Pulmonary Hypertension

Overview

Definition

Pulmonary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension ( PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance) is defined as elevated pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs. 

• Elevated pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs consistent with PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance:
  • Historical definition:
    • ≥ 25 mm Hg at rest
    • ≥ 30 mm Hg during exercise
  • 2018 consensus opinion from the 6th World Symposia on Pulmonary Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension: mean pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs > 20 mm Hg at rest
• Normal pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs: 10–14 mm Hg
• May be primary (uncommon) or secondary (common):
  • Primary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance is referred to as pulmonary arterial hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension ( PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration).
  • Secondary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance may be due to chronic heart, lung, or systemic diseases.

Epidemiology

Secondary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance is much more common than the primary variant. The epidemiology of secondary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance is similar to the underlying condition. 

Primary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance/ PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration:

• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: approximately 15 cases in 1 million adults
• Schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis is the most common cause worldwide.
• In areas without endemic schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis:
  • 50% of cases are idiopathic Idiopathic Dermatomyositis.
  • 10% of cases are familial.
• Gender Gender Gender Dysphoria bias Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases: women > men
• Most common age at presentation: 4th–5th decades
• Mortality Mortality All deaths reported in a given population. Measures of Health Status rate: approximately 5.4 per 100,000

Anatomy review

Blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure through the cardiac and pulmonary circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment takes the following path:

• Deoxygenated systemic blood returns to the right side of the heart through the superior and inferior venae cavae Venae Cavae The inferior and superior venae cavae. Veins: Histology.
  • Vena cava → right atrium → tricuspid valve Tricuspid valve The valve consisting of three cusps situated between the right atrium and right ventricle of the heart. Heart: Anatomy → right ventricle → pulmonary valve Pulmonary valve A valve situated at the entrance to the pulmonary trunk from the right ventricle. Heart: Anatomy → pulmonary trunk Pulmonary Trunk Truncus Arteriosus
  • Pulmonary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology → pulmonary capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology (blood is oxygenated) → pulmonary veins Pulmonary veins The veins that return the oxygenated blood from the lungs to the left atrium of the heart. Lungs: Anatomy 
• Oxygenated blood returns to the left side of the heart.
  • Pulmonary veins Pulmonary veins The veins that return the oxygenated blood from the lungs to the left atrium of the heart. Lungs: Anatomy → left atrium → mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy → left ventricle → aortic valve Aortic valve The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. Heart: Anatomy → aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy
  • The aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy leads blood into the systemic arterial circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment.

Classification and Etiology

The WHO has classified PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance into 5 categories based on the etiology:

Group 1: PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration

Group 1 refers to cases of increased pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs in the absence of underlying heart or lung disease and was previously called (and can still be conceptualized as) primary PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. The etiologies of group 1 include:

• Idiopathic Idiopathic Dermatomyositis PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration (most common cause of PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration)
• Familial PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration: due to mutations in the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types morphogenic protein-receptor-2 (BMPR2) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, several other rare mutations, or unknown causes
• Drugs or toxins:
  • Appetite suppressants:
    • Amphetamines Amphetamines Analogs or derivatives of amphetamine. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation. Stimulants
    • Fenfluramine
    • Aminorex
  • Rapeseed oil
  • Cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics
• Associated with:
  • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology disease (primarily scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma)
  • HIV HIV Anti-HIV Drugs infection
  • Portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension
  • Congenital Congenital Chorioretinitis left-to-right shunts Left-to-right shunts Development of the Heart
  • Schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis (among the most common causes of PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration worldwide)
• Pulmonary veno-occlusive disease
• Pulmonary capillary hemangiomatosis (PCH)
• Persistent PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance of the newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn

Group 2: PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to left heart disease

Left-sided heart disease can cause pressure backup through the pulmonary vasculature leading to PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance, and is the most common cause of PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance overall. Etiologies include:

• Left-sided atrial or ventricular heart disease
• Left-sided valvular heart disease
• Obstruction of the left heart inflow or outflow tracts ( congenital Congenital Chorioretinitis or acquired)
• Congenital Congenital Chorioretinitis cardiomyopathies Cardiomyopathies A group of diseases in which the dominant feature is the involvement of the cardiac muscle itself. Cardiomyopathies are classified according to their predominant pathophysiological features (dilated cardiomyopathy; hypertrophic cardiomyopathy; restrictive cardiomyopathy) or their etiological/pathological factors (cardiomyopathy, alcoholic; endocardial fibroelastosis). Cardiomyopathy: Overview and Types

Group 3: PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to chronic lung disease and/or hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage

Hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage leads to physiological vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure of the pulmonary vasculature to prevent ventilation-perfusion mismatch. As a result, chronic hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage, as well as destructive lung diseases, can lead to chronic PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. Etiologies include:

• Chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)) (most common)
• Interstitial lung disease
• Pulmonary diseases with mixed restrictive and obstructive patterns
• Sleep-disordered breathing Sleep-disordered breathing Bradyarrhythmias (e.g., obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea)
• Alveolar hypoventilation disorders:
  • Obesity hypoventilation syndrome Obesity hypoventilation syndrome Hypoventilation syndrome in very obese persons with excessive adipose tissue around the abdomen and diaphragm. It is characterized by diminished to absent ventilatory chemoresponsiveness; chronic hypoxia; hypercapnia; polycythemia; and long periods of sleep during day and night (hypersomnolence). It is a condition often related to obstructive sleep apnea but can occur separately. Obstructive Sleep Apnea
  • Congenital Congenital Chorioretinitis central alveolar hypoventilation syndrome
  • Hypothalamic dysfunction
• Chronic exposure to high altitude

Group 4: PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to chronic thromboembolic disease

Group 4 cases are diagnosed when there is an increase in pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs with documentation Documentation Systematic organization, storage, retrieval, and dissemination of specialized information, especially of a scientific or technical nature. It often involves authenticating or validating information. Advance Directives of pulmonary arterial obstruction. Etiologies include:

• Chronic pulmonary thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus
• Nonthrombotic pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism:
  • Tumor Tumor Inflammation embolisms (late-stage manifestations of certain malignancies with embolization Embolization A method of hemostasis utilizing various agents such as gelfoam, silastic, metal, glass, or plastic pellets, autologous clot, fat, and muscle as emboli. It has been used in the treatment of spinal cord and intracranial arteriovenous malformations, renal arteriovenous fistulas, gastrointestinal bleeding, epistaxis, hypersplenism, certain highly vascular tumors, traumatic rupture of blood vessels, and control of operative hemorrhage. Gastrointestinal Bleeding of tumor Tumor Inflammation particles themselves)
  • Foreign material (most commonly silicone, after surgical injection)

Group 5: PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to unclear or multifactorial causes

Pulmonary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension is classified as Group 5 when the elevation in pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs is associated with a systemic disease, where a causal relationship is not clearly understood or thought to be multifactorial. Etiologies include:

• Hematological disorders:
  • Chronic hemolytic anemias:
    • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
    • Thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia
    • Spherocytosis
  • Chronic myeloproliferative disorders
  • Splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen
• Systemic disorders:
  • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
  • Pulmonary histiocytosis
  • Lymphangioleiomyomatosis Lymphangioleiomyomatosis A disease characterized by the progressive invasion of smooth muscle cells into the lymphatic vessels, and the blood vessels. The majority of the cases occur in the lungs of women of childbearing age, eventually blocking the flow of air, blood, and lymph. The common symptom is shortness of breath (dyspnea). Interstitial Lung Diseases
• Metabolic disorders:
  • Glycogen storage disease Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors
  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease
  • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disorders
• Others:
  • Tumoral obstruction
  • Fibrosing mediastinitis Fibrosing Mediastinitis Mediastinitis
  • Chronic renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome

Pathophysiology

Overview

• ↑ Pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs leads to:
  • Enlarged proximal pulmonary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology
  • Right ventricular hypertrophy Right Ventricular Hypertrophy Tetralogy of Fallot
  • Tricuspid regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)
  • Right atrial dilation
  • Ultimately results in cor pulmonale Cor Pulmonale Cor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom. Cor Pulmonale ( right-sided heart failure Right-Sided Heart Failure Ebstein’s Anomaly).
• Mean pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs = (Q x PVR) + pulmonary capillary wedge pressure
  • Q: right-sided cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics
  • PVR: pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
  • Pulmonary capillary wedge pressure estimates left atrial pressure.
• ↑ Pulmonary arterial pressure Pulmonary Arterial Pressure Pulmonary Hypertension Drugs may be due to:
  • ↑ Pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing (most common)
  • ↑ Flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure through the pulmonary vasculature
  • ↑ Left-sided pressures

Increased pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing

Increased pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing is the primary cause of PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance in most cases and may be due to:

• Occlusive vasculopathies of the small pulmonary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology/ arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology: remodel the vasculature and alter the tone (e.g., idiopathic Idiopathic Dermatomyositis PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration)
• ↓ In the area of the pulmonary vascular bed: 
  • Pulmonary emboli
  • Interstitial lung disease
• Hypoxic vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure:
  • Hypoventilation syndromes
  • Parenchymal lung disease
• ↑ Pulmonary venous pressure:
  • Mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy disease
  • Left ventricular dysfunction
  • Constrictive pericarditis Constrictive pericarditis Inflammation of the pericardium that is characterized by the fibrous scarring and adhesion of both serous layers, the visceral pericardium and the parietal pericardium leading to the loss of pericardial cavity. The thickened pericardium severely restricts cardiac filling. Clinical signs include fatigue, muscle wasting, and weight loss. Pericarditis
  • Restrictive cardiomyopathy Restrictive Cardiomyopathy Restrictive cardiomyopathy (RCM) is a fairly uncommon condition characterized by progressive stiffening of the cardiac muscle, which causes impaired relaxation and refilling of the heart during diastole, resulting in diastolic dysfunction and eventual heart failure. Restrictive Cardiomyopathy
  • Pulmonary venous obstruction

Increased flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure through the pulmonary vasculature

Typically, increased flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure triggers vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs of the pulmonary vasculature. In cases where this increase in flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure is chronic, PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance may develop. Chronic increases in flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure can also induce vascular changes leading to increased pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing.

• Congenital Congenital Chorioretinitis heart defects with left-to-right shunt:
  • Atrial septal defects
  • Ventricular septal defects
  • Patent ductus arteriosus Ductus arteriosus A fetal blood vessel connecting the pulmonary artery with the descending aorta. Patent Ductus Arteriosus (PDA)
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• Chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
• Arteriovenous malformations Arteriovenous malformations Congenital vascular anomalies in the brain characterized by direct communication between an artery and a vein without passing through the capillaries. The locations and size of the shunts determine the symptoms including headaches; seizures; stroke; intracranial hemorrhages; mass effect; and vascular steal effect. Intracerebral Hemorrhage

Genetic mutations Genetic Mutations Carcinogenesis

Familial PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration is most commonly due to mutations in the BMPR2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.

• BMPR2
  • 80% of familial cases are due to an inactivating mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in BMPR2.
  • BMPR2 normally inhibits vascular smooth muscle proliferation.
  • With BMPR2 inactivated, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are unable to prevent vascular smooth muscle proliferation → PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration
• Several other rare mutations have been identified.

Pathogenesis by classification group

Clinical Presentation

History

• Symptoms:
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea on exertion leading to dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea at rest (primary symptom)
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways (angina) 
  • Exertional syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
• Considerations from past medical history Past Medical History Adult Health Maintenance:
  • COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)/ emphysema Emphysema Enlargement of air spaces distal to the terminal bronchioles where gas-exchange normally takes place. This is usually due to destruction of the alveolar wall. Pulmonary emphysema can be classified by the location and distribution of the lesions. Chronic Obstructive Pulmonary Disease (COPD)
  • Interstitial lung disease
  • Heart disease
  • Sickle cell anemia Sickle cell anemia A disease characterized by chronic hemolytic anemia, episodic painful crises, and pathologic involvement of many organs. It is the clinical expression of homozygosity for hemoglobin S. Sickle Cell Disease
  • Travel to regions with endemic schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis 
  • Hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States states/history of thromboembolic disease

Physical exam

Exam findings consistent with PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance include:

• Raised jugular venous pulsation (JVP)
• Heart sounds Heart sounds Heart sounds are brief, transient sounds produced by valve opening and closure and by movement of blood in the heart. They are divided into systolic and diastolic sounds. In most cases, only the first (S1) and second (S2) heart sounds are heard. These are high-frequency sounds and arise from aortic and pulmonary valve closure (S1), as well as mitral and tricuspid valve closure (S2). Heart Sounds:
  • Pronounced 2nd heart sound (due to a louder P2 component)
  • Fixed splitting Splitting Defense Mechanisms of S2 S2 Heart Sounds
  • Presence of extra right-sided heart sounds Heart sounds Heart sounds are brief, transient sounds produced by valve opening and closure and by movement of blood in the heart. They are divided into systolic and diastolic sounds. In most cases, only the first (S1) and second (S2) heart sounds are heard. These are high-frequency sounds and arise from aortic and pulmonary valve closure (S1), as well as mitral and tricuspid valve closure (S2). Heart Sounds:
    • S3 S3 Heart Sounds: can be heard in ventricular volume overload and heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (HF)
    • S4 S4 Heart Sounds: ↑ resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to ventricular filling Ventricular filling Cardiac Cycle due to ↓ ventricular compliance Compliance Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. Veins: Histology
• Murmurs:
  • Tricuspid regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD): pansystolic murmur Pansystolic Murmur Transposition of the Great Arteries heard at the left sternal border
  • Mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS): diastolic murmur heard at the apex
  • Aortic stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS): midsystolic murmur heard best at the right 2nd intercostal space, radiating to the carotids
• Signs of right-sided heart failure Right-Sided Heart Failure Ebstein’s Anomaly:
  • Peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema
  • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
  • Hepatomegaly

Diagnosis

Diagnosis of group 1 PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration is typically one of exclusion, after ruling out etiologies in groups 2–5, which can be made by the following tests:

• Echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA)
  • Best initial test
  • Allows for assessment of:
    • Ventricular and atrial size and function
    • Valve function (e.g., presence of stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) or regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD))
    • Evidence of volume overload on either side
  • Findings may include:
    • ↑ Thickness of ventricular walls
    • Ventricular hypokinesis
    • Valvular regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)
• ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG):
  • Important for:
    • Ruling out PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to left-sided heart disease
    • Assessing right-sided heart function
  • Findings of right heart disease may include:
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
    • Right axis deviation
    • Upright R waves in V1–V3 
• Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests findings:
  • Enlargement of central pulmonary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology and the main branches 
  • Tapering of distal vessels
  • Findings consistent with heart disease: cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly, pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
  • Findings consistent with lung disease: COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD), interstitial lung disease
  • Note: Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests is often normal or with minimal findings.
• Ventilation-perfusion lung scan:
  • Helps differentiate group 3 (lung/hypoxic disease) from group 4 (chronic thromboembolic disease)
  • Findings may include:
    • Group 3: diffuse mottled perfusion
    • Group 4: segmental mismatched defects
• Pulmonary function tests:
  • Useful in diagnosing lung and/or hypoxic disorders
  • Obstructive patterns: COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
  • Restrictive patterns: interstitial lung disease
• Right-sided cardiac catheterization Cardiac Catheterization Procedures in which placement of cardiac catheters is performed for therapeutic or diagnostic procedures. Cardiac Surgery:
  • Most accurate test for confirming the diagnosis, especially in idiopathic Idiopathic Dermatomyositis cases of PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration
  • Invasive procedure
  • Allows for evaluation of:
    • Hemodynamics Hemodynamics The movement and the forces involved in the movement of the blood through the cardiovascular system. Vascular Resistance, Flow, and Mean Arterial Pressure of the cardiac chambers and large vessels
    • Cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics
    • Cardiac shunting
    • Other causes of dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea or angina
  • Allows for testing of vasoreactivity in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with group 1 PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration:
    • Administer a short-acting vasodilatory substance (e.g., inhaled NO) and assess response.
    • Important for managing patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with group 1 PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration
• Laboratory tests: can help identify other causes of PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance
  • CBC: to rule out anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests: to rule out liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease as a cause of symptoms
  • HIV HIV Anti-HIV Drugs testing 
  • ANA: test to screen for scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma
  • Assays for schistosomiasis Schistosomiasis Infection with flukes (trematodes) of the genus schistosoma. Three species produce the most frequent clinical diseases: Schistosoma haematobium (endemic in Africa and the Middle East), Schistosoma Mansoni (in Egypt, northern and southern Africa, some West Indies islands, northern 2/3 of South america), and Schistosoma japonicum (in Japan, China, the Philippines, Celebes, Thailand, Laos). S. mansoni is often seen in Puerto Ricans living in the United States. Schistosoma/Schistosomiasis

Management

For groups 2–5, management should be directed at treating the underlying condition. In addition, management should focus on maintaining/improving oxygenation. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be referred to specialists at tertiary centers for management, which is often complex.

Vasodilatory agents

• Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers ( CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)):
  • Only effective in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who are vasoreactive
  • CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) block the inward movement of calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes into:
    • Endothelial cells → vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
    • Sinoatrial (SA) and atrioventricular (AV) nodes → ↓ cardiac conduction and contractility
  • Dihydropyridines Dihydropyridines Pyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position. Pulmonary Hypertension Drugs:
    • Primarily vasodilators Vasodilators Drugs used to cause dilation of the blood vessels. Thromboangiitis Obliterans (Buerger Disease) at therapeutic doses
    • Examples: amlodipine Amlodipine A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. Hypertension Drugs, nifedipine Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
  • Non-dihydropyridines:
    • Have inhibitory effects at the SA and AV nodes
    • Examples: diltiazem Diltiazem A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers), verapamil Verapamil A calcium channel blocker that is a class IV anti-arrhythmia agent. Pulmonary Hypertension Drugs
  • High doses may produce a dramatic reduction in pulmonary artery Pulmonary artery The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. Lungs: Anatomy pressure.
• Vasodilatory prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids: 
  • Prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids ( PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis₂) is a natural vasodilatory substance.
  • PGI PGI An aldose-ketose isomerase that catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate. In prokaryotic and eukaryotic organisms it plays an essential role in glycolytic and gluconeogenic pathways. In mammalian systems the enzyme is found in the cytoplasm and as a secreted protein. This secreted form of glucose-6-phosphate isomerase has been referred to as autocrine motility factor or neuroleukin, and acts as a cytokine which binds to the autocrine motility factor receptor. Deficiency of the enzyme in humans is an autosomal recessive trait, which results in congenital nonspherocytic hemolytic anemia. Glycolysis₂ analogs: epoprostenol Epoprostenol A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Hemostasis, treprostinil Treprostinil Pulmonary Hypertension Drugs
• Endothelin receptor antagonists Endothelin Receptor Antagonists Compounds and drugs that bind to and inhibit or block the activation of endothelin rececptors. Pulmonary Hypertension Drugs:
  • Endothelins Endothelins 21-amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1; endothelin-2; and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. Hemostasis are natural vasoconstrictors.
  • Competitively antagonize endothelin receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → ↓ pulmonary vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
  • Examples: bosentan Bosentan Pulmonary Hypertension Drugs, ambrisentan Ambrisentan Pulmonary Hypertension Drugs
• Phosphodiesterase inhibitors Phosphodiesterase inhibitors Phosphodiesterase (PDE) inhibitors are a group of drugs that act by inhibiting PDE enzymes. Phosphodiesterase inhibitors have various mechanisms of action depending on the subtype of PDE targeted, but their main action is increasing the amount of intracellular cAMP or cGMP, which in turn results in physiologic effects such as reducing inflammation, promoting smooth muscle relaxation, and vasodilation. Phosphodiesterase Inhibitors ( PDE-5 inhibitors PDE-5 inhibitors Pulmonary Hypertension Drugs):
  • PDE-5 degrades cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors.
  • PDE-5 inhibitors PDE-5 inhibitors Pulmonary Hypertension Drugs ↓ degradation of cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors → ↑ cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors → ↑ smooth muscle relaxation 
  • Results in ↑ pulmonary and systemic vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • Examples: sildenafil Sildenafil A phosphodiesterase type-5 inhibitor; vasodilator agent and urological agent that is used in the treatment of erectile dysfunction and primary pulmonary hypertension. Phosphodiesterase Inhibitors (Viagra), tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors
• Guanylate cyclase Guanylate cyclase An enzyme that catalyzes the conversion of GTP to 3. Diarrheagenic E. coli activators
  • Soluble guanylate cyclase Guanylate cyclase An enzyme that catalyzes the conversion of GTP to 3. Diarrheagenic E. coli (sGC) is an intracellular receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors for NO.
  • sGC ↑ cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors within the cell → vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • Examples: cinaciguat, riociguat Riociguat Pulmonary Hypertension Drugs

Other nonsurgical management options

• Supportive measures:
  • Oxygen therapy
  • Low-sodium diet 
  • Physical therapy Physical Therapy Becker Muscular Dystrophy/supervised exercise to improve functional capacity
  • Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination
  • Birth control to prevent pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care due to high risk of maternal mortality Mortality All deaths reported in a given population. Measures of Health Status associated with PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance in pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
• Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication:
  • Indication: patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with right-sided volume overload ( edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites)
  • Avoid hypovolemia Hypovolemia Sepsis in Children ( patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with right-sided heart failure Right-Sided Heart Failure Ebstein’s Anomaly are preload Preload Cardiac Mechanics dependent).
  • Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication are typically 1st-line drugs (e.g., furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics).
• Anticoagulation Anticoagulation Pulmonary Hypertension Drugs:
  • Indications:
    • Group 4 ( PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance due to chronic thromboembolic disease)
    • Group 1 PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration that is either idiopathic Idiopathic Dermatomyositis or familial
    • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation
  • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants is usually the drug of choice.
• Digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides:
  • Indications:
    • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) due to systolic dysfunction Systolic dysfunction Dilated Cardiomyopathy 
    • Certain supraventricular tachyarrhythmias
  • Effects:
    • Positive inotrope
    • Can reduce sympathetic activation

Surgical options

• Lung transplantation Lung transplantation The transference of either one or both of the lungs from one human or animal to another. Organ Transplantation:
  • Indications for referral:
    • Rapidly progressive disease on therapy
    • Use of parenteral prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids
    • Known or suspected pulmonary venoocclusive disease
  • Procedures of choice:
    • Bilateral lung transplant
    • Heart-lung transplant
• Creation of a right-to-left shunt
  • Can be temporizing (as a bridge to transplant) or palliative
  • Procedures:
    • Atrial septostomy Atrial Septostomy Tricuspid Valve Atresia (TVA)
    • Transcatheter Potts shunt: placement of a shunt between the left pulmonary artery Pulmonary artery The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. Lungs: Anatomy and the descending aorta Descending aorta Mediastinum and Great Vessels: Anatomy
• Endovascular thrombectomy Thrombectomy Surgical removal of an obstructing clot or foreign material from a blood vessel at the point of its formation. Removal of a clot arising from a distant site is called embolectomy. Vascular Surgery: in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with chronic thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus and a known source

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration is progressive and may be fatal if left untreated.
• Untreated, group 1 PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration has the worst prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
  • 1-year survival: 85%
  • 3-year survival: 68%
  • 5-year survival: 57%
• Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas depends on the underlying cause.
• The main cause of death is right ventricular failure.
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be monitored by a specialist to assess for a decline in functional status.

Clinical Relevance

• HF: the inability of the heart to supply the body with normal cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics to meet metabolic needs. Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) can lead to group 2 PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. Echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA) can confirm the diagnosis and provide information about the EF EF Cardiac Cycle. Treatment is directed at the removal of excess fluid and decreasing oxygen demand of the heart. 
• Coronary artery Coronary Artery Truncus Arteriosus disease: occurs due to a stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) of the coronary arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology, leading to ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage of the heart. Symptoms include chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Diagnosis is based on history, ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) findings, cardiac stress tests, and/or cardiac catheterizations. Treatment is primarily based on reducing oxygen demand of the heart and increasing the delivery of oxygen.
• Tricuspid regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD) (TR): a valvular defect that allows the backflow of blood from the right ventricle to the right atrium during systole Systole Period of contraction of the heart, especially of the heart ventricles. Cardiac Cycle. Tricuspid regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD) may be asymptomatic or present with systemic venous congestion due to increased right atrial and venous pressures. Tricuspid regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD) can also result from PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance, but intrinsic valve disease should be considered in the differential diagnosis of PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. Echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA) can help establish the diagnosis. Treatment focuses on heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) management, and surgery is reserved for severe disease.
• Pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans: a rapidly progressive interstitial lung disease with few available therapies. As pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans progresses, group 3 PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance can develop. The average life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids is 3–4 years from diagnosis. Lung transplantation Lung transplantation The transference of either one or both of the lungs from one human or animal to another. Organ Transplantation is the only curative intervention, provided candidacy. 
• COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD): a lung disease usually caused by smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases, and characterized by progressive, largely irreversible airflow obstruction secondary to chronic inflammation Chronic Inflammation Inflammation. Chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis is one of the primary causes of group 3 PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance and the symptoms include progressive dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and chronic cough. The diagnosis is confirmed with a pulmonary function test Pulmonary function test Pulmonary function tests are a group of diagnostic procedures yielding useful, quantifiable information about the rate of the flow of air through the individual’s airways, lung capacity, and the efficiency of gas exchange in relation to time. The most commonly utilized tests include spirometry (before and after bronchodilator use), lung volumes, and quantitation of diffusing capacity for carbon monoxide (CO). The tests can be influenced by the individual’s effort/fatigue, disease state, or anatomical malformation. Pulmonary Function Tests. Management includes smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation, pulmonary rehabilitation, and pharmacotherapy.
• Pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism: a result of the intraluminal obstruction of the main pulmonary artery Pulmonary artery The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. Lungs: Anatomy or its branches by certain components (e.g., thrombus, cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, air, amniotic fluid Amniotic fluid A clear, yellowish liquid that envelopes the fetus inside the sac of amnion. In the first trimester, it is likely a transudate of maternal or fetal plasma. In the second trimester, amniotic fluid derives primarily from fetal lung and kidney. Cells or substances in this fluid can be removed for prenatal diagnostic tests (amniocentesis). Placenta, Umbilical Cord, and Amniotic Cavity, or fat). The most common presenting symptom is dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Initial management is supportive (focusing on restoring oxygenation and hemodynamic stability), which is followed by systemic anticoagulation Anticoagulation Pulmonary Hypertension Drugs and interventional therapies. Chronic thromboembolic events can lead to group 4 PH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance.