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Management of Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction Elie Kozaily1 · Ecem Raziye Akdogan1 · Natalie Stringer Dorsey2 · Ryan J. Tedford1,3$7.99
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Management of Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction Elie Kozaily1 · Ecem Raziye Akdogan1 · Natalie Stringer Dorsey2 · Ryan J. Tedford1,3
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Management of Pulmonary Hypertension in the Context of Heart
Failure with Preserved Ejection Fraction
Elie Kozaily1
· Ecem Raziye Akdogan1
· Natalie Stringer Dorsey2
· Ryan J. Tedford1,3
Management of Pulmonary Hypertension in the Context of Heart
Failure with Preserved Ejection Fraction
Elie Kozaily1 · Ecem Raziye Akdogan1 · Natalie Stringer Dorsey2 · Ryan J. Tedford1,3
Abstract
Purpose of Review To review the current evidence and modalities for treating pulmonary hypertension (PH) in heart failure
with preserved ejection fraction (HFpEF).
Recent Findings In recent years, several therapies have been developed that improve morbidity in HFpEF, though these stud-
ies have not specifically studied patients with PF-HFpEF. Multiple trials of therapies specifically targeting the pulmonary
vasculature such as phosphodiesterase (PDE) inhibitors, prostacyclin analogs, endothelin receptor antagonists (ERA), and
soluble guanylate cyclase stimulators have also been conducted. However, these therapies demonstrated lack of consistency
in improving hemodynamics or functional outcomes in PH-HFpEF.
Summary There is limited evidence to support the use of pulmonary vasculature-targeting therapies in PH-HFpEF. The
mainstay of therapy remains the treatment of the underlying HFpEF condition. There is emerging evidence that newer HF
therapies such as sodium-glucose transporter 2 inhibitors and angiotensin-receptor-neprilysin inhibitors are associated
with improved hemodynamics and quality of life of patients with PH-HFpEF. There is also a growing realization that
more robust phenotyping PH and right ventricular (RV) function may hold promise for therapeutic strategies for patients
with PH-HFpEF.
Introduction 5]. PH-HFpEF is classified under the World Symposium on
Pulmonary Hypertension (WSPH) group 2 PH, or PH due to
Heart failure with preserved ejection fraction (HFpEF) is at left heart disease. The latter is defined hemodynamically as
least as common as heart failure with reduced ejection frac- mean pulmonary artery pressure (mPAP) > 20 mmHg along
tion (HFrEF) and generally carries a similar prognosis with with pulmonary artery wedge pressure (PAWP) > 15 mmHg
a high burden of morbidity and mortality [1]. The prevalence [6]. It is further subclassified as isolated post-capillary pul-
of HFpEF is only projected to increase [2, 3]. Pulmonary monary hypertension (IpcPH) when PVR < 2 Woods Unit
hypertension (PH) is frequently co-morbid with HFpEF. The (WU) or combined pre- and post-capillary pulmonary hyper-
prevalence of PH in HFpEF may be up to 80% [4], yet its tension (CpcPH) when PVR ≥ 2WU [7]. The recent lowering
definition and prevalence vary widely between studies [3, of both the mPAP as well as PVR cut points was based on
large populations studies of normative data [8]. IpcPH is
more prevalent than CpcPH, with some studies reporting
* Ryan J. Tedford IpcPH at least twice as prevalent [9, 10]. CpcPH, however, is
TedfordR@musc.edu
associated with pulmonary congestion, worse right ventricle
1
Division of Cardiology, Department of Medicine, Medical (RV) function, more impairment in oxygen delivery with
University of South Carolina, Charleston, SC 29425, USA hypoxemia during exertion [9, 11], and ultimately higher
2
Department of Medicine, Medical University of South risk of mortality [11].
Carolina, Charleston, SC, USA Because PH is both a marker of disease severity in
3
Advanced Heart Failure & Transplant Fellowship Training HFpEF and has hemodynamic characteristics shared with
Program, Medical University of South Carolina (MUSC), 30 pulmonary arterial hypertension (PAH), it naturally follows
Courtenay Drive, BM215, MSC592, Charleston, SC 29425, that targeting the pulmonary vasculature may constitute a
USA
Vol.:(0123456789)
, Current Hypertension Reports
therapeutic target in patients with HFpEF. The goal of this Outcomes in NYHA Class III Heart Failure Patients).
review is to provide an update on the management of PH in Benza et al. found that patients with PH (17.5% with pre-
the context of HFpEF. served LVEF) had a significant 36% decrease in HF hos-
pitalizations but a non-significant difference in mortality
[19]. This reduction in HF hospitalizations was consist-
Management of PH in HFpEF ent across subgroups of patients with PVR ≥ 3 WU and
PVR < 3 WU. Assmus et al. investigated the effects of
The first goal of treating PH in HFpEF is to target the cardioMEMS using the MEMS-HF data where 35% of
underlying heart failure syndrome and its potential causes. patients with PH had preserved LVEF [20]. The authors
HFpEF is associated with multiple comorbidities such as observed a significant and comparable reduction in HF
type 2 diabetes mellitus, systemic hypertension, atrial hospitalizations in patients with IpcPH (55% reduction)
fibrillation (AF), obstructive sleep apnea (OSA), and and CpcPH (63% reduction) as well as a meaningful
obesity. Controlling these comorbidities with dietary improvement in health-related quality-of-life surveys.
modification, weight loss, aerobic exercise, and even drug
therapy improves outcomes in HFpEF [3].
Mineralocorticoid Receptor Antagonists
Loop Diuretics The use of mineralocorticoid receptor antagonists (MRA)
is currently given a class IIB recommendation in the ACC/
In the ACC/AHA heart failure guidelines, loop diuretics AHA heart failure guidelines for treating HFpEF [12].
have a class I indication to achieve and maintain euvolemia Spironolactone for the treatment of HFpEF was studied
[12]. Normalization of left heart filling pressures will also in a randomized, double-blind, placebo-controlled trial of
lead to a reduction in pulmonary pressures. Additionally, N = 3445 patients with HFpEF (TOPCAT, Treatment of Pre-
reduction in left heart filling pressures results in both an served Cardiac Function Heart Failure with an Aldosterone
increase in pulmonary artery compliance (calculated as the Antagonist). Spironolactone was associated with reduction
ratio of stroke volume to pulmonary artery pulse pressure) in HF hospitalizations but did not significantly reduce the
and a decrease in PVR—the net effect is a reduction of incidence of the primary composite outcome of death from
RV afterload [13]. RV function is a critical determinant of cardiovascular causes, aborted cardiac arrest, or HF hospi-
mortality in HFpEF [14]. The benefits of loop diuretics on talization [21]. Notably, a post hoc analysis examined the
PH were demonstrated in studies that involved pulmonary regional differences in outcomes in participants from the
artery (PA) pressure monitoring devices (cardioMEMS) Americas (USA, Canada, Brazil, and Argentina) to par-
and tailored diuresis. Titrating loop diuretics based on PA ticipants from Eastern Europe (Russia and the Republic
pressure reduced HF hospitalizations [15, 16]. of Georgia) [22]. As compared to placebo, spironolactone
Even though some small studies suggested the benefits reduced primary outcome in the Americas but not in Rus-
of torsemide compared with other loop diuretics on myo- sia/the Republic of Georgia. This was accompanied with an
cardial fibrosis and ventricular remodeling [17, 18], there overall low event rate of primary outcome for both spironol-
are no studies to compare between different loop diuret- actone and placebo in participants from Russia/the Republic
ics in the context of PH-HFpEF. The recently published of Georgia 2.5 and 2.3 per 100 patient-years, respectively,
open-label, pragmatic clinical trial TRANSFORM-HF compared to 10.4 and 12.6 per 100 patient-years in the
(Torsemide Comparison With Furosemide for Manage- Americas, respectively. In addition, an analysis of spironol-
ment of Heart Failure) compared torsemide and furosem- actone metabolite in the urine revealed the absence of urine
ide in N = 2859 patients with heart failure of which 25% metabolite was more common in subjects from Russia and
had HFpEF. There was no difference in hospitalization the Republic of Georgia (30% vs 3%) casting doubts over
rates at 12 months, regardless of LVEF [18]. The trial did compliance with the trial drug [23].
not specifically account for PH. While MRA may be considered for treatment of HFpEF
Therefore, loop diuretics should be used as needed for regardless of the presence of PH [3], there is some evidence
volume management in patients with PH-HFpEF. No cur- to suggest MRA may have direct impacts on the pulmonary
rent evidence suggests the superiority of one loop diuretic vasculature. MRA has been shown to reverse aldosterone
over the other in this context. inhibiting effect on endothelin-type B in endothelial cells
The utility of cardioMEMS to guide diuresis in PH within pulmonary vessels. Endothelin-type B has a major
associated with left heart disease was described in a sub- vasodilatory effect on pulmonary artery endothelial cells
sequent analysis of the CHAMPION trial (CardioMEMS [24, 25]. An experimental animal study showed that spirono-
Heart Sensor Allows Monitoring of Pressure to Improve lactone and epleronone did not reduce PA pressure or reverse
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