PPH is a disorder intrinsic to the pulmonary vascular bed that is characterized by sustained eleirations in PA pressure and vascular resistance that generally lead to right ventricular (RV) failure and death. The diagnosis of PPH requires the exclusion on clinical grounds of other conditions that can result in PAH. PPH cases are not uncommon in India.
The clinical diagnosis of PPH rests on three different types of evidence:
1) Clinical, radiographic, and electrocardiographic manifestations of PAH.
2) Hernodynamic features consisting of abnormally high PA pressure and pulmonary vascular resistance in association witR normal left-sided filling pressures and a normal or low cardiac output.
3) Exclusion of other causes of secondary PAH.
Etiology
There is injury to the layers of the vascular wall of the small muscular pulmonary arteries and arterioles followed by intimal proliferation of the media and hypertrophy of the affected vessels.The exact cause of PPH remains elusive. Ingestion of weight reducing dlvgs like fenfluranline and its isomer dexfenfluramine has been demonstrated to markedly increase the risk of PPH. Other conditions like ingestion of toxic oil, .HIV infection,even in the absence of the acquired immune deficiency syndrome can also produce picture like PPH. Auto immune vasculitis is also postulated as one of the etiological factor.
ClinicaI Features
After puberty, females predominate, those between 10 and 40 years of age being most often affected. Before puberty, no sex difference is discernible. The characteristic picture of a patient with PPH is that of a young woman in the prime of life who develops one or more of the symptoms described in Table 11 without discernible cause. Sex and age are sometimes useful in distinguishing clinically between the likelihood of PPH and pulmonary thromboembolic disease. The latter generally favors men, particularly in their later years.
In its early stages, the disease is difficult to recognize. In the sporadic case, the first clue is often an abnormal chest radiograph or ECG indicative of RVH. Both are late manifestations. The existence of RV enlargement is generally confilmed by echocardiography.' By the time these changes appear, however, PAH is moderate to severe. Lnitial complaints, particularly easy fatigability and dyspnea are often ignored.When the disease is advanced, the activities of daily life are progressively circumscribed by increasing no specific discomfort. Dyspnea, particularly during physical activity, becomes incapacitating. Some patients develop an angina type of chest paill along with breathlessness. Other common symptoms are weakness, fatigue,and exertional or post exertional syncope. Infrequently, an enlarged pulmonary arterycauses hoarseness because of compression of the left recurrent laryngeal nerve. In time, right-sided heart failure develops.Patients with severe PAH seem prone to sudden death. Death has occurred unexpectedly during normal activities, cardiac catheterization, surgical procedures and after the administration of barbiturates or anesthetic agents.
On physical examination, (he jugular venous pulse usually shows a prominent a wave.RVH causes a heave along the left sternal border, and a distinct systolic impulse is palpable over the region of the main pulmonary artety. The pulmonic component of the second sound is markedly accentuated, the second heart sound is narrowly split,and an ejection click is heard in the pulmonic asea. Often a fourth heart sound emanating from the hypertrophied right ventricle is heard at the lower left steinal border. The murmur of bicuspid regurgitation is best heard along the sternal border with the patient in the supine position and can be accentuated with inspiration. In some patients, a mid systolic murmur is audible at the pulmonic area; as PA pressures approximate systemic arterial levels, the murmur of pulmonary valvular regurgitation often appears.
The onset of RV failure is accompanied by jugular venous distention and a gallop (S3); inspiration intensifies the gallop. The liver becomes enlarged and tender, and hepatojugular reflux can be elicited. Hydrothorax and ascites are seen as RV failure progresses.
Investigations
Chest Radiography and Electrocardiography
In the early stages, the chest radiograph is generally normal. Later it shows cardiac enlargement in association with enlargement of the pulmonary tnink, while the peripheral pulmonary arterial branches are attenuated; the lung fields appear oligemic.Radiographic evidence of RV enlargement usually becomes overt only late in the course of the pulmonary hypertension. Figure shows chest X- ray in a patient with PPH where significant dilatation of main and right pulmonary artery is evident.The ECG almost always shows RAD, RVH, and usually RAE (qR pattern). It is very common to find ST segment depression in anterior and inferior leads indicating light ventricular ischemia.
Echocardiography
Two dimensional echocardiography confirms the enlargement and hypestrophy of the right atrium, ventricle and pulmonary arteries. At the same time, other secondary caused of PAH are excluded. The magnitude of the velocity of the tricuspid regurgitant jet using Doppler techniques can provide a noninvasive estimate of PA pressure. Doppler technique reliably demoilstrates pulmonzuy and tiicuspjd incompetence frequently seen in advanced cases.
Ventihtion Perfusion Lung Scans
Lung scans are particularly helpful in excluding the possibility of large, long standing organized clots in the major pulmonary arteries that may be amenable to surgical removal (thromboendarterectamy). The lung scan in PPH fails to disclose inajor perfusion defects. CTPA is needed lo exclude pulmonary emboli in cases where the scan is equivocal.
Right Heart Catheterization
Cardiac catheterization is rarely needed in the current era of echocardiography and other non-invasive techniques which often provide complete diagnosis. In fact cardiac catherization should be avoided as it can rarely cause death.Cardiac catheterization in today's date is indicated only in advanced institutions for performing therapeutic atiial septostomy, for drug testing and prior to lung transplantation.
Management
Despite several advances over the years, the treatment of PPH remains unsatisfactory.There have been several agents which have been utilized for reducing PA pressure.
Vasodilator Agents
Vasodilator drugs were used in the hope that an increase in pullnonary vascular tone contributed importantly to the high PA pressures. Unfortunately, the use of vasodilators, which could affect the systemic as well as the pulmonary circulation were often acconlpanied by uildesirable side effects and led to disenchantment.Various agents have been tiied over the years as pulmonary vasodilators. These include - adrenergic antagonists, adrenergic agonists, diazoxide, hydralazine, nitrates,calcium blockers and ~ g i o t e n s i n converting enzyme inhibitors. In general, these have not with stood the rest of time. Experience has laught that untoward reaction can occur with any pulmonary vasodilator, even when low doses are used. Despite the disappointments, three categories of agents [calcium channel blocking agenls,arachidonic acid metabolites, and nitric oxide (NO)] continue to hold promise.
Arachidonic Acid Metabolites
Arachidonic acid metabolites epoprostenol, a metabolite of arachidon;~ acid is currently being tried in some studies. It is attractive for the treatment of PPH on vasodilator, (2) it inhibits platelet aggregation, several accounts: (1) it is a p~~lnlonary and (3) it inhinits proliferation of vascular smooth muscle. Unfortunately, it suffers the disadvantage of requiring continuous intravenous infusion, which is cui-rently being done using portable pumps. This is an extremely expensive treatment and is no! available in our country. Analogues that can be given orally, subcutaneously, or by the inhaled route are under investigation. Success in long-term management recently have been reported using aerosolized iloprost, a stable prostacyclin analogue. Currently, its most effective use is for long-term management in patients with severe (NYHA classes TI1 or IV) PPH who are unresponsive to or'are not candidates for therapy with calcium channel blockers.
Phasphodiestrase (PDE) Inhibitors
Sidenafil has been shown to be useful in PPH and reduces PA pressure significantly in some patients. Early reports with its clinical use are encouraging.
Ailticoagulation
Oral anticoagulation with warfarin or other agent should be used in patients of PPH and an INR of 2-2.5 should be maintained. This practice is supported by the high incidence of clots found at autopsy in the small pulmonary arteries and arterioles of patients with PPH. In addition, the advent of RV failure increases the prosperity for clotting in the pulmonary circulation and favours the use of oral anticoagulation.
Digoxin and Diuretics
Diuretics are often required in patient who developed RVF and systemic congestion. Digoxin is often utilized in similar situation but is of debatable value.
AMal Septosto~ny
Blade balloon septostomy has been performed in patients with severe RV pressur'e and volume overload refractory to maximal medical therapy. The goal of this approach is to decompress the overloaded right heart and improve systemic output of the under filled left venl~icle. h p r o ~ e m e n t s in exercise functjon and signs of severe right sided heart dysfunction such as syncope and ascites have been observed.
Lung Transplantation
Lung transplantation is tun-ently being done at specialized centers and is almost invariably handicapped by a shorlage of donor lungs, which can lead to long delays,Single - or double - lung transplantation has largely replaced heait-lung transplantation Often, hernodynamic impr,ovemenl is dramatic, but transplantation for p p poses not only a considerable surgical risk but also the prospect of opportunistic infections that accompanies life long immunosuppression.
Prognosis
ppH c a ~ i e a s poor prognosis. Alt110~1gh dcath usually occurs within a few years after the onset of symptoms, instances of long-lenn survival do occur. Although sudden death accounts for 10 to 15 per cent of all PPH-related deaths, the prognosis is largely determined by the severity of PAI-I arid right sided heart dysfunction.The median survival of patients according to New York Heart Association functional classification is 6 months for class lV, 2 1/2 years for class 111, and 6 years for classes I and 11.
The clinical diagnosis of PPH rests on three different types of evidence:
1) Clinical, radiographic, and electrocardiographic manifestations of PAH.
2) Hernodynamic features consisting of abnormally high PA pressure and pulmonary vascular resistance in association witR normal left-sided filling pressures and a normal or low cardiac output.
3) Exclusion of other causes of secondary PAH.
Etiology
There is injury to the layers of the vascular wall of the small muscular pulmonary arteries and arterioles followed by intimal proliferation of the media and hypertrophy of the affected vessels.The exact cause of PPH remains elusive. Ingestion of weight reducing dlvgs like fenfluranline and its isomer dexfenfluramine has been demonstrated to markedly increase the risk of PPH. Other conditions like ingestion of toxic oil, .HIV infection,even in the absence of the acquired immune deficiency syndrome can also produce picture like PPH. Auto immune vasculitis is also postulated as one of the etiological factor.
ClinicaI Features
After puberty, females predominate, those between 10 and 40 years of age being most often affected. Before puberty, no sex difference is discernible. The characteristic picture of a patient with PPH is that of a young woman in the prime of life who develops one or more of the symptoms described in Table 11 without discernible cause. Sex and age are sometimes useful in distinguishing clinically between the likelihood of PPH and pulmonary thromboembolic disease. The latter generally favors men, particularly in their later years.
In its early stages, the disease is difficult to recognize. In the sporadic case, the first clue is often an abnormal chest radiograph or ECG indicative of RVH. Both are late manifestations. The existence of RV enlargement is generally confilmed by echocardiography.' By the time these changes appear, however, PAH is moderate to severe. Lnitial complaints, particularly easy fatigability and dyspnea are often ignored.When the disease is advanced, the activities of daily life are progressively circumscribed by increasing no specific discomfort. Dyspnea, particularly during physical activity, becomes incapacitating. Some patients develop an angina type of chest paill along with breathlessness. Other common symptoms are weakness, fatigue,and exertional or post exertional syncope. Infrequently, an enlarged pulmonary arterycauses hoarseness because of compression of the left recurrent laryngeal nerve. In time, right-sided heart failure develops.Patients with severe PAH seem prone to sudden death. Death has occurred unexpectedly during normal activities, cardiac catheterization, surgical procedures and after the administration of barbiturates or anesthetic agents.
On physical examination, (he jugular venous pulse usually shows a prominent a wave.RVH causes a heave along the left sternal border, and a distinct systolic impulse is palpable over the region of the main pulmonary artety. The pulmonic component of the second sound is markedly accentuated, the second heart sound is narrowly split,and an ejection click is heard in the pulmonic asea. Often a fourth heart sound emanating from the hypertrophied right ventricle is heard at the lower left steinal border. The murmur of bicuspid regurgitation is best heard along the sternal border with the patient in the supine position and can be accentuated with inspiration. In some patients, a mid systolic murmur is audible at the pulmonic area; as PA pressures approximate systemic arterial levels, the murmur of pulmonary valvular regurgitation often appears.
The onset of RV failure is accompanied by jugular venous distention and a gallop (S3); inspiration intensifies the gallop. The liver becomes enlarged and tender, and hepatojugular reflux can be elicited. Hydrothorax and ascites are seen as RV failure progresses.
Investigations
Chest Radiography and Electrocardiography
In the early stages, the chest radiograph is generally normal. Later it shows cardiac enlargement in association with enlargement of the pulmonary tnink, while the peripheral pulmonary arterial branches are attenuated; the lung fields appear oligemic.Radiographic evidence of RV enlargement usually becomes overt only late in the course of the pulmonary hypertension. Figure shows chest X- ray in a patient with PPH where significant dilatation of main and right pulmonary artery is evident.The ECG almost always shows RAD, RVH, and usually RAE (qR pattern). It is very common to find ST segment depression in anterior and inferior leads indicating light ventricular ischemia.
Echocardiography
Two dimensional echocardiography confirms the enlargement and hypestrophy of the right atrium, ventricle and pulmonary arteries. At the same time, other secondary caused of PAH are excluded. The magnitude of the velocity of the tricuspid regurgitant jet using Doppler techniques can provide a noninvasive estimate of PA pressure. Doppler technique reliably demoilstrates pulmonzuy and tiicuspjd incompetence frequently seen in advanced cases.
Ventihtion Perfusion Lung Scans
Lung scans are particularly helpful in excluding the possibility of large, long standing organized clots in the major pulmonary arteries that may be amenable to surgical removal (thromboendarterectamy). The lung scan in PPH fails to disclose inajor perfusion defects. CTPA is needed lo exclude pulmonary emboli in cases where the scan is equivocal.
Right Heart Catheterization
Cardiac catheterization is rarely needed in the current era of echocardiography and other non-invasive techniques which often provide complete diagnosis. In fact cardiac catherization should be avoided as it can rarely cause death.Cardiac catheterization in today's date is indicated only in advanced institutions for performing therapeutic atiial septostomy, for drug testing and prior to lung transplantation.
Management
Despite several advances over the years, the treatment of PPH remains unsatisfactory.There have been several agents which have been utilized for reducing PA pressure.
Vasodilator Agents
Vasodilator drugs were used in the hope that an increase in pullnonary vascular tone contributed importantly to the high PA pressures. Unfortunately, the use of vasodilators, which could affect the systemic as well as the pulmonary circulation were often acconlpanied by uildesirable side effects and led to disenchantment.Various agents have been tiied over the years as pulmonary vasodilators. These include - adrenergic antagonists, adrenergic agonists, diazoxide, hydralazine, nitrates,calcium blockers and ~ g i o t e n s i n converting enzyme inhibitors. In general, these have not with stood the rest of time. Experience has laught that untoward reaction can occur with any pulmonary vasodilator, even when low doses are used. Despite the disappointments, three categories of agents [calcium channel blocking agenls,arachidonic acid metabolites, and nitric oxide (NO)] continue to hold promise.
Arachidonic Acid Metabolites
Arachidonic acid metabolites epoprostenol, a metabolite of arachidon;~ acid is currently being tried in some studies. It is attractive for the treatment of PPH on vasodilator, (2) it inhibits platelet aggregation, several accounts: (1) it is a p~~lnlonary and (3) it inhinits proliferation of vascular smooth muscle. Unfortunately, it suffers the disadvantage of requiring continuous intravenous infusion, which is cui-rently being done using portable pumps. This is an extremely expensive treatment and is no! available in our country. Analogues that can be given orally, subcutaneously, or by the inhaled route are under investigation. Success in long-term management recently have been reported using aerosolized iloprost, a stable prostacyclin analogue. Currently, its most effective use is for long-term management in patients with severe (NYHA classes TI1 or IV) PPH who are unresponsive to or'are not candidates for therapy with calcium channel blockers.
Phasphodiestrase (PDE) Inhibitors
Sidenafil has been shown to be useful in PPH and reduces PA pressure significantly in some patients. Early reports with its clinical use are encouraging.
Ailticoagulation
Oral anticoagulation with warfarin or other agent should be used in patients of PPH and an INR of 2-2.5 should be maintained. This practice is supported by the high incidence of clots found at autopsy in the small pulmonary arteries and arterioles of patients with PPH. In addition, the advent of RV failure increases the prosperity for clotting in the pulmonary circulation and favours the use of oral anticoagulation.
Digoxin and Diuretics
Diuretics are often required in patient who developed RVF and systemic congestion. Digoxin is often utilized in similar situation but is of debatable value.
AMal Septosto~ny
Blade balloon septostomy has been performed in patients with severe RV pressur'e and volume overload refractory to maximal medical therapy. The goal of this approach is to decompress the overloaded right heart and improve systemic output of the under filled left venl~icle. h p r o ~ e m e n t s in exercise functjon and signs of severe right sided heart dysfunction such as syncope and ascites have been observed.
Lung Transplantation
Lung transplantation is tun-ently being done at specialized centers and is almost invariably handicapped by a shorlage of donor lungs, which can lead to long delays,Single - or double - lung transplantation has largely replaced heait-lung transplantation Often, hernodynamic impr,ovemenl is dramatic, but transplantation for p p poses not only a considerable surgical risk but also the prospect of opportunistic infections that accompanies life long immunosuppression.
Prognosis
ppH c a ~ i e a s poor prognosis. Alt110~1gh dcath usually occurs within a few years after the onset of symptoms, instances of long-lenn survival do occur. Although sudden death accounts for 10 to 15 per cent of all PPH-related deaths, the prognosis is largely determined by the severity of PAI-I arid right sided heart dysfunction.The median survival of patients according to New York Heart Association functional classification is 6 months for class lV, 2 1/2 years for class 111, and 6 years for classes I and 11.
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