an abnormal increase of pressures in the pulmonary vascular bed , or ph , can be a relatively common consequence of several cardiac , pulmonary , and systemic disorders   but also of the aging process . left heart diseases ( lhds ) , mainly hf with preserved or reduced ejection fraction ( hfpef or hfref ) and valvular heart disease , represent the most frequent causes of ph ( ph - lhd ) through the increase of left ventricular filling pressures and pulmonary venous pressures . presence of ph - lhd is associated with a decrease in exercise tolerance , worsening of dyspnea , and reduced survival [ 2 - 5 ] . several drug regimens approved for pah ( a rare disease ) have been tested in clinical trials to treat heart failure , with or without ph - lhd : all have yielded disappointing results so far . this emphasizes the specificities of ph - lhd , the importance of an appropriate hemodynamic classification , and the need for a strict selection of patients and endpoints for clinical trials . in this brief review , we will provide insights into the main areas of controversy in ph - lhd . ph - lhd is diagnosed by right or left heart catheterization ( or both ) when the mean pulmonary pressure ( papm ) is superior to 25 mm hg and the pulmonary capillary wedge pressure ( pawp ) or the left ventricular end - diastolic pressure exceeds 15 mm hg . pawp is definitely a surrogate measure for left ventricular end - diastolic pressure that is increased by a variety of cardiac diseases . the mechanism of ph - lhd is represented in figure 1 . in the resting pulmonary circulation , in which approximately 1:1 backward transmission of pressure can be observed between the left atrium and the diastolic pulmonary pressure ( papd ) , every 1 mm hg increase of left atrial pressure corresponds to a 1 mm hg increase in papd . this relatively simple equation displays how hfpef , hfref , and valvular heart disease may generate ph . however , the increase in left atrial pressures has a much more prominent impact on the elevation of systolic pulmonary arterial pressure and mean pulmonary pressures than of papd and further depends on cardiac output . in rare cases , patients will develop a significant pre - capillary pulmonary vascular disease that is not entirely explained by a passive increase in left atrial pressure . to date , the pre - capillary , or arterial , component of ph - lhd has been defined on the basis of transpulmonary gradient ( tpg ) ( that is , tpg = papm  pawp ; normal tpg  12 mm hg ) with a wide variety of definitions and terminologies ( among others ,  reactive  ,  out of proportion  , and  mixed  ph ) . confusion has been further promoted by the inappropriate extension of vasodilator testing to this subgroup of patients , with consequent spreading of an anomalous overlap between pah and ph - lhd and some expectation for a treatable component of the disease . abbreviations : bnp , brain natriuretic peptide ; et-1 , endothelin-1 ; la , left atrium ; mpap , mean pulmonary arterial pressure ; mr , mitral regurgitation ; pawp , pulmonary capillary wedge pressure ; pvd , pulmonary vascular disease ; rv , right ventricle . reproduced with permission of the editor from vachiery and colleagues . in the attempt to harmonize definitions , an updated hemodynamic classification based on the diastolic pulmonary difference ( dpd ) has been recently proposed for ph - lhd . the dpd has several advantages : it is virtually absent in healthy individuals , is less dependent than the transpulmonary gradient ( tpg = papm  pawp ; normal tpg  12 mm hg ) from stroke volume and pawp , and has been shown to provide added prognostic value to the tpg . this classification labels patients with high pawp ( > 15 mm hg ) and low dpd ( < 7 mm hg ) as having  isolated post - capillary ph  and patients with high pawp and dpd ( > 7 mm hg ) as having  combined post - capillary ph and pre - capillary ph  ( cpcph ) . essentially , this describes the hemodynamic status while avoiding any forecast on the components of vasoconstriction and remodeling . as previously mentioned , the lack of a uniform definition limits the comparison among available studies as well as the precise estimation of incidence and prevalence of ph - lhd . the existing variations in the epidemiology of ph - lhd depend largely on differences in methodology of evaluation ( prospective versus retrospective ) , disease classification , patient selection criteria ( age , risk factors , and left ventricular systolic function ) , technique of pulmonary pressure assessment ( hemodynamic versus non - invasive ) , and previous fluid optimization . as an example , the prevalence of moderate to severe ph at echocardiography among 11,327 suspected hf patients retrospectively included in the euro heart survey was 16%   but rose to 62% at invasive evaluation in a smaller prospective study performed by ghio and colleagues   in 379 consecutive patients with an ejection fraction of less than 35% . more recently , damy and colleagues , using an echocardiographic cut - off value of 35 mm hg for the tricuspid gradient , showed respective proportions of ph in 30% , 18% , and 4% of hfref , hfpef , and no - hf patients , respectively ; of note , the prevalences fell to 6% , 7% , and 8% when those without a measurable tricuspid regurgitation jet were included . applying the same echocardiographic limit to a population of 244 consecutive patients with hfpef , another study yielded a remarkable 83% prevalence of ph . well how definitions and diagnostic protocols may affect results and the importance of invasive evaluation as gold standard for quantifying pressures , cardiac output , and pulmonary vascular resistances ( pvrs ) in ph . recent data suggest that the prevalence of cpcph is around 12% in patients with hf . clear evidence that ph increases mortality in hf independently from the underlying cause emerged from the first reports more than 20 years ago . the available data confirm that prognosis of hfpef is comparable to or only faintly better than that of hfref ; moreover , in both conditions , the decrease in survival is similarly proportional to the elevation of pulmonary systolic pressure even if the majority of patients will present with only a mild to moderate degree of ph . accuracy of risk estimation can be further increased on the basis of the ph subtype : mixed ph ( or combined pre- and post - capillary ph , pvr of at least 3 wood units ) has a largely higher risk of death than passive ph ( or isolated post - capillary ph , pvr of less than 3 wood units hazard ratio 1.55 ) . in the previously mentioned study from ghio and colleagues , right ventricular function , new york heart association functional class , left ventricular end - diastolic diameter index , and papm were all independent survival predictors at multivariate analysis ; interestingly , despite confirmation that papm and right ventricular ejection fraction are inversely related , the latter kept its prognostic value only in the subgroup of patients with high papm . this confirms the importance of the right ventricular response to afterload over the absolute value of pressures as a determinant for survival in ph - lhd . at present , fewer data are available on the prognostic impact of other parameters employed for diagnosis , such as dpd and tpg . in a recent work , dpd increased prediction of survival in 1094 patients undergoing invasive evaluation for confirmation of ph : at a median follow - up of 78 months , combined pre- and post - capillary ph had the same worse outcomes as pre - capillary ph . however , this was not confirmed by a subsequent retrospective analysis of the hemodynamic data of 5827 orthotopic heart transplant recipients with pre - transplant ph and elevated tpg and pvr : the post - transplant survival rate at five years was similar when a stratification on the basis of dpg was performed . one of the limitations of the latter lies in the selected population studied ; that is , only the patients undergoing transplant were studied , and naturally patients with significant pulmonary vascular disease were excluded . besides the controversies in definition and diagnosis of ph - lhd , the general agreement is that treatment of ph - lhd should start with aggressive management of the underlying cardiac disease and of any other potential confounding factor , such as respiratory tract infections , sleep apnea syndrome , arrhythmias , or pulmonary embolism . diuretics are the mainstay of medical treatment for fluid control and relief of congestion , whereas angiotensin - converting enzyme inhibitors and -blockers are indicated to improve morbidity and long - term survival in hf . some subsets of patients may benefit from invasive monitoring and cyclic inotropic support to optimize volume status , alleviate symptoms , or reduce hospitalizations ( or a combination of these ) , although the long - term benefit of this strategy remains uncertain . when appropriate , corrective / palliative surgery for valvular heart disease should be considered , along with the implantation of cardiac resynchronization therapy or implantable cardiac defibrillators for those with qrs of more than 120 ms and ejection fraction of less than 35% . if clinically indicated , younger patients unresponsive to medical treatment should be evaluated for heart transplantation or implantation of ventricular assist devices to support cardiac output , either as a bridge to transplant or as destination therapy . for this indication , the appealing hypothesis of targeting ph - lhd with drugs approved for pah has been supported by affinities in the increase of endothelin-1 levels and in the impairment of nitric oxide - mediated vasodilation ; small single - center therapeutic trials have reported improvement of exercise capacity and hemodynamic parameters [ 16 - 18 ] . however , the results of randomized trials have been largely unsatisfactory , if not detrimental , with most of the compounds . in our opinion first , patients were generally not stratified on the basis of ph , nor was hemodynamic evaluation systematically performed . second , with the exception of phosphodiesterase-5 inhibitors , mostly patients with hfref were enrolled and patients with valvular heart disease were excluded . lastly , high dosages of compounds were used in order to attain systemic effects . as a result , data coming from multicenter randomized trials are scarce . in fact , only two of these trials are available in the literature . in a multicentric placebo - controlled trial , riociguat ( a soluble guanylate cyclase stimulator approved for pah and chronic thromboembolic pulmonary hypertension ) was compared with placebo in 201 patients with ph due to hf - ref during 16 weeks . no effect on the primary endpoint ( a change in papm after 16 weeks ) was observed at any dose of riociguat compared with placebo . a proof - of - concept study to test the acute effects of riociguat in patients with ph associated with diastolic dysfunction ( nct01172756 ) two multicenter clinical trials in ph - lhd are currently under way with the phosphodiesterase 5 inhibitors sildenafil ( nct01616381 ) and tadalafil ( nct01910389 ) . although these trials plan to include a well - defined population with ph due to systolic hf , the absence of right heart catheterization validation of ph might represent a significant limitation . finally , a pilot phase ii study with the endothelin receptor antagonist macitentan ( melody-1 ) ( nct02070991 ) is the only trial including patients falling in the new definition of cpcph . until results from large trials are available , ph - lhd despite several advances in assessment and classification , ph - lhd is still an under - recognized threatening complication of lhds . a new definition and harmonized terminology will provide a better identification of a subset of patients who deserve special attention . in this area of unmet clinical need , proof - of - concept studies are needed to implement larger randomized trials , along with robust clinical end - points . combined pre- and post - capillary ph appears to be one of the main fields of interest for therapeutic trials with pah - specific drugs . this should lead to better use of resources , at least by decreasing inappropriate off - label drug use in this context . jean luc vachiery has received consultancy and speaker fees from actelion pharmaceuticals and bayer schering .
left heart failure is currently the most prevalent cause of pulmonary hypertension ( ph ) worldwide and this is due mainly to the increased left ventricular and pulmonary venous pressures seen in this condition . 
 still , a quota of patients with left heart failure will have a pulmonary arterial disease 
 disproportionate  to the initial increase of left - sided pressures . 
 whatever the mechanism involved , the appearance of ph is a powerful marker , as it determines decreased exercise tolerance and survival . to date , all trials using therapies approved for pulmonary arterial hypertension ( pah ) failed to demonstrate a benefit in the context of heart failure ( hf ) without or with ph . 
 in addition , the comparison among studies is limited by relevant differences in definitions , methodology , and timing of assessment . a novel rigorous hemodynamic classification based on the diastolic pulmonary gradient 
 has been recently proposed to better characterize this form of ph . 
 this will promote uniformity in patient populations and end - points for future clinical trials .