It has been more than a decade since

doi: 10.1111/j.1751-7133.2010.00192.x R EVIEW P APER Differentiating Pulmonary Arterial and Pulmonary Venous and the Implications for Therapy It has been more than a decade since the Second World Symposium on Pulmonary designated a new class of pulmonary hypertension (PH): PH associated with chronic left ventricular failure. 1 This class of PH became Group 2, or pulmonary venous hypertension (PVH), under the updated World Health Organization classification of the disease (Table I). 2,3 The acknowledgment of PH as a pathophysiologic sequelae of chronic left heart failure (HF) has led to some uncertainty about the appropriate diagnostic approach to certain patients with Group 2 hypertension. There exists a subset of Group 2 PH patients who develop a reactive hemodynamic profile that resultsinsevereph,similartothatseen in Group 1 PH or pulmonary arterial hypertension (PAH). While right heart catheterization (RHC) has become an essential tool in the diagnosis of Group 1PH,ithasbeenusedlessconsistently in the work-up of this subset of reactive Group 2 PH patients. Reliance on echocardiography alone for the clinical assessment of PVH can lead to misdiagnosis in these patients. PVH (also called postcapillary PH) arises as a consequence of either left HF, most commonly left ventricular () diastolic dysfunction, or valvular disease. 4 Elevated filling pressures in the setting of abnormal ventricular relaxation and compliance are transmitted back to the pulmonary venous circulation. Similarly, increased pulmonary blood flow resulting from mitral valve disease (functional or structural mitral regurgitation, mitral stenosis) can lead to elevations in pulmonary pressure. Traditionally, postcapillary PH has been defined as mean pulmonary artery pressure (mpap) 25 mm, pulmonary Pulmonary arterial and pulmonary venous hypertension develop from distinctly different etiologies. Pulmonary arterial hypertension (PAH), or Group 1 pulmonary hypertension (PH), is a precapillary PH that arises idiopathically or as the result of a divergent array of causes, including connective tissue disease. Pulmonary venous hypertension (PVH), or Group 2 PH, primarily manifests as a postcapillary PH in the setting of left heart failure or valvular disease. A subset of PVH patients, however, develop a reactive precapillary component of PH that mimics PAH.These patients can be misdiagnosed as having Group 1 PH by 2-dimensional echocardiography and are sometimes treated as such, which leads to exacerbation of heart failure. Therefore, 2-dimensional or Doppler echocardiography alone cannot be used to differentiate between these two classifications of PH. This highlights the need for right heart catheterization in the clinical assessment and diagnostic work-up of PH. The combination of imaging and invasive hemodynamic assessment by right heart catheterization provides the best diagnostic approach to ensure proper delineation of pulmonary arterial and pulmonary venous hypertension, and in turn leads to appropriate treatment. Congest Heart Fail. 2010;16:287 291. Ó 2010 Wiley Periodicals, Inc. Sina Dadfarmay, MD; 1 Robert Berkowitz, MD; 2 Bernard Kim, MD; 1 Rama Bindu Manchikalapudi, MD 1 From the Heart Failure and Pulmonary Program, Heart and Vascular Center, Hackensack University Medical Center, Hackensack, NJ, 1 and the Department of Medicine, 2 Hackensack University Medical Center, Hackensack, NJ Address for correspondence: Sina Dadfarmay, MD, Hackensack University Medical Center, Heart Failure and Pulmonary Program, 20 Prospect Avenue, Hackensack, NJ 07601 E-mail: zerangi@hotmail.com Manuscript received November 23, 2009; revised April 10, 2010; accepted April 25, 2010 capillary wedge pressure (PCWP) 15 mm, and transpulmonic gradient (mpap)pcwp) <10 mm. However, in recent years, two different hemodynamic profiles in PVH have been recognized: passive and reactive postcapillary PH. In the former, there is passive retrograde transmission of elevated PCWP into the pulmonary venous system, causing a passive and mild increase in upstream PAP. 4 mpap increases only enough to overcome PCWP and maintain forward flow. As a result, the transpulmonic gradient (TPG) remains <10 mm. In contrast, in PAH, the TPG is 10 mm due to a low downstream PCWP (PCWP <15 mm ). In patients with passive PVH, PH can be reduced or attenuated by treatment of left HF and alleviation of elevated downstream wedge pressure or left atrial pressure. A subset of postcapillary PH patients, however, presents with a reactive hemodynamic profile and significantly elevated pulmonary pressures. These patients develop reactive changes in the pulmonary vasculature whereby increased pulmonary venous pressure triggers vascular smooth muscle and other vasoproliferative changes in the pulmonary arteries. This leads to obliter- differentiating pulmonary arterial and pulmonary venous hypertension november december 2010 287

Table I. Revised World Health Organization Classification of Pulmonary Group 1: Pulmonary arterial hypertension Idiopathic (formerly primary pulmonary hypertension) Familial Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension Human immunodeficiency virus Drugs and toxins (eg, cocaine) Glycogen storage disease Gaucher disease Hereditary hemorrhagic telangiectasia Hemoglobinopathies Myeloproliferative disorders Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Group 2: Pulmonary venous hypertension Left ventricular systolic diastolic heart failure Left-sided valvular disease Group 3: Pulmonary hypertension associated with hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Obstructive sleep apnea Alveolar hypoventilation disorders Long-term exposure to high altitude Group 4: Pulmonary hypertension due to chronic thromboembolic disease Group 5: Miscellaneous Sarcoidosis Langerhans cell histiocytosis (histiocytosis X) Lymphangiomatosis Compression of pulmonary vessels (tumor, fibrosing mediastinitis) Adapted from Farber et al. 2 ative arteriopathy, a process thought to be mediated in part by endothelin. 5 The net result is reactive pulmonary vasoconstriction (both on the arterial and venous side), resulting in marked increases in PAP beyond that which is necessary to overcome elevated downstream PCWP. 4 Thus, these patients manifest with a precapillary component of PH marked by a TPG 10 mm as well as a significantly elevated pulmonary artery diastolic pressure (PADP > PCWP), hemodynamic changes that mimic PAH. Indeed, histological changes in the pulmonary vasculature of reactive PVH patients are indistinguishable from those of PAH patients. 1 PAP in this case does not normalize with treatment of underlying HF. Reactive PVH can occur in diastolic HF as well as in cases in which diastolic and systolic dysfunction coexist. It does not appear to develop in isolated systolic HF. 7 It was previously thought that the severity of PVH strongly correlated with the degree of systolic dysfunction. However, studies involving invasive measurements in patients with postcapillary PH showed that pulmonary pressures correlated more closely with diastolic indices, such as mitral valve deceleration time, than with systolic indices. 8,9 In fact, there was a poor correlation between PH and systolic indices in these patients. 8,9 Moreover, patients with the greatest degree of diastolic dysfunction had the highest PAP. 5 Thus, PVH is strongly associated with diastolic dysfunction, and, indeed, degree of diastolic dysfunction acts as an independent predictor of the severity of PH in HF. Patients with high-grade diastolic dysfunction who manifest with severe postcapillary PH may ultimately go on to develop a severe precapillary component of PH, which, in turn, can lead to right ventricular (RV) failure. In contrast, patients with isolated systolic HF develop a passive component of PH resulting from retrograde transmission of elevated filling pressure; however, they do not develop a reactive precapillary component. As such, they do not develop RV failure. PH in these patients is mitigated with diuretic therapy. In all PH patients, echocardiography is an essential tool in the initial clinical evaluation. PVH is typically diagnosed during the work-up of congestive HF and is most consistently seen in patients with diastolic dysfunction. 7 In the subset of patients with reactive PVH, the end result is similar to PAH. The right ventricle initially hypertrophies in response to the higher afterload brought on by increased PAP. Over time, this ultimately leads to dilatation and RV failure as the right ventricle is unable to maintain that level of systolic stress. 5 The echocardiographic findings in reactive PVH are nearly identical to those of PAH. There is marked RV and right atrial (RA) enlargement, flattening and leftward displacement of the interventricular septum, and, consequently, compression of the left ventricle. Classically, this results in a D-shaped left ventricle, as seen in the parasternal short-axis view. This process of ventricular interdependence is most prominent at endsystole. Therefore, there is a convergence of echocardiographic findings in Group 1 and reactive Group 2 PH whereby the same structural changes have evolved in response to different, but ultimately converging, pathophysiologies. We present two different cases of PH that exemplify the process of structural convergence as seen in this setting. Both patients were admitted to our HF service and initially diagnosed by echocardiography and subsequently by RHC. The first case is that of a 21-year-old woman (J.S.) with a history of atrial septal defect (ASD) who developed PAH (Group 1 PH) as a result of left-to-right intracardiac shunt and increased pulmonary flow. Over time and with the development of increasing pressures in the pulmonary circulation, her shunt became bidirectional and she developed Eisenmenger syndrome. Figure 1 illustrates the apical four-chamber view on echocardiogram demonstrating extensive RA and RV enlargement as a consequence of severe pressure overload on the right heart. The interventricular septum is flattened and displaced leftward, causing encroachment and compression of the left ventricle. Pulmonary artery systolic pressure (PASP) in this patient was estimated by echocardiogram to be 120 mm. Figure 2 shows the classic D-shaped left ventricle during systole in the same patient, again the result of severe pressure and volume overload on the right ventricle. The second case is that of a 70-yearold man (D.P.) with diastolic congestive HF who similarly developed right HF from severe PH. In this patient, diastolic dysfunction initially led to PVH by the mechanisms described earlier. Like other Group 2 PH patients with a reactive hemodynamic profile, our patient went on to develop a precapillary component of PH as a consequence of remodeling and vasoconstriction of the pulmonary arterial bed. As a result, he developed the hallmarks of acute RV failure, including peripheral edema, hepatomegaly, and ascites. As can be 288 differentiating pulmonary arterial and pulmonary venous hypertension november december 2010

RV RA Figure 1. Apical four-chamber view on echocardiogram in a patient with Group 1 pulmonary hypertension. The right atrium (RA) and right ventricle (RV) are severely dilated and there is flattening and reversal of septal curvature. The left ventricle () is small and compressed. indicates interventricular septum; LA, left atrium. RV Figure 2. Parasternal short-axis view of the interventricular septum () and left ventricle () showing a D-shaped morphology resulting from flattening and leftward displacement of the septum. RV indicates right ventricle. seen (Figure 3 and Figure 4), the echocardiographic findings in this patient closely mirror those of our PAH patient (J.S.), with severe enlargement of the right-sided chambers, flattening and leftward displacement of the septum, and the resultant formation of a D-shaped left ventricle. Following initial diagnostic evaluation by echocardiogram, each patientunderwentrhc forinvasive hemodynamic assessment. The results are shownintableii.thekeydifference between the Group 1 and Group 2 PH patients was the filling pressure, reflected by the PCWP. The wedge pressure was significantly elevated in the patient with left HF, as expected, but normal in the patient with PAH. Mean LA PAPs in both patients were severely increased; PASP obtained by RHC mirrored values obtained by echocardiography. Similar to the Group 1 patient, the Group 2 patient manifested with a transpulmonic gradient >10 mm, indicating a precapillary, reactive component to the PH. Thus, although there was a structural convergence in the evolution of precapillary PH in these two patients, as demonstrated by two-dimensional echocardiogram, only by catheterization were the two differing etiologies discernable. Interestingly, in both patients, cardiac output was seemingly preserved. Typically in cases of severe precapillary PH in which the right ventricle is dilated and hypokinetic, there is a diminution of cardiac output. As a result, these patients tend to be hypotensive. In the Group 1 patient (J.S.), cardiac output was maintained by bidirectional shunting through the ASD. In the Group 2 patient (D.P.), the high cardiac output was likely the result of shunting secondary to hepatic insufficiency along with global reduction in systemic vascular resistance in the setting of liver failure and congestive hepatopathy. A useful adjunct to traditional two-dimensional echocardiography for the assessment of LA and filling pressure as well as diastolic dysfunction in patients with postcapillary PH is Doppler echocardiography. Doppler parameters predicting increased PCWP include shortened deceleration time of early diastolic mitral inflow velocity (E), the ratio between mitral inflow velocity and mitral annular velocity in early diastole (E E 0 ), and the difference between pulmonary vein atrial flow reversal velocity (PVa) and mitral inflow velocity during atrial systole (A). E A ratios are used to quantify grade of diastolic dysfunction. While these variables may suggest elevated wedge pressure and associated diastolic dysfunction, a definitive measurement of PCWP and corresponding end-diastolic pressure is best determined by RHC, as demonstrated above. Hence, Doppler examination can be a useful noninvasive tool in the work-up of PH, but more invasive hemodynamic evaluation is required to ultimately differentiate precapillary from postcapillary PH. Apart from the difference in PCWP, the other important feature distinguishinggroup1andgroup2phpatientsis grade of diastolic dysfunction. Group 1 patients with RV failure develop low-grade diastolic dysfunction as a result of ventricular interdependence, as described above. However, the grade of diastolic dysfunction in these patients almost never exceeds grade 1, and this does not change with therapy. In contrast, Group 2 PH patients with RV failure (ie, patients with a reactive precapillary PH component) nearly always manifest with grade 2 to 3 diastolic dysfunction. Indeed, what appears to predict the development of a precapillary differentiating pulmonary arterial and pulmonary venous hypertension november december 2010 289

Figure 3. Apical four-chamber view on echocardiogram in a patient with Group 2 pulmonary hypertension. Note severe enlargement of the right atrium(ra), right ventricle (RV), and reciprocal compression of the left ventricle () by a displaced septum. indicates interventricular septum; LA, left atrium. Table II. Right Heart Catheterization Data HEMODYNAMIC VARIABLES RV Figure 4. Parasternal short-axis view exhibiting the formation of a D-shaped left ventricle () in a patient with Group 2 pulmonary hypertension. RV indicates right ventricle;, interventricular septum. PATIENT 1 (PAH, GROUP 1 PH) PATIENT 2 (PVH, GROUP 2 PH) RAP, mm 13 29 RVP, mm 108 15 72 0 PAP, mean, mm 112 49 (76) 82 47 (63) PCWP, mm 13 42 CO, L min a 5.84 8.46 CI, L min m 2 2.84 3.55 Abbreviations: CI, cardiac index; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVH, pulmonary venous hypertension; RAP, right atrial pressure; RVP, right ventricular pressure. a Cardiac output (CO) was measured by Fick. component in Group 2 PH is the severity of diastolic dysfunction. These cases illustrate the importance of RHC in the clinical assessment and diagnosis of PH. Doppler echocardiography is an appropriate initial screening tool in patients with suspected PH based on history or physical examination findings. When echocardiographic findings reveal PH based on elevated RV systolic pressure and there is evidence of RV dilatation and or RV systolic dysfunction, patients must be referred for RHC as the next step. As demonstrated here by structural convergence, a diagnosis of PAH vs reactivepvhcannotbemadebyechocardiography alone. Sole reliance on imaging for a diagnosis of PAH in patients found to have severely elevated PAP and echocardiographic evidence of right HF can lead to misdiagnosis of a Group 2 PH patient as Group 1 PH. This, in turn, has dangerous implications on treatment of these patients, as studies have shown that pulmonary vasodilator therapy worsens HF in Group 2 PH patients. Vasodilators increase venous return to the left heart, which, in the setting of already elevated filling pressures, can precipitate pulmonary edema. In fact, epoprostenol has been associated with increased mortality in patients with systolic HF. 4 No treatment has been shown to be effective for reactive PVH in patients with left HF. This holds true even after normalization of wedge pressure in these patients following diuretic therapy. RHC remains the gold standard for the diagnosis of PH and its divergent causes. Table III shows the classic hemodynamic profile for precapillary and postcapillary PH obtained by RHC. Comprehensive clinical assessment in every patient should never rely on imaging alone but rather the integration of echo-doppler with invasive hemodynamic data. Understanding the physiology and hemodynamic profile of the RV,, and pulmonary circulation is critical for differentiating between precapillary and postcapillary PH and, in turn, ensures the appropriate treatment (Figure 5). Further testing is necessary to discern other non Group 1 causes of precapillary PH that may not be amenable to pulmonary vasodilator therapy. 290 differentiating pulmonary arterial and pulmonary venous hypertension november december 2010

Table III. Hemodynamic and Echo-Doppler Differences Between Group 1 and Group 2 Pulmonary CLASSIFICATION PCWP MPAP TRANSPULMONIC GRADIENT a PA EDP-PCWP GRADE OF DIASTOLIC DYSFUNCTION Group 1 PH (PAH) <15 25 10 10 None or 1 Group 2 PH (PVH) Passive 15 25 <10 <10 1 Reactive 15 25 10 10 2 4 All pressures are given in mm and derived by right heart catheterization. Diastolic grade was obtained from Doppler echocardiographic evaluation of transmitral velocities as well as tissue Doppler echocardiography. Abbreviations: mpap, mean pulmonary artery pressure; PA EDP, pulmonary artery end-diastolic pressure; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVH, pulmonary venous hypertension. a Transpulmonic gradient = mpap)pcwp. PA Precapillary Pulmonary Postcapillary Pulmonary LA Group 1 PH (PAH) o PCWP < 15 mm o PAP-PCWP > 10 mm Diastolic heart failure with reactive PH o PCWP 15 mm o PAP-PCWP > 10 mm Systolic heart failure Diastolic heart failure with passive PH o PCWP 15 mm o PAP-PCWP< 10 mm Valvular heart disease Figure 5. Anatomic overview of precapillary and postcapillary pulmonary hypertension (PH). PA indicates pulmonary artery; RA, right atrium; RV, right ventricle; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure; LA, left atrium;, left ventricle. REFERENCES 1 Bonderman D, Martischnig AM, Moertl D, Lang IM. Pulmonary hypertension in chronic heart failure. Int J Clin Pract. 2009;63:4 10. 2 Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351: 1655 1665. 3 Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 suppl S): 5S 12S. 4 Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation. 2008;118: 2190 2199. 5 Zakir RM, Al-Dehneh A, Maher J, et al. Right ventricular failure in patients with preserved ejection fraction and diastolic dysfunction: an underrecognized clinical entity. Congest Heart Fail. 2007;13(3):164 169. 6 Hemnes AR, Forfia PR, Champion HC. Assessment of pulmonary vasculature and right heart by invasive haemodynamics and echocardiography. Int J Clin Practice. 2009;63: 4 19. 7 Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure. Circulation. 2000;102:1718 1723. 8 Enriquez-Sarano M, Rossi A, Seward JB, et al. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997;29(1):153 159. 9 Capomolla S, Febo O, Guazzotti G, et al. Invasive and non-invasive determinants of pulmonary hypertension in patients with chronic heart failure. J Heart Lung Transplant. 2000;19:426 437. differentiating pulmonary arterial and pulmonary venous hypertension november december 2010 291