Pulmonary hypertension

Pulmonary hypertension (pulmonary arterial hypertension) is an increase in pressure in the pulmonary artery system, which may be due to an increase in resistance in the bloodstream of the lungs or a significant increase in pulmonary blood flow. This pathology is in most cases secondary; when the cause is unknown, it is called primary. In primary pulmonary hypertension, the pulmonary vessels constrict, hypertrophy and fibrosis.

Pulmonary hypertension leads to right ventricular overload and insufficiency. Symptoms of pulmonary hypertension are fatigue, shortness of breath on exertion and, sometimes, chest discomfort and fainting. The diagnosis is made by measuring the pressure in the pulmonary artery. Treatment of pulmonary hypertension is carried out with vasodilators and, in some severe cases, with lung transplantation. The prognosis is generally unfavorable if there is no curable cause.

Normal pressure in the pulmonary artery is:

• systolic - 23-26 mm Hg.
• diastolic - 7-9 mm Hg
• average -12-15 mm Hg

According to the WHO recommendations, the upper limit of normal for systolic pressure in the pulmonary artery is 30 mm Hg, diastolic pressure - 15 mm Hg.

[1], [2], [3],

Causes of the pulmonary hypertension

Pulmonary hypertension occurs if the mean pulmonary arterial pressure is> 25 mmHg. Art. Alone or> 35 mmHg. Art. During load. Many conditions and drugs cause pulmonary hypertension. Primary pulmonary hypertension - pulmonary hypertension in the absence of such causes. However, the outcome may be similar. Primary pulmonary hypertension is rare, the incidence is 1-2 people per million.

Primary pulmonary hypertension affects women 2 times more often than men. The average age of diagnosis is 35 years. The disease can be familial or sporadic; sporadic cases occur about 10 times more often. The majority of familial cases have mutations in the gene for bone morphogenetic protein type 2 (BMPR2) from the family of receptors for transforming growth factor (TGF) -beta. Approximately 20% of sporadic cases also have BMPR2 mutations. Many people with primary pulmonary hypertension have elevated levels of angioprotein-1; Angioprotein-1 is likely to down-regulate BMPR1A, a BMPR2-related, and can stimulate the production of serotonin and the proliferation of smooth muscle endothelial cells. Other possible concomitant factors include disorders in serotonin transport and infection with the human herpes virus 8.

Primary pulmonary hypertension is characterized by variable vasoconstriction, smooth muscle hypertrophy and vessel wall remodeling. Vasoconstriction is considered to be a consequence of an increase in the activity of thromboxane and endothelin 1 (vasoconstrictors), on the one hand, and a decrease in the activity of prostacyclin and nitric oxide (vasodilators), on the other. Increased pulmonary vascular pressure, which is caused by vascular obstruction, aggravates endothelial damage. Damage activates coagulation on the intima surface, which can worsen hypertension. This can also be promoted by thrombotic coagulopathy due to an increase in the content of the plasmogen activator inhibitor type 1 and fibrinopeptide A and a decrease in the activity of the tissue plasmogen activator. Focal coagulation on the surface of the endothelium should not be confused with chronic thromboembolic pulmonary arterial hypertension, which is caused by organized pulmonary thromboembolic disease.

Ultimately, in most patients, primary pulmonary hypertension leads to right ventricular hypertrophy with dilation and right ventricular failure.

The causes of pulmonary hypertension are presented in the classification.

[4], [5], [6], [7], [8], [9], [10]

Etiological classification of pulmonary hypertension

Left ventricular failure

1. Ischemic heart disease.
2. Hypertension.
3. Aortic valve malformations, coarctation of the aorta.
4. Mitral regurgitation.
5. Cardiomyopathy.
6. Myocarditis.

Increased pressure in the left atrium

1. Mitral stenosis.
2. Tumor or thrombosis of the left atrium.
3. Three-atrial heart, mitral ring over valve.

Pulmonary vein obstruction

1. Mediastinal fibrosis.
2. Pulmonary venous thrombosis.

Parenchymal lung disease

1. Chronic obstructive pulmonary disease.
2. Interstitial lung diseases (disseminated processes in the lungs).
3. Acute severe lung injury:
   • adult respiratory distress syndrome;
   • severe diffuse pneumonitis.

Pulmonary artery disease

1. Primary pulmonary hypertension.
2. Repeated or massive pulmonary embolism.
3. Thrombosis "in situ" of the pulmonary artery.
4. Systemic vasculitis.
5. Distal stenosis of the pulmonary artery.
6. Increased pulmonary blood flow:
   • congenital heart disease with bleeding from left to right (ventricular septal defect, atrial septal defect);
   • open arterial duct.
7. Pulmonary hypertension caused by drugs and food.

Pulmonary hypertension in newborns

1. Persistent fetal circulation.
2. Hyaline membrane disease.
3. Diaphragmatic hernia.
4. Aspirating meconium.

Hypoxia and / or hypercapnia

1. Accommodation in highland areas.
2. Upper airway obstruction:
   • enlarged tonsils;
   • sleep obstructive apnea syndrome.
3. Hypoventilation syndrome in the obese (Pickwick syndrome).
4. Primary alveolar hypoventilation.

Many authors consider it appropriate to classify pulmonary hypertension, depending on the timing of its development and to allocate acute and chronic forms.

Causes of Acute Pulmonary Hypertension

1. Pulmonary embolism or thrombosis "in situ" in the pulmonary artery.
2. Acute left ventricular failure of any origin.
3. Asthmatic status.
4. Respiratory distress syndrome.

Causes of Chronic Pulmonary Hypertension

1. Increased pulmonary blood flow.
   1. Defect of interventricular septum.
   2. Defect of interatrial septum.
   3. Open arterial duct.
2. Increased pressure in the left atrium.
   1. Mitral valve defects.
   2. Myxoma or thrombus of the left atrium.
   3. Chronic left ventricular failure of any origin.
3. Increased resistance in the pulmonary artery system.
   1. Hypoxic genesis (chronic obstructive pulmonary disease, altitude hypoxia, hypoventilation syndrome).
   2. Obstructive genesis (recurrent pulmonary embolism, influence of pharmacological agents, primary pulmonary hypertension, diffuse connective tissue diseases, systemic vasculitis, veno-occlusive disease).

[11], [12], [13], [14], [15]

Symptoms of the pulmonary hypertension

The first clinical symptoms of pulmonary hypertension appear with an increase in blood pressure in the pulmonary artery by 2 times or more compared with the norm.

The main subjective manifestations of pulmonary hypertension are almost the same for any etiological forms of this syndrome. Patients concerned about:

• shortness of breath (the earliest and most frequent complaint of patients) at first with physical exertion, and later at rest;
• weakness, fatigue ;
• fainting (due to hypoxia of the brain, most characteristic of primary pulmonary hypertension);
• pain in the region of the heart of a constant nature (in 10-50% of patients, regardless of the etiology of pulmonary hypertension); due to relative coronary insufficiency due to severe right ventricular myocardial hypertrophy;
• hemoptysis - a frequent symptom of pulmonary hypertension, especially with a significant increase in pressure in the pulmonary artery;
• hoarseness (noted in 6-8% of patients and is caused by compression of the left recurrent nerve by the greatly expanded pulmonary artery);
• pain in the liver and swelling in the feet and legs (these symptoms appear during the development of pulmonary heart disease in patients with pulmonary hypertension).

Progressive shortness of breath with exertion and easy fatigability are found in almost all cases. Dyspnea may be accompanied by atypical discomfort in the chest and dizziness or fainting during exercise. These symptoms of pulmonary hypertension are primarily caused by inadequate cardiac output. Raynaud's phenomenon occurs in approximately 10% of patients with primary pulmonary hypertension, of whom 99% are women. Hemoptysis is rare, but can be fatal; dysphonia due to compression of the recurrent laryngeal nerve by the enlarged pulmonary artery (Ortner syndrome) is also rare.

In advanced cases, symptoms of pulmonary hypertension may include a bulging of the right ventricle, a spilled second tone (S2) with an emphasized pulmonary component S (P), a click of the pulmonary expulsion, a third tone of the right ventricle (S3), and swelling of the jugular veins. In the later stages, liver congestion and peripheral edema are often noted.

[16], [17], [18]

Portopulmonary hypertension

Portopulmonary hypertension - severe pulmonary arterial hypertension with portal hypertension in patients without secondary causes.

Pulmonary hypertension occurs in patients with a variety of conditions leading to portal hypertension with or without cirrhosis. Portopulmonary hypertension is less common than hepatopulmonary syndrome in patients with chronic liver disease (3.5-12%).

The first symptoms are shortness of breath and fatigue, there can also be chest pains and hemoptysis. Patients have physical manifestations and ECG changes characteristic of pulmonary hypertension; signs of pulmonary heartbeat (pulsation of the jugular veins, edema) may develop. Regurgitation on the tricuspid valve is frequent. The diagnosis is suspected based on echocardiography data and is confirmed by catheterization of the right heart.

Treatment - therapy of primary pulmonary hypertension, excluding hepatotoxic drugs. In some patients, vasodilator therapy is effective. Outcome determines the underlying pathology of the liver. Portopulmonary hypertension is a relative contraindication of liver transplantation due to the increased risk of complications and mortality. After transplantation, in some patients with moderate pulmonary hypertension, reverse pathology develops.

[19], [20], [21], [22],

Diagnostics of the pulmonary hypertension

An objective examination reveals cyanosis, and with the long-term existence of pulmonary hypertension, the distal phalanges of the fingers take the form of “drumsticks”, and the nails look like “watch glasses”.

At auscultation of the heart, characteristic signs of pulmonary hypertension are revealed - emphasis (often splitting) of II tone over a.pulmonalis; systolic murmur over the xiphoid process, aggravated by inspiration (Rivero-Corvallo symptom) is a sign of the relative insufficiency of the tricuspid valve, which is formed due to severe right ventricular myocardial hypertrophy; in the later stages of pulmonary hypertension, diastolic murmur in the second intercostal space on the left (over a.pulmonalis) can be determined, due to the relative insufficiency of the pulmonary valve with its significant expansion (Graham-Still’s noise).

With percussion of the heart, symptoms that are pathognomonic for pulmonary hypertension are usually not detected. It is rarely possible to detect the expansion of the border of vascular dullness in the second intercostal space on the left (due to the expansion of the pulmonary artery) and the displacement of the right border of the heart outwards from the right parasternal line due to right ventricular myocardial hypertrophy.

Pathognomonic for pulmonary hypertension are: hypertrophy of the right ventricle and right atrium, as well as signs indicating increased pressure in the pulmonary artery.

To identify these symptoms are used: radiography of the chest cells, ECG, echocardiography, right heart catheterization with pressure measurement in the right atrium, right ventricle, and also in the trunk of the pulmonary artery. When conducting catheterization of the right heart, it is also advisable to determine the pulmonary capillary pressure or the wedge pressure of the pulmonary artery, reflecting the level of pressure in the left atrium. Pulmonary artery wedge pressure increases in patients with heart disease and left ventricular failure.

To identify the causes of pulmonary hypertension, it is often necessary to use other methods of investigation, such as x-ray and computed tomography of the lungs, ventilation and perfusion radionuclide scintigraphy of the lungs, and angiopulmonography. Using these methods allows you to determine the pathology of the parenchyma and vascular system of the lungs. In some cases, it is necessary to resort to lung biopsy (for the diagnosis of diffuse interstitial lung diseases, pulmonary veno-occlusive disease, pulmonary capillary granulomatosis, etc.).

In the clinical picture of the pulmonary heart, hypertensive crises can be observed in the pulmonary artery system. The main clinical manifestations of the crisis:

• sharp suffocation (most often appears in the evening or at night);
• severe cough, sometimes with sputum mixed with blood;
• orthopnea;
• pronounced general cyanosis;
• excitement is possible;
• pulse frequent, weak;
• pronounced pulsation a.pulmonalis in the second intercostal space;
• bulging of the a.pulmonalis cone (with percussion, it is manifested by an expansion of vascular dullness in the second intercostal space on the left);
• pulsation of the right ventricle in the epigastrium;
• accent II tone on a.pulmonalis;
• swelling and pulsation of the neck veins;
• the appearance of vegetative reactions in the form of urina spastica (the release of a large number of light urine with low density), involuntary defecation after the end of the crisis;
• the appearance of the Plesch reflex (hepatic jugular reflex).

The diagnosis of "primary pulmonary hypertension" is suspected in patients with significant shortness of breath with exertion in the absence of other diseases in history, capable of causing pulmonary hypertension.

Patients initially perform chest radiography, spirometry and ECG to identify more frequent causes of shortness of breath, then a doppler echocardiography is performed to measure pressure in the right ventricle and pulmonary arteries, and to identify possible anatomical anomalies that cause secondary pulmonary hypertension.

The most frequent X-ray findings in primary pulmonary hypertension are the expansion of the roots of the lungs with a pronounced narrowing to the periphery (“chopped off”). Spirometry and lung volumes may be normal or show a moderate limitation, but the diffusion capacity of carbon monoxide (DL) usually decreases. General ECG changes include the deviation of the electrical axis to the right, R> S to V; SQ T and peak teeth P.

Additional studies are performed to diagnose secondary causes that are not clinically apparent. These include perfusion-vent scan for thromboembolic disease; lung function tests to identify obstructive or restrictive lung diseases and serological tests to confirm or exclude rheumatic diseases. Chronic thromboembolic pulmonary arterial hypertension is suggested by CT scan or pulmonary scan, and is diagnosed by arteriography. Other studies, such as an HIV test, liver function tests, and polysomnography, are performed in appropriate clinical situations.

If the initial examination does not reveal any conditions associated with secondary pulmonary hypertension, a pulmonary artery catheterization is required, which is necessary to measure pressure in the right heart and pulmonary arteries, wedge pressure in the pulmonary capillaries, and cardiac output. In order to eliminate the defect of the interatrial septum, it is necessary to measure the saturation of O ₂ blood in the right sections. Primary pulmonary hypertension is defined as the average pressure in the pulmonary artery over 25 mmHg. Art. In the absence of possible reasons. However, most patients with primary pulmonary hypertension have significantly higher pressure (for example, 60 mmHg). During the procedure, vasodilating drugs are often used (for example, inhaled nitric oxide, intravenous epoprostenol, adenosine); reducing the pressure in the right sections in response to these drugs helps in the choice of drugs for treatment. Previously widely used biopsy, but due to the high frequency of complications and mortality is currently not recommended.

If the patient is diagnosed with primary pulmonary hypertension, his family history is examined to identify possible genetic transmission, indicated by cases of premature death of relatively healthy people in the family. In cases of familial primary pulmonary hypertension, genetic counseling is necessary to inform family members about the risk of the disease (approximately 20%) and recommend them to be examined (echocardiography). In the future, a test for BMPR2 mutations in familial primary pulmonary hypertension may be important.

[23], [24], [25]

Treatment of the pulmonary hypertension

Treatment of secondary pulmonary hypertension is aimed at treating the underlying pathology. Patients with severe pulmonary arterial hypertension due to chronic thromboembolism should undergo pulmonary thromboendarteriectomy. This is a more complicated operation than emergency surgical embolectomy. Under extrapulmonary circulation, an organized vascular thrombus is excised along the pulmonary trunk. This procedure cures pulmonary arterial hypertension in a significant percentage of cases and restores extrapulmonary function; in specialized centers, operational mortality is less than 10%.

Treatment of primary pulmonary hypertension is developing rapidly. It starts with oral calcium channel blockers, and when they are used, the pressure in the pulmonary artery or the pulmonary resistance of the vessels can be reduced in approximately 10-15% of patients. There are no differences in efficacy between different types of calcium channel blockers, although most experts avoid verapamil due to its negative inotropic effects. The response to this therapy is a favorable prognostic sign, and patients should continue this treatment. If there is no response to treatment, other drugs are prescribed.

Intravenous epoprostenol (a prostacyclin analog) improves function and increases survival even in patients resistant to vasodilators during catheterization. Disadvantages of treatment include the need for a permanent central catheter and significant undesirable effects, including hot flashes, diarrhea, and bacteremia due to the prolonged location of the central catheter. Alternative drugs - inhalation (iloprost), oral (beraprost) and subcutaneous (treprostinil) prostacyclin analogues - are under study.

Oral antagonist of endothelin receptor bosentan is also effective in some patients, usually with a milder disease and not sensitive to vasodilators. Sildenafil oral and L-arginine are also at the research stage.

Forecast

Lung transplantation  offers the only hope for a cure, but carries a high risk of complications due to problems of rejection and infection. Five-year survival rate is 60% due to bronchiolitis obliterans. Lung transplantation is prescribed to patients with heart failure degree IV according to the classification of the New York Heart Association (defined as shortness of breath with minimal activity, leading to involuntary staying in a bed or chair), which prostacycpine analogues do not help.

Many patients require additional medications for the treatment of heart failure, including diuretics, and they must also receive warfarin to prevent thromboembolism.

The median survival of patients without treatment is 2.5 years. The cause is usually sudden death due to right ventricular failure. The five-year survival rate for epoprostenol treatment is 54%, while a minority of patients who respond to calcium channel blockers exceed 90%.

Pulmonary hypertension has an unfavorable prognosis if symptoms such as low cardiac output, higher pressure in the pulmonary artery and right atrium, lack of response to vasodilators, heart failure, hypoxemia, and deterioration in overall functional status are present.

[26], [27], [28]