Persistent Pulmonary Hypertension: Symptoms, Types, Causes and Treatment

Persistent pulmonary hypertension (PH) is a complex and life-altering condition that affects people of all ages, including newborns and adults. Whether arising from unresolved medical issues or as a consequence of certain diseases or surgeries, persistent PH can severely diminish quality of life and, if left unmanaged, may lead to life-threatening complications. In this article, we will delve into the key symptoms, types, causes, and modern treatments for persistent pulmonary hypertension, drawing on recent research and patient experiences to provide a comprehensive, evidence-based overview.

Symptoms of Persistent Pulmonary Hypertension

Persistent pulmonary hypertension often presents with a variety of symptoms that can significantly impact daily life. Recognizing these signs early is crucial, as timely diagnosis and intervention can improve outcomes and quality of life for those affected.

Symptom	Impact	Patient Experience	Source
Shortness of breath	Limits daily activities	Most bothersome, persistent	1, 2, 4
Fatigue	Reduces energy/mobility	Frequent, disabling	1, 2
Swelling (Edema)	Discomfort, mobility	Lower limbs, hands, face	1, 2
Cough	Disrupts sleep/social	Chronic or dry	1, 2
Dizziness/Syncope	Danger, falls risk	Sometimes leads to fainting	2, 4
Palpitations	Anxiety, discomfort	Irregular heartbeat	2
Chest pain	Activity limitation	Sign of heart strain	4, 5

Table 1: Key Symptoms of Persistent Pulmonary Hypertension

Shortness of Breath and Fatigue

The most prominent and distressing symptom for people with persistent PH is shortness of breath (dyspnea), especially during exertion but often even at rest as the disease progresses. This symptom alone can make everyday activities like walking, climbing stairs, or even talking difficult for patients. Fatigue often accompanies breathlessness, leading to reduced energy and a significant loss of independence 1, 2, 4.

Swelling and Edema

Fluid retention, particularly in the legs, ankles, hands, and sometimes the face, is common in persistent PH. Edema arises because the right side of the heart, which pumps blood into the lungs, has to work harder against the increased pressure in the pulmonary arteries. When the heart struggles, fluid backs up into the body’s tissues 1, 4.

Cough, Dizziness, and Palpitations

A persistent cough—sometimes dry and sometimes productive—can disrupt sleep and social interactions. Dizziness and, in severe cases, fainting (syncope) may occur due to reduced blood flow to the brain during physical activity or even at rest. Palpitations (irregular heartbeats) are also frequently reported and can cause significant anxiety 2, 4.

Emotional and Quality of Life Impacts

Beyond physical symptoms, persistent PH deeply affects emotional well-being. Patients often report frustration, anxiety, isolation, and even depression, all of which can further diminish their quality of life 1, 2. Reduced mobility and the inability to participate in hobbies, travel, or social events amplify these emotional burdens.

Types of Persistent Pulmonary Hypertension

Persistent pulmonary hypertension is not a single disease but a group of related disorders categorized based on their underlying causes and clinical characteristics. Understanding these types is essential for accurate diagnosis and targeted treatment.

Type	Description/Mechanism	Main Feature	Source
Group 1: PAH	Pulmonary arterial hypertension; includes idiopathic, heritable, and associated PAH	Vascular remodeling	3, 4, 5, 7
Group 2: PH-LHD	Due to left heart disease (LHD)	Raised left heart pressures	3, 5, 6, 8
Group 3: PH-CLD	Due to chronic lung disease (CLD)	Hypoxia, lung pathology	1, 2, 3, 5
Group 4: CTEPH	Chronic thromboembolic PH	Unresolved blood clots	3, 5, 12, 13, 16
Group 5: Miscellaneous	Multifactorial, unclear mechanisms	Heterogeneous causes	3, 5
Persistent PPHN (Newborns)	Failure of normal drop in pulmonary resistance after birth	Neonatal hypoxemia	9, 10

Table 2: Types of Persistent Pulmonary Hypertension

Group 1: Pulmonary Arterial Hypertension (PAH)

This group includes idiopathic PAH, heritable forms (often linked to BMPR2 gene mutations), and PAH associated with connective tissue diseases, HIV, and certain drugs. The hallmark is progressive narrowing and remodeling of the small pulmonary arteries, leading to increased resistance and pressure 3, 4, 7.

Group 2: PH Due to Left Heart Disease (PH-LHD)

The most common type, PH-LHD arises when left-sided heart conditions (such as heart failure, valve disease, or diastolic dysfunction) cause back-pressure into the lungs. This can lead to both isolated post-capillary PH and combined pre- and post-capillary PH 3, 5, 6, 8.

Group 3: PH Due to Chronic Lung Disease (PH-CLD)

Chronic lung conditions, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and pulmonary fibrosis, can cause PH through low oxygen levels and structural changes in the lung’s blood vessels 1, 2, 3, 5.

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

CTEPH stems from unresolved blood clots (emboli) in the lungs that become organized and obstruct blood flow, leading to persistent high pressure. This type is unique in that it is potentially curable with surgery in many cases 3, 5, 12, 13, 16.

Group 5: Multifactorial/Unclear Mechanisms

This diverse group includes PH caused by rare diseases, blood disorders, metabolic syndromes, or systemic conditions with unclear or mixed mechanisms 3, 5.

Persistent Pulmonary Hypertension of the Newborn (PPHN)

In newborns, persistent PH results from the failure of the normal drop in pulmonary vascular resistance after birth. PPHN leads to right-to-left shunting and severe hypoxemia—rapid recognition and intervention are critical 9, 10.

Causes of Persistent Pulmonary Hypertension

Understanding the underlying causes of persistent PH is key to both prevention and treatment. Causes vary widely depending on the type and can range from genetic mutations to unresolved medical events.

Cause Category	Key Examples or Mechanisms	Associated Type(s)	Source
Genetic mutations	BMPR2, ACVRL1, ENG, Smad8	PAH	3, 4, 7, 11
Left heart disease	Heart failure, valve disease	PH-LHD	3, 5, 6, 8
Chronic lung diseases	COPD, ILD, pulmonary fibrosis	PH-CLD	1, 2, 3
Chronic thromboembolism	Unresolved pulmonary emboli	CTEPH	3, 5, 12, 13, 16
Neonatal maladaptation	Birth asphyxia, congenital anomalies	PPHN	9, 10
Systemic/rare diseases	Sickle cell, metabolic, unclear causes	Group 5	3, 5

Table 3: Causes of Persistent Pulmonary Hypertension

Genetic and Molecular Factors

Heritable forms of PAH are most often linked to mutations in the BMPR2 gene, which regulates blood vessel growth and repair. Other less common genetic mutations include ACVRL1, ENG, and Smad8. These mutations lead to abnormal cell proliferation and resistance to cell death, resulting in narrowing and stiffening of the pulmonary arteries 3, 4, 7, 11.

Heart and Lung Disease

• Left heart diseases: Heart failure (especially with preserved ejection fraction), mitral or aortic valve disease, and left ventricular dysfunction can all cause increased pressure in the lungs 3, 5, 6, 8.
• Chronic lung diseases: Long-term exposure to low oxygen (hypoxia) from COPD, ILD, and other lung diseases leads to constriction and remodeling of pulmonary vessels 1, 2, 3.

Chronic Thromboembolic Disease

CTEPH arises when blood clots in the lungs fail to resolve and become organized, blocking blood flow and raising pressure. Not all patients with pulmonary embolism develop CTEPH, but risk increases with recurrent or large clots 12, 13, 16.

Neonatal Factors

Persistent pulmonary hypertension of the newborn (PPHN) often results from perinatal factors such as:

• Birth asphyxia
• Meconium aspiration
• Sepsis
• Congenital diaphragmatic hernia
• Maternal risk factors (obesity, diabetes, certain medications) 9, 10

Multifactorial and Systemic Causes

Some cases are associated with blood disorders (e.g., sickle cell anemia), systemic diseases, or a combination of metabolic, inflammatory, and immune factors, as seen in Group 5 PH 3, 5.

Treatment of Persistent Pulmonary Hypertension

Effective treatment of persistent PH depends on its type and underlying cause. While some forms are potentially curable, most require a combination of medications, lifestyle adjustments, and sometimes surgical or interventional procedures.

Treatment Type	Main Approaches/Medications	Indications	Source
Targeted drug therapy	Prostanoids, endothelin receptor antagonists, PDE-5 inhibitors, soluble guanylate cyclase stimulators	PAH, selected CTEPH	3, 4, 5, 14, 15, 16
Surgical intervention	Pulmonary endarterectomy (PEA)	Operable CTEPH	12, 13, 14, 16
Balloon angioplasty	BPA	Inoperable or residual CTEPH	12, 16
Oxygen therapy	Supplemental oxygen	Hypoxemia (especially PH-CLD, PPHN)	2, 10
Diuretics/anticoagulation	Fluid management, clot prevention	Right heart failure, CTEPH, PAH	3, 5, 14
Treat underlying disease	Heart failure, lung disease management	PH-LHD, PH-CLD	5, 6, 8, 14

Table 4: Main Treatments for Persistent Pulmonary Hypertension

Targeted Drug Therapies

Modern management of PAH and, in select cases, CTEPH includes drugs that relax blood vessels and reduce pressure:

• Prostanoids (e.g., epoprostenol, treprostinil, iloprost) improve symptoms and survival in PAH.
• Endothelin receptor antagonists (e.g., bosentan, ambrisentan) block a key pathway in vasoconstriction.
• Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) and soluble guanylate cyclase stimulators (e.g., riociguat) enhance the effects of nitric oxide, a natural vasodilator 3, 4, 5, 14, 15, 16.

For inoperable or persistent CTEPH, riociguat is the only approved medication and has demonstrated sustained benefits 16.

Surgical and Interventional Treatments

• Pulmonary endarterectomy (PEA) is the gold-standard, potentially curative surgery for eligible CTEPH patients. However, about 25% of patients may have persistent PH after surgery and require additional therapies 12, 13, 14, 16.
• Balloon pulmonary angioplasty (BPA) is an emerging, minimally invasive option for patients with inoperable or residual CTEPH, improving hemodynamics and walking ability 12, 16.

Supportive and Adjunctive Therapies

• Supplemental oxygen is vital for patients with significant hypoxemia, particularly those with chronic lung disease and newborns with PPHN. Oxygen can dramatically improve mobility and quality of life 2, 10.
• Diuretics help control fluid overload in right heart failure, while anticoagulation is essential in certain types, particularly CTEPH and PAH, to prevent further clot formation 3, 5, 14.

Treating Underlying Conditions

For PH due to left heart or lung disease, the primary approach is to optimize management of the underlying condition—such as adjusting heart failure therapy or aggressively treating lung disease. Use of pulmonary vasodilators in these groups is not routinely recommended and may even be harmful in some cases 5, 6, 8, 14.

Special Considerations in Newborns

Management of PPHN in newborns focuses on:

• Optimizing oxygenation and ventilation
• Inhaled nitric oxide (or sildenafil if unavailable)
• Fluid and cardiovascular support
• Avoiding factors that exacerbate pulmonary resistance 10

Conclusion

Persistent pulmonary hypertension is a multifaceted and serious condition that requires careful diagnosis and individualized treatment. Advances in targeted drug therapy, surgical options, and supportive care have improved outcomes for many patients, but persistent PH remains a major challenge in cardiopulmonary medicine.

Key Takeaways:

• Symptoms commonly include shortness of breath, fatigue, edema, cough, dizziness, and palpitations, all of which can profoundly limit daily activity and quality of life.
• Types of persistent PH are classified into five major groups based on underlying cause, with a special category for newborns (PPHN).
• Causes range from genetic mutations and chronic heart/lung disease to unresolved blood clots and perinatal complications.
• Treatment varies by type: PAH and some CTEPH respond to targeted drugs; CTEPH may be curable with surgery or angioplasty; PH due to heart or lung disease requires management of the primary condition; supportive care such as oxygen and diuretics is essential in many cases.

By understanding the symptoms, types, causes, and treatments of persistent pulmonary hypertension, patients and healthcare providers can work together to improve outcomes and quality of life for those living with this challenging condition.