Reactive pulmonary hypertension in left heart disease “Post-capillary PH with a pre-capillary component”

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Aneida Hodo Vevecka1, Marinela Șerban3, Ruxandra Jurcuț2,3, Carmen Ginghină2,3

1 University Hospital ‘Mother Thereza” Tirane, Albania
2 University of Medicine and Pharmacy „Carol Davila”, Bucharest
3 Emergency Institute for Cadiovascular Diseases “Prof. Dr. C. C. Iliescu”, Bucharest, Romania


Left heart diseases (LHDs) are the most frequent cause of pulmonary hypertension (PH). LHDs determine an increase in left ventricular filling pressures and pulmonary venous pressures (1). Presence of PH in patients with LHD and heart failure is associated with a decrease in exercise tolerance, worsening of dyspnea and increased mortality, independently from the underlying cause (2-6). PH due to LHD is defined as combination of both elevated mPAP (≥25 mmHg) and elevated capillary wedge pressure PCWP (>15 mmHg). PH secondary to LHD is classified in Group two of PH in the most recent classification of PH and includes three etiologies: left heart systolic dysfunction, left heart diastolic dysfunction, and left valvular disease (7).

An important group of patients with LHDs have a disposition to develop a pre-capillary component to the increased pulmonary pressure, resulting in a mixed picture of pre-capillary and post-capillary PH (7). These patients present with a reactive or “out of proportion” PH defined as elevated pulmonary vascular resistance (PVR ≥3 Wood units) and increased transpulmonary gradient (TPG ≥12 mmHg), where the TPG is the difference between mean pulmonary pressure and left atrial pressure. Another term used to define this clinical entity is “mixed PH” as to emphasize both pre-cappilary and post-capillary contributions to the elevated pulmonary arterial pressure (PAP)8.

Definitions and Terminology

Based on the TPG and PVR values, there are two major distinct categories of PH due to LHD: Passive and Reactive PH (Table 1). Passive Group 2 PH is defined by normal TPG and PVR with elevated mPAP values corresponding to the PCWP values. This type of PH represents the form with the highest prevalence and is seen most often in the early stages of HF. There are no significant associated abnormalities in the pulmonary artery structure or function, therefore specific pulmonary artery vasodilatator therapy is not considered.

Reactive Group 2 PH is defi ned by an elevated TPG ≥12 mmHg and PVR ≥3 Wood units, indicating the presence of functional and/or structural abnormalities of the pulmonary arterial vasculature besides the elevated PCWP. The mPAP values are disporotionally increased compared to the PCWP.

Reactive PH is further classified into reversible or irreversible PH, depending on the response of TPG and PVR to pharmacological interventions. Reactive reversible Group 2 PH is defined by normalization of the TPG and PVR during vasodilator challenge, suggesting a predominance of functional over structural abnormalities of the pulmonary arteiral vessels. This type of PH may represent the transition from passive to reactive PH (9).

Reactive irreversible Group 2 PH is defined by a PVR which can not be reduced to of the high downstream pressure. Structural over functional abnormalities of the pulmonary arterial vascular bed are presumed to exist. Histological changes of pulmonary vasculature bed appear to be the same as in precapillary forms of PH (10). Thus, this group may be considered as a target for therapy with a specific pulmonary artery vasodilatator agent.


PH due to LHD has a highly variable prevalence. Although it represents the most common form of PH, there are less epidemiological data for this group compared to other forms of PH (11). Different studies have shown that PH is present in 68% to 78% of patients with heart failure with reduced ejection fraction (HfrEF) being associated with an increased morbidity and mortality (12-14).

Table 1. Classification of PH due to LHD (Group 2)

Hemodynamic criteria
1. Passive PH Group 2 with elevated
left cardiac
filling pressure
(passive congestion)
Mean PAP ≥25
mmHg, PCWP
≥12 mmHg, TPG
≤12 mmHg or
PVR ≤3.0 WU
2. Reactive PH Grup 2 PH with
elevated left
ventricular cardiac
pressure and
increased PVR
Pre- and
TPG ≥12 mmHg
or PVR ≥3.0 WU
2.1 Reactive reversible PH Responsive to pharmacologic (vasodilators and/or inodilators) TPG ≤12 mmHg or PVR ≤3.0 WU
2.2 Reactive irreversible PH – Not responsive to
TPG ≥12 mmHg
or PVR ≥3.0 WU

In a recent study, 80% to 90% of patients with HF had PH, and over half had reactive PH regardless of left ventricle ejection fraction (15). More recent data suggest that the prevalence of reactive PH is similar in all ejection fraction groups of patients with LHD. Ghio et al, reported reactive PH in >60% of their patients with moderate or severe HF (16). Other studies reported an incidence of reactive PH in symptomatic HFrEF of 36% to 47% (8,17). Furthermore, as the severity of HF increases, reactive PH is more likely to be present (8). In a series of 242 patients with acute decompensated heart failure, reactive PH was present in 40% of patients (18). Similarly, reactive PH was present in 41% to 50% of a pretransplant HF population (19,20). In left sided valvular diseases, the prevalence of PH increases with the severity of the defect and of the symptoms. Wood observed severe precapillary PH (PVR ≥6 WU) in 26% of 300 patients with mitral stenosis (21). According to a recent study, PH can be found in virtually all patients with severe symptomatic mitral valve disease and over half of them present reactive PH (22). Another study showed that 65% of patients with symptomatic aortic stenosis present PH and almost one third of them reactive PH (23). Furthermore, it appears that women are more prone to reactive PH, suggesting that hormonal and autoimmune pathways may be implicated in this pathology (24).


In all patients with LHD the primary event leading to PH is a passive backward transmission of filling pressures, mostly caused by left ventricular diastolic dysfunction (10). Several studies suggest that venous congestion might trigger pulmonary vasoconstriction and vascular remodeling in this PH population (25,26). Pulmonary vasoconstriction in PH due to LHD is caused by endothelial dysfunction, primarily as a consequence of the imbalances between nitric oxide (NO) and endothelin 1 (ET1) signaling (27,28). Nitric oxide is important in regulating pulmonary vascular tone in patients with HF and PH. It has been shown that infusions of NG-mono-methyl-l-arginine, an inhibitor of NO production, results in a lower degree of dose dependent vasoconstriction in heart failure patients with reactive PH compared with those with passive PH or healthy individuals (27). ET1, a peptide with vasoconstrictor and platelet aggregating actions, is widely dispersed in the pulmonary endothelium and abundant in the pulmonary vascular endothelial cells in patients with PH due to LHD (28-30). Pulmonary vascular remodeling is initiated by local activation of growth stimuli, such as angiotensin II, endothelin 1 and hypoxia (31). ET1, apart from its vasoconstriction effect, causes proliferation and hypertrophy of vascular smooth muscle cells and increases collagen synthesis (29). Muscularization of the acinar arterioles is determined by fi broproliferative changes of the myofibroblasts derived from the arterial media. It has been shown that in patients with advanced HF awaiting heart transplantation, the pathological changes seen in small and medium pulmonary arteries lead to pulmonary vascular disease, increased right ventricle (RV) afterload, and RV failure (32). Transition from passive to reactive PH is highly variable in LHD patients and does not appear to be consistently related to the severity of PWC elevation (10,13). In this context, it was suggested that a genetic component plays a role in the pathophysiology of these patients. Thus, a reduced expression of bone morphogenetic pro tein receptor, coupled with increased expression of angio poietin-1, was found in various forms of PH, including PH secondary to mitral valve diseases, suggesting a common pathway in disease progression (33). However, the genetic substrate responsible for the remodeling processes within individual patients with PH secondary to LHD remains poorly undestood.

Clinical profile

The clinical profile of patients with PH due to LHD does not usually help in differentiating the reactive from the passive forms of HP. However, patients with reactive PH may present with signs and symptoms that are generally not found in other forms of PH such as orthopnoea and paroxysmal nocturnal dyspnoea (11). Their chest radiographs may show additional pulmonary vascular congestion, pleural effusion, and left ventricle hypertrophy may be evident on electrocardiogram. The clinical distinction between PH due to HF with preserved ejection fraction (PH – HfpEF) and pulmonary arterial hypertension (PAH) is important because often these two groups of patients share similar hemodynamic profile but very distinct therapeutic strategies. Compared with patients with PAH, patients with reactive PH – HFpEF are older and have a higher prevalence of cardiovascular comorbidities. They had worse exercise capacity and renal function and more frequently left atrial enlargement. Also, PH is less severe in PH – HFpEF patients than in PAH patients and they have higher cardiac output (34).

Diagnosis and important hemodynamic concerns

PH due to LHD is defi ned as combination of both elevated mPAP (≥25 mmHg) and elevated capillary wedge pressure PCWP (>15 mmHg) (7). Although echocardiography may be a useful screening tool, invasive measures of PCWP, TPG and PVR by RHC may be needed in order to confirm a diagnosis of reactive PH due to LHD. The PVR and TPG are commonly used in clinical practice but with the disadvantage of representing a composite variable, with an interdependent numerator and denominator (changes in flow influence pressure in the pulmonary circulation). Therefore, they are highly sensitive to changes in both flow and filling pressures but do not refl ect changes in the pulmonary circulation at rest (35,36). In contrast, diastolic PAP when compared with systolic pulmonary artery pressure and mPAP is less influenced by PAWP, which might be explained by a lower sensitivity to vessel distensibility (35). In normal subjects, diastolic pulmonary artery gradient (DPD) lies in the 1-mmHg to 3-mmHg range, and in patients evaluated for cardiac disease the DPD remains ≤5 mmHg in 94% of the cases (37,38). This suggests that, when PH develops in heart diseases, DPD increases >5 mmHg in one-half of the cases and that the increase in diastolic PAP is somehow unrelated to the changes in PAWP. Th erefore, the DPD might be seen as a potential marker of changes in the pulmonary circulation. Although based on a strong pathophysiological reasoning, the respective value of the DPD should be further explored, including its role in predicting outcome (38).


There is no specific treatment for PH due to LHD. The basic treatment of this pathology is the management of the underlying cardiac disease (8,15). In PH due to LHD, the reduction in pulmonary pressure by LHD suitable therapy is mainly due to wedge pressure reduction and it occurred in all patients, suggesting that a passive element is also present in patients with reactive PH (39). However, for patients with reactive PH, the reductiod in PWCP does not lead to a normalization of the TPG and mPAP, suggesting that other therapeutic strategies, aimed at the arterial pulmonary vasculature, might be useful in these patients (40,41). In candidates for heart transplantation with reactive forms of PH not responding to vasodilatory treatment, left ventricular assist device (LVAD) improved pulmonary hemodynamics. Moreover, the significant reduction of the PVR secondary to LVAD use improved the operability of these patients and was associated with good post transplantation outcomes (42-46). Although no definite evidence is available for supporting the use of PAH therapies in PH associated to LHD, the hemodynamic status of the reactive forms of PH suggests a role for specific vasodilator therapies. Several trials have tested PAH approved therapies in PH-LHD patients: bosentan (47,48), epoprostenol (49) or darusentan (50,51), all showing clinical and hemodynamic negative results. However, none of the studies stratified patients for the type of PH, passive or reactive, although some reported on invasive hemodynamic status. Given the important role of ET-1 in the pathophysiology of reactive PH, ET antagonists may be effective for ameliorating PH and reversing pulmonary vascular remodeling. In heart transplantation candidates, acute administration of sildenafi l prompted a greater improvement in PVR, exercise tolerance and hemodynamics before the transplantation (52-58). Comparable results in exercise tolerance were continuous up to six months with sildenafi l in another study (59). However, the interpretation of these results must be made with great caution, as higher doses of sildenafi (l) than those used to treat PAH were used and there were single center studies. PAH therapies might be harmful in patients with HFpEF as vasodilator exposure in these patients can lead to a decreased stroke volume (60). However, in a recent study performed in this PH-population, sildenafil improved clinical and hemodynamic status after six months, with sustained beneficial effects up to one year (61,62).


The type of PH is a pivotal determinant of outcome in LHD patients. Survival of these patients is negatively related to the severity of PH and further risk estimation can be increased on the basis of the PH subtype where reactive PH has significant higher risk of death than passive PH (15). Further studies reported that among patients admitted with acutely decompensated HF, six month mortality increased progressively from approximately 8% in no PH to 22% in passive PH and to further 48% in reactive PH (18). Also, it was shown shown that HF patients with reactive PH and right ventricle (RV) dysfunction have a 2-fold increase in mortality than patients with preserved RV function and comparable LVEF (16,63,64). Other studies of heart transplantation can didates reported that reactive PH was associated with up to a 3 fold increase in risk of RV failure and early post transplant mortality but if the PVR can be lowered pharmacologically this risk may be reduced (19,20).

Summary and future directions

In many patients with LHDs, the degree of PH will be “out of proportion” to the distal PCWP, resulting in a mixed picture of precapillary and postcapillary PH. The outcomes appear to be significantly worse in this case and the optimal therapeutic strategy in these patients remains unknown. The cornerstone of managing PH due to LHD is primary treatment of the LHD but it remains unclear whether PH itself should be a target of therapy. Appropriately powered clinical trials based on pathophysiologic mechanisms will provide an evidence for the efficacy and safety of PH specific therapy, assuming PH due to LHD is a risk factor with a direct deleterious effect rather than simply a marker of outcome.


1. Vachiéry J-L, Adir Y, Barberà JA, Champion H, Coghlan JG, at al: Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013, 62(25 Suppl):D100-8.
2. Bursi F, McNallan S, Redfi eld MM, Nkomo VT, at al: Pulmonary Pressures and Death in Heart Failure: A Community Study. J Am Coll Cardiol 2012, 59:222-31.
3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006, 355:251-9.
4. Damy T, Goode KM, Kallvikbacka-Bennett A, Lewinter C, at al: Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J 2010, 31:2280-90.
5. Abramson SV, Burke JF, Kelly JJ, Kitchen JG 3rd, Dougherty MJ, at al: Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992, 116:888-95.
6. Costard-Jackle A, Fowler MD: Influence of Preoperative Pulmonary Artery Pressure on Mortality After Heart Transplantation: Testing of Potential Reversibility of Pulmonary Hypertension With Nitroprusside Is Useful in Defining a High Risk Group. J Am Coll Cardiol 1992, 19:48-54.
7. Galiè N, Hoeper MM, Humbert M, et al. ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension; Eur Heart J 2009;30:2493–537.
8. Khush KK, Tasissa G, Butler J, McGlothlin D, De Marco T. Effect of pulmonary hypertension on clinical outcomes in advanced heart failure:analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database. Am Heart J 2009;157:1026-34.
9. Marco Guazzi at al. Pulmonary Hypertension Due to Left Heart Disease. Circulation. 2012;126:975-990.
10. Delgado JF, Conde E, Sanchez V, Lopez-Ríos F, Gomez-Sanchez MA, at al. Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure. Eur J Heart Fail. 2005;7:1011–1016.
11. Guazzi M, Arena R. Pulmonary hypertension with left-sided heart disease. Nat Rev Cardiol. 2010;7:648–659
12. Ghio S. Pulmonary hypertension in advanced heart failure. Herz 2005; 30:311-7.
13. Butler J, Chomsky DB, Wilson JR. Pulmonary hypertension and exercise intolerance in patients with heart failure. J Am Coll Cardiol 1999;34:1802-6.
14. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality aft er heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48-54.
15. Tatebe S, Fukumoto Y, Sugimura K, Miyamichi-Yamamoto S, at al. Clinical significance of reactive post-capillary pulmonary hypertension in patients with left heart disease. Circ J. 2012;76:1235–1244.
16. Ghio S, at al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001;37: 183–188.
17. Lewis G, Murphy R, Shah R, et al. Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circ Heart Fail 2011;4: 276-85.
18. Aronson D, Eitan A, Dragu R, Burger AJ. The relationship between reactive pulmonary hypertension and mortality in patients with acute decompensated heart failure. Circ Heart Fail 2011;4:644-50.
19. Chang PP at al. Mild vs severe pulmonary hypertension before heart transplantation: different effects on posttransplantation pulmonary hypertension and mortality. J Heart Lung Transplant 2005;24:998–1007.
20. Costard-Jackle A, Fowler MB. Infl uence of preoperative pulmonary artery pressure on mortality aft er heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48–54.
21. Semler HJ, Shepherd JT, Wood EH. Th e role of vessel tone in maintaining pulmonary vascular resistance in patients with mitral stenosis. Circulation 1959;19:386-94.
22. Badesch BD, Champion HC, Gomez-Sanchez MA, Hoeper M,at al A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55–S56.
23. Oudiz RJ. Pulmonary hypertension associated with left -sided heart disease. Clin Chest Med 2007;28:233–241.
24. Thenappan Thenappan, MD; Sanjiv J. Shah, MD; Mardi Gomberg-Maitland at al. Clinical Characteristics of Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction. Circ Heart Fail. 2011;4:257-265.
25. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation 2012;126:975–90.
26. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102:1718–23.
27. Cooper CJ, Jevnikar FW, Walsh T, et al. The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure. Am J Cardiol 1998; 82: 609–614.
28. Ray L et al. Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Exp Physiol. 2008;93:434–442.
29. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation. 1992;85:504–509.
30. Hülsmann M at al. Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure. J Am Coll Cardiol. 1998;32:1695–1700.
31. Guazzi M. Alveolar gas diffusion abnormalities in heart failure. J Card Fail. 2008;14:695–702.
32. Rabinovitch M. EVE and beyond, retro and prospective insights. Am J Physiol. 1999;277:L5–L12.
33. Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation. 2009;119:2663–2670.
34. Vasiliki V. Georgiopoulou, MD et al; Left Ventricular Dysfunction With Pulmonary Hypertension Part 1: Epidemiology, Pathophysiology, and Definitions. Circ Heart Fail. 2013;6:344-354.
35. Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 2013;41:217–23.
36. Provencher S, Hervé P, Sitbon O, Humbert M, Simonneau G, Chemla D. Changes in exercise haemodynamics during treatment in pulmonary arterial hypertension. Eur Respir J 2008;32:393–8.
37. Rapp A. at al. Relation of pulmonary arterial diastolic and mean pulmonary arterial wedge pressures in patients with and without pulmonary hypertension. Am J Cardiol 2001;88:823–4.
38. Gerges C, Gerges M, Lang MB, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest 2013;143:758–66.
39. Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology. Eur Heart J 2008; 29:2388–2442.
40. Drazner MH, Hamilton MA, Fonarow G, Creaser J, Flavell C, Stevenson LW. Relationship between right and left -sided fi lling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant. 1999;18:1126–1132
41. Elliott AR, Fu Z, Tsukimoto K, Prediletto R, Mathieu-Costello O, West JB. Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure. J Appl Physiol. 1992;73:1150 –1158.
42. Bogaard H J, Natarajan R, Henderson SC, Long CS, Kraskauskas D, at al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation. 2009;120:1951–1960.
43. Haddad H, Elabbassi W, Moustafa S, Davies R, Mesana T, at al. Left ventricular assist devices as bridge to heart transplantation in congestive heart failure with pulmonary hypertension. ASAIO J. 2005;51:456–460.
44. Martin J, et al. Implantable left ventricular assist device for treatment of pulmonary hypertension in candidates for orthotopic heart transplantation-a preliminary study. Eur J Cardiothorac Surg. 2004;25:971–977.
45. Salzberg SP, Lachat ML, von Harbou K, Zünd G, Turina MI. Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates. Eur J Cardiothorac Surg. 2005; 27:222–225.
46. Zimpfer D, Zrunek P, Sandner S, Schima H, Grimm M, at al. Posttransplant survival aft er lowering fixed pulmonary hypertension using left ventricular assist devices. Eur J Cardiothorac Surg. 2007;31:698–702.
47. John R et al. Effects on pre- and posttransplant pulmonary hemodynamics in patients with continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2010;140:447–452.
48. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail 2005;11:12–20.
49. Kalra P. at al. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Intl J Cardiol 2002;85:195–7.
50. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:44–54
51. Anand I, McMurray J, Cohn JN, et al., EARTH investigators. Longterm effects of darusentan on left -ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:347–54.
52. Lüscher TF, Enseleit F, Pacher R, et al. Heart Failure ET(A) Receptor Blockade Trial. Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation 2002;106:2666–72.
53. Bocchi EA, Guimarães G, Mocelin A, Bacal F, Bellotti G, Ramires JF. Sildenafi l effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebocontrolled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002;106:1097–103.
54. Gomez-Sanchez MA et al. Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafi l in candidates for heart transplantation. Eur J Heart Fail 2004;6:615–755.

55. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafi l on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677–80.
56. Lewis GD, Shah R, Shahzad K, et al. Sildenafi l improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007;116:1555–62.
57. Lewis GD, Lachmann J, Camuso J, et al. Sildenafi l improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation 2007;115:59–66.
58. Guazzi M, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafi l on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 2004; 44:2339–48.
59. Melenovsky V et al. Transpulmonary B-type natriuretic peptide uptake and cyclic guanosine monophosphate release in heart failure and pulmonary hypertension: the effects of sildenafi l. J Am Coll Cardiol 2009;54:595–600.
60. Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafi l in the therapeutic management of heart failure. J Am Coll Cardiol 2007;50: 2136–44.
61. Schwartzenberg S at al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 2012; 59:442– 51.
62. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011;124: 164–74.
63. Miller Wl at al: Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail 2013, 1:290-9.
64. Karatasakis GT, Karagounis LA, Kalyvas PA, Manginas A, at al. Prognostic significance ofechocardiographically estimated right ventricular shortening in advanced heart failure. Am J Cardiol. 1998;82:329–334.

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