Pulmonary Hypertension in Patients with Heart Failure and Preserved Ejection Fraction: Differential Diagnosis and Management

Abstract

The most common cause of pulmonary hypertension (PH) due to left heart disease (LHD) was previously rheumatic mitral valve disease. However, with the disappearance of rheumatic fever and an aging population, nonvalvular LHD is now the most common cause of group 2 PH in the developed world. In this review, we examine the challenge of investigating patients who have PH and heart failure with preserved ejection fraction (HF-pEF), where differentiating between pulmonary arterial hypertension (PAH) and PH-LHD can be difficult, and also discuss the entity of combined precapillary and postcapillary PH. Given the proven efficacy of targeted therapy for the treatment of PAH, there is increasing interest in whether these treatments may benefit selected patients with PH associated with HF-pEF, and we review current trial data.

Keywords

pulmonary arterial hypertension combined pre- and postcapillary pulmonary hypertension heart failure with preserved ejection fraction diastolic dysfunction

Pulmonary hypertension (PH) is defined (Table 1) by a mean pulmonary arterial pressure (PAP) of ≥25 mmHg at right heart catheterization (RHC), with the most recent classification identifying 5 groups (Fig. 1):² group 1, pulmonary arterial hypertension (PAH), which can be idiopathic (IPAH) or associated with other conditions (most frequently systemic sclerosis and congenital heart disease); group 2, PH owing to left heart disease (PH-LHD); group 3, PH owing to lung disease (PH-Lung); group 4, chronic thromboembolic PH (CTEPH); and group 5, PH owing to unclear or multifactorial mechanisms. Accurate classification of disease is important in identifying the most appropriate form of therapy³ and defining prognosis.⁴ This requires a systematic approach to the evaluation of the breathless patient and an awareness of conditions associated with particular forms of PH.

Figure 1.

Classification of adult pulmonary hypertension. Adapted from Figure 1 of Kiely et al.³ COPD: chronic obstructive pulmonary disease; PH: pulmonary hypertension.

Table 1.

Hemodynamic definitions of pulmonary hypertension (PH)¹

Definition	Characteristics	Clinical groups
PH	mPAP ≥ 25 mmHg	All
Precapillary PH	mPAP ≥ 25 mmHg; PAWP ≤ 15 mmHg; CO normal or low	PAH (1), PH-Lung (3), CTEPH (4), unclear/multifactorial (5)
Postcapillary PH	mPAP ≥ 25 mmHg; PAWP > 15 mmHg; CO normal or low	PH-LHD (2)

Note: CO: cardiac output; CTEPH: chronic thromboembolic pulmonary hypertension; mPAP: mean pulmonary artery pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PH-LHD: PH due to left heart disease; PH-Lung: PH due to lung disease.

The most commonly encountered form of PH is related to left heart disease (LHD).^5,6 PH may be seen in heart failure with preserved ejection fraction (HF-pEF) and heart failure with reduced ejection fraction (HF-rEF), and its presence in HF-rEF is known to convey a poor prognosis.⁷ HF-pEF accounts for approximately half of all new heart failure (HF) diagnoses.^8,9 While HF-pEF was initially believed to confer a better outcome than HF-rEF, the two conditions have equivalent morbidity and mortality.^10–12

The prevalence of PH-HF-pEF is unclear and varies with diagnostic criteria. Studies quote rates of between 53% and 83% (based on an echocardiographic systolic PAP [sPAP] > 35 mmHg or mean PAP > 25 mmHg at RHC).^13–15 A recent study¹⁶ found that only 7% of heart failure (HF) patients had PH (but used an sPAP cutoff of ≥45 mmHg at echocardiography).

PATHOPHYSIOLOGY OF PH-LHD

PAH, PH-Lung, and CTEPH are precapillary in nature, caused by obstruction or destruction of the pulmonary arterial bed, whereas PH-LHD is thought to be primarily due to postcapillary abnormalities.⁵ In patients with LHD, an increase in left ventricular (LV) and left atrial (LA) filling pressures results in back-pressure to the pulmonary veins and a rise in PAP.¹⁷ This is often termed “passive” or “pulmonary venous” hypertension. Over time, persistent increases in pressure cause loss of the cellular integrity of the alveolar-capillary barrier, resulting in capillary leakage and alveolar edema.^18,19 This can eventually lead to irreversible remodeling and type IV collagen deposition,²⁰ causing a change in distal pulmonary arteries and increasing pulmonary vascular resistance (PVR).²¹ Endothelial damage results in an imbalance of vasoactive substances, such as reduced nitric oxide (NO)²² and elevated endothelin-1 (ET-1),²³ resulting in vasoconstriction. Interestingly, infusions of ET-1 in humans have been shown to impair ventricular systolic and diastolic function,²⁴ and elevated levels are an independent predictor of mortality in HF-rEF.²⁵ Unlike the pathological changes that occur in PAH, there are no true plexiform lesions seen in group 2 PH.²⁶

Echocardiographic studies have shown that restrictive mitral inflow patterns are associated with PH in those with reduced LV ejection fraction,²⁷ and in aortic stenosis, diastolic dysfunction, rather than severity of stenosis, correlated better with the degree of PH.²⁸ Other studies have also suggested that PH may be related to the severity of diastolic dysfunction.²⁹

CLINICAL IMPLICATIONS OF PH IN HF-PEF

Severe PH in LV diastolic dysfunction was described more than 30 years ago³⁰ and is a poor prognostic marker.³¹ A study by Lam et al.¹⁴ found elevated sPAP to be associated with increased mortality. One study, following HF-pEF patients after admission to hospital, showed that 3-year survival was ≍60% with sPAP < 39 mmHg at echocardiography, compared with ≍30% with higher PAP.³¹ In those with stable HF-pEF and PH, 3-year survival was higher, at ≍80%.⁴ We have shown that outcomes in PH due to HF-pEF can be further stratified according to the gas transfer factor for carbon monoxide (TLco) and incremental shuttle walk distance.³²

In patients with advanced HF-rEF, studies have shown that right ventricular (RV) function predicts survival.^33–35 Until recently there were few data published on RV function and survival in HF-pEF, but Melenovsky et al.³⁶ recently showed that RV dysfunction was present in a third of patients with HF-pEF. Those with RV dysfunction and HF-pEF had worse hemodynamics at RHC, and RV dysfunction was a strong predictor of mortality.

COMBINED POSTCAPILLARY AND PRECAPILLARY PH

In some patients, chronic passive backward transmission of filling pressures might trigger superimposed pulmonary vasoconstriction, decreased NO availability, and increased ET-1, leading to vascular remodeling.³⁷ At this point, mean PAP may increase disproportionately to the rise in pulmonary arterial wedge pressure (PAWP),³⁸ leading to pulmonary vascular disease (PVD). The transpulmonary gradient (TPG), calculated as (mean PAP) - PAWP, is commonly used to distinguish “passive” PH (TPG ≤ 12 mmHg) from “reactive” PH (TPG > 12 mmHg).¹ However, this definition alone has proved unsatisfactory. Some favor the use of PVR to identify the two patient groups, and a number of studies have shown that elevated PVR predicts outcome better than TPG in PH-LHD.^39,40 But PVR itself is a composite variable derived from TPG/cardiac output. A different variable is required that reflects changes in the pulmonary vasculature, is less dependent on changes in PAWP and stroke volume, and takes into account pulmonary artery distensibility.⁴¹

Recently, the diastolic pressure gradient (DPG; calculated as (diastolic PAP) - PAWP) has been proposed as an alternative method to establish the presence of PVD. The DPG is less sensitive to changes in pulmonary compliance, stroke volume, and PAP. In normal subjects, diastolic PAP should equal mean PAWP ± 2 mmHg.⁴² A retrospective study has shown that, in patients with HF and PVR < 200 dynes/s/cm⁻⁵, DPG was <6 mmHg in 94% of cases. But when PVR increased, half the patients had DPG > 5 mmHg, suggesting that the increase in diastolic PAP is unrelated to changes in PAWP.⁴³ Gerges et al.⁴⁴ investigated the prognostic influence of DPG in a recent paper. In that study, PH-LHD patients were separated into “passive” and “reactive” categories by TPG. Among those with reactive PH-LHD (identified by a TPG of >12 mmHg), receiver-operating-characteristic analysis demonstrated that a DPG of ≥7 mmHg predicted a worse survival rate. Survival in those with raised TPG and DPG was similar to that seen in PAH. Pulmonary vascular remodeling was also seen in the small number of lung biopsies taken from this group.

As a result, recent recommendations have proposed two types of PH-LHD based on DPG: “isolated postcapillary PH” (PAWP > 15 mmHg and DPG < 7 mmHg) and “combined postcapillary and precapillary PH” (PAWP > 15 mmHg and DPG ≥ 7 mmHg).⁴¹ However, Tedford et al.⁴⁵ have since shown that raised DPG was not associated with worse survival in patients after cardiac transplantation. In a study looking at hemodynamic markers in PH-LHD, Tampakakis et al.⁴⁶ demonstrated that DPG was not significantly associated with mortality, whereas PVR was. Although some of the study cohort did have HF-pEF, they were mostly young individuals with HF-rEF. The incidence of PH-LHD with DPG ≥ 7 was low (13%). Also, the DPG itself is a small number and therefore prone to errors in measurement, limiting its power to detect differences in survival in patients with PH and HF-pEF.⁴⁷ Thus, it has been suggested by some investigators that DPG is more likely to be of use as a diagnostic tool rather than as a prognostic one and that its significance should be placed in context with other hemodynamic parameters (such as TPG and PVR). Survival with PH in HF-pEF is probably linked more closely to other factors, such as RV adaption to afterload.

DIFFERENTIATING PAH FROM HF-PEF

Misdiagnosing patients with PAH results in inappropriate use of expensive therapies, inappropriate genetic counseling, and incorrect information regarding prognosis.⁴ Distinguishing between HF-pEF and other forms of PH can be difficult, as both have a near-normal LV ejection fraction. Here we examine criteria that might help us to differentiate between these two entities.

Risk factors

Risk factors are an important way of identifying the probability that a patient has PAH or PH-LHD. A number of associated conditions increase the likelihood of precapillary PH, such as systemic sclerosis or portal hypertension in PAH or previous pulmonary embolism (particularly if recurrent or large) in CTEPH, whereas those with HF-pEF have a preponderance of cardiovascular risk factors (see Fig. 2).^48,49 However, as the population ages, comorbidities present in HF-pEF are increasingly seen in PAH, and their presence does not exclude PAH.^50,51 The occurrence of metabolic disease and obesity is growing (in the United States, almost a third of the population over the age of 20 has metabolic syndrome).⁵² Metabolic syndrome has been shown to increase the risk of developing HF-rEF⁵³ and has also been associated with HF-pEF.¹⁴ Experimental studies have shown potential links between metabolic syndrome and PVD, evidenced by a reduction in vascular remodeling after targeting adiponectin and peroxisome proliferator-activated receptor γ pathways.^54,55 In two small studies of symptomatic patients, metabolic syndrome was found to be associated with both PAH⁵⁶ and pulmonary venous hypertension.⁴⁹ Recently, Gopal et al.⁵⁷ have demonstrated that metabolic syndrome is associated with RV diastolic dysfunction, increased pulmonary artery diameter, and raised PAP (10 mmHg higher than in controls). These findings persisted even when the increased LV diastolic dysfunction found in the group with metabolic syndrome was accounted for. This suggests that metabolic syndrome itself may predispose to PVD; however, the mechanism for this process is unclear, with potential alterations in a number of metabolic pathways.⁵⁸ HF-pEF patients often have symptoms of orthopnea and tend to have a worse exercise capacity than their PAH counterparts.⁵⁹

Figure 2.

Suggested algorithm for the investigation of patients with suspected pulmonary hypertension (PH) and preserved ejection fraction. AF: atrial fibrillation; CAD: coronary artery disease; CTEPH: chronic thromboembolic PH; DM: diabetes mellitus; DPG: diastolic pressure gradient; DVT: deep-vein thrombosis; ECG: electrocardiograph; ECHO: echocardiograph; HF-pEF: heart failure with preserved ejection fraction; HF-rEF: heart failure with reduced ejection fraction; LA: left atrium; LVEF: left ventricular ejection fraction; LVH: left ventricular hypertrophy; mPAP: mean pulmonary artery pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PE: pulmonary embolism; PVR: pulmonary vascular resistance; RAD: right-axis deviation; RHC: right heart catheterization; RV: right ventricular; SLE: systemic lupus erythematosus; sPAP: systolic pulmonary artery pressure; WU: Wood units.

Electrocardiograph, chest x-ray, and lung function

Pleural effusions on a chest radiograph⁶⁰ are seen more frequently in LHD (although they may be present in severe PAH). Left-axis deviation and LV hypertrophy on an electrocardiograph are more often seen in HF-pEF,⁶¹ whereas patients with advanced PAH tend to show evidence of R-wave dominance in V1, right-axis deviation, and more RV strain.^50,62 Also, end-tidal CO₂⁶³ and TLco⁴ have been found to be lower in patients with PAH than in those with PH and HF-pEF.

Echocardiography

Although current guidelines emphasize the use of RHC to differentiate PAH from PH-LHD,⁶⁴ it has been recognized that patients with HF-pEF may present with normal PAWP and, conversely, that those with PAH may have a high PAWP at RHC.⁶⁵ Echocardiography can be used to help differentiate PAH from HF-pEF. Mitral annular tissue Doppler velocity on echo can be used to estimate LV end-diastolic pressure (LVEDP) and assess diastolic function.⁶⁶ An E/e′ of <9 has been shown to differentiate advanced IPAH from PH-LHD.⁶⁷ A small study has shown that the majority of patients with PAH had grade I LV diastolic dysfunction but that only 2% had grade II or III dysfunction.⁶⁸ Care must be taken when assessing LV diastolic function, however, as interaction from the interventricular septum in the presence of a pressure-loaded RV can alter LV filling.⁶⁹ Patients with HF-pEF often have left rather than right atrial enlargement.⁵⁹ Studies have attempted to use echo variables to help improve the prediction of PVD. Arkles et al.⁷⁰ showed that “notching” of the RV outflow tract Doppler signal could help to predict increased PVR and poor vascular compliance. The lack of notching was highly predictive of a PVR of <3 Wood units (WU) and a PAWP of >15 mmHg. Opotowsky et al.⁷¹ took this a step farther by deriving a score based on LA dimension, midsystolic notching of RV outflow tract Doppler signal, and E/e′. A score of ≥0 had 100% sensitivity and 69% positive predictive value for PVD.⁷¹ We have recently shown that sPAP measured at echocardiography is often significantly raised in HF-pEF but that an sPAP of >70 mmHg is likely to represent PVD and not just pulmonary venous hypertension (sensitivity: 75%, specificity: 78%).⁷²

Cardiac magnetic resonance (CMR) and computer tomography (CT) imaging

CT pulmonary angiography (CTPA) is used to assess patients with unexplained PH, where it may identify a cause such as CTEPH. Although CTPA is an ungated scan, it allows for evaluation of cardiac chambers, structural changes in vessels, lung parenchyma, and the mediastinum.⁷³ It has been shown to be helpful in assessing disease severity in PAH, and characteristic features such as biatrial dilation can be appreciated in LHD.³ More recently, there has been interest in the use of CMR imaging in the assessment of PH. Swift et al.⁷⁴ have shown that RV mass was lower in patients with PH and HF-pEF, with better-preserved cardiac function and less late gadolinium hinge-point enhancement, than in patients with precapillary disease such as IPAH and CTEPH, where PVR was significantly elevated.

RHC

Although PAWP approximates LVEDP, this is not always the case.⁷⁵ It has been suggested that using digitalized mean PAWP instead of end-expiratory PAWP may underestimate true LA pressure;⁷⁶ however, others have reached the opposite conclusion.⁷⁷ If in doubt, wedge position may be confirmed by blood oxygen saturation equal to systemic saturations, taken from catheter tip with the balloon inflated.⁷⁸ It should be recognized that PAWP may overestimate LA pressure,⁷⁹ and one must be cautious in interpreting raised PAWP in the setting of a normal-sized LA. An elevated measured PAWP may also be seen in CTEPH as a result of the presence of laminated clot and webs in the pulmonary arteries.⁸⁰ LVEDP measurement by left heart catheterization may be required in selected cases to avoid misclassification.⁶⁴

Fluid challenge

Fluid challenges may help unmask patients with reduced atrial compliance.^81,82 A fluid bolus of 500 mL administered over 5 minutes appears to be safe and can help identify patients with HF-pEF but normal PAWP at baseline. However, larger volumes may cause a rise in PAWP, even in healthy individuals.⁸³ Thus, rapid infusion of intravenous fluid while monitoring for a rise in the PAWP may help to uncover pulmonary venous hypertension, but the results must be interpreted cautiously.

Exercise challenge

The role of exercise in the differential diagnosis of PH-LHD has not been clearly established. PAP increases in normal individuals on exertion.⁴² In a study on exercise-induced PH, PAWP > 15 mmHg was found in half the healthy control group. Borlaug et al.⁸⁴ looked at the use of exercise in unmasking patients with suspected HF-pEF but normal PAWP (<15 mmHg). They found that during exercise, end-expiration PAWP rose considerably higher than that in controls (32 ± 6 vs. 13 ± 5 mmHg). Nevertheless, current guidelines do not advocate the use of exercise challenges.⁶⁴

Diagnostic algorithm

A suggested algorithm to differentiate HF-pEF from precapillary PH is shown in Figure 2. An estimated sPAP on echocardiography of ≤36 mmHg makes the presence of PH unlikely.¹ If a patient presents with HF and/or echocardiography demonstrates an sPAP of >36 mmHg in the presence of risk factors for PAH/CTEPH, that patient must undergo further evaluation to investigate for the presence of PH, given the relatively high pretest probability of disease. In the absence of risk factors for PAH/CTEPH and even if at least 2 risk factors for HF-pEF exist, if severe rises of sPAP are seen (>70 mmHg), RV function is significantly impaired, or paradoxical septal motion exists, then patients should undergo further investigation to exclude other causes of PH that may coexist with LV diastolic dysfunction. Where at least 2 risk factors for HF-pEF exist in the absence of risk factors for PAH/CTEPH, no further investigation is usually required in patients with modest elevation of sPAP where RV function is normal or mildly impaired and there is absence of paradoxical septal motion.

Charalampopoulos et al.⁵⁰ demonstrated that patients with PAH often had at least one cardiovascular risk factor but that those with PH-LHD had more. However, each case must be assessed in its clinical context, and if there is ongoing concern that a patient may have precapillary disease, there should be further investigation. Table 2 summarizes the investigations that can be used to identify a cause for PH.³

Table 2.

Investigations to determine causes of pulmonary hypertension (PH)

Investigation	Diagnostic use
Blood tests
ANA, ENA, DS-DNA	CTD-associated PAH
HIV	0.5% of patients with HIV have PAH
Lung function
Spirometry	Mild PH common in severe respiratory disease, e.g., FEV1 < 40%
TLco	Often reduced but usually >60% predicted in PH-LHD; if TLco < 50% predicted, consider lung disease or underlying CTD
SaO₂	If <92% at rest, consider respiratory disease or R-L shunt
Imaging
Lung perfusion scan	Normal scan excludes CTEPH; quantitative Q scan can be used to identify R-L shunts
HRCT	May demonstrate emphysema/ILD; mosaic perfusion patterns may be seen in CTEPH, and centrilobular ground glass common in PAH
CTPA^a	May show acute emboli; or chronic disease identified by webs, stenosis, and mural thrombus; demonstrates cardiac chamber sizes and vascular anatomy, e.g., APVD
ECHO/CMR	Assessment of ventricular function; paradoxical septal motion, RVH, and D-shaped LV associated with increased likelihood of precapillary PH
MRA	Normal 3D perfusion maps exclude CTEPH; used with CTPA to select patients for pulmonary endarterectomy; can identify R-L shunts

Note: ANA: antinuclear antibodies; APVD: anomalous pulmonary venous drainage; CMR: cardiac magnetic resonance imaging; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; CTPA: computed tomography pulmonary angiography; DS-DNA: double-stranded DNA; ECHO: echocardiography; ENA: extractable nuclear antigens; FEV1: forced expiratory volume in 1 second; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; LV: left ventricle; MRA: magnetic resonance angiography; PAH: pulmonary arterial hypertension; PH-LHD: PH due to left heart disease; R-L: right-left; RVH: right ventricular hypertrophy; SaO₂: oxygen saturation; TLco: gas transfer factor for carbon monoxide; 3D: 3-dimensional.

Although large defects are usually identified, nonspecialist pulmonary vascular radiologists may miss features such as webs and the absence of perfusion. For this reason lung perfusion scanning is often the preferred test for excluding CTEPH.

We have already discussed the advantages and shortcomings of different hemodynamic parameters used to separate HF-pEF from combined pre- and postcapillary PH. Although none are perfect, both PVR³⁹ and DPG⁴⁴ have been shown in recent studies to affect prognosis. Tampakakis et al.⁴⁶ have shown that PVR is predictive of outcome at 2, 2.5, 3, and 3.5 WU. We have chosen a PVR of 3 WU because this usually denotes the presence of PVD in patients with PAH. Although Tampakakis et al.⁴⁶ did not show additional benefit in determining prognosis when combining PVR and DPG, we believe that DPG still has strong physiological grounding and that its role should not be dismissed. This does leave us with a group of patients who have DPG ≥ 7 mmHg and PVR < 3 WU or DPG < 7 mmHg and PVR ≥ 3 WU, whose phenotype is presently unclear. These suggestions are summarized in Table 3.

Table 3.

Proposed classification of group 2 PH-LHD

	TPG, mmHg	DPG, mmHg	PVR, WU
Isolated postcapillary PH	<12	<7	<3
Combined pre- and postcapillary PH	≥12	≥7	≥3
Unclear phenotype	≥12	≥7	<3
Unclear phenotype	≥12	<7	≥3

Note: DPG: diastolic pressure gradient; PH: pulmonary hypertension; PH-LHD: PH due to left-heart disease; PVR: pulmonary vascular resistance; TPG: transpulmonary gradient; WU: Wood units.

Current guidelines rely on the use of elevated PAWP (>15 mmHg) at RHC to differentiate PAH from PH-LHD.¹ However, patients with features of PAH may present with high PAWP, and those with a diagnosis of HF-pEF can have a resting PAWP of ≤15 mmHg,⁶⁵ for example, in those who have undergone forced diuresis.⁸⁵ Thus, it is vital to take into account not only the RHC results but also a complete assessment of each patient's medical history, risk factors, and noninvasive imaging when making a diagnosis.

TREATMENT OPTIONS IN PH ASSOCIATED WITH HF-PEF

European Society of Cardiology guidelines currently state that treatment with targeted PH therapy is not recommended because of a lack of evidence and the risk of pulmonary edema.¹ Current management is aimed at optimizing the underlying condition and volume status of the patient, along with aggressive management of risk factors. While a number of drugs improve mortality in HF-rEF, the usage of these drugs in HF-pEF has yielded disappointing results.⁸⁶

Endothelial dysfunction in HF has been suggested as a cause of PH³⁷ and therefore seems a reasonable target for treatment. A number of trials using targeted PAH therapies in HF have been conducted (Table 4), and while some have reported hemodynamic improvement, there is as yet no conclusive evidence of benefit. However, many are small, single-center studies with no randomization process. HF patients are a very heterogeneous population, and to date trials have not focused on patients with potential combined postcapillary and precapillary PH or RV dysfunction, who are likely to have the greatest degree of pulmonary vascular remodeling and are theoretically more likely to respond to treatment.

Table 4.

Key trials of PH-specific therapy in left heart failure

Trial name	Drug	Study design	Year	Inclusion criteria^a	n	Length of follow-up, months	Primary outcome	Result^a
EMRC⁸⁷	Epoprostenol	Prospective, controlled, nonrandomized	1995	LVEF < 30%, NYHA III/IV	33	3	6MWD	↑6MWD
FIRST⁸⁸	Epoprostenol	Prospective, controlled, nonrandomized	1997	LVEF < 30%, NYHA III/IV	471	9	Mortality	Terminated early because of ↑ mortality
Serra et al.⁸⁹	Prostaglandin El	Prospective, controlled, nonrandomized	2008	LVEF < 35%, NYHA III/IV	45	36	Mortality	No effect
REACH-1⁹⁰	Bosentan	Double-blind, placebo controlled, randomized	2002	LVEF < 35%, NYHA III/IV	370	6	Mortality/worsening HF	No effect; terminated early because of LFT abnormalities
HEAT⁹¹	Darusentan	Double-blind, placebo controlled, randomized	2002	LVEF ≤ 35%, CI ≤ 2.6 L/min, PAWP > 12 mmHg	157	1	CI/PAWP	No effect
ENABLE⁹²	Bosentan	Prospective, placebo controlled, randomized	2003	LVEF < 35%, NYHA III/IV	1,613	18	Mortality/hospitalization	Early worsening of HF
EARTH⁹³	Darusentan	Double-blind, placebo controlled, randomized	2004	LVEF < 35%, NYHA II-IV	642	6	LV end-systolic volume	No effect
Kaluski et al.⁹⁴	Bosentan	Double-blind, placebo controlled, randomized	2008	LVEF < 35%, sPAP > 40 mmHg, NYHA III/IV	94	5	sPAP	No effect
Lewis et al.⁹⁵	Sildenafil	Double-blind, placebo controlled, randomized	2007	LVEF < 40%, mPAP > 25 mmHg	34	3	Peak $\overset{\cdot}{V}$ o₂	↑Peak $\overset{\cdot}{V}$ o₂
Behling et al.⁹⁶	Sildenafil	Double-blind, placebo controlled, randomized	2008	LVEF ≤ 40%, stable HF symptoms	19	1	Peak $\overset{\cdot}{V}$ o₂, sPAP	↑Peak $\overset{\cdot}{V}$ o₂, ↓sPAP
Guazzi et al.⁹⁷	Sildenafil	Double-blind, placebo controlled, randomized	2011	LVEF ≥ 50%, sPAP > 40 mmHg, signs/symptoms of HF	44	12	Pulmonary hemodynamics, RV performance	↓mPAP + PAWP, ↓RV size + RAP, ↑TAPSE
Guazzi et al.⁹⁸	Sildenafil	Double-blind, placebo controlled, randomized	2012	LVEF < 45%, mPAP = 25–35 mmHg	32	12	EOB, peak $\overset{\cdot}{V}$ o₂	EOB reversed, ↑peak $\overset{\cdot}{V}$ o₂
RELAX⁹⁹	Sildenafil	Double-blind, placebo controlled, randomized	2013	LVEF 50% + NYHA II-IV and hospitalization for HF or treatment with diuretics + ↑LA size or ↑LVEDP	216	6	Peak $\overset{\cdot}{V}$ o₂	No effect
LEPHT¹⁰⁰	Riociguat	Double-blind, placebo controlled, randomized	2013	LVEF ≤ 40%, mPAP ≥ 25 mmHg	201	4	mPAP	No effect

Note: CI: cardiac index; EOB: exercise oscillatory breathing; HF: heart failure; LA: left atrial; LFT: liver function test; LV: left ventricular; LVEDP: LV end-diastolic pressure; LVEF: LV ejection fraction; mPAP: mean pulmonary artery pressure; NYHA: New York Heart Association class of heart failure; PAWP: pulmonary arterial wedge pressure; PH: pulmonary hypertension; RAP: right atrial pressure; RV: right ventricular; sPAP: systolic pulmonary artery pressure; TAPSE: transannular planar systolic excursion; $\overset{\cdot}{V}$ o₂: oxygen consumption as measured by cardiopulmonary exercise testing; 6MWD: 6-minute walk distance.

The symbols ↑ and ↓ indicate increased and decreased, respectively.

Prostanoids

Prostanoids were the first drug group to demonstrate a mortality benefit in PAH in a placebo-controlled randomized trial.¹⁰¹ It was postulated that their vasodilatory effects in the pulmonary and systemic circulation might help patients with advanced HF by reducing afterload. The FIRST trial was the largest randomized controlled trial involving intravenous epoprostenol in patients with HF-rEF,⁸⁸ but it was terminated early because of a trend toward increased mortality and reduced 6-minute walk distance (6MWD) in the treatment group. To date, no trials have been conducted in patients with HF-pEF.

Phosphodiesterase 5 inhibitors

Sildenafil has been used for erectile dysfunction by improving NO. However, phosphodiesterase 5 is also found in pulmonary and vascular endothelium and hypertrophied myocardium. Downregulating its expression appeared to improve hemodynamics and LV remodeling in experimental animal models.¹⁰² A small, placebo-controlled study of sildenafil in patients with PH and HF-pEF demonstrated a significant improvement in hemodynamics and symptoms at 6 months, with benefits persisting at 1 year.⁹⁷ A larger randomized, controlled trial involving HF-pEF patients, the RELAX study,⁹⁹ did not show any difference in the primary end point of $\overset{\cdot}{V}$ o₂ _max or in secondary end points of 6MWD and clinical-status score. CMR assessment of LV mass and echocardiographic parameters of diastolic function were also unchanged by the use of sildenafil. However, the presence of PH was not an entry criterion.

Endothelial receptor antagonists

Bosentan is a nonselective ET-1 receptor antagonist, and encouraging results were observed when it was used in animal models of HF.¹⁰³ A number of trials looking at various endothelial receptor antagonists in PH and HF-pEF are currently in progress. The BADDHY study (ClinicalTrials.gov identifier: NCT00820352) looking at the safety and efficacy of bosentan in patients with HF-pEF and PH-associated RV dysfunction has recently been completed, and results are awaited. The Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan (NCT00840463) was set up in 2009 but as yet has not finished recruitment. The MELODY-1 study (NCT02070991) is a safety and tolerability study looking at the use of macitentan in patients with combined pre- and postcapillary PH and is currently enrolling, with results expected in 2016.

Guanylate cyclase inhibitors

Riociguat is a new drug that aims to cause vasodilation by activation of the cyclic guanosine monophosphate pathway via direct stimulation and sensitization to NO.¹⁰⁴ It has already been shown to be of benefit in patients with CTEPH¹⁰⁵ and PAH.¹⁰⁶ The DILATE study (NCT01172756), which tested the effect of riociguat in patients with HF-pEF and a mean PAP of ≥25 mmHg at RHC, has been completed. Initial phase-2a results from DILATE-1 have been published that aimed to characterize the hemodynamic effects, safety, and pharmacokinetics of single oral doses of riociguat in patients with HF-pEF and PH.¹⁰⁷ Riociguat was well tolerated, and at 6 hours after dose demonstrated a reduction in RV end-diastolic dimension and an increase in stroke volume but no improvement in other invasive parameters, such as mean PAP or PVR.

Recommendations

The management of patients with PH and HF-pEF remains a challenge, given the lack of evidence from large randomized, controlled trials (the results of a number of studies are awaited). Systematic assessment is key to excluding other causes of PH, and overreliance on a single investigation can result in misdiagnosis. For the majority of patients with PH in HF-pEF and normal/mildly impaired RV function, our approach is to optimize fluid balance, modify risk factors such as hypertension, and treat prevalent comorbidities such as sleep apnea. For the minority of patients diagnosed with severe PH and HF-pEF (after fluid balance has been optimized, comorbidities have been treated, and other diagnoses have been excluded by systematic assessment including blood testing, echocardiography, CTPA, CMR, exercise testing, and RHC), should there be evidence of a potential vasculopathy with at least moderate RV impairment and raised TPG, DPG, and PVR, we would consider a trial of sildenafil in selected patients. We would review the patient 4 months after initiation of treatment with a clinical assessment, exercise testing, and RHC, and if there was no evidence of benefit, we would discontinue therapy.

CONCLUSIONS

PH is associated with HF-pEF, and it has a substantial adverse impact on symptoms and survival. Distinguishing patients with HF-pEF from those with PAH can be difficult but has important consequences for prognosis and treatment. We have attempted to provide an algorithm that may help with this assessment.

Passive elevation in PAP is the most common cause of PH in HF-pEF, but in a select few patients, a series of changes to the pulmonary vasculature may occur, resulting in potential combined postcapillary and precapillary PH. A number of indicators (in particular DPG) have been suggested to help differentiate these patient groups, but so far studies have yielded mixed results.

There is currently no approved treatment for patients with PH and HF-pEF. Studies using therapies targeted at the pulmonary vasculature in patients with HF have not yielded positive results, but this may be a reflection of their entry criteria. They have enrolled patients with a wide variety of hemodynamics and have rarely stratified for PH. There is a clear need for further research in this area in order to better understand the prevalence, natural history, and pathophysiology of PH in HF-pEF, to enable us to develop new therapeutic options for this expanding patient group.

Footnotes

ACKNOWLEDGEMENTS

RC, CAE, and DGK are investigators within the National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit.

Source of Support: NH is partially funded as a clinical research fellow by an unrestricted educational grant from Actelion.

Conflict of Interest: CAE has sat on advisory boards for, received consultancy and lecturing fees from, and been funded to attend conferences by Actelion, Bayer, Encysive, GlaxoSmithKline (GSK), Pfizer, and United Therapeutics. RC has received honoraria for lecturing from Actelion and GSK, has sat on advisory boards for Actelion and Bayer and has received conference funding from Actelion, GSK, Pfizer, and United Therapeutics. DGK has sat on advisory boards for and received consultancy and lecturing fees from Actelion, Bayer, Encysive, GSK, Pfizer, and United Therapeutics. All other authors: none declared.

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