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Reprint requests: Marco Guazzi, MD, PhD, FACC, Department of Biomedical Sciences for Health, University of Milano, Heart Failure Unit, Cardiology, IRCCS Policlinico San Donato, Piazza E. Malan 2, San Donato Milanese, Milano 20097, Italy. Telephone and Fax: +39-02-52774966
Department of Physical Therapy and Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois Chicago, Chicago, Illinois
In heart failure with preserved ejection fraction (HFpEF), an entity that remains challenging and difficult to treat, the development of pulmonary hypertension (PH), via an increase in left atrial pressure, is the direct consequence of reduced relaxation and enhanced stiffness of the left ventricle and is now viewed as an important contributor to clinical worsening and increased mortality. PH becomes a relevant clinical phenotype in approximately 50% of patients with HFpEF and represents a true challenge in the clinical follow-up and management of these patients. Along with these epidemiologic insights, there has been increasing recognition of the pathophysiology of PH and its consequences on the right ventricle in patients with HFpEF. Novel and effective therapeutic interventions aimed at preventing and reversing PH are highly relevant in the attempt to modify the poor clinical trajectory and growing health care burden of HFpEF. Many theoretical rationales as well as progressively accumulating evidence support the usefulness of nitric oxide pathway–potentiating compounds in targeting the lung vasculature through phosphodiesterase 5 inhibitors or guanylate cyclase stimulators to produce vasodilation and potentially a biologic effect. These pharmacologic strategies may be clinically effective options for the treatment of PH in patients with HFpEF; however, large controlled trials are necessary to address definitively the safety, tolerability, and potential impact on morbidity and mortality. This review details the pathophysiologic process, prevalence, and consequences of HFpEF-associated PH and discusses current and emerging treatment strategies to prevent or treat this deleterious sequela when present.
Heart failure with preserved ejection fraction (HFpEF) is a costly syndrome that is observed primarily in elderly patients with a high rate of associated comorbid factors and shows a reverse trend in prevalence compared with HF with reduced ejection fraction (HFrEF).
Pulmonary hypertension (PH) is well known to be associated with left-sided HF and is probably the most common cause of an abnormally elevated mean pulmonary artery pressure (mPAP; i.e., ≥ 25 mm Hg by consensus). Development of PH in HFpEF has undoubtedly been underestimated in the past as a significant contributor to disease progression and unfavorable outcome.
This underestimation may be related to the still incompletely defined issue of whether PH complicating HFpEF may be a marker rather than a risk factor and reflect unmeasured confounders such as duration of disease and dynamic mitral regurgitation. Impaired relaxation and augmented stiffness of the myocardium, which is due partly to stiffening of the arterial system yielding to an increase in left ventricular (LV) afterload, are main cardiac features in patients with HFpEF.
When the left ventricle becomes noncompliant and its filling is impaired, augmented atrial pump activity becomes an essential compensatory mechanism with atrial emptying that must rely more on the self-generated vis a tergo than on the ventricular-generated vis a fronte. A typical hemodynamic cascade is promoted where atrial compensation does not preclude a progressive pressure back reflection with a stepwise increase in the venous, capillary, and arterial pulmonary system pressures. The resulting retrograde circulatory alterations may eventually lead to episodes of acute decompensation, specifically pulmonary interstitial or alveolar edema.
In the long-term, the left atrial-venous pressure increase drives a progressive pulmonary artery pressure (PAP) elevation increasing the pulsatile loading of the right ventricle.
Subsequent development of right ventricular (RV) dysfunction and failure leads to biventricular decompensation, making the clinical condition critical (Figure 1).
Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (tapse) among out-patients referred for the evaluation of heart failure.
Prevalence, clinical phenotype, and outcomes associated with normal b-type natriuretic peptide levels in heart failure with preserved ejection fraction.
Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction.
Figure 1 Cascade of PH development, from etiology to its determinants: impaired LV relaxation and stiffness, increased capillary and pulmonary pressures, and RV failure. JVD, jugular venous distention; LAP, left atrial pressure; PA, pulmonary artery.
These pathophysiologic findings and associated poor clinical outcomes have prompted exploration of a more focused treatment strategy aimed at preventing or treating left-sided PH in patients with HFpEF.
Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): a randomized, double blinde, placebo-controlled, single-dose study.
This review details the pathophysiologic process, prevalence, and consequences of HFpEF-associated PH and discusses current and emerging treatment strategies to prevent or treat this deleterious sequela.
Definition and prevalence
Left-sided or group 2 PH is defined as a mPAP > 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest.
Coexistence of significant mitral incompetence is an additional feature that differentiates left-sided PH from other forms. Although mitral regurgitation is more common in HFrEF, it has also been reported as a key pathophysiologic factor in HFpEF.
Independently of left ventricular ejection fraction (LVEF), group 2 PH may become a meaningful component of HF syndrome in acute and chronic settings. In acute HF, PH occurs as a precipitating factor in de novo HF and chronic HF exacerbation.
and its clinical relevance is invariably related to the severity of the background disorder.
On the surface, reported PH prevalence in HFpEF broadly approximates the prevalence observed in HFrEF, although differences in case series and method of PAP assessment may significantly affect actual prevalence. However, in PH associated with HFpEF, an increased pulmonary artery systolic pressure (PASP) is more frequently observed in elderly patients with hypertensive heart disease, diabetes, and obesity
The Aspire Registry data support the premise that pulmonary hemodynamics are qualitatively similar in HFpEF and HFrEF, but PH is more prevalent in HFpEF.
Most recently, the TOPCAT (Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist) trial documented a PH prevalence of 36% of cases (ClinicalTrials.gov Identifier: NCT00094302).
Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial.
The precise mechanism whereby high blood pressure affects the heart and/or the pulmonary vessels is undefined. However, in patients with high blood pressure, the tone and reactivity of pulmonary vessels at baseline
are higher than normal. This finding suggests specific pathways for an abnormal sensitivity of the pulmonary arterial tree.
In a study comparing patients with PH-HFpEF vs idiopathic pulmonary artery hypertension (PAH) and HFpEF without PH, a similar degree of mean PAP elevation was found between PH-HFpEF and PAH. Patients with PH-HFpEF were older and had more cardiovascular comorbidities, lower functional capacity, and worse renal function than patients with idiopathic PAH.
Compared with patients without PAP elevation, more patients with PH-HFpEF were women and had RV enlargement and hypertrophy to a degree comparable to that in PAH. According to Leung et al,
PH-HFpEF is more frequently associated with higher LV end-diastolic pressure, more advanced age, atrial arrhythmias, obesity, and chronic obstructive pulmonary disease compared with HFpEF with normal PAP. In 2 reports comparing PH-HFpEF and PH-HFrEF
Outcomes in World Health Organization group II pulmonary hypertension: mortality and readmission trends with systolic and preserved ejection fraction induced pulmonary hypertension.
atrial fibrillation was the comorbid condition that best differentiated HFpEF. An echocardiography-derived PASP ≥ 39 mm Hg identifies a worse prognosis in HFpEF vs HFrEF,
Outcomes in World Health Organization group II pulmonary hypertension: mortality and readmission trends with systolic and preserved ejection fraction induced pulmonary hypertension.
The alterations of anatomy and physiology of the pulmonary capillary system triggered by left atrial pressure elevation have not been well defined or considered strongly in the pathophysiology of HFpEF. There is consistent basic science evidence that lung structural remodeling warrants consideration as an important contribution to the outcome of patients with left-sided heart disease. A better understanding of the pathobiology of lung vessels is relevant for the identification of novel and specific therapeutic targets.
A sudden increase in left atrial pressure produces what has been described as stress failure of the alveolar-capillary junction—a barotrauma that injures the microvessels; alters endothelial permeability, fluid filtration, and reabsorption; and definitively leads to gas exchange impairment. Interstitial edema and alveolar flooding are the most significant consequences of stress failure.
When left atrial elevation is less striking and is long-lasting, true remodeling of capillaries and small arteries occurs. A cascade of hormonal and cytotoxic activation is involved in the remodeling process. Although acute stress failure of the alveolar-capillary membrane is reversible in most cases, regression of arteriolar remodeling is doubtful.
Animal models help in the understanding of molecular and cellular mechanisms involved in the capillary injury process. In a mouse model of PH-HFpEF with LV hypertrophy and left atrial pressure elevation induced by aortic banding, PH development caused lung fibrosis and leukocyte infiltration and increased lung weight secondary to tissue and vascular changes as opposed to increased extravascular lung water and arteriolar remodeling (Figure 2).
In other studies using the same animal model, lungs had (1) alveolar-capillary changes reminiscent of stress failure and (2) endothelial dysfunction attributable to impaired [Ca2+]i endothelial homeostasis, as reflected by the lack of [Ca2+]i oscillations and attenuation of the response to mechanical stress or chemical stress with histamine, acetylcholine, or thapsigargin.
Whether these findings may mimic human pathophysiology and clinical correlates is still waiting a definitive answer.
Figure 2 Data from an animal model of LV dysfunction and hypertrophy induced by 4 weeks of aortic banding. (A) Changes in non-muscular to muscularized arterioles progressively increase from HF LVEF > 50% to LVEF < 50%. These changes occur along with leukocyte infiltration (B) and fibrosis (C). Adapted from Chen Y, Guo H, Xu D, et al. Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease. Hypertension 2012;59:1170-8.
Nonetheless, evidence obtained in human left-sided heart disease/dysfunction demonstrates that impaired gas exchange may reflect stress failure of the alveolar-capillary membrane.
Regardless of LVEF, the abnormally high mPAP (i.e., > 25 mm Hg) initially increases in proportion to PCWP, which is defined as hemodynamically abnormal when ≥15 mm Hg. According to the classic definition, there is a balanced increase between mPAP and PCWP, enough to maintain a normal transpulmonary gradient (TPG; <12 mm Hg) and no elevation in pulmonary vascular resistance (PVR; <1.5 Wood units), is termed passive or proportionate PH. This stage is interpreted as reflecting no vascular component in the mPAP elevation. As the pulmonary pressure increase becomes sustained, mPAP shows an increase that exceeds what would be expected from the increase in PCWP, indicated by a TPG > 12 mm Hg and/or elevated PVR > 3 Wood units; this is referred to as reactive or mixed PH. Once reactive, PH generally becomes out of proportion and may be characterized as reversible or fixed in response to a vasodilator challenge (Figure 3A).
Figure 3Definition and classification of group 2 PH according to TPG (A) vs DPG (B). When mPAP is increased in the presence of a normal TPG (mPAP-PCWP < 12 mm Hg), PH is defined as passive. When TPG is > 12 mm Hg, PH is defined as reactive or mixed, and it may be in proportion (parallel increase in mPAP vs PCWP) or out of proportion (abnormal increase in mPAP vs PCWP) and reversible or not to pharmacologic challenge. The Nice consensus conference working group has established a 4-level DPG scale, proposing 2 PH categories on the basis of the level of the DPG: isolated post-capillary PH (PCWP > 15 mmHg and DPG < 7 mmHg) and combined post-capillary and pre-capillary PH (PCWP > 15 mmHg and DPG ≥ 7 mmHg). The DPG classification eliminates the definition of “out of proportion PH,” a condition for which terminology may generate confusion with the hemodynamic picture of other forms of PAH.
There is some interindividual variability in the time course of these changes with a different extent of adaptation and reversibility for similar hemodynamic patterns. In a study involving patients with HFpEF of differing severity, a significant correlation was found between the degree of TPG and PVR with the degree of LV myocardial extracellular matrix accumulation assessed by cardiac magnetic resonance T1 mapping analysis and biopsy tissue analysis,
establishing a potential cardiac correlate to vascular remodeling.
The definition of TPG that becomes significant for a limit ≥12 mm Hg has been questioned as to whether or not it is reflective of a constitutive vascular component. Following what was originally proposed by Harvey et al,
based on the main concept that the gradient between mPAP and PCWP is sensitive to changes in cardiac output and loading conditions, especially related to the pulsatile load.
However, both recruitment and distention of the pulmonary vessels may decrease the backward transmission of left atrial pressure. The dominant concept behind the DPG measure is that the pulmonary flow is maximum during systole and negligible at end diastole, and in a normal population, diastolic PAP is approximately equal to the pressure in the left atrium. Consistently in normal subjects, DPG is in the range of 1 to 3 mm Hg, and in patients evaluated for cardiac disease (excluding shunts), the DPG is <5 mm Hg in most cases.
The Nice consensus conference working group has established a 4-level DPG scale, proposing 2 PH categories on the basis of the level of the DPG: isolated post-capillary PH (PCWP > 15 mm Hg and DPG <7 mm Hg) and combined post-capillary and pre-capillary PH (PCWP > 15 mm Hg and DPG ≥ 7 mm Hg) (Figure 3B).
The DPG classification eliminates the definition of “out of proportion PH,” a condition for which terminology may generate confusion with the hemodynamic picture of other forms of PAH.
The prognostic significance of the DPG has been investigated by Gerges et al,
who retrospectively assessed a group of patients with HFrEF and showed that in cases with post-capillary PH and a TPG > 12 mm Hg, a worse median survival was associated with a DPG ≥ 7 mm Hg compared with a DPG <7 mm Hg (101 months; p = 0.010). However, the main survival curve separation was observed between the non-PH vs passive PH group rather than passive vs pre-capillary PH. Although an elevated DPG (≥7 mm Hg) was associated with more advanced pulmonary vascular remodeling, some histologic abnormalities (intimal fibrosis and medial hypertrophy) were already reported in patients with passive PH (Figure 4), suggesting that a pure hemodynamic definition may not plausibly match a biologic one. The definitive clinical and prognostic implications of using a DPG classification remain to be elucidated, especially considering that an extensive analysis
Prognostic value of the pre-transplant diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.
of the prognostic significance of DPG performed in >5,000 patients with group 2 PH has shown a lack of any prognostic discriminatory power when event-free survival was analyzed according to different DPG thresholds. In this analysis, patients with a lower DPG showed the highest PCWP values.
Figure 4 Survival course and modifications of small arteries according to increasing levels of DPG. Adapted from 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.
The diagnosis of PH-HFpEF may be problematic in a situation such as when a patient complains of dyspnea with a PCWP that is normal at rest but abruptly increases during physiologic stresses such as exercise
More recent observations strongly support the idea of incorporating these provocative tests for early diagnosis and treatment of PH-HFpEF, although there are still few data to support this practice, mainly because of a lack of clarity in defining a normal pulmonary pressure response during exercise or fluid challenge and what rate of increase for specific workload or fluid amount/rate must be considered significant for a PH diagnosis. In 55 patients with dyspnea on exertion, a confirmed euvolemic condition, normal B-type natriuretic peptide assay, and normal systolic LV function, a bout of maximal exercise with simultaneous right-heart catheterization assessment clearly induced a significant consensual increase in PCWP and LV end-diastolic pressure in almost 50% of cases. This finding strongly suggests that HFpEF symptoms and pulmonary hemodynamics may be exacerbated by exercise, anticipating a true diagnosis.
performed an analysis by challenging LV filling pressure with saline infusion (0.5-liter bolus of saline in 5–10 minutes) in 287 patients with PH that was by definition classified as group 2 in 36 subjects. After saline infusion, 46 patients initially labeled as non–group 2 PH displayed a fluid-mediated increase in PCWP > 15 mm Hg, which the authors reclassified as occult venous PH. As anticipated, these patients had a high rate of reported typical HFpEF risk factors, such as hypertension, older age, female gender, and higher body mass index.
RV function
The right ventricle empties its volume into a very low impedance circuit and maintains cardiac output according to venous return. The first response to an increase in afterload is a decrease in cardiac output. Adaptive mechanisms entail the development of hypertrophy and, subsequently, dilation, the main consequences of which are a geometric unfavorable change with tricuspid regurgitation; the normal right ventricle crescent shape transforms into a more spherical structure with a leftward shift of the septum, impaired filling of the left ventricle, with further increase of left atrial pressure, and an elevation of central venous pressure.
There may be a spectrum of clinical phenotypes in cardiac PH that might evolve from one to the other, from isolated post-capillary PH with a minimal effect on the right ventricle to more advanced disease where the failing right ventricle is the key determinant of outcome.
Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.
Am J Physiol Heart Circ Physiol.2013; 305: H1373-H1381
Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (tapse) among out-patients referred for the evaluation of heart failure.
Prevalence, clinical phenotype, and outcomes associated with normal b-type natriuretic peptide levels in heart failure with preserved ejection fraction.
Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.
Am J Physiol Heart Circ Physiol.2013; 305: H1373-H1381
The prevalence of RV dysfunction as assessed by fractional area and S prime is common in patients with HFpEF, but it seems to be milder than in HFrEF. A large cohort analysis
Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (tapse) among out-patients referred for the evaluation of heart failure.
confirmed that the right ventricle is depressed in 50% of HFpEF cases and showed that the percentage of cases with severely compromised RV function (tricuspid annular plain systolic excursion [TAPSE] <14 mm) is lower (19%) in cohorts with preserved compared with reduced LVEF (69%). In this study, the prognostic power of TAPSE was similar regardless of the type of LV dysfunction producing left-sided PH. Prognostic stratification improves when TAPSE is categorized according to different levels of PASP.
Combining TAPSE and PASP and assuming their relationship as reflective of RV contractility provides meaningful prognostic data regardless of the degree of LVEF (Figure 5A).
Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.
Am J Physiol Heart Circ Physiol.2013; 305: H1373-H1381
A similar approach using RV fractional area vs PASP has shown that a lower and steeper slope in HFpEF indicates depressed RV contractility and higher afterload sensitivity in addition to more severe PH (Figure 5B).
The most recent evidence suggests that RV geometric alterations (negative) and RV hypertrophy (positive) in HFpEF play a significant role in predicting survival rate.
Figure 5(A) TAPSE vs PASP relationship as indicator of RV contractility showing a similar distribution for HFpEF and HFrEF. Adapted from Guazzi M, Bandera F, Pelissero G, Castelvecchio S, Menicanti L, Ghio S, Temporelli PL, Arena R. Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis. Am J Physiol Heart Circ Physiol. 2013 ;305:H1373-81.
Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.
Am J Physiol Heart Circ Physiol.2013; 305: H1373-H1381
(B) Right ventricle fractional area vs mean PAP showing a lower and steeper slope in HFpEF with RV dysfunction and PH. FAC, fractional area changes. Adapted from Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J 2014 May 29. pii: ehu193 [Epub ahead of print].
An interesting finding that awaits further evidence is that levels of circulating b-type natriuretic peptide can determine the severity of the disease and define prognosis.
Prevalence, clinical phenotype, and outcomes associated with normal b-type natriuretic peptide levels in heart failure with preserved ejection fraction.
In a large population of patients with PH-HFpEF, hyponatremia was associated with an 82% increased risk of mortality compared with normal sodium level, and the risk of events in patients with concomitant RV dysfunction was >2-fold, even after adjustment for clinical, echocardiographic, and laboratory variables.
Data concerning the rate of passive and mixed PH subgroups in HFpEF are not homogeneous and are limited by small- to medium-size, single-center case series. Studies of right heart catheterization in patients with PH-HFpEF have provided some discrepant information when DPG rather than TPG is used.
Prevalence, clinical phenotype, and outcomes associated with normal b-type natriuretic peptide levels in heart failure with preserved ejection fraction.
Collectively, these studies show that type of PH (passive or reactive) is unrelated to the value of PAP or PCWP, and an increase in TPG is associated with a corresponding increase in DPG of 3 to 7 mm Hg, which seems the most usual pattern. These changes may reflect an increased vascular tone and/or intrinsic remodeling of the pulmonary arterioles. In different studies, clinical severity was not closely related to the degree of the pulmonary pressure elevation. This finding is in favor of an individual biologic variability in the evolution process that is at least partly separated from the hemodynamic staging and may suggest that distinct therapeutic targets are needed.
reported that the survival of a patient with PH-HFpEF at 1 year is worse than the survival of a patient with group 1 PAH. The authors created a risk score to determine the prognosis of these patients. They assessed 2 independent cohorts of patients retrospectively and prospectively, and several clinical characteristics as relevant and independent predictors of all-cause death with the combination of 8 variables (New York Heart Association Functional Class, RV hypertrophy, diffusing capacity for carbon monoxide, serum creatinine, diastolic blood pressure, pulmonary artery saturation measured at right heart catheterization, and interstitial lung disease) were identified as combined prognosticators in a multistep regression analysis. The clinical utility of this risk score needs further evaluation.
Therapeutic interventions
Although it is intuitive that the management of PH-HFpEF should be aimed at improving LV diastolic properties and pulmonary venous pressure, there is a sufficient rationale for considering lung vascular disease as a primary therapeutic target. Despite this rationale, reports are scanty on the topic. Endothelin receptor antagonists (ERAs) and epoprostenol, although beneficial in PAH, have provided neutral or negative results in patients with HFrEF and concomitant group 2 PH.
There are 2 ongoing ERA trials in PH-HFpEF. The Safety and Efficacy Trials to Treat Diastolic Heart Failure Using Ambrisentan (ClinicalTrial gov. identifier: NCT00840463) has as primary end-point of safety of ambrisentan at 16 weeks and World Health Organization functional class, 6-minute walk test distance, and a Short Form Health Survey score improvement as secondary outcomes. The Safety and Efficacy of Bosentan in Patients with Diastolic Heart Failure and Secondary Pulmonary Hypertension (BADDHY; ClinicalTrial gov. identifier NCT00820352) is planned to test the efficacy of bosentan on 6-minute walk test distance and quality of life.
Evidence is accumulating that phosphodiesterase 5 (PDE5) inhibition, by avoiding cyclic guanosine monophosphate breakdown, can effectively and safely target the pulmonary vessels and unload the right ventricle in left-sided PH.
Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide.
The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure.
Pattern of resolution of pulmonary hypertension, long-term allograft right ventricular function, and exercise capacity in high-risk heart transplant recipients listed under oral sildenafil.
PDE5 inhibition. The mounting evidence of the benefits of PDE5 inhibition is posited to be due to the abundant PDE5 inhibition expression in the pulmonary vessels and to the unique properties of PDE5 inhibition selectively targeting pulmonary and intrapulmonary circulation rather than the systemic circulation.
In this way, the untoward systemic vasodilation that is common with other pulmonary vasodilators, such as prostanoids and ERAs, is prevented. However, the mechanism by which other pulmonary vasodilators increase PCWP, whereas PDE5 inhibitors do not, is unclear; it may relate to the direct beneficial effects on LV diastolic stiffness with PDE5 inhibitors, mediated by cyclic guanosine monophosphate–dependent phosphorylation of titin
PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
we tested long-term (1-year) PDE5 inhibition in a selected population of 44 patients with PH-HFpEF resulting from high blood pressure and depressed RV function. The drug was well tolerated and was effective in reducing pulmonary arteriolar resistance and right atrial pressure. RV contractile function and dimensions and lung diffusion capacity (as an index of interstitial lung water) were improved. Benefits were also significant for LV mass, tissue Doppler measures of diastolic LV function, and PCWP. In the placebo arm, there was a progressive increase in mPAP. The associated increase of pulmonary arteriolar resistance with stable PCWP suggests that changes in pressure in these patients were due to evolution of the vascular disease rather than LV diastolic dysfunction. Improvement or no progression of the diastolic disorder offers the double advantage of improving the background pathophysiology and preventing worsening of PCWP that may occur with other pulmonary vasodilators. Consequently, in a rat experimental model of HFpEF caused by aortic banding,
PDE5 inhibition with sildenafil was found to improve pulmonary endothelial function and to reverse vessel remodeling and LV hypertrophy. More significantly, the right ventricle tended to assume normal geometry, reduced mass, and improved systolic function.
Along with the overall consistent evidence, the RELAX Study (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure, ClinicalTrials.gov Identifier: NCT00763867),
Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
involving a larger number of patients with HFpEF, has failed to show any benefit with sildenafil administration 60 mg 3 times a day for 24 weeks. However, the trial did not evaluate pulmonary hemodynamic assessment or RV function. In addition, PH, either passive or reactive in origin, was not a pre-specified entry criterion. These unfavorable results do not answer the question if a more selective HFpEF-PH cohort may benefit from PDE5 inhibition.
Large morbidity and mortality trials and more targeted well-designed smaller trials will ultimately be required to address definitively the role of these agents in the management of left-sided PH.
Soluble guanylate cyclase stimulators are another class of agents that selectively target the intracellular nitric oxide (NO) pathway. Riociguat is the first of this class of agents tested in humans. The soluble guanylate cyclase–stimulating activity of riociguat is both direct and NO mediated.
It is currently undergoing regulatory review for indication in PAH and inoperable chronic thromboembolic PH. Its application in PH-HFpEF is being tested in a phase 2 study (A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Diastolic Dysfunction [DILATE] ClinicalTrials.gov identifier: NCT01172756), showing that riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.
Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): a randomized, double blinde, placebo-controlled, single-dose study.
Development of PH in HFpEF is an unfavorable evolving feature that can worsen morbidity and mortality, mainly when RV failure develops with a cascade of interacting multiorgan life-threatening events. The eliciting trigger is elevated left atrial pressure secondary to impaired LV relaxing properties, which may be followed by capillary injury, arteriolar vasoconstriction, and remodeling. When PH-HFpEF develops, the vascular component seems to become dominant, and lung vasodilators may have an indication, especially agents with a downstream overexpressing activity on the NO pathway. Continued study is needed to determine better the phenotype of patients who may benefit from more selective pulmonary vascular agents.
Disclosure statement
This manuscript was supported by the Monzino Foundation, Milano, Italy.
References
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Heart failure with preserved ejection fraction: a clinical dilemma.
Prevalence of, associations with, and prognostic value of tricuspid annular plane systolic excursion (tapse) among out-patients referred for the evaluation of heart failure.
Prevalence, clinical phenotype, and outcomes associated with normal b-type natriuretic peptide levels in heart failure with preserved ejection fraction.
Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction.
Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): a randomized, double blinde, placebo-controlled, single-dose study.
Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial.
Prognostic value of the pre-transplant diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.
Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis.
Am J Physiol Heart Circ Physiol.2013; 305: H1373-H1381
Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide.
The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure.
Pattern of resolution of pulmonary hypertension, long-term allograft right ventricular function, and exercise capacity in high-risk heart transplant recipients listed under oral sildenafil.
PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.
Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
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