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Pulmonary Hypertension and Right Heart Failure in Patients With β-Thalassemia Intermedia
Pulmonary Hypertension and Right Heart Failure in Patients With {3- Thalassemia lntermedia* Athanassios Aessopos, MD; Georgios Stamatelos, MD; Vassilios Skoumas, MD; Georgios Vassilopoulos, MD; Marina Mantzourani, MD; and Dimitris Loukopoulos, MD We analyzed seven patients with ,8-thalassemia intermedia presenting with congestive heart failure secondary to pulmonary hypertension. This condition has been recognized only recently as part of the clinical spectrum of ,8-thalassemia. Our group of patients included two men and five women with the clinical picture and laboratory data typical of ,8-thalassemia intermedia. The mean age was 37.7 ± 11.4 years, mean hematocrit value was 28.5 ± 1.8%, mean number of transfused blood units was 171 ± 153, and mean serum ferritin levels were 4,428 ± 2,006 ng/ mL. All but one of these patients had undergone splenectomy. Common findings of the investigative procedures include the following: dilatation of the main pulmonary artery and cardiac enlargement in the chest radiograph; signs of right ventricular hypertrophy in the ECG; and dilated right ventricle with good left ventricular function in the echo study. Right heart catheterization showed the pulmonary systolic pressure
to range from 55 to 90 mm Hg (74.1 ± 10.3), pulmonary diastolic pressure from 25 to 50 mm Hg (37. 7 ± 8. 7), mean pressure from 35 to 60 mm Hg (49.7 ± 7.9), and pulmonary vascular resistance from 267 to 667 dynes • s • cm- 5• Pulmonary capillary wedge pressure was within the normal range of values. The pathophysiologic condition of pulmonary hypertension in these patients is most probably associated with,B-thalassemia. There are mechanisms that increase cardiac output and at the same time restrict the pulmonary vascular bed. The results of this study imply that treatment decisions should be reconsidered for such patients. (Chest 1995; 107:50-53)
/-l-thalassemia (/3-thal) are a group of genetically fJ inherited hemoglobin disorders characterized by chronic hemolytic anemia of variable severity. The genetic heterogeneity of this disorder results in a wide spectrum of clinical phenotypes that may vary from mild chronic hemolysis to a severe transfusiondependent hemolytic anemia.l The most common complications are related to iron overload, secondary to the overtransfusion regimen that most treatment centers follow today. The heart is the main site where iron deposition causes life-threatening problems.2 Among these problems are left-sided cardiac failure, cardiac arrhythmias, and pericarditis. An uncommon finding that we describe in this study is right-sided cardiac failure secondary to pulmonary hypertension.
patients with !3-thal who are receiving regular follow-up at the cardiology outpatient clinic, a service provided by the First Department of Medicine, University Hospital of Athens (Greece). The patients, two men and five women, ranged in age from 26 to 62 years (Table 1). All of them had commenced blood transfusions after age 5 years and their mean hematocrit (Hct) values were 28.5 ± 1.8%. The total number of blood units that they had received prior to their inclusion in this study ranged from lO to 430 (171 ± 153). Iron chelation therapy had not, as a rule, been performed optimally and serum ferritin levels above 1,500 ng/mL were measured in all of them (4,430±2,000). With the exception of patient 1, all had undergone splenectomy. The peripheral blood showed high numbers of erythroblasts and platelets while results of their liver function tests were out of normal range. According to their medical histories, all had reported some kind of pulmonary infection. Patients 2 and 5 are smoking mildly (1 and 2.5 pack-years, respectively).
MATERIALS AND METHODS
We investigated the clinical and laboratory data of seven patients with !3-thal intermedia who developed right heart failure and pulmonary hypertension. This group is a part of the group of
*From the First Department of Medicine, University of Athens, Laiko General Hospital, Athens, Greece. Manuscript received December 28, 1993; revision accepted April 18, 1994 Reprint requests: Dr. Aessopos, 17 AG Thoma Str. , Athens 11527 Greece
50
!3-thal=P-thalassemia; Hb=hemoglobin; PCWP=pulmonary capillary wedge pressure; RBBB=right bundle branch block
Key words: /)-thalassemia; pulmonary hypertension ; right heart
RESULTS
Signs and symptoms of congestive heart failure were present in all: fatigue, dyspnea, peripheral edema mainly in the feet and ankles, prominent jugular veins, and profound liver enlargement (about 12 em below the right costal margin) . The nonsplenectomized individual had significant splenomegaly (15 em below the left costal margin). All patients had warm extremities. Heart examination revealed vivid parasternal impulse, gallop rhythm, loud second heart sound over the pulmonary valve, and an ejection murmur of variable intensity heard over the left
Pulmonary Hypertension and Right Heart Failure in IJ-Thalassemia lntermedia (Aessopos eta/)
Table !-Patient Characteristics: Hematologic Data* Case No.
Sex Age, yr Transfusion onset, age, yr TBTU Chelation therapy , yr Serum ferritin , ng/ mL Splenectom y, age, yr Mean Hct value, % Erythroblasts, / mm 3 Platelets, / mm 3 PT, s SGOT-SGPT, U/ L ALP, U/ L -y-globulins, g/ dL
M 62 40 350 5 4,000 No 25 85,000 19 85-54 352 1.95
2
3
F 26 12 430 6 8,500 12 28 15,500 595,000 18.5 110-55 380 3.57
F 41 24 140 5,300 27 27 60,000 87,600 20.5 91-45 402 2.52
4
5
6
F 39 23 10
M 38 23 50
F 32 7 20
4,500 33 30 5,625 443,000 19 69-40 348 3.65
1,500 27 30 53,000 618,000 18.5 64-73 335 1.82
7 F 26 5 200 4 4,200 9 30 337,000 410,000 18.5 68-43 372 2.11
3,000 9 30 80,000 611,000 19.5 78-56 405 3.05
*TBTU=total blood transfusions units; PT=prothrombin time; ALP=alkaline phosphatase. Normal limits: PTcontrol, 12 s; SCOT, <27U / L; SGPT, <30U / L; ALP, 49-306 U/ L; -y-globulins, 0.70-1.50 gr/ dL.
fourth and fifth intercostal space at the parasternal border or over the cardiac apex. Common findings on the chest radiograph were cardiomegaly, dilatation of the main pulmonary artery , and widening of the ribs. The presence of pleural fluid was found in patients 1, 2, and 3, while thoracic sites of extramedullary erythropoiesis were noted in patient 3 (Table 2) . The ECG showed evi-
dence of right ventricular hypertrophy. All but one of the patients had tall R waves in V1 while right bundle branch block (RBBB) and right axis deviation were present in all. Echocardiographic studies (Mmode, 2D) showed right ventricular dilatation and good left ventricle function. Patients 1, 4, 5, 6, and 7 had a dilated left atrium. Right heart catheterization (Table 3) showed pul-
Table 2-Radiographic, Electrocardiographic (ECG), and Echocardiographic (U/ S) Data* Case No.
Chest radiograph Cardiomegaly Prominent pulomonary artery Rib enlargement Pleural effusion Extramedullary hemopoietic sites
+ + + +
2
3
4
5
6
7
+ + + +
+ + + + +
+ + +
+ + +
+ + +
+ + +
ECG
Heart U/ S (M-mode, 2D) RVD, em LVEDD, em LVESD, em SF, % IVS, em PWT, em LAD, em ARD, em PE
Normal Valuesf 0.9-2.6 3.5-5.7 2.6-3.6 >30 0.6-l.l 0.6-l.l 1.9-4.0 2.0-3.7
RBBB lAD DeepS Vs V6 bradyarrhythmia
RBBB RAD Tall R, VI
RBBB RAD Tall R, V1
RBBB VAD Tall R, V1
RBBB RAD Tall R, VI
RBBB VAD Tall R, Vt
RBBB RAD Tall R, Vt
4 5 3 40 1.0 0.93 5 4 Small
4 4 1.7 57.5 0.83 0.80 3.8 2.6 No
3.7 4.8 2.4 50 0.94 0.90 3.8 3.1 Small
3.3 5.4 2.8 48 0.90 0.85 4.1 3 No
3.5 5.8 2.8 51 1.10
2.9 5 3. 1 38 0.90 0.80 4.1 3.2 No
4 4.2 2.2 47 0.83 0.80 3.4 3 Small
4.2 3.2 No
*RBBB=right bundle branch block; RAD=right axis deviation; IAD=indefinable axis deviation; VAD= vertical axis deviation; RVD=right ventricle diameter; LVEDD=left ventricle end-diastolic diameter; LVESD=left ventricle end-systolic diameter; SF=shortening fraction; IVS=interventricular septum thickness; PWT=posterior wall thickness; LAD=left atrial diameter; ARD=aortic root diameter; PE=pericardial effusion. fSee reference 12. CHEST / 107 / 1 I JANUARY, 1995
51
Table 3-Right Heart Catheterization: Pulmonary Function Tests* Case No.
Right heart catheterization RAP M, mm Hg RYP S/ D, mm Hg PAP S/ D M, mm Hg PAWP / M, mm Hg CO, L/ min CI, L/ min/ m 2 PYR, dynes • s • em-s Arterial blood gases pH Po2 Pco2 HC03 Spirometry YC, Lit (% of predicted) F EY 1 (% of predicted ) FEYd YC X 100%
Normal valuesf 2-8 15-30/ 2-8 15-30/ 4-12/ 9-18 2-12 5-6 2.6-4. 2 20-103
1
2
3
4
5
6
7
15 80/ 15 80/ 25/ 43 17 7.80 5.03 267
20 70/ 20 70/ 40/ 50 18 3.63 2.60 705
10 90/ 14 90/ 40/ 57 Unsuccessful 3.90 2.70
5 57/ 8 55/ 25/ 35 5 7.90 6.30 304
8 70/ 13 68/ 40/ 49 10 8.30 4.51 376
10 75/ 12 75/ 44/ 54 12 6.20 4.33 542
18 81 / 20 81 / 50/ 60 10 6 4.28 667
7.36 49 41. 8 23.8
7.41 66.1 37 23.5
7.37 59.6 41.2 23.3
7.43 71.7 38.4 25.3
7.41 55.1 39.4 24.5
37.3 21.1
7.44 77 33 22.5
1.10 (30) 0.88 (34) 80
1.12 (29) 0.95 (28) 84.5
1.05 (25.3) 0.90 (26.3) 85.8
2.57 (75 ) 2.03 (72) 79
2.40 (44.5 ) 1.65 (36.3) 68.8
2.95 (78.5) 2.30 (71.7) 78
2.92 (75 8) 2.15 (63.8) 73.6
7.37 71
*RAP=right atrial pressure; RYP=right ventricular pressure; PAP=pulmonary artery pressure; PAWP=pulmonary artery wedge pressure; CO=cardiac output; CI= cardiac index; PYR=pulmonary vascular resistance; S=systolic; D=diastolic; M= mean; YC = vital capacity; FEY 1 =forced expiratory volum e in 1 s. f See reference 13.
monary systolic pressure to range from 55 to 90 mm Hg (74.1 ± 10.3), pulmonary diastolic pressure from 25 to 50 mm Hg (37.7 ± 8.7), and mean systolic pressure from 35 to 60 mm Hg (49.7 ± 7.9) , while pulmonary capillary wedge pressure (PCWP) was within normal limits (<15 mm Hg). In case 3, PCWP could not be measured because of the extremely high pressures in the pulmonary artery. There was no oxygen step-up in the right ventricle. Pulmonary vascular resistance was found to be high in all patients (from 267 to 667 dynes • s • cm- 5 ). All our patients, with the exception of cases 2 and 3, were in a state of high cardiac output, as calculated by thermodilution technique. Pulmonary function tests showed a restrictive syndrome, while arterial blood gas (ABC) values indicated highly variable hypoxia. Characteristic findings of chest radiograph and ECG of patient 7 are shown in Figures 1 and 2, respectively.
lecular level can affect both hemoglobin (Hb) production and Hb function, while on the other hand, treatment decisions regarding transfusion rate, desired Hb level, and iron chelation therapy can all alter the clinical picture of the patients. Our sample consists of rather old patients with ,8-thal living on low Hb levels, who had received a varying number of blood transfusions with minimal iron chelation therapy and high ferritin levels. In such cases,
DISCUSSION
Cardiovascular complications, and most notably congestive heart failure resulting from dilatation and decreased left ventricular function, are the most common cause of death in patients with ,B-thai.3 Pulmonary hypertension is a clinical picture less commonly reported, although our preliminary findings and some evidence from the literature 4 suggest that it requires further investigation. The wide spectrum of clinical manifestations of ,8-thal mostly depend on the following two general factors: on the one hand, heterogeneity at the mo52
l. Chest radiograph of patient 7 showing main pulmonary artery bulging, widening of the ribs, and diffuse osteoporotic lesions. FIGURE
Pulmonary Hypertension and Right Heart Failure in tl-Thalassemia lntermedia (Aessopos eta/)
FIGURE 2. ECG of patient 7 showing signs of right ventricular hypertrophy.
pulmonary hypertension is most probably a late complication of a certain {J-thal clinical picture. Both pulmonary vascular resistance and cardiac output can be affected, resulting in an elevated pressure in the pulmonary vascular bed. Factors that affect pulmonary vascular resistance by restricting the pulmonary vascular bed include chronic pulmonary hemosiderosis, peculiar formation of the chest, recurrent respiratory tract infections, and the presence of extramedullary sites of hemopoiesis in the thoracic cavity. Similar vascular injury may be precipated from a transient increase of PCWP, due to systolic and/ or diastolic5 dysfunction during effort, although resting PCWP was measured as normal. The low Po 2 values noted in all our patients (including the nonsplenectomized individual) could per se also effect vasoconstriction and increase the vascular resistance.O Hypoxia has also been reported in a group of splenectomized patients with compound heterozygote {J-thal/ HbE and was attributed to the presence of thromboembolic lesions and myeloid elements found in the lungs.7•8 Finally, liver fibrosis and functional impairment, as described in our patients, may also lead to restriction of the pulmonary vascular bed, either through emboli generated in the portal vein and bypassing the liver or through circulating vasoconstrictive substances that fail to detoxify in the liver. 9 High cardiac output in patients with {J-thal is a compensatory mechanism to a number of factors. Anemia, low Poz, altered oxygen delivery from abnormal Hb, and low 2,3DPG in transfused blood results in tissue hypoxia that requires a state of high cardiac output. Likewise, bone marrow expansion, spleen enlargement, 10 and liver fibrosis 11 result in the development of shunts with an analogous effect on heart function. High cardiac output increases the pulmonary pressure in patients with a constricted pulmonary vascular bed and aggravates the vascular injury. The persistence of high cardiac output in our group suggests that this is an important factor in the
establishment of pulmonary hypertension. Apparently, pulmonary hypertension is a multifactorial disorder in which different factors may prevail in every single patient. The treatment of patients with {J-thal intermedia is still a matter of controversy. The conservative strategy is to start transfusions only after the patient has been on a low Hb level for a long time. This strategy inevitably leads to the development of considerable bone marrow expansion and spleen enlargement, resulting in a high cardiac output state. When associated with vascular lesions in the lungs, this will in turn lead to pulmonary hypertension. It is therefore important to select, according to clinical and laboratory data, those patients with {J-thal intermedia who should receive transfusions and iron chelation therapy early in life. This will protect the patients both from significant bone deformities and from the development of high cardiac output. For patients who already present with pulmonary hypertension, like those in our sample, keeping the Hb level close to normal should be part of the treatment. Further clinical trials are required to clarify this issue. The prescription of antithrombotic agents (aspirin, dipyridamole) for patients who have undergone splenectomy has also been recommended .
REFERENCES
1 Kazazian HH Jr. The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Semin Hematol1990; 27:209-28 2 Fosburg M, Nathan D. Treatment of Cooley's anemia. Blood 1990; 76:435-44 3 Zurlo MG, DeStefanoP, Borgna-Pignatti C. Survival and causes of death in thalassaemia major. Lancet 1989; 2:27-30 4 Grisaru D , Rachmilewitz EA, Mosseri M, Gotsman M, et al. Cardiopulmonary assessment in Beta-thalassemia major. Chest 1990; 98:1138-42 5 Spirito P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation 1990; 82:88-94 6 Braunwald E. Heart disease, 3rd ed. Philadelphia: WB Saunders, 1988; 795 7 Sonakul D, Pacharee P, Laohapand T, Fucharoen S, Wasi P. Pulmonary artery obstruction in thalassemia. Southeast Asian J Trop Med Public Health 1980; 11:516-23 8 Fucharoen S, Youngchaiyud P, Wasi P. Hypoxaemia and the effect of aspirin in thalassemia. Southeast J Trop Med Public Health 1981 ; 12:90-3 9 Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension; analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coli Cardiol1991; 17:492-98 10 Garnet ES, Goddard BA, Markby D, Webber CE. The spleen as an arteriovenous shunt. Lancet 1969; 1:386-88 11 Braunwald E. Heart disease, 3rd ed. Philadelphia: WB Saunders, 1988; 789 12 Feigenbaum H. Echocardiography, 4th ed. Philadelphia: Lea & Febiger, 1986 13 Grossman W. Cardiac catheterization and angiography. 2nd ed. Philadelphia: Lea & Febiger, 1980 CHEST / 107 / 1 / JANUARY, 1995
53
to range from 55 to 90 mm Hg (74.1 ± 10.3), pulmonary diastolic pressure from 25 to 50 mm Hg (37. 7 ± 8. 7), mean pressure from 35 to 60 mm Hg (49.7 ± 7.9), and pulmonary vascular resistance from 267 to 667 dynes • s • cm- 5• Pulmonary capillary wedge pressure was within the normal range of values. The pathophysiologic condition of pulmonary hypertension in these patients is most probably associated with,B-thalassemia. There are mechanisms that increase cardiac output and at the same time restrict the pulmonary vascular bed. The results of this study imply that treatment decisions should be reconsidered for such patients. (Chest 1995; 107:50-53)
/-l-thalassemia (/3-thal) are a group of genetically fJ inherited hemoglobin disorders characterized by chronic hemolytic anemia of variable severity. The genetic heterogeneity of this disorder results in a wide spectrum of clinical phenotypes that may vary from mild chronic hemolysis to a severe transfusiondependent hemolytic anemia.l The most common complications are related to iron overload, secondary to the overtransfusion regimen that most treatment centers follow today. The heart is the main site where iron deposition causes life-threatening problems.2 Among these problems are left-sided cardiac failure, cardiac arrhythmias, and pericarditis. An uncommon finding that we describe in this study is right-sided cardiac failure secondary to pulmonary hypertension.
patients with !3-thal who are receiving regular follow-up at the cardiology outpatient clinic, a service provided by the First Department of Medicine, University Hospital of Athens (Greece). The patients, two men and five women, ranged in age from 26 to 62 years (Table 1). All of them had commenced blood transfusions after age 5 years and their mean hematocrit (Hct) values were 28.5 ± 1.8%. The total number of blood units that they had received prior to their inclusion in this study ranged from lO to 430 (171 ± 153). Iron chelation therapy had not, as a rule, been performed optimally and serum ferritin levels above 1,500 ng/mL were measured in all of them (4,430±2,000). With the exception of patient 1, all had undergone splenectomy. The peripheral blood showed high numbers of erythroblasts and platelets while results of their liver function tests were out of normal range. According to their medical histories, all had reported some kind of pulmonary infection. Patients 2 and 5 are smoking mildly (1 and 2.5 pack-years, respectively).
MATERIALS AND METHODS
We investigated the clinical and laboratory data of seven patients with !3-thal intermedia who developed right heart failure and pulmonary hypertension. This group is a part of the group of
*From the First Department of Medicine, University of Athens, Laiko General Hospital, Athens, Greece. Manuscript received December 28, 1993; revision accepted April 18, 1994 Reprint requests: Dr. Aessopos, 17 AG Thoma Str. , Athens 11527 Greece
50
!3-thal=P-thalassemia; Hb=hemoglobin; PCWP=pulmonary capillary wedge pressure; RBBB=right bundle branch block
Key words: /)-thalassemia; pulmonary hypertension ; right heart
RESULTS
Signs and symptoms of congestive heart failure were present in all: fatigue, dyspnea, peripheral edema mainly in the feet and ankles, prominent jugular veins, and profound liver enlargement (about 12 em below the right costal margin) . The nonsplenectomized individual had significant splenomegaly (15 em below the left costal margin). All patients had warm extremities. Heart examination revealed vivid parasternal impulse, gallop rhythm, loud second heart sound over the pulmonary valve, and an ejection murmur of variable intensity heard over the left
Pulmonary Hypertension and Right Heart Failure in IJ-Thalassemia lntermedia (Aessopos eta/)
Table !-Patient Characteristics: Hematologic Data* Case No.
Sex Age, yr Transfusion onset, age, yr TBTU Chelation therapy , yr Serum ferritin , ng/ mL Splenectom y, age, yr Mean Hct value, % Erythroblasts, / mm 3 Platelets, / mm 3 PT, s SGOT-SGPT, U/ L ALP, U/ L -y-globulins, g/ dL
M 62 40 350 5 4,000 No 25 85,000 19 85-54 352 1.95
2
3
F 26 12 430 6 8,500 12 28 15,500 595,000 18.5 110-55 380 3.57
F 41 24 140 5,300 27 27 60,000 87,600 20.5 91-45 402 2.52
4
5
6
F 39 23 10
M 38 23 50
F 32 7 20
4,500 33 30 5,625 443,000 19 69-40 348 3.65
1,500 27 30 53,000 618,000 18.5 64-73 335 1.82
7 F 26 5 200 4 4,200 9 30 337,000 410,000 18.5 68-43 372 2.11
3,000 9 30 80,000 611,000 19.5 78-56 405 3.05
*TBTU=total blood transfusions units; PT=prothrombin time; ALP=alkaline phosphatase. Normal limits: PTcontrol, 12 s; SCOT, <27U / L; SGPT, <30U / L; ALP, 49-306 U/ L; -y-globulins, 0.70-1.50 gr/ dL.
fourth and fifth intercostal space at the parasternal border or over the cardiac apex. Common findings on the chest radiograph were cardiomegaly, dilatation of the main pulmonary artery , and widening of the ribs. The presence of pleural fluid was found in patients 1, 2, and 3, while thoracic sites of extramedullary erythropoiesis were noted in patient 3 (Table 2) . The ECG showed evi-
dence of right ventricular hypertrophy. All but one of the patients had tall R waves in V1 while right bundle branch block (RBBB) and right axis deviation were present in all. Echocardiographic studies (Mmode, 2D) showed right ventricular dilatation and good left ventricle function. Patients 1, 4, 5, 6, and 7 had a dilated left atrium. Right heart catheterization (Table 3) showed pul-
Table 2-Radiographic, Electrocardiographic (ECG), and Echocardiographic (U/ S) Data* Case No.
Chest radiograph Cardiomegaly Prominent pulomonary artery Rib enlargement Pleural effusion Extramedullary hemopoietic sites
+ + + +
2
3
4
5
6
7
+ + + +
+ + + + +
+ + +
+ + +
+ + +
+ + +
ECG
Heart U/ S (M-mode, 2D) RVD, em LVEDD, em LVESD, em SF, % IVS, em PWT, em LAD, em ARD, em PE
Normal Valuesf 0.9-2.6 3.5-5.7 2.6-3.6 >30 0.6-l.l 0.6-l.l 1.9-4.0 2.0-3.7
RBBB lAD DeepS Vs V6 bradyarrhythmia
RBBB RAD Tall R, VI
RBBB RAD Tall R, V1
RBBB VAD Tall R, V1
RBBB RAD Tall R, VI
RBBB VAD Tall R, Vt
RBBB RAD Tall R, Vt
4 5 3 40 1.0 0.93 5 4 Small
4 4 1.7 57.5 0.83 0.80 3.8 2.6 No
3.7 4.8 2.4 50 0.94 0.90 3.8 3.1 Small
3.3 5.4 2.8 48 0.90 0.85 4.1 3 No
3.5 5.8 2.8 51 1.10
2.9 5 3. 1 38 0.90 0.80 4.1 3.2 No
4 4.2 2.2 47 0.83 0.80 3.4 3 Small
4.2 3.2 No
*RBBB=right bundle branch block; RAD=right axis deviation; IAD=indefinable axis deviation; VAD= vertical axis deviation; RVD=right ventricle diameter; LVEDD=left ventricle end-diastolic diameter; LVESD=left ventricle end-systolic diameter; SF=shortening fraction; IVS=interventricular septum thickness; PWT=posterior wall thickness; LAD=left atrial diameter; ARD=aortic root diameter; PE=pericardial effusion. fSee reference 12. CHEST / 107 / 1 I JANUARY, 1995
51
Table 3-Right Heart Catheterization: Pulmonary Function Tests* Case No.
Right heart catheterization RAP M, mm Hg RYP S/ D, mm Hg PAP S/ D M, mm Hg PAWP / M, mm Hg CO, L/ min CI, L/ min/ m 2 PYR, dynes • s • em-s Arterial blood gases pH Po2 Pco2 HC03 Spirometry YC, Lit (% of predicted) F EY 1 (% of predicted ) FEYd YC X 100%
Normal valuesf 2-8 15-30/ 2-8 15-30/ 4-12/ 9-18 2-12 5-6 2.6-4. 2 20-103
1
2
3
4
5
6
7
15 80/ 15 80/ 25/ 43 17 7.80 5.03 267
20 70/ 20 70/ 40/ 50 18 3.63 2.60 705
10 90/ 14 90/ 40/ 57 Unsuccessful 3.90 2.70
5 57/ 8 55/ 25/ 35 5 7.90 6.30 304
8 70/ 13 68/ 40/ 49 10 8.30 4.51 376
10 75/ 12 75/ 44/ 54 12 6.20 4.33 542
18 81 / 20 81 / 50/ 60 10 6 4.28 667
7.36 49 41. 8 23.8
7.41 66.1 37 23.5
7.37 59.6 41.2 23.3
7.43 71.7 38.4 25.3
7.41 55.1 39.4 24.5
37.3 21.1
7.44 77 33 22.5
1.10 (30) 0.88 (34) 80
1.12 (29) 0.95 (28) 84.5
1.05 (25.3) 0.90 (26.3) 85.8
2.57 (75 ) 2.03 (72) 79
2.40 (44.5 ) 1.65 (36.3) 68.8
2.95 (78.5) 2.30 (71.7) 78
2.92 (75 8) 2.15 (63.8) 73.6
7.37 71
*RAP=right atrial pressure; RYP=right ventricular pressure; PAP=pulmonary artery pressure; PAWP=pulmonary artery wedge pressure; CO=cardiac output; CI= cardiac index; PYR=pulmonary vascular resistance; S=systolic; D=diastolic; M= mean; YC = vital capacity; FEY 1 =forced expiratory volum e in 1 s. f See reference 13.
monary systolic pressure to range from 55 to 90 mm Hg (74.1 ± 10.3), pulmonary diastolic pressure from 25 to 50 mm Hg (37.7 ± 8.7), and mean systolic pressure from 35 to 60 mm Hg (49.7 ± 7.9) , while pulmonary capillary wedge pressure (PCWP) was within normal limits (<15 mm Hg). In case 3, PCWP could not be measured because of the extremely high pressures in the pulmonary artery. There was no oxygen step-up in the right ventricle. Pulmonary vascular resistance was found to be high in all patients (from 267 to 667 dynes • s • cm- 5 ). All our patients, with the exception of cases 2 and 3, were in a state of high cardiac output, as calculated by thermodilution technique. Pulmonary function tests showed a restrictive syndrome, while arterial blood gas (ABC) values indicated highly variable hypoxia. Characteristic findings of chest radiograph and ECG of patient 7 are shown in Figures 1 and 2, respectively.
lecular level can affect both hemoglobin (Hb) production and Hb function, while on the other hand, treatment decisions regarding transfusion rate, desired Hb level, and iron chelation therapy can all alter the clinical picture of the patients. Our sample consists of rather old patients with ,8-thal living on low Hb levels, who had received a varying number of blood transfusions with minimal iron chelation therapy and high ferritin levels. In such cases,
DISCUSSION
Cardiovascular complications, and most notably congestive heart failure resulting from dilatation and decreased left ventricular function, are the most common cause of death in patients with ,B-thai.3 Pulmonary hypertension is a clinical picture less commonly reported, although our preliminary findings and some evidence from the literature 4 suggest that it requires further investigation. The wide spectrum of clinical manifestations of ,8-thal mostly depend on the following two general factors: on the one hand, heterogeneity at the mo52
l. Chest radiograph of patient 7 showing main pulmonary artery bulging, widening of the ribs, and diffuse osteoporotic lesions. FIGURE
Pulmonary Hypertension and Right Heart Failure in tl-Thalassemia lntermedia (Aessopos eta/)
FIGURE 2. ECG of patient 7 showing signs of right ventricular hypertrophy.
pulmonary hypertension is most probably a late complication of a certain {J-thal clinical picture. Both pulmonary vascular resistance and cardiac output can be affected, resulting in an elevated pressure in the pulmonary vascular bed. Factors that affect pulmonary vascular resistance by restricting the pulmonary vascular bed include chronic pulmonary hemosiderosis, peculiar formation of the chest, recurrent respiratory tract infections, and the presence of extramedullary sites of hemopoiesis in the thoracic cavity. Similar vascular injury may be precipated from a transient increase of PCWP, due to systolic and/ or diastolic5 dysfunction during effort, although resting PCWP was measured as normal. The low Po 2 values noted in all our patients (including the nonsplenectomized individual) could per se also effect vasoconstriction and increase the vascular resistance.O Hypoxia has also been reported in a group of splenectomized patients with compound heterozygote {J-thal/ HbE and was attributed to the presence of thromboembolic lesions and myeloid elements found in the lungs.7•8 Finally, liver fibrosis and functional impairment, as described in our patients, may also lead to restriction of the pulmonary vascular bed, either through emboli generated in the portal vein and bypassing the liver or through circulating vasoconstrictive substances that fail to detoxify in the liver. 9 High cardiac output in patients with {J-thal is a compensatory mechanism to a number of factors. Anemia, low Poz, altered oxygen delivery from abnormal Hb, and low 2,3DPG in transfused blood results in tissue hypoxia that requires a state of high cardiac output. Likewise, bone marrow expansion, spleen enlargement, 10 and liver fibrosis 11 result in the development of shunts with an analogous effect on heart function. High cardiac output increases the pulmonary pressure in patients with a constricted pulmonary vascular bed and aggravates the vascular injury. The persistence of high cardiac output in our group suggests that this is an important factor in the
establishment of pulmonary hypertension. Apparently, pulmonary hypertension is a multifactorial disorder in which different factors may prevail in every single patient. The treatment of patients with {J-thal intermedia is still a matter of controversy. The conservative strategy is to start transfusions only after the patient has been on a low Hb level for a long time. This strategy inevitably leads to the development of considerable bone marrow expansion and spleen enlargement, resulting in a high cardiac output state. When associated with vascular lesions in the lungs, this will in turn lead to pulmonary hypertension. It is therefore important to select, according to clinical and laboratory data, those patients with {J-thal intermedia who should receive transfusions and iron chelation therapy early in life. This will protect the patients both from significant bone deformities and from the development of high cardiac output. For patients who already present with pulmonary hypertension, like those in our sample, keeping the Hb level close to normal should be part of the treatment. Further clinical trials are required to clarify this issue. The prescription of antithrombotic agents (aspirin, dipyridamole) for patients who have undergone splenectomy has also been recommended .
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