Careful monitoring of disease progression is vital to ensuring that patients with pulmonary arterial hypertension receive maximal therapy before the onset of overt right-sided heart failure. Routine follow-up includes the evaluation of symptoms, functional class, and exercise capacity and assessment of pulmonary pressures and right ventricular (RV) function. Transthoracic echocardiography (TTE) offers a noninvasive and fairly reliable technique for monitoring pulmonary artery pressure (PAP) and structural changes of the right side of the heart. However, TTE does not reliably assess cardiac output, right-sided filling pressures, or pulmonary venous pressure. Pulmonary artery catheterization may be particularly useful in patients who have inconsistent findings, such as a reduction in PAP measured by TTE in the presence of worsening symptoms or other signs of disease progression. An increase in RV end-diastolic pressure, usually above 10 mm Hg, is a concern and warrants consideration of additional therapy even if other hemodynamic and clinical parameters are unchanged. (J Respir Dis. 2009;30(1-2)
ABSTRACT: Careful monitoring of disease progression is vital to ensuring that patients with pulmonary arterial hypertension receive maximal therapy before the onset of overt right-sided heart failure. Routine follow-up includes the evaluation of symptoms, functional class, and exercise capacity and assessment of pulmonary pressures and right ventricular (RV) function. Transthoracic echocardiography (TTE) offers a noninvasive and fairly reliable technique for monitoring pulmonary artery pressure (PAP) and structural changes of the right side of the heart. However, TTE does not reliably assess cardiac output, right-sided filling pressures, or pulmonary venous pressure. Pulmonary artery catheterization may be particularly useful in patients who have inconsistent findings, such as a reduction in PAP measured by TTE in the presence of worsening symptoms or other signs of disease progression. An increase in RV end-diastolic pressure, usually above 10 mm Hg, is a concern and warrants consideration of additional therapy even if other hemodynamic and clinical parameters are unchanged.
Pulmonary arterial hypertension (PAH) is a disease of the pulmonary arterial tree that results in progressive remodeling and obliteration of the small pulmonary arterioles leading to right ventricular (RV) failure and usually death.1 Although the disease may affect anyone, it is more common in women and often affects young, otherwise healthy persons.2
The devastating effects that PAH has on function and survival have led to an intensive research effort during the past 25 years that has provided intriguing insight into numerous cellular and molecular pathways that are important in pulmonary vascular remodeling. One of the greatest accomplishments has been the identification of a single genetic defect that appears to be present in nearly half of all sporadic cases of PAH and in almost three-quarters of familial cases, providing hope that one day a cure for this tragic disease may be found.3-5
In the meantime, therapies have been developed that slow disease progression and improve survival. Several reviews describing the safety and efficacy of available therapies have proposed treatment algorithms that guide drug selection on the basis of patient characteristics and disease severity (Figure 1).6-8 Implicit in these treatment protocols is the idea that patients should be closely monitored for response to therapy and that therapy should become more aggressive if there is evidence of disease progression.
Footnote to figure 1:a Strength of ACCP recommendation: A, strong; B, moderate; C, weak; E/A, strong based on expert opinion only; E/B, moderate based on expert opinion only; E/C, weak based on expert opinion only.
b In patients in World Health Organization functional class II or III, oral therapy can be started with an endothelin receptor antagonist or a phosphodiesterase inhibitor. Patients in a more advanced functional class may require prostacyclin or combination therapy. Patients who present with or progress to the worst functional class (class IV) should be given intravenous prostacyclin infusion.
c Not in order of preference.
PAH, pulmonary arterial hypertension; IPAH, idiopathic PAH; ACCP, American College of Chest Physicians.
Adapted from Badesch DB et al. Chest. 2007.7
The purpose of this 2-part article is to review the currently available methods for assessing disease severity in patients with PAH and monitoring patient response to therapy. Despite important therapeutic advances, PAH remains an incurable disease and few patients will experience normalization of pulmonary hemodynamics or exercise function. Thus, early identification of disease progression is vital in maximizing patient response to therapy.
Pulmonary hypertension is defined as increased pressure in the arterial side of the pulmonary circulation. Normally, the pulmonary circulation is a low-pressure, high-flow vascular bed. Marked increases in blood flow that occur during strenuous exercise are accommodated by vasodilation and the recruitment of underfilled vessels, resulting in a fall in pulmonary vascular resistance (PVR) and little rise in pulmonary artery pressure (PAP). Similarly, the right ventricle is a highly compliant, low-pressure pump that is well designed for accommodating large increases in right-sided filling volumes but is intolerant of sudden increases in afterload.
Elevation of PAP in PAH is the result of increased pulmonary vascular tone and extensive remodeling of pulmonary arteries and arterioles.9 Structural and functional changes of the pulmonary arterial circulation result in significant reduction of the total pulmonary vascular luminal area and loss of the normal vasodilatory responses to increased flow. The PAP and PVR are elevated at rest and rise further during exercise. As RV afterload increases, RV systolic function declines, the right ventricle dilates, and cardiac output begins to fall (Figure 2). Patients begin to have clinical manifestations of right-sided heart failure and become progressively more intolerant of exercise.
Figure 2 – The hemodynamic changes associated with disease progression in patients with pulmonary arterial hypertension are illustrated here. Pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) rise while patients are asymptomatic. Further elevation in resistance causes symptoms of exercise limitation, but cardiac output (CO) at rest is maintained. In the final stages, PAP may fall even as PVR increases as a result of declining right-sided heart function. The fall in right ventricular systolic function and CO is often heralded by a rise in right ventricular end-diastolic pressure and right atrial pressure (RAP). (Adapted from Hill NS. In: Hill NS, ed. Pulmonary Hypertension Therapy. 2006.28)
Medical therapy for PAH in the United States currently consists of 3 classes of drugs: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Three different prostanoid preparations are available, which allows treatment to be administered by continuous intravenous or subcutaneous infusion or intermittent inhalation (Table 1). Two endothelin receptor antagonists are available. Bosentan, which is a nonselective endothelin receptor antagonist, has similar affinity for both endothelin A-type (ETA) and B-type receptors, whereas ambrisentan is highly selective for ETA. Sildenafil and, more recently, the longer-acting tadalafil are the phosphodiesterase type 5 inhibitors approved for the treatment of PAH.
No large randomized clinical trials have compared the efficacy or safety of any class of drug with that of another. However, the clinical experience of most practitioners is that endothelin receptor antagonists and phosphodiesterase type 5 inhibitors have similar efficacy and that continuous prostanoid infusion is superior to either. The strong sentiment among practitioners who treat patients who have PAH that prostanoid infusion therapy is superior to oral therapy with either an endothelin receptor antagonist or a phosphodiesterase type 5 inhibitor is demonstrated by algorithms published by several professional societies to guide the treatment of PAH.6-8 These guidelines recommend that patients with early PAH who have minimal to moderate symptoms without right-sided heart failure be given oral therapy with either an endothelin receptor antagonist or a phosphodiesterase type 5 inhibitor or inhaled prostacyclin. Patients who present with or who progress to the worst functional class are treated with intravenous prostacyclin.
The dilemma faced by most physicians treating patients with PAH is how to determine when the inconvenience, expense, and adverse effects of continuous infusion therapy are justified by the severity of disease progression. To properly address this challenge, the practitioner must be able to reliably determine when a patient with PAH is improving, has stabilized, or is deteriorating.
The greatest advantage of these often overlooked tools for monitoring disease progression is their ability to be used repeatedly with minimal expense and no harm to the patient. The timeline for progression in PAH can be as short as several weeks to months. Indeed, in some clinical trials, patients with PAH randomized to receive placebo had significant declines in functional capacity, including several deaths in as little as 12 weeks.10
Therefore, most patients who require medical therapy for PAH should be examined frequently until the physician is confident that they are improving or that their disease has remained stable. In our center, patients with PAH are seen every 4 weeks for the first 6 months and every 6 to 12 weeks thereafter, if their disease appears to be controlled.
The history taking should focus on the patients' perception of their functional capacity. Patients who were fairly active should be able to report that they can do more, have more energy, or can do previous activities faster or with less dyspnea than before starting therapy. Patients who were more incapacitated by PAH may report increased mobility at home, less difficulty with activities of daily living, and decreased fatigue. One problem practitioners may face in trying to ascertain improvement in functional capacity is the generally low level of activity that many persons have before they become ill.
As described above, the pulmonary circulation is designed to maintain low resistance even under high-flow states. Early symptoms of PAH are limited almost entirely to those that occur with exertion. Dyspnea, chest pain, and light-headedness occur during stressful activity well before they occur with ordinary activity or at rest. The World Health Organization (WHO) revision of the New York Heart Association functional classification is designed to assess disease severity on the basis of the level of activity required to produce symptoms (Table 2). However, unless patients attempt more than ordinary activity, it can be difficult to determine their true functional class. Frequently, patients are asked whether they have difficulty in walking up an incline, climbing stairs, or carrying heavy objects, but many have learned to avoid these activities or to perform them slowly enough not to induce symptoms.
The subjective quality of the WHO functional classification has limited its usefulness in monitoring disease progression in individual patients. In particular, patients can have considerable disease progression as they move from early class III to late class III, causing some physicians to divide these patients into class IIIA and IIIB. These designations are entirely subjective and depend on each practitioner's interpretation. In general, a favorable response to therapy should result in a decrease in at least 1 functional class-for example, from WHO class IV to III or from III to II.
The physical examination can provide more objective data for monitoring. Distention of the internal jugular vein can be measured in centimeters above the clavicle and provide a reasonable estimate of right-sided filling pressures. Weight gain should be measured carefully, accounting for differences in scales and clothing. Hepatomegaly can be assessed by percussing the liver or by the number of centimeters the liver is displaced below the costal margin.
The intensity of the pulmonic component of the second heart sound (heard best at the second intercostal space of the left sternal border), the RV impulse, and the degree of lower extremity edema are more operator-dependent but should be noted and recorded as carefully as possible. A decrease in systemic blood pressure can occur with worsening right-sided heart function and is often accompanied by an increase in resting heart rate.
The greatest limitation of the physical examination is that it is best at detecting evidence of RV failure-a late finding in PAH. More sensitive measures of disease progression are usually needed to determine the optimal time to intervene with increased medical therapy.
Posteroanterior and lateral chest radiographs provide fairly good information about RV size and can detect enlargement of proximal pulmonary arteries. A baseline radiograph is important for excluding acute or chronic lung disease and may present findings suggestive of chronic thromboembolic disease or pulmonary venous hypertension resulting from left-sided heart disease or pulmonary veno-occlusive disease. However, its ability to detect moderate changes in pulmonary hemodynamics or early signs of RV dysfunction is fairly limited.
ECG evidence of RV hypertrophy or strain is not uncommon in patients who have PAH. One study found right axis deviation in about three-quarters of the patients studied.11 Less common findings included a qR and rSR′ pattern in V1, T-wave inversion inferiorly, ST-T segment depression in the precordial leads, and complete right bundle-branch block. An ECG is important in the initial evaluation of patients with PAH and should be repeated at least annually, but it is usually not helpful in detecting gradual disease progression.
Echocardiography has played a major role in the rapid growth in the diagnosis and monitoring of PAH over the past 20 years. This rapid, noninvasive imaging technique can be performed almost anytime with virtually no risk to the patient. Ultrasonic images attained using current technologies provide clear 2-dimensional images of the atria and ventricles in most patients, revealing important information on right atrial (RA) and RV size and function. Doppler ultrasonography allows reasonable estimates of peak RV systolic pressure by measuring the speed of the tricuspid regurgitant jet and using a modification of the Bernoulli equation: RV systolic pressure = 4(tricuspid regurgitant velocity)2 + RA pressure.
In the absence of a significant pulmonary stenosis or insufficiency, RV and pulmonary artery systolic pressures (sPAP) are considered to be equal. The RA pressure (RAP) cannot be measured by echocardiography and is usually assigned an estimated value of 5 to 15 cm H2O, depending on the size of the right atrium or the degree of inferior vena cava collapse during inspiration. In one study, RAP was estimated to be 5, 10, or 15 cm H2O depending on whether inferior vena cava collapse during inspiration was complete, partial, or absent.12 However, some investigators have found that estimated RAP does not improve the accuracy of PAP measured by echocardiography, and some echocardiography laboratories choose to report RV systolic pressure alone.13
Pulmonary artery diastolic pressure can also be estimated by measuring the velocity of the pulmonary insufficiency jet at end-diastole. However, this measurement has not been as readily adopted by most practitioners because the Doppler envelope of the pulmonary insufficiency jet can be difficult to obtain.
Transthoracic echocardiography (TTE) estimates of PAP have been reported to correlate well with measurements obtained at catheterization. However, measurements within any individual may vary considerably. Chow and associates14 found an excellent correlation (r = 0.90) between sPAP measured by TTE and right heart catheterization in 28 patients with chronic thromboembolic pulmonary hypertension, but the difference in individual measurements in many patients was significant (standard error of the estimate, 11.5 mm Hg).
Part of the discrepancy between PAP measurements may be the lack of simultaneous recording. Berger and associates13 found a mean difference in sPAP of less than 5 mm Hg when TTE was done at the same time as right heart catheterization in 69 patients who were being evaluated for a variety of pulmonary hypertensive diseases. However, in a study of 81 patients with PAH who were treated with epoprostenol, sPAP measured by TTE within 24 hours of catheterization was 11 ± 2 mm Hg lower on average, and it was 20 mm Hg lower in 31% of the patients.15
Transesophageal echocardiography (TEE) provides better visualization of posteriorly located cardiac structures, such as the left atrium and mitral valve, but it has not been shown to be superior to TTE for the estimation of sPAP. In one report of patients with advanced lung disease who had been studied before lung transplant, 20% of patients who had an sPAP of 45 mm Hg or higher during right heart catheterization had an sPAP of less than 35 mm Hg when measured by TEE.12 Thus, although echocardiography provides a useful assessment of sPAP, measurements should be confirmed by pulmonary artery catheterization at the time of initial diagnosis and whenever these measurements fail to agree with the clinical assessment of pulmonary hemodynamics.
In addition to estimating PAP, echocardiography provides important information about left-sided heart function and pulmonary venous pressure. Elevated PVR impedes pulmonary blood flow and reduces left ventricular filling. Left atrial enlargement is distinctly unusual in patients with PAH, and its presence should prompt further investigation to exclude left-sided heart disease, mitral valve disease, or an atrial septal defect.
Serial measurements of PAP, RV and RA size, and RV contractility greatly aid in determining disease progression in patients. As mentioned above, a fall in peak PAP may not always reflect a decrease in PVR, but when seen in combination with a decrease in RV and RA size and improved RV contractility, it is highly likely that the patient is improving.
Reliable estimation of RV ejection fraction (RVEF) is difficult to attain with 2-dimensional echocardiography. Ultrasonography provides only 2-dimensional images, making it impossible to accurately measure RV end-systolic and end-diastolic volumes. Fractional shortening, derived from the differences in end-systolic and end-diastolic diameters, has been used as an index of RVEF, but the unique geometry of the right ventricle makes it difficult to consistently repeat measurements from the same area.
Other measurements have been developed that provide reasonable estimates of RV performance. The Doppler RV index, or Tei index, is calculated by dividing the sum of isovolumetric contraction and isovolumetric relaxation times by ejection time (defined as duration of pulmonic outflow).16 As RV function declines, this index increases. The Doppler RV index has been shown to be higher in patients with PAH than in healthy controls and to be an independent predictor of mortality.17
Conversely, RV size measured by echocardiography has been shown to decrease in patients who had favorable responses to calcium channel blockers, prostacyclin, lung transplant, or thromboendarterectomy.18-21 An adequate tricuspid regurgitant jet for measuring RV pressure is detectable in more than 80% of patients with PAH, although some series have reported failure rates as high as 40% to 70%.13-15,22
Overall, TTE offers a safe, noninvasive, and fairly reliable technique for monitoring PAP and right-sided heart structural changes in patients undergoing treatment for PAH. However, its inability to reliably assess cardiac output, right-sided filling pressures, and pulmonary venous pressure makes it inadequate as a single test for monitoring disease progression. In particular, patients who have a reduction in the peak PAP measured by TTE but have worsening symptoms or other signs of disease progression require further evaluation, usually with pulmonary artery catheterization.
The morbidity and mortality of PAH is caused by impaired blood flow through the pulmonary circulation, which, in turn, is determined by RV output and PVR. Right heart and pulmonary artery catheterization has been the gold standard for assessing disease severity in PAH patients because it can most accurately measure both pressure and flow. In addition, pulmonary artery catheterization provides accurate measurements of other hemodynamic variables, such as cardiac output, RAP, and RV end-diastolic pressure, that have been found to be better prognostic indicators than PAP.23-25
Changes in peak PAP alone can be difficult to use for assessing disease progression without knowing the change in cardiac output. In fact, in one study, a fall in PAP correlated negatively with survival.26 RAP and RV end-diastolic pressure typically rise before RV systolic function deteriorates and have been shown to be better predictors of mortality than PAP alone. RAP greater than 15 mm Hg is associated with a nearly 2-fold greater mortality.27 A rise in RAP may result from worsening tricuspid insufficiency or from elevation of RV end-diastolic pressure.
The importance of RV function in PAH cannot be overemphasized. Most patients tolerate an elevated PVR fairly well, provided that they have a pump that is strong enough to maintain adequate flow through the lungs. A rise in RV end-diastolic pressure generally means that RV systolic function is unable to compensate for the sustained elevation in afterload, and the right ventricle is attempting to compensate by increasing preload.
The normal right ventricle can maintain systolic function as filling pressure increases, but increases in afterload are not as well tolerated as they are in the left ventricle (Figure 3). At a certain point, further increases in RV afterload result in decreased stroke volume and cardiac failure. An increase in RV end-diastolic pressure, usually above 10 mm Hg in a patient with PAH, is concerning and warrants consideration of additional therapy to lower PVR even if the patient's other hemodynamic and clinical parameters are unchanged.
Figure 3 – These are the effects of right and left ventricular filling pressures and afterload on stroke volume in dogs. Stroke volume is better maintained by the right ventricle (RV) than by the left ventricle (LV) as filling pressure increases (A), but systolic function deteriorates rapidly as right ventricular afterload is increased by constriction of the pulmonary artery (B). (Reproduced with permission from Braunwald E et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 2004.29)
Unfortunately, pulmonary artery catheterization is an expensive and invasive procedure that is not without risk of serious complications and can expose the patient to high levels of radiation. These limitations frequently dampen the enthusiasm that many practitioners have for the technique, so it often is the diagnostic test of last resort. This is unfortunate, because by the time the patient's condition has worsened, pulmonary artery catheterization is more likely to confirm clinical findings than to supply new information that may have helped prevent or slow disease progression. In many pulmonary hypertension centers, right heart catheterization is often repeated routinely after the first 6 to 12 months of therapy, even in patients whose conditions have not deteriorated, to ensure that findings from less invasive monitoring techniques are accurate.
REFERENCES1. Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006;3:111-115.
2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216-223.
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. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000;26:81-84.
5. Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004;43(12 suppl S):33S-39S.
6. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.
7. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-1928.
8. Galiè N, Seeger W, Naeije R, et al. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):81S-88S.
9. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):13S-24S.
10. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334:296-302.
11. Bossone E, Paciocco G, Iarussi D, et al. The prognostic role of the ECG in primary pulmonary hypertension. Chest. 2002;121:513-518.
12. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735-740.
13. Berger M, Haimowitz A, Van Tosh A, et al. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol. 1985;6:359-365.
14. Chow LC, Dittrich HC, Hoit BD, et al. Doppler assessment of changes in right-sided cardiac hemodynamics after pulmonary thromboendarterectomy. Am J Cardiol. 1988;61:1092-1097.
15. Hinderliter AL, Willis PW 4th, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation. 1997;95:1479-1486.
16. Kim WH, Otsuji Y, Seward JB, Tei C. Estimation of left ventricular function in right ventricular volume and pressure overload. Detection of early left ventricular dysfunction by the Tei index. Jpn Heart J. 1999;40:145-154.
17. Yeo TC, Dujardin KS, Tei C, et al. Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157-1161.
18. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497-503.
19. Ritchie M, Waggoner AD, Dávila-Román VG, et al. Echocardiographic characterization of the improvement in right ventricular function in patients with severe pulmonary hypertension after single-lung transplantation. J Am Coll Cardiol. 1993;22:1170-1174.
20. Menzel T, Kramm T, Bruckner A, et al. Quantitative assessment of right ventricular volumes in severe chronic thromboembolic pulmonary hypertension using transthoracic three-dimensional echocardiography: changes due to pulmonary thromboendarterectomy. Eur J Echocardiogr. 2002;3:67-72.
21. GalièN, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:1380-1386.
22. Chemla D, Castelain V, Hervé P, et al. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J. 2002;20:1314-1331.
23. Sandoval J, Bauerle O, Palomar A, et al. Survival in primary pulmonary hypertension: validation of a prognostic equation. Circulation. 1994;89:1733-1744.
24. Rajasekhar D, Balakrishnan KG, Venkitachalam CG, et al. Primary pulmonary hypertension: natural history and prognostic factors. Indian Heart J. 1994;46:165-170.
25. Glanville AR, Burke CM, Theodore J, Robin ED. Primary pulmonary hypertension. Length of survival in patients referred for heart-lung transplantation. Chest. 1987;91:675-681.
26. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788.
27. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115:343-349.
28. Hill NS. Historical perspective and classification. In: Hill NS, ed. Pulmonary Hypertension Therapy. Armonk, NY: Summit Communications, LLC; 2006:9.
29. Braunwald E, Zipes DP, Libby P, Bonow R, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: WB Saunders Company; 2004.