A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART DISEASE: THE KEY STAGES OF DIAGNOSIS




Zhuravlyova L.V., Filonenko M.V., Lopina N.I.
A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART
DISEASE: THE KEY STAGES OF DIAGNOSIS
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Zhuravlyova L.V., Filonenko M.V., Lopina N.I.
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A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART DISEASE: THE KEY STAGES OF DIAGNOSIS
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Abstract
Despite the progress achieved in the development of new directions in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, it remains one of the most severe and prognostically unfavorable diseases. The article presents a clinical case and an algorithm for diagnosis of this rare disease, in respect to the decisionmaking in clinical practice. The present case underscores the need to consider a broad differential diagnosis for marked dyspnea in mature patients, especially when the intensity of dyspnea is out of proportion to the severity of underlying heart or lung diseases, or when symptoms fail to subside as expected in response to conventional therapy. Early diagnosis of idiopathic pulmonary arterial hypertension is vitally important for initiating modern therapy in order to improve the quality and duration of life in such patients.
Keywords: pulmonary hypertension; right ventricle failure; right heart catheterization; calcium channel blockers; modern targeted therapy.

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Introduction. The term idiopathic pulmonary arterial hypertension (IPAH) was used for the first time in 1951 by Dresdale. This clinical condition is characterized by the presence of pre-capillary PH, in the absence of other causes of pre-capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases [1]. IPAH corresponds to sporadic disease; the lowest estimates of its prevalence are 5.9 cases/ million in the adult population. IPAH affects women two times more often than men. The mean age of diagnosis making is 35 years. The disease has no family history of PH or known triggering factor [2]. However, specific gene mutations have been identified in such patients, including the bone morphogenetic protein receptor 2 gene, the activin receptorlike kinase type-1 gene and the endoglin gene [3, 4]. It is a severe chronic disease with an unfavorable prognosis. The symptoms of IPAH are caused by developing RV hypertrophy and failure. They are usually non-specific and include breathlessness, fatigue, weakness, angina, syncope, and abdominal distension. In advanced cases symptoms such as jugular vein distension, hepatomegaly, peripheral oedema, and ascites might occur [5, 6]. In untreated patients with IPAH or heritable PAH, historical data showed a median survival of 6 months for WHO-FC (World Health Organization -Functional Class) IV, 2.5 years for WHO-FC III, and 6 years for WHO-fC I and II. The most common causes of death are terminal right ventricle failure and cardiac arrest [7].
Case report. The case patient, a 47-year-old man checked into Kharkiv Regional Hospital with marked dyspnea during minimal physical activity (walking up to 70 m, climbing half flight of stairs), paroxysms of nocturnal dyspnea, tachycardia, chest pain, fatigue, and episodical increases of blood pressure. Symptoms were typically absent at rest.
The described above symptoms of disease are nonspecific and may correspond to multiple clinical conditions, capable of provoking
significant dyspnea, including heart diseases (systolic dysfunction, diastolic dysfunction, and valvular disease), lung diseases (chronic obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, etc), systemic disorders, tumoral obstruction, connective tissue diseases and many others. Differential diagnosis is difficult.
In 1988 the patient noticed increased blood pressure (BP) up to 160/100 mm Hg for the first time. His general condition was satisfactory, and therefore the man didnt seek any medical advice. Beginning in 2000 he began to experience undue dyspnea, chest pain and fatigue during ordinary physical activity. At this point, he started to take antihypertensive drugs episodically, only during significant increases of BP. In 2009 he suffered from myocardial infarction and was treated properly at a specialized regional center. Since the beginning of 2011 the patient has been experiencing significant deterioration of his general condition: marked limitation of physical activity due to progressive dyspnea, fatigue, angina as well as episodes of tachycardia, and unstable BP. The patient is comfortable at rest, but sometimes has paroxysmal nocturnal dyspnea. Due to the severity of his condition, the patient was admitted to a local hospital with the diagnosis of coronary artery disease and arterial hypertension; however, there was no improvement as a result of treatment. In the beginning of 2012 the patient had a few episodes near syncope in addition to the previously mentioned complaints. He was hospitalized in a specialized regional center for additional diagnostic procedures and amendments of treatment.
As we know, the most common known causes for dyspnea are left side heart disease and lung diseases. At a first glance, the patients medical history suggests a diagnosis of left side heart failure due to ischemic heart disease and arterial hypertension (especially when taking into consideration myocardial infarction



Zhuravlyova L.V., Filonenko M.V., Lopina N.I.
A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART
DISEASE: THE KEY STAGES OF DIAGNOSIS
in 2009). However, the first manifestation of undue dyspnea refers to 2000, when the patient was quite young and didnt have any symptoms other than rare moderate elevations of blood pressure. Besides, the ineffectiveness of in-hospital treatment for coronary artery disease in 2011 is a sufficient reason to recheck the patients physical status.
The physical examination revealed left parasternal lift, an accentuated pulmonary component of second heart sound, a pansystolic murmur of tricuspid regurgitation, a diastolic murmur of pulmonary insufficiency, and a right ventricle third sound. His blood pressure was 120/80 mm Hg, and his heartbeat rate was 102 beats per minute. The patients lung sounds were normal, and his respiratory rate was 20 breaths per minute. Hepatomegaly was found, with no signs of ascites. A slight oedema of ankles and legs was revealed. His extremities were cool, especially wrists. His skin and mucosa were normal color. His BMI was 26,2 kg/m2.
According to the physical examination the patient has typical signs of pulmonary hypertension (PH), including signs of right ventricle overload, relative insufficiency of the tricuspid valve and increased blood pressure in the pulmonary artery. There is slight tachycardia and breathlessness. Hepatic congestion suggests further examinations to check the condition of his kidneys. Normal lung sounds assume the absence of chronic obstructive pulmonary disease, however further examinations should be performed to confirm this statement.
An electrocardiogram upon admission showed sinus rhythm, a heart rate of 96 beats per minute, right bundle-branch block, left posterior hemiblock, right venrticle hypertrophy and strain, and right atrial dilatation. The findings of the chest radiograph included central pulmonary arterial dilatation in contrast to the pruning of the peripheral blood vessels, an enlarged right atrium and right ventricle. Transthoracic echocardiography confirmed the presence of marked dilatation of the right
heartchambers(end-systolic dimensionof right atrium 78 mm, lateromedial measurement; end-diastolic dimension of right ventricle 55 mm, short axis parasternal view) as well as dilation of pulmonary artery trunk (40 mm). The systolic pulmonary artery pressure was 101 mm Hg. There was fourth grade tricuspid regurgitation, and the gradient of regurgitation was 86 mmHg. Concerning the left heart chambers, a moderate enlargement of the left atrium (end-systolic dimension 56 mm, anteroposterior measurement), and normal sizes of the left ventricle were revealed; the ejection fraction was 66% and systolic output was 52 ml. The thickness of the interventricular septum was 18 mm. Hypokinetic motion of the posterobasal segment of the left ventricle was detected. There were no signs of systolic dysfunction. No remarkable changes of the mitral and aortic valves were found, and there were no signs of pericardial effusion.
The results of the coronarography show initial signs of atherosclerosis in both the left and right coronary arteries without significant derangements of haemodynamics. As confirmed by clinical findings, the patient has pronounced PH, complicated by right heart dilatation and right bundle-branch block. A few factors favoring a diagnosis of left ventricular diastolic dysfunction in the presence of PH can be found in this patient: hypertension, coronary artery disease, left atrial enlargement, and left ventricle hypertrophy (mainly the interventricular septum). However, the ejection fraction and systolic output are normal. Coronary arteries are almost intact. The PH seems to be out of proportion to the severity of left side heart disease in this particular patient. The other causes for PH, starting with lung diseases, should be looked for. As chest X-ray didnt show any remarkable changes in the lungs, other noninvasive methods should be applied to assess lung structure and function.
Pulmonary function tests showed moderate reduction of FEV and FVC1. High-resolution computed tomography showed pronounced dilatation of the pulmonary artery
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trunk as well as main, lobar and segmental arteries, and tortuosity of the arteries (Figure 1). The structure of the lungs and airways was normal; no signs of interstitial lung disease and emphysema were found. No signs of pulmonary embolism were detected.
The mild to moderate reduction of lung volume is typical for PH. It can also be seen in patients with chronic obstructive pulmonary disease, asthma, and other pulmonary diseases with mixed restrictive and obstructive patterns. As the patient didnt have symptoms, signs or history of chronic lung diseases and no pathognomonic findings were revealed by additional assessment, the diagnosis of lung disease as a possible cause for PH was rejected.
Laboratory studies revealed a red blood cell count of 5.31012 per cubic liter (normal range, 4.0 to 5.1), hemoglobin 168 grams per liter (normal range, 130 to 160), hematocrit 50.1%, and the erythrocyte sedimentation rate 29 mm per hour. Serum chemical profiles were notable for a blood urea level of 11.6 mmol per liter (normal range, 3.3 to 6.6), and serum uric acid 428 mmol per liter (normal range, 208 to 420).
It is not surprising to observe a secondary erythrocytosis in patients with pronounced PH. A compensatory mechanism of increased red cell production is being launched by hypoxia in case of heart failure. Increased levels of blood urea and uric acid in the presence of unremarkable urine analysis suggest the presence of kidney congestion as the aftermath of congestive heart failure. Serum uric acid is also a marker of an impaired oxidative metabolism in the ischaemic peripheral tissue. High uric acid levels are known to relate to poor survival in patients with PH.
We performed a ventilation/perfusion lung scan in order to look for segmental perfusion defects as markers of less common diseases capable of provoking PH development.
The normal results of this scan helped us to exclude chronic thromboembolic pulmonary hypertension, pulmonary veno-occlusive disease,
and pulmonary capillary haemangiomatosis as possible causes for the PH.
Next, we considered the possibility of other uncommon causes of PH, starting with pulmonary artery hypertension, and a decision to perform right heart catheterization (RHC) was made.
The data obtained by the RHC included: systolic pulmonary artery pressure = 92 mm Hg, diastolic pulmonary artery pressure = 35 mm Hg, mean pulmonary artery pressure (mPAP) = 52 mmHg, pulmonary wedge pressure (PWP) = 13 mm Hg, right atrial pressure = 18 mm, and cardiac output = 5.2 liters per minute. Pulmonary vascular resistance = 4.1 Wood Units. A vasoreactivity test with adenosine revealed a drop in mPAP of 16 mm Hg to the level of 36 mm Hg.
According to the findings of the RHC, the patient has pre-capillary PH. This statement fully denies the probability of PH as the result of left side heart disease. The good news is that the patient is a positive acute responder due to the results of the vasoreactivity test, so he may benefit from long-term therapy with calcium channel blockers (CCBs). A positive test is more often observed in patients with pulmonary artery hypertension (PAH): idiopathic or anorexigen associated. Nevertheless, other rare reasons for PAH should be considered.
When looking at connective tissue disease as a possible cause of PAH we were mainly concerned with systemic sclerosis, as it is the most common systemic disease PAH is associated with. As the patient was complaining of cold wrists, especially when exposed to a cold environment, and physical examination also revealed that they were pale and cold as a result of palpation, we suspected the presence of Raynauds phenomenon, which can be one of the symptoms of systemic sclerosis.
An antinuclear antibody test and an anticentromere antibody test were both negative. A nailfold capillaroscopy test was normal. Thermography with cold challenge showed a slight lowering of all indexes.



Zhuravlyova L.V., Filonenko M.V., Lopina N.I.
A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART
DISEASE: THE KEY STAGES OF DIAGNOSIS
Limited cutaneous systemic sclerosis (LCSS) may have slow onset and symptoms may be relatively unnoticed until internal complications occur. An anti-centromere antibody test seen almost only in patients with LCSS was essential for our patient, because it is associated with increased risk of PH. As the patient didnt have any other clinical signs of systemic sclerosis, autoantibody tests were negative, and the nailfold capillaroscopy test was normal, we diagnosed primary Raynauds phenomenon. However, the origin of PAH still needed to be specified.
The patient reported no history suggestive of HIV or hepatitis. The history was supported by the negative results of serological testing. There were no physical signs or echocardiographic confirmation of congenital heart disease. History, physical examination and laboratory data revealed no signs of chronic hemolysis and shistosomiasis. Thyroid function test showed normal levels of thyroid hormones.
History of the patients exposure to drugs and toxins known to induce PAH was carefully collected. The patient had never take anorexigens, selective serotonin reuptake inhibitors, phenylpropanolamine, cocaine, pergolide or amphetamines.
As the result of our investigation, the differential diagnosis had narrowed to two possible causes for PAH: idiopathic or heritable PAH. The patient reported no family history of PAH. Therefore, the only remaining diagnosis in this case was idiopathic PAH.
IPAH remains a chronic disease without a cure. However, modern drug therapy leads to a significant improvement in patients symptoms and a slower rate of clinical deterioration [8, 9]. The management of IPAH in patients with comorbid coronary artery disease (CAD) is even more difficult. We followed the guidelines of the European Society of Cardiology and American Heart Association concerning the treatment of PH in our case patient [10, 11, 12].
As we know, only approximately 10% of patients with IPAH can be defined as positive acute responders by the results of RHC. Such patients are most likely to show a sustained response to long-term treatment with high doses of CCBs and they are the only patients that can safely be treated with this type of therapy [13]. Our patient was lucky to be one of them. The presence of relative tachycardia (100-110 beats per minute) favored the prescription of diltiazem (480 mg daily) for our patient. The heartbeat rate reduced to 90 beats per minute after 1 week of treatment and didnt show further dynamics. Adding 7.5 mg of ivabradine twice daily decreased the heart rate to 68-74 beats per minute. Also, a modern targeted IPAH treatment was started: 2.5 mcg of iloprost inhaled 6 times daily. In few days jaw pain developed as a side effect, but it didnt require the termination of therapy. Other components of therapy were: 2,5 mg of warfarin once daily under the control of the international normalized ratio to prevent thrombotic events, and 12,5 mg of captopril three times daily to enhance blood pressure control. The followup done in 3 months showed an increase in exercise capacity according to a 6-minute walking test (300m in comparison to 120m at the beginning of therapy) and improvement in clinical symptoms. The B-type natriuretic peptide level was still moderately elevated, but lower than at the beginning of therapy. As the result of treatment the severity of pulmonary hypertension in our patient changed from the III to the II functional class according to WHO (1998) [14].
Conclusion. The present case underscores the need to consider a broad differential diagnosisformarkeddyspneainmaturepatients, especially when the intensity of dyspnea is out of proportion to the severity of underlying heart or lung diseases, or when symptoms fail to subside as expected in response to conventional therapy. Early diagnosis of IPAH is vitally important for initiating modern therapy in order to improve the quality and duration
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of life in such patients. As a result of the treatment, the significant clinical improvement was achieved in the patient, including reduced severity of symptoms, enhanced tolerance to physical exercise according to the 6-minute walk test, reduced functional class of heart failure and improved prognosis.
References:
1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119:2250-2294.
2. Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. Cleve Clin J Med 2003; 70 Suppl 1:2-8.
3. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737-744.
4. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37:741-745.
5. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:55-66.
6. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010; 137:376-387.
7. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36:549-555.
8. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:78-84.
9. Heresi GA, Heresi RA, Dweik A. 2007. Pulmonary hypertension: evaluation and management. Compr Ther 33(3):150-161.
10. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30:2493-2537.
11. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219-1263.
12. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114:1417-1431.
13. Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 2010; 104:481-496.
14. Rich S. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998, Evian, France. World Health Organization 1998.
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1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119:2250-2294.



Zhuravlyova L.V., Filonenko M.V., Lopina N.I.
A CLINICAL CASE OF IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IN PATIENT WITH COMORBID ISCHEMIC HEART
DISEASE: THE KEY STAGES OF DIAGNOSIS
2. Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. Cleve Clin J Med 2003; 70 Suppl 1:2-8.
3. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737-744.
4. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37:741-745.
5. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:55-66.
6. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010; 137:376-387.
7. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36:549-555.
8. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:78-84.
9. Heresi GA, Heresi RA, Dweik A. 2007. Pulmonary hypertension: evaluation and management. Compr Ther 33(3):150-161.
10. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493-2537.
11. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219-1263.
12. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006; 114:1417-1431.
13. Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 2010; 104:481-496.
14. Rich S. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998, Evian, France. World Health Organization 1998.
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DATA ABOUT THE AUTHORS
Zhuravlyova Larysa Vladimirovna,
Chief of the Department of Internal Medicine N3, Doctor of Medical Science, Professor. Kharkov National Medical University, 4, Lenina ave, Kharkov, 61000, Ukraine
e-mail: l.zhuravlyova@mail.ru Filonenko Maryna Vyacheslavovna,
Assistant of the Department of Internal Medicine N3, Candidate of Medical Science.
Kharkov National Medical University, 4, Lenina ave, Kharkov, 61000, Ukraine e-mail: filmarina@rambler.ru Lopina Natalia,
doctor, Cardiological Department of Kharkiv Regional Hospital, 13, Pravdy ave,
Kharkov, 61023, Ukraine e-mail: alamajor@yandex.ua
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Figure 1. High-resolution computed tomography showing pronounced dilatation of the pulmonary artery trunk as well as main, lobar and segmental arteries, and tortuosity of the arteries