levels are at an increased risk of poor outcomes. If an echocardiography shows pericardial effusion, the patient is considered high risk. Under lung function studies, a lower predicted DLCO is considered higher risk. Finally, the hemodynamic parameters associated with an increased risk are: higher mRAP, higher PVR, lower CO, and lower CI. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. 9

Patient 3-Year Survival Rates: REVEAL Registry
Barst and colleagues published results from the REVEAL registry regarding patient survival (total cohort, N = 982). The researchers found an increase in 3-year survival in those patients who improved their functional classification, specifically from functional class III to functional I or II within one year of enrollment. In contrast, those patients who had an unchanged functional classification (remained at functional class III) had a reduced percent survival rate. Those patients who had a worsening of functional classification (change in functional class III to IV) had the poorest rates of survival. The differences in survival rates were statistically significant (P < 0.05). N = 263 N = 645 N = 74 Barst, et al. Chest. 2013;144(1):160-8. 10

Pathology of Pulmonary Hypertension
Overview Pulmonary hypertension (PH) is an obstructive lung panvasculopathy Patient prognosis is primarily determined by the functional status of the right ventricle (RV) Most common cause of death is RV failure To begin, pulmonary hypertension (PH) can be considered an obstructive lung panvasculopathy. The right ventricle plays an important role in the pathology of the disease. In fact, patient prognosis is primarily determined by the functional status of the right ventricle. Indeed, the most common cause of death is RV failure. Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 11

Proliferative, apoptosis-resistant state Metabolic dysfunction Disordered mitochondrial structure Persistent inflammation Dysregulation of growth factors The factors believed to be responsible for the development of pulmonary hypertension are numerous and varied. Tuder and colleagues opined that an interplay of several pathobiological and environmental factors on a “background of genetic predisposition” were likely causative. Included would be metabolic dysfunction, disordered mitochondrial structure, early and persistent inflammation, and dysregulation of growth factors. These events, in a genetically-susceptible individual, would lead to a proliferative, apoptosis-resistant state. Over time, the aforementioned pathology would lead to disease. Interplay of several pathobiological and environmental factors on a “background of genetic predisposition” Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 12

Increased pulmonary vascular resistance Sustained vasoconstriction Excessive pulmonary vascular remodeling In situ thrombosis Increased pulmonary vascular resistance is the hallmark of pulmonary hypertension. This increase is due to: sustained vasoconstriction, excessive pulmonary vascular remodeling, and in situ thrombosis. Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 13

Mechanisms of Pathology for PAH
Endothelin pathway Prostacyclin pathway Nitric oxide pathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelin-1 Prostaglandin I2 sGC stimulator Endothelin-receptor A GTP Endothelin-receptor B The graphic shows three pathways that are believed to play a key role in the pathology of PAH: the endothelin pathway, nitric oxide pathway, and the prostacyclin pathway. The illustration also shows the sites and targets for common treatment options. Endothelin receptor antagonists act on the endothelin receptors in that pathway. The target for the phosphodiesterase-5 inhibitors, as well as the newly-approved agent riociguat, is the nitric oxide pathway. Meanwhile, the prostacyclin analogs target the prostacyclin pathway. Exogenous nitric oxide Prostacyclin derivates Endothelin-receptor antagonists cGMP cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Adapted from: Humbert, et al. N Engl J Med. 2004;351: 14

Genetic Mutations in PAH
BMPR2 Major predisposing gene Over 300 mutations have been identified Found in >70% of patients with heritable PAH Found in ≈ 20% of patients with idiopathic PAH ALK-1 Major gene when PAH is associated with hereditary hemorrhagic telanglectasia (HHT) Less common mutations: Endoglin, SMAD9, Caveolin-1, KCNK3 BMPR2 = bone morphogenetic protein receptor type 2; ALK-1 = activin A receptor type II-like kinase-1 Image of BMPR2: kimgen677s10.weebly.com/protein-3d-structure.html Hereditary predisposition to PAH is an important area of research in this field. Over 300 BMPR2 mutations have been identified. This mutation has been found in over 70% of patients with heritable PAH. ALK1 is recognized as the major gene when PAH is associated with hereditary hemorrhagic telanglectasia. Less common mutations include: endoglin, SMAD9, and Caveolin-1. Recently, researchers uncovered a missense variant in the potassium channel, KCNK3, while exome sequencing a group of family members with heritable PAH. Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. 15

Genetic Screening and Counseling
Screening recommendations Subject to debate since it is impossible to determine which carriers of a mutation will develop PAH Patients with a family history of heritable PAH Patients with idiopathic PAH, to determine if they are genetic carriers Counseling Schedule for routine evaluation / follow-up Considerations for family planning Given the strong genetic link that has been confirmed for PAH, screening for PAH-associated genetic mutations has been recommended by many researchers. However, identification of a mutation in a high-risk individual does not guarantee future development of the disease. The expense and availability of genetic screening must be taken into consideration. Patients who are likely candidates for genetic profiling include those with a family history of heritable PAH and those with idiopathic PAH, in order to determine if they are genetic carriers. If they are indeed carriers, referral for reproductive education / family planning is recommended. If the patient (with a family history) has a mutation, then a plan for routine monitoring for PAH should be set in motion. Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. 16

Definition of Pulmonary Hypertension
General definition Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization Hemodynamic characterization of PAH Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance Several recommendations were published following the 5th world symposium on pulmonary hypertension. First, the general definition for pulmonary hypertension was agreed to be a mean PAP ≥ 25 mm Hg at rest as measured by right heart catheterization. Also, the hemodynamic characterization of PAH was determined to be a mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, and an elevated PVR (> 3 Wood Units). Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 17

Diagnostic Algorithm for PAH
PAH is a diagnosis of exclusion V/Q = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; RHC = right heart catheterization; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; WU = wood units A step-wise approach can be taken when evaluating patients for possible diagnosis of PAH. A diagnosis of PAH requires the exclusion of other causes of pulmonary hypertension. As such, heart and lung disease need to be ruled out. Also, chronic thromboembolic pulmonary hypertension (CTEPH) is ruled out by performing a V/Q scan and obtaining negative results. Right heart catheterization is mandatory for diagnostic confirmation. Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 18

Clinical Symptoms Associated with PAH
Suspicion of pulmonary hypertension Clinical symptoms Unexplained dyspnea on exertion Presyncope Syncope Signs of right ventricular dysfunction Other non-specific symptoms in patients with PAH Fatigue, weakness, angina, abdominal distension, edema In general, the clinical symptoms associated with PAH are rather non-specific, and may go unreported by patients or unrecognized by clinicians. Patients can present with one or more of the following symptoms: breathlessness, fatigue, weakness, angina, syncope, abdominal distension, and edema. Patients who present with unexplained dyspnea on exertion, presyncope, syncope, or signs of right ventricular dysfunction are candidates for additional diagnostic screening. Galie, et al. Eur Heart J. 2009;30: Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. 19

Echocardiography for PAH
Doppler ECHO PAH can not be diagnosed with ECHO Non-invasive estimation of pulmonary artery pressure (PAP) Examine ECHO results for: Left ventricular systolic and diastolic dysfunction Left-sided chamber enlargement Valvular heart disease Examine ECHO with contrast results for: Intracardiac shunting Doppler ECHO gives a non-invasive estimation of PAP, but it can not definitively diagnose PAH. Instead, ECHO results can be examined for left ventricular (LV) systolic and diastolic dysfunction, left-sided chamber enlargement, and valvular heart disease. ECHO with contrast can show if intracardiac shunting is present. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. 20 20 20

Echocardiography for PAH
“Right ventricular hypertrophy and dilatation at initial investigation with transthoracic echocardiography. “ Image for educational purposes: Springerimages.com 21

Screening Tools and Tests
Electrocardiogram (ECG) RV hypertrophy and strain; right atrial dilatation Chest x-ray Enlarged pulmonary arteries, right heart structures PFT and ABG Airflow obstruction V/Q scan Pulmonary disease; CTEPH CT scan and pulmonary angiogram Pulmonary disease; CTEPH Blood tests and immunology Liver disease, CTD, HIV Abdominal ultrasound Liver disease, portal hypertension RV = right ventricle; PFT = pulmonary function tests; ABG = arterial blood gases; V/Q scan = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; CTD = connective tissue disease There are tests and procedures that can assist in the diagnosis of PAH. Included in these screening tools and test are: electrocardiogram, chest radiography, pulmonary function tests and arterial blood gases, ventilation / perfusion lung scan, CT scan and pulmonary angiography, blood tests, and abdominal ultrasound. Galie, et al. Eur Heart J. 2009;30: Preston. Am J Cardiol. 2013;111(8):S2-9. 22

Right Heart Catheterization for PAH
Diagnostic confirmation Measures: Pulmonary artery pressure (PAP) Pulmonary artery wedge pressure (PAWP) Cardiac output (CO) Right atrial pressure (RAP) Allows calculation of resistance Pulmonary and systemic vascular resistance Right heart catheterization is mandatory for all patients being tested for PAH. This diagnostic test measures PAP, CO, RAP, and PAWP. It allows calculation of pulmonary and systemic vascular resistance. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. 23

Clinical Classification of Pulmonary Hypertension
The clinical classification for patients with pulmonary hypertension was updated at the 5th world symposium on pulmonary hypertension. Group 1 includes patients with pulmonary arterial hypertension (PAH). Of note are the designations of a group 1’ – patients with pulmonary veno-occlusive disease and / or pulmonary capillary hemangiomatosis, and a group 1” – patients with persistent pulmonary hypertension of the newborn (PPHN). The other groups are as follows: group 2 – pulmonary hypertension due to left heart disease; group 3 – pulmonary hypertension due to lung diseases and / or hypoxia; group 4 – chronic thromboembolic pulmonary hypertension; and group 5 – pulmonary hypertension with unclear multifactorial mechanisms. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 24

Clinical Classification of Pulmonary Hypertension
The next several slides focus on the subcategories of group 1 PAH. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 25

Types of PAH Idiopathic Heritable Drug- and toxin-induced
BMPR2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Unknown Heritable Drug- and toxin-induced Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Associated with: BMPR2 = bone morphogenetic protein receptor type 2; ALK-1 = activin A receptor type II-like kinase-1; ENG = endoglin; CAV1 = caveolin-1 The types of PAH are listed on the slide. Idiopathic PAH is designated as Heritable PAH is designated as 1.2 and includes patients with the following genetic mutations: BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3, and unknown. Drug and toxin induced PAH is designated as Associated conditions are found under the last category of PAH (1.4) and include: connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and Schistosomiasis. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 26

Drug- and Toxin-Induced PAH
Definite Aminorex • Toxic rapeseed oil Fenfluramine • Benfluorex Dexfenfluramine • SSRIs Likely Amphetamines L-Tryptophan Methamphetamines Dasatinib Possible Cocaine • Chemotherapeutic agents Phenylpropanolamine • Interferon α and β St. John’s wort • Amphetamine-like drugs Unlikely Oral contraceptives Estrogen Cigarette smoking The list of substances that can potentially induce PAH was updated at the 5th world symposium on pulmonary hypertension. The categories are: definite, likely, possible, and unlikely. These designations are based on clinical research and case reports, and they describe the likelihood of a substance leading to PAH in a given individual. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 27

PAH Associated With Connective Tissue Disease
Scleroderma Most studied type of PAH associated with connective tissue disease Rate of occurrence of PAH = 7 to 12% of patients with scleroderma Prognosis is poorer than other types of PAH 1 year mortality rate = 30% The most studied type of connective tissue disease, in terms of PAH associated connective tissue disease, would be scleroderma. The rate of occurrence of PAH in patients with scleroderma ranges between 7 and 12 percent. Researchers have noted that the long-term prognosis in these patients is diminished compared to other types of PAH. In fact, the 1 year mortality rate is high, at an estimated 30%. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 28

PAH Associated With HIV Infection
Rate of occurrence of PAH = 0.5% of patients with HIV Improvement in patient survival rates since the advent of highly-active antiretroviral therapies (HAART) French registry: 5 year survival rate > 70% Simonneau and colleagues reported a stabilizing of the percent prevalence of PAH in patients with HIV over the last decade. Currently, the rate of occurrence of PAH is 0.5% of patients with HIV. In addition, patient prognosis has improved since the introduction of aggressive treatment of HIV in the form of highly-active antiretroviral therapy (HAART). In fact, the French registry noted a 5-year survival rate of over 70%. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 29

PAH Associated With Portal Hypertension
Rate of occurrence of PAH = 2 to 6% of patients with portal hypertension Patient prognosis is negatively impacted by: Severity of liver disease / cirrhosis Cardiac dysfunction Portal hypertension is another associated condition for PAH. The rate of occurrence ranges between 2 and 6% of patients with portal hypertension. Long-term survival in patients with PAH associated with portal hypertension is related to the severity of liver disease (or cirrhosis) and to cardiac dysfunction. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 30

PAH Associated With Congenital Heart Disease
Greater numbers of children with congenital heart disease survive into adulthood Rate of occurrence of PAH = 10% of adults with congenital heart disease The presence of PAH has a profound negative impact on the clinical course for this complex patient group Due to improvements in disease management, there are greater numbers of children with congenital heart disease that survive into adulthood. This means a greater number of adults with congenital heart disease. The rate of occurrence of PAH in these adults is approximately 10%. The presence of PAH only serves to confound the complex management of this patient group. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 31

PAH Associated With Schistosomiasis
Disease caused by parasitic worms (blood flukes) of the genus Schistosoma Developing countries are the most affected, with more than 200 million people infected worldwide Of those infected, 10% develop hepatosplenic schistosomiasis Rate of occurrence of PAH = 5% of patients with hepatosplenic schistosomiasis 3 year mortality rate ≈ 15% According to the Centers for Disease Control (CDC), schistosomiasis, also known as bilharzia, is a parasitic disease caused by blood flukes. The number of patients infected worldwide is over 200 million. Of these individuals, 10% develop hepatosplenic schistosomiasis. The presence of hepatosplenic schistosomiasis puts the patient at risk of developing PAH. The 3-year mortality rate of PAH associated schistosomiasis is approximately 15%. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 32

Type of PAH: REVEAL Registry
N = 2967 1.9% 3.5% 5.3% 5.3% 9.8% 46.2% 25.3% Badesch and colleagues recorded the types of PAH present in the nearly 3,000 patients they evaluated (interim analysis, published in 2010) from the REVEAL registry. Idiopathic PAH was present in almost half the study population. CTD-associated PAH was present in a quarter of the population. 2.7% CTD = connective tissue disease; CHD = congenital heart disease Badesch, et al. Chest. 2010;137(2):

WHO Functional Classification for PAH
No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and / or fatigue may be present at rest; discomfort is increased by any physical activity. The functional classification for PAH as developed and approved by the NYHA and WHO is listed in the table. A patient’s physical activity and abilities, comfort, and symptoms are used to determine the functional class. The class number increases as the patient’s health deteriorates. The classification is used to guide treatment selection. Taichman, et al. Clin Chest Med. 2007;28:1-22. 34 34 34

Anatomy and Physiology of the Ventricles
Right Ventricle (RV) Thin walled Crescent shaped Peristaltic contraction begins at the inflow region and progresses toward the outflow tract (apex to base) Can adapt to volume overload conditions Left Ventricle (LV) Greater thickness Cone / spherical shaped Contracts in a squeezing, twisting motion from the LV apex to the outflow tract (base) Can adapt to pressure overload conditions The anatomy and physiology of the right ventricle is quite different to that of the left ventricle. First, the thickness of the ventricles varies. The right ventricle is thin walled, while the left ventricle has a greater thickness. The right ventricle is crescent in shape and the left ventricle is cone or spherical shaped. Ventricular contraction is also different. For the right ventricle, peristaltic contraction begins at the inflow region and progresses toward the outflow tract (apex to base). In contrast, the left ventricle contracts in a squeezing, twisting motion from the apex to the outflow tract. The right ventricle can adapt to volume overload conditions, which is an important compensation in patients with PAH. The left ventricle can adapt to pressure overload conditions. Rich. Cardiol Clin. 2012;30: 35

The Role of the Right Ventricle (RV)
Represents a complex interplay between contractility, afterload, compliance, and heart rate Unlike the left ventricle (LV), the RV is thin walled and distensible; therefore, it is subject to significant size and shape change The normal functioning of the right ventricle is said to represent a complex interplay between contractility, afterload, compliance, and heart rate. Anatomically and physiologically, the right ventricle is quite dissimilar to the left ventricle. It is thin walled and distensible, which makes it capable of significant size and shape adaptation. Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. 36

RV in Patients with PAH RV failure: High RV filling pressures, diastolic dysfunction, ↓ CO Contractile dysfunction progresses RV dilatation Progressive contractile impairment Adaptive RV hypertrophy Pulmonary hypertension ↑ PAP (pressure overload) PAP = pulmonary artery pressure; CO = cardiac output A cascade of pathologic events involving the right ventricle (RV) occurs in patients with PAH. Even though the RV is highly adaptive, progressive impairment in patients with PAH is inevitable. In patients with pulmonary hypertension, pressure overload and elevated PAP are present. This starts the cascade of events. The first adaptation by the RV is myocardial hypertrophy. The hypertrophy eventually impairs contractility. In order to compensate, the RV dilates. Contractile dysfunction continues, and RV failure occurs. The RV failure is characterized by high RV filling pressures, diastolic dysfunction, and a reduced cardiac output. Badano, et al. Eur J Echocardiography. 2010;11(1):27-37.

RV Remodeling in Patients with PAH
Extent of RV remodeling is influenced by: Neurohormonal and immunological activation Coronary perfusion Myocardial metabolism Rate and time of onset of pulmonary hypertension Etiologic cause of PAH Genetic factors Right ventricular (RV) adaptation and remodeling in patients with PAH is a complex, multifactorial process. The overall extent of remodeling is influenced by the following: neurohormonal and immunological activation, coronary perfusion, myocardial metabolism, the rate and time of onset of pulmonary hypertension, the underlying cause of PAH, and genetic or epigenetic factors. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. 38

RV Remodeling in Patients with PAH
Patterns of Ventricular Remodeling Adaptive remodeling Concentric remodeling (greater mass-to-volume ratio) Preserved systolic and diastolic function Maladaptive remodeling Eccentric hypertrophy Poor systolic and diastolic function Contributes to RV stress Researchers describe two distinct patterns of right ventricular remodeling in patients with PAH. These patterns differ based on morphology and cardiac function. With adaptive remodeling, the remodeling is concentric, with a greater mass-to-volume ratio. In addition, the systolic and diastolic function is intact. With maladaptive remodeling, the RV hypertrophy is eccentric, and the systolic and diastolic function is poor. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. 39

Continuum of RV Impairment and Action Towards Reversal
When compensatory mechanisms in the RV are exceeded, RV dysfunction develops Right heart failure manifests clinically as exercise limitation and fluid retention FDA-approved therapies for PAH reverse RV remodeling Reduction of afterload Vasodilation For patients with PAH, the compensatory mechanisms of the RV are eventually overwhelmed and RV dysfunction takes place. Right heart failure is a complex clinical syndrome that manifests in patients as significant exercise limitation and fluid retention. Treatments for PAH improve exercise capacity and pulmonary vascular resistance, as well as reverse remodeling of the RV. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. 40

Evaluation of RV Function
Right Heart Catheterization Right atrial pressure Cardiac index Cardiac output (CO) Echocardiography Pericardial effusion TAPSE Right atrial area Left ventricular eccentricity 2D, 3DE volumes / ejection fraction RV strain Tei index Biomarkers BNP / NT-proBNP Troponin Uric acid Sodium TAPSE = tricuspid annular plane systolic excursion; BNP = brain natriuretic peptide; NT-proBNP = N-terminal-pro-fragment BNP There are multiple tools and assessments used to monitor patients with PAH. These tools can be used to evaluate RV function and monitor disease progression. The table lists the hemodynamic and other variables measured via right heart catheterization, echocardiography, and biomarkers. Indeed, changes in markers are not yet correlated with patient outcomes. Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. 41

Evaluation of RV Function: Echocardiography
Most common method used in clinical practice to evaluate the RV Used in patient monitoring to: Assess the RV Evaluate RV size and function Determine cardiac performance impairment Measure right atrial size Assess pericardial effusion Echocardiography not only aids in the screening of patients for PAH, but it also is used for patient monitoring. It can be used to assess and measure the size and functioning of the RV. Clinicians should consider imaging techniques, such as Echocardiography and cardiac MRI, as complementary instead of alternative. Echocardiography is widely available; however, the RV mass and volumes are correctly measured using cardiac MRI. Agarwal, et al. Am Heart J. 2011;162: 42

Evaluation of RV Function: Cardiac MRI
Most accurate method for evaluating: RV mass RV volume RV ejection fraction (RVEF) Possible uses: Quantify regurgitant volumes, delayed enhancement, myocardial strain, coronary perfusion, and pulmonary pulsatility Clinicians and researchers have found cardiac MRI to be the most accurate method for evaluating RV mass, volume, and ejection fraction in patients with PAH. Other potential uses for cardiac MRI include: to quantify regurgitant volumes, delayed enhancement, myocardial strain, coronary perfusion, and pulmonary pulsatility. Clinicians should consider imaging techniques, such as ECHO cardiography and cardiac MRI, as complementary instead of alternative. ECHO cardiography is widely available; however, the RV mass and volumes are correctly measured using cardiac MRI. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. 43

Impact of RV Function on Therapy
RV function can highlight the subtle changes in early disease and prompt rapid initiation of therapy RV function determines the patient’s functional capacity and survival Deterioration in RV function mirrors disease progression Treatment escalation can be guided by RV function correlates Regular assessment of RV function can guide decision making regarding drug therapy in patients with PAH. The RV is sensitive to the early, subtle changes of disease and can prompt initiation of treatment. The RV function is used to determine a patient’s functional capacity. Deterioration in RV function means disease progression; therefore, RV function correlates can be used to determine if intervention and treatment escalation is necessary. Badano, et al. Eur J Echocardiography. 2010;11(1):27-37. 44

Diagnostic Issues Misdiagnosis1 Diagnostic delay1
Most patients see three or more physicians over a three- year period before an accurate diagnosis is made Diagnostic delay1 Time to reach diagnosis has not improved in 20 years Advanced disease at diagnosis2 Approximately 75% of patients have advanced disease at diagnosis (functional class III and IV) The gravity of issues regarding proper diagnosis of PAH can not be understated. Most patients see three or more physicians over a three-year period before an accurate diagnosis is made. The delay in diagnosis is significant, and time to reach diagnosis has not improved in 20 years. Lastly, due to misdiagnosis and diagnostic delay, nearly 75% of patients have advanced disease at diagnosis (functional class III and IV). 1) Deano, et al. JAMA Intern Med. 2013;173(10): ) Thenappan, et al. Eur Respir J. 2007;30(6): 45

Diagnostic Delay REVEAL Interim analysis1 (N = 2967)
Mean duration between symptom onset and diagnostic right heart catheterization = 2.8 years Cohort study2 (N = 2493) 21% of patients had symptoms for > 2 years before diagnosis Delay was more common in younger patients (< 36 years old) and those with a history of respiratory disorders Clinicians should be suspicious if symptoms are out of proportion to “underlying disease” or they are not responding to treatment An interim analysis of the REVEAL patient registry was completed, with study data reported by Badesch and colleagues. A total of 2967 patients were evaluated. The investigators found the following patient demographics: mean age of 53 years old; 79.5% of the population was female; mean duration between symptom onset and diagnostic right heart catheterization of 2.8 years. A cohort study of the REVEAL registry data was completed by Brown and colleagues. They found approximately one in five patients (N = 2493) had symptoms for more than 2 years before being diagnosed. The diagnostic delay was more common in younger patients and those with a history of respiratory disorders (e.g. obstructive lung disease or sleep apnea). Based on the results of the study, the investigators encourage clinicians to be suspicious when a patient’s symptoms are out of proportion to the suspected, underlying disease, or when the patient is not responding to the traditional treatments for the suspected disease. Such patients would be candidates for evaluation and screening for pulmonary hypertension. 1) Badesch, et al. Chest. 2010;137(2): ) Brown, et al. Chest. 2011;140(1):19-26 46

Screening High-Risk Patients
Patients with a family history of PAH Heritable PAH Patients with a history of high-risk drug / toxin use Drug- and toxin-induced PAH Patients with an associated condition: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Associated conditions Patients at high risk of developing PAH should be routinely screened for the disease, especially when multiple risk factors are present or symptomatology exists. Patients with a family history of PAH are candidates for screening. Another subpopulation at risk would be patients who have taken one or more of the recognized drug / toxins that can lead to PAH. Finally, those with an associated condition (listed on the slide) are at a greater risk for developing PAH; therefore, evaluation for PAH should be included as part of routine patient monitoring. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. 47

Comorbid Conditions in Patients With PAH
NIDDM = non-insulin dependent diabetes mellitus; COPD = chronic obstructive pulmonary disease The presence of comorbid conditions can confound the timely diagnosis of PAH. Results from the REVEAL patient registry have recently been published. Poms and colleagues reported demographic information regarding the enrolled patients. A range of comorbid conditions have affected patients with PAH. The chart displays the percent occurrence of a number of these comorbidities in the nearly three thousand patients followed as part of the REVEAL registry. Coexisting systemic hypertension and obesity were the most common comorbid conditions. Poms, et al. Chest. 2013;144(1):

Summary Greater number of treatment options for PAH has advanced patient survival. Right heart catheterization is mandatory for diagnostic confirmation. Both a delay in diagnosis and misdiagnosis are common and have a catastrophic impact on outcomes. Screening of high-risk patients is essential. The continuum of RV impairment in patients should be met with action towards reversal. To summarize this lecture, the slide lists several key, take-home points. Thankfully, treatment options for PAH have expanded, and as a result, patient survival rates have increased. Keep in mind that right heart catheterization is mandatory for diagnostic confirmation of PAH. Even though the care of patients with PAH has advanced, room-for-improvement remains. Indeed, diagnostic delay and misdiagnosis are common and can have a catastrophic impact on patient morbidity and mortality. Therefore, screening of high-risk patients is essential. The pathology of PAH severely impacts the structure and function of the right ventricle. As such, the continuum of RV impairment in patients should be met with action steps taken by the clinician to reverse this maladaptation. 49

Diagnostic Assessment and Confirmation of PAH

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Diagnostic Assessment and Confirmation of PAH

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