
==== Front
Am J Physiol Heart Circ Physiol
Am J Physiol Heart Circ Physiol
AJPHEART
American Journal of Physiology - Heart and Circulatory Physiology
0363-6135
1522-1539
American Physiological Society Rockville, MD

38639739
H-00068-2024
H-00068-2024
10.1152/ajpheart.00068.2024
Review
molecular-and-cellular-physiology-of-heart-failure-and-cardiomyopathyMolecular and Cellular Physiology of Heart Failure and CardiomyopathyNovel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction
NOVEL INSIGHTS INTO PATHOBIOLOGY OF PH-HFpEF
https://orcid.org/0009-0004-0548-5403
Aradhyula Vaishnavi 1
Vyas Rohit 1
Dube Prabhatchandra 1
https://orcid.org/0000-0002-6919-6342
Haller Steven T. 1
https://orcid.org/0000-0001-7428-7671
Gupta Rajesh 1
https://orcid.org/0000-0003-1445-791X
Maddipati Krishna Rao 2
https://orcid.org/0000-0001-5265-0142
Kennedy David J. 1
Khouri Samer J. 1
1Department of Medicine, University of Toledo College of Medicine and Life Sciences , Toledo, Ohio, United States
2Department of Pathology, Lipidomics Core Facility, Wayne State University , Detroit, Michigan, United States
Correspondence: S. J. Khouri (samer.khouri@utoledo.edu); D. J. Kennedy (david.kennedy@utoledo.edu).
1 6 2024
19 4 2024
19 4 2024
326 6 H1498H1514
2 2 2024
1 4 2024
15 4 2024
Copyright © 2024 The Authors.
2024
The Authors.
https://creativecommons.org/licenses/by/4.0/ Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.

diastolic HF
; HFpEF
; PH
PH-HFpEF
; PUFA
; Adela and Alfred Mundt Foundation for Heart Failure Research S.J.K. David and Helen Boone Foundation Research Fund D.J.K. University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center D.J.K. and S.T.H.HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) 10.13039/100000050 HL-137004 D.J.K. and S.T.H.Call for PapersTrue
==== Body
pmcINTRODUCTION

Pulmonary hypertension (PH) is a progressive, debilitating disease with poor patient outcomes. One of the leading causes of PH is heart failure (HF) with preserved ejection fraction (HFpEF), or PH-HFpEF. As summarized in Table 1, PH-HFpEF is classified as World Health Organization (WHO) Group II PH because of left heart disease (PH-LHD) and carries a significant healthcare burden because of its high morbidity and mortality. Despite advances in our understanding of pathophysiology, the underlying molecular mechanisms are largely unknown. PH-HFpEF presents as a spectrum, initially presenting as isolated postcapillary PH (ipc-PH) that can progress to the severe combined pre- and postcapillary PH (cpc-PH). Cpc-PH consists of more extensive pulmonary vascular (PV) remodeling than ipc-PH and can trigger right ventricle (RV) dysfunction. Biological factors such as oxidative stress, inflammation, and metabolic derangements have been suggested to be associated with RV dysfunction in PH-HFpEF; however, the mechanisms underlying this association remain unclear. A significant unresolved question is why a subset of patients with HFpEF develop only ipc-PH, cpc-PH, or do not develop PH at all.

Table 1. Definitions of pulmonary hypertension by the World Health Organization

Group					
 PAH; WHO Group I	PH-LHD; WHO Group II	PH due to chronic lung disease and/or hypoxia;WHO Group III	CTEPH; WHO Group IV	PH secondary to other diseases; WHO Group V	
Examples					
 Idiopathic PAH, heritable PAH, drug and toxin-induced, veno-occlusive disease, secondary to portal hypertension, congenital heart diseases, human immunodeficiency virus infection, connective tissue disease	Left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital cardiac anomalies/outflow tract obstruction	Chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, alveolar hypoventilation disorders	CTEPH	Chronic hemolytic anemia, splenectomy, sarcoidosis, metabolic disorders	
Subtypes					
 Idiopathic/heritable	Isolated postcapillary PH/combined pre- and postcapillary PH	Nonsevere PH/severe PH	N/A	Hematologic/systemic disorders	
Pathophysiology					
 • Increased vasoconstrictors,
decreased vasodilators
• Extracellular matrix remod
eling, vascular proliferation,
and inflammatory cell infil
tration
• Right ventricular
dysfunction	• Elevated left heart pres
sure transmitted to pulmo
nary vasculature leading
to pulmonary
vascular remodeling
• Molecular mechanisms
behind pulmonary vascu
lar remodeling are largely
unknown
• Right ventricular
dysfunction	• Chronic hypoxia leads to
pulmonary vasoconstric
tion, which leads to
increased pulmonary vas
cular resistance and PH
• Inflammation and fibrosis
contribute to remodeling
• Right ventricular
dysfunction	• Persistent clotting
• Pulmonary vascular
remodeling
• Right ventricular
dysfunction	• Variable
pathophysiology	
Pulmonary hypertension (PH) refers to any cause of high blood pressure in the lungs. The World Health Organization (WHO) defines five major groups of PH based on different etiologies. CTEPH, chronic thromboembolic pulmonary hypertension; N/A, not applicable; PAH, pulmonary arterial hypertension; PH-LHD, PH due to left heart disease.

Despite mechanistic similarities between PH-HFpEF and WHO Group I pulmonary arterial hypertension (PAH), such as elevated endothelin 1 (ET-1), lack of nitric oxide (NO), and decreased prostacyclin (PGI2), previous clinical trials that therapeutically targeted these pathways were beneficial in PAH, but demonstrated minimal or no effects in patients with PH-LHD (1). PH-LHD also consists of PH attributable to HF with reduced ejection fraction (HFrEF), or PH-HFrEF; however, PH-HFrEF differs from PH-HFpEF in etiology, cardiac remodeling, pathophysiology, comorbid diseases, and therapeutic response (1). PH-HFpEF is a lethal manifestation that lacks evidence-based approaches in diagnosis, prognosis, pathophysiology, and treatment (2). According to the 2022 American Heart Association (AHA) Science Advisory’s Call to Action, lack of standardization over diagnostic protocols, inconsistent interpretation of results, lack of reliable noninvasive diagnostic procedures, and poor mechanistic understanding of cpc-PH pathophysiology contribute to this growing epidemic (2).

Given the central role of inflammation in cardiovascular disease, examining the regulatory mechanisms that promote or resolve inflammatory processes may identify innovative therapeutic targets for PH-HFpEF. Incorporating noncardiac lipid contributors in the current paradigm is necessary for the understanding of PH-HFpEF to further close critical knowledge gaps. We review the current clinical understanding of PH-HFpEF, examine animal models that elucidate its pathophysiology, and describe novel inflammatory biomarkers contributing to pathological pulmonary vasculature changes.

EPIDEMIOLOGY OF PH-HFpEF

Approximately half of all patients with HF have HFpEF, yet management of this form of HF remains a diagnostic and therapeutic challenge. Patients with HF can be divided into those with HFrEF and HFpEF. Regardless of ejection fraction (EF) value, these patients share many similar features across the EF spectrum, including abnormal left ventricular (LV) filling dynamics, diastolic dysfunction, impaired exercise tolerance, hospitalization for decompensated HF, and most importantly, reduced survival (3). Studies have shown that compared with HFrEF, the incidence of HFpEF increases more rapidly with age and is closely associated with chronic metabolic diseases such as obesity, type 2 diabetes mellitus, hypertension, pulmonary disease, and liver disease (4). Obesity is a powerful and independent predictor of HFpEF development; however, interestingly, after HFpEF diagnosis, the presence of obesity is protective in what is known as the obesity paradox (5). This paradox is inversed when obesity is concomitantly present with type 2 diabetes (5). More than 50% of patients with HFpEF have five or more metabolic syndrome (metS) comorbidities, and the highest risk of hospitalization and death is in patients with comorbid metabolic conditions (3). Although observational studies have reported increased prevalence among women, after adjusting for age and other risk factors, the incidence of HFpEF was numerically but not statistically higher in women compared with men (6). The severity of HFpEF also increases more rapidly with aging, suggesting a close interplay with age-related inflammatory progression compared with HFrEF (7). In addition, randomized clinical trials highlighted by the American College of Cardiology (ACC)/AHA hypertension treatment guidelines have shown that the treatment for hypertension reduces HFpEF incidence by up to 40% over 2–8 years (8).

Risk Factors for PH-HFpEF

PH-LHD is associated with a 60% 5-years mortality rate and 50% 6-mo hospitalization rate (9). PH is a strong predictor of morbidity and mortality in patients with HFpEF. Reports from the Olmsted County Heart Failure Surveillance Study have shed light on the prevalence of PH-HFpEF in both the general community and in patients with HFpEF (10). These studies showed that aging, increased LV pressures, and systemic vascular stiffening were associated with increasing pulmonary arterial systolic pressure (PASP) (10). PASP was the strongest predictor of mortality in comparison with established markers, and these outcomes were similarly reflected in the general population as well (10). Overall, the prevalence of PH-HFpEF has been shown to range from 36 to 83% (10). The wide range can be attributed to the variability of studies based on diagnostic methods, definitions, study design, and populations. PH-HFpEF is a poor prognostic indicator, with PASP greater than 44 mmHg on echocardiography being associated with increased 5-years mortality, independent of the severity of HF (11).

As shown in Table 2, Stolfo et al. (12) identified that female sex, obesity, and hypertension were more prevalent in patients with HFpEF compared with HFrEF. Fayyaz et al. (16) also described body mass index (BMI) and dyslipidemia as risk factors between HF-PH versus no HF-PH. In addition, Rezaee et al. (13) observed age, BMI, and type 2 diabetes as risk factors more significant in patients with ipc-PH versus cpc-PH. Opitz et al. (14) identified that compared with WHO Group I idiopathic PAH, patients with PH-HFpEF had older age, higher BMI, more frequent hypertension, and type 2 diabetes as significant risk factors. Finally, Thenappan et al. (15) established that female sex carries a higher risk burden for PH-HFpEF compared with HFpEF.

Table 2. Demographic risk factors of PH-HFpEF

	Stolfo et al. (12)	Rezaee et al. (13)	Opitz et al. (14)	Thenappan et al. (15)	
	HFpEF	HFrEF	Ipc-PH	Cpc-PH	PH-HFpEF	PAH	HFpEF	PH-HFpEF	
n	18,165	40,893	457	54	226	421	45	100	
Age, yr	80	76	66.3 ± 11.3	63.9 ± 10.5	73.2 ± 8.3‡	61.5 ± 17.3	67 ± 11	64 ± 13	
Female, n (%)	9,731 (53.6)*	11,846 (29)	198 (43.3)	26 (48.2)	140 (61.9)	250 (59.4)	26 (58)§	82 (82)	
BMI, kg/m2	27 [24, 31]	26 [23, 30]	32.0 [N/A]	34.3 [N/A]	29.6 [25.7, 34]‡	26 [23.3, 29.8]	DNP	DNP	
Conditions, n (%)									
 Obesity	3,259 (31.2)*	5,875 (23.8)	87 (23.8)†	14 (31.8)	106 (47.1)‡	99 (23.5)	22 (49)	46 (46)	
 Hypertension	12,313 (67.8)*	20,401 (49.9)	287 (64.6)	34 (64.2)	208 (91.9)‡	182 (43.2)	33 (77)	79 (79)	
 Type 2 diabetes	4,291 (27.1)	10,125 (24.8)	161 (36.6)	20 (37.0)	93 (41.2)‡	45 (10.7)	12 (28)	37 (37)	
Values are means ± SD, n, number of patients (%), or medians [interquartile ranges]. Cpc-PH, combined pre- and postcapillary pulmonary hypertension; DNP, data not provided; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ipc-PH, isolated postcapillary pulmonary hypertension; PAH, pulmonary arterial hypertension; PH-HFpEF, pulmonary hypertension in the setting of HFpEF; N/A, not applicable.

* P < 0.05 vs. HFrEF; †P < 0.05 vs. cpc-PH; ‡P < 0.001 vs. PAH; §P < 0.05 vs. PH-HFpEF.

Cpc-PH and ipc-PH in HFpEF

Although ipc-PH is the most prevalent form of PH-HFpEF (10), cpc-PH is considered a more serious form than ipc-PH, with prevalence as high as 69% in patients with HFpEF compared with 47% in HFrEF (16). Studies have demonstrated mortality rates in HF with cpc-PH to be 2.5 times higher compared with ipc-PH and 5.3 times higher compared with no PH (13). Assad et al. (17) found that patients with cpc-PH were more likely younger, female, with more severe PV disease, higher brain-type natriuretic peptide (BNP) values, higher glycated hemoglobin (HbA1c) values, and worse renal function despite similar comorbidities and LV remodeling. Innovative solutions to understand PV remodeling via molecular profiling of transpulmonary blood samples are critical to detail the mechanisms behind cpc-PH due to the poor prognosis and poorly anticipated response to PAH therapy (17).

HEMODYNAMIC DEFINITIONS OF PH-HFpEF

HFpEF is characterized by normal LV ejection fraction (LVEF), normal LV end-diastolic volume, and abnormal diastolic function. These findings often accompany LV concentric remodeling/hypertrophy and left atrial (LA) enlargement. The 2022 ACC/AHA/Heart Failure Society of America (HFSA) guidelines for the management of HF define HFpEF as an LVEF of ≥50% (18). A key hemodynamic feature that differentiates PH-HFpEF from WHO Group I PAH is PA wedge pressure (PAWP) elevation >15 mmHg.

Hemodynamic definitions of ipc-PH and cpc-PH overlap and are also distinctive. Identical demographic groups with ipc-PH and cpc-PH demonstrate higher mortality in cpc-PH when defined according to PV resistance (PVR) (17, 19). As shown in Fig. 1, according to the 2022 European Society of Cardiology/European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension, the current hemodynamic definition of ipc-PH is mean pulmonary arterial pressure (mPAP) >20 mmHg, PAWP >15 mmHg, and PVR ≤2 wood units (WU) (19). The current definition of cpc-PH is mPAP >20 mmHg, PAWP >15 mmHg, and PVR >2 WU, making PVR as the discerning criteria between ipc-PH versus cpc-PH (19).

Figure 1. Hemodynamic definitions of pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF). PH due to HFpEF (PH-HFpEF) can be classified into compensated HFpEF, HFpEF with isolated postcapillary PH (ipc-PH), or HFpEF with pre- and postcapillary PH (cpc-PH). With the use of right heart catheterization, the gold standard tool for diagnosis, the mean pulmonary arterial pressure (mPAP) can be identified. According to the 2022 European Society of Cardiology/European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension, if the mPAP is <20 mmHg, the patient is characterized as having compensated HFpEF, defined as a pulmonary capillary wedge pressure (PCWP) < 15 mmHg at rest or >15 mmHg on provocation with fluid challenge or exercise, pulmonary vascular resistance (PVR) ≤ 2 wood units (WU), and transpulmonary gradient (TPG) ≤ 12 mmHg. Conversely, if the mPAP is >20 mmHg, patients can be defined as either having HFpEF with ipc-PH or with cpc-PH. The defining factor between ipc-PH vs. cpc-PH is PVR. A PVR of ≤2 WU is quantified as ipc-PH, where patients have increased PAWP >15 mmHg, but normal or low TPG of ≤12 mmHg. A PVR >2 is defined as cpc-PH, characterized by PAWP >15 mmHg, but TPG >12, signifying a distinctive hemodynamic process from ipc-PH. Figure was created with a licensed version of BioRender.com.

Right Ventricular-Pulmonary Artery Coupling

Right ventricular (RV)-pulmonary artery (PA) coupling is a well-established tool that characterizes the interaction between myocardial contractile function and the load opposed by arterial circulation. RV-PA coupling can be evaluated by the ratio of the tricuspid annular plane systolic excursion (TAPSE) to the PASP. This ratio of TAPSE:PASP has been found to be worse in cpc-PH compared with ipc-PH (20). More importantly, TAPSE:PASP has been recently implicated as a powerful prognostic factor in HF and valvular heart disease (21, 22). This parameter is investigational and has not been incorporated into any proposed diagnostic criteria for cpc-PH. Echocardiographic assessment of PVR is possible but is dependent on obtaining an adequate imaging window and a measurable tricuspid regurgitation jet. Given the crescent shape of the RV, three-dimensional echocardiography and cardiac magnetic resonance imaging have also been proposed to assess RV in patients with PH-HFpEF (23).

Pulmonary Arterial Compliance

Finally, LA hypertension and PVR can impact both PA compliance and elastance, defined by PASP-to-stroke volume ratio. These factors better represent the total RV afterload compared with precapillary parameters and are better predictors of PH-HFpEF; however, these factors are not useful to distinguish between ipc-PH and cpc-PH. PVR increases over time with chronic elevation of the intracardiac pressure, which widens the pressure difference between the LA and the PA, or the transpulmonary gradient (TPG). TPG is normally <12 mmHg. As the PVR and TPG increase, RV afterload also increases gradually and ultimately leads to RV dysfunction and failure.

DIAGNOSIS OF PH-HFpEF

The current diagnosis of PH-HFpEF requires comprehensive clinical, echocardiographic, and hemodynamic assessments, as it can be easily misdiagnosed for WHO Group I PAH. Supportive laboratory evaluation typically shows elevated BNP levels. Transthoracic echocardiography (TTE) is the first step in the evaluation of patients with suspected PH to differentiate between HFpEF and HFrEF (24). Doppler echocardiography may show elevated PASP with variable accuracy between studies due to issues with image quality, limited acoustic windows, or lack of measurable tricuspid regurgitation (25). Pulmonary function testing and ventilation perfusion scanning can be useful to differentiate the subtypes of PH, such as WHO Groups III and IV PH (26).

Via the Bernoulli equation, TTE can estimate PASP by measuring peak tricuspid regurgitation velocity using estimation of right atrial (RA) pressures via inferior vena cava size; however, PASP estimates can have reduced accuracy due to inability to obtain adequate images, lack of measurable tricuspid regurgitation velocity, or inability to visualize the inferior vena cava (27). Therefore, right heart catheterization (RHC) is essential and is the gold standard for PH-HFpEF diagnosis and to differentiate between ipc-PH and cpc-PH. RHC provides direct hemodynamic data that can determine cardiac output, evaluate intracardiac shunts and valvular dysfunction, provide direct intracardiac chamber pressure measurements, and correctly classify PH-LHD versus other causes of PH (26, 28).

PAWP, which is the core value to diagnose PH-HFpEF, is elevated in PH-HFpEF and typically low or normal in WHO Group I PAH. PAWP is usually measured at end expiration during normal respiration; indeed, presence of a characteristic “wedge” tracing and a sample oxyhemoglobin saturation greater than 90% can confirm a true wedge position during RHC. However, many of these patients are already on diuretic therapy, which may result in a normal PAWP. In such cases, provocative maneuvers can be performed during RHC (28, 29). Such maneuvers can include fluid challenge or exercise during RHC. Recent investigations have demonstrated the utility of passive leg raise and exercise for the diagnosis of HFpEF among subjects with normal resting PAWP (30). Robbins et al. (29) confirmed that more than 20% of patients initially diagnosed with PAH by RHC were reclassified to PH-LHD with elevated PAWP after receiving 500 mL rapid fluid challenge.

A different pulmonary hemodynamic response is seen in PH-HFpEF versus PH-HFrEF for a similar average PAWP, suggesting divergent PV pathophysiological changes (31). These changes can be further defined with combining exercise-stress echocardiography with exercise testing, which evaluate the role of LA function and RV-PA uncoupling in prognosis across the HF spectrum (32). Magnetic resonance imaging-derived indices correlate with RHC results and exhibit differences in function, motion, and deformation of LV and RV between PH-HFpEF and HFrEF (33).

PATHOPHYSIOLOGY OF PH-HFpEF

The pathophysiology of PH-HFpEF (Fig. 2) is complex, multifactorial, and multisystemic. In patients with HFpEF, the heart is unable to fill properly during diastole because of hypertension-induced ventricular hypertrophy and inflammation-induced myocardial fibrosis. Cardiac output, however, remains preserved or near normal because of compensation by abnormal myocardial active relaxation and increased LV stiffness, elevating LV and LA pressures. The impaired cardiac relaxation in HFpEF is attributed to multiple causes. Molecular changes in key calcium handling proteins in the LV such as sarcoplasmic reticulum calcium ATPases can lead to reduced calcium removal and cause LV diastolic dysfunction (34). In addition, increased ventricular load leads to a stiffened arterial system, resulting in ventricular-vascular uncoupling. LV wall stress leads to cardiomyocyte hypertrophy and interstitial fibrosis (2). In response to hypoxemia, cardiomyocytes release proinflammatory cytokines and chemokines, which initiate cardiac fibrosis and myocardial stiffness. Consequently, the pulmonary vasculature is exposed to a pressure challenge and acute pulmonary edema. Sustained backward pressure transmission increases RV load, triggers PH, and leads to classic symptom exacerbation. Although the primary anomaly is abnormal diastology and subtle irregularities in systolic function, limitations in LV systolic reserve, LA size and compliance, pulmonary vasculature, RV function, arterial stiffening, peripheral impairments, and extensive molecular and inflammatory changes contribute to HFpEF. In contrast, the HFrEF phenotype presents LA enlargement and increased LA pressures due to severe mitral regurgitation, highlighting that varying comorbidities present convergent PV changes. In fact, atrial fibrillation-predominant HFpEF presents similarly to PH-HFrEF and is associated with mitral regurgitation, higher PVR, and worse outcomes (35).

Figure 2. Development of pulmonary hypertension (PH) in heart failure (HF) with preserved ejection fraction (HFpEF). Pathophysiology of PH in HFpEF (PH-HFpEF) is complex. Features of metabolic syndrome (metS), such as type 2 diabetes, dyslipidemia, obesity, aging, and hypertension have been well studied to be risk factors and comorbidities of HFpEF via cardiac remodeling and diastolic dysfunction. Subsequent volume overload and increase in left atrial (LA) pressures lead to increased pulmonary venous pressures and isolated postcapillary PH (ipc-PH). Transition from ipc-PH to the more severe, irreversible pulmonary vascular (PV) remodeling and increased PV resistance (PVR) seen in combined pre- and postcapillary PH (cpc-PH) is not well studied. We predict that low-grade inflammation, through lipid metabolism dysregulation, decreased nitric oxide (NO) bioavailability, and increased endothelin-1 (ET-1) contribute to cpc-PH in HFpEF. LV, left ventricular; mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; WU, wood units. Figure was created with a licensed version of BioRender.com.

Biomechanics of ipc-PH and cpc-PH

The pulmonary vascular bed is initially quite distensible; however, the sensitivity of the PVR and PV compliance to the elevated left-sided pressures introduces new hemodynamic consequences of LHD. Tedford et al. (36) studied the relationship between RV afterload and pulmonary circulation in PH, and this study provided further insight into the compensatory role of increasing pulmonary compliance on reducing RV dysfunction. Specifically, this study demonstrated that PH and fibrosis do not change the relationship between PV resistance and compliance, which could explain why resistance-decreasing therapies do not reduce consequential RV afterload (36). In addition, increased PAWP augments complexity by increasing RV afterload further and may contribute to RV dysfunction. The role of PAWP can be attributed to PH-LHD and highlights key mechanistic differences between PAH and Group II PH.

PH-HFpEF can be broken into a continuum that starts with patients who are asymptomatic with normal intracardiac pressures at rest. As end diastolic pressure increases, PH develops and is divided into two components: the ipc-PH component and cpc-PH component (14). In ipc-PH, the mPAP is elevated solely from the passive transmission of increased left-sided filling pressures to the pulmonary circulation. The mPAP increases slowly, and capillary barotrauma does not occur, as occurs with pulmonary edema. Primary adaptive changes include increased parietal thickness, collagen deposition, and lumen narrowing of the pulmonary veins in a process known as “arteriolarization” (16). This process is reversible once the LA decompression is removed, if the arteriolarization has not yet occurred (16). In cpc-PH, the mPAP is elevated from passive transmission of chronic, severe LA hypertension and dysfunction leading to PV remodeling and increased PVR. Initially, pulmonary arterioles and small arteries are affected, but eventually medium and larger arteries are affected, which further compromises the compliance of the PA bed (37).

Recent theories suggest the role of vascular biomechanical forces, such as cyclic stretch and wall lumen shear stress, which are transduced into biological signals in a process called mechanotransduction (38). Mechanotransduction transmits and induces biological signals that drive vascular remodeling, including hypertrophy, hyperplasia, apoptosis, and extracellular matrix (ECM) synthesis and degradation (38). This remodeling decreases vessel compliance via cytoskeleton remodeling and increased intimal thickness, which has been shown in human PV tissues as a key histological feature of PH-LHD (16). The combination of intimal thickness and rise in mPAP with subsequent increase in cyclic stretch injures pulmonary capillaries and leads to stress failure. The chronic elevated pulmonary pressure and decreased venous mechanical properties eventually lead to further irreversible PA remodeling, inflammation-induced remodeling, upregulation of ET-1, and downregulation of vasodilatory NO, marking the transition to cpc-PH (14, 16). Interestingly, these characteristics of cpc-PH more closely resemble PAH than ipc-PH; however, pulmonary venules are more extensively involved in the vascular remodeling in cpc-PH than in PAH (37).

Abnormal Calcium Handling

Although calcium regulation and defective excitation-contraction coupling underlie abnormal contractility in HFrEF, very little is known about how calcium handling is regulated in HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, has been shown to benefit mouse models of HFpEF with comorbid metS by reversing mitochondrial function and decreasing reactive oxygen species (ROS) production (39). In fact, Levosimendan also reduced PAWP in a phase II clinical trial of patients with PH-HFpEF, suggesting a key role of calcium desensitization in the pathogenesis of PH-HFpEF (40). The drug was also shown to induce venodilation in the systemic and pulmonary vasculature, stimulating positive effects on RV function (40).

RV Dysfunction in cpc-PH

Cpc-PH leads to reduced RV function as PVR increases. As the RV normally ejects into the low impendence and highly distensible PV bed, it has a higher afterload sensitivity compared with the LV. Despite adaptive compensatory hypertrophy and increased contractility, the RV eventually develops systolic dysfunction because of afterload mismatch. The consequences of RV failure include increased central venous pressure and systemic circulation congestion, which lead to a myriad of systemic disorders that increase morbidity and mortality. The precapillary component of cpc-PH introduces the increased afterload and remodeling that accelerates HFpEF (41). Multiple studies have investigated the prevalence and prognostic relevance of RV dysfunction in HFpEF and found RV dysfunction to be a powerful predictor of mortality in HFpEF (42).

Plexiform Lesions Distinguishing cpc-PH and PAH

Assad et al. (17) demonstrated shared genetic variants characterizing WHO Group I PAH and Group II cpc-PH, suggesting shared vascular remodeling pathways; however, the cause of PVR is a key pathophysiologic factor that can distinguish PH-LHD from PAH. Plexiform lesions, characterized by typical smooth muscle proliferation and hypertrophy, highlight the core pathological findings and etiology of increased vascular resistance and remodeling in PAH. Conversely, canine models of pace-induced HF have shown true increase in membrane and capillary arterial wall thickness, characterized by changes in basement membrane composition and deposition of type IV collagen (43). These changes lead to increased PVR or cpc-PH rather than the plexiform complex seen in typical PAH (43). Patients with PH-HFpEF display multifactorial PV remodeling, correlating with intimal thickening in pulmonary veins. This intimal thickening is seen in greater than 50% of patients with HFpEF, indicating an unknown variability (16).

Comorbid Lung Disease

Chronic obstructive pulmonary disease (COPD) and HF share many risk factors and co-occur, challenging diagnosis of PH-HFpEF versus comorbid COPD and HF. Patients with COPD are more commonly predisposed to HFpEF than HFrEF because of chronic hypoxia and PV remodeling, and misdiagnosis is common (44). Key differences lie between COPD and PH-HFpEF, such as RA enlargement, and higher mean RA pressure, a predictor of mortality in COPD (45); however, cpc-PH presents with similar hemodynamic features, leading to a perplexing clinical case. Due to the clinical implications and distinct therapeutic targets of these disease conditions, succinct identification of PH-HFpEF is important to develop evidence-based therapeutic guidelines.

VASOACTIVE NEUROHORMONAL ENDOTHELIAL MEDIATORS

Endothelial dysfunction is thought to play a central role in the pathogenesis of PH by mediating structural changes in the pulmonary vasculature. Evidence suggests that endothelial cells participate in the process of vascular injury and immune activation by existing in a circulating form (46). Increased circulating cells have been demonstrated to predict adverse cardiovascular events in acute coronary syndromes and vascular injury (46). Endothelial cells induced to undergo premature senescence were observed to have higher RV systolic pressure and increased RV mass compared with controls, indicating exacerbated PH (47). The most credited hypothesis of HFpEF pathogenesis suggests that HFpEF and comorbidity burden impair the coronary endothelium, activating complex molecular pathways that converge to generate myocardial stiffening, fibrosis, and diastolic dysfunction (48). The lack of human HF pulmonary vascular tissue poses a significant shortcoming to PH-HFpEF biomolecular research in understanding PA endothelial response (2).

Decreased Nitric Oxide Bioavailability

Studies have demonstrated that endothelial dysfunction in PH-HFpEF is caused by an imbalance between nitric oxide (NO) and ET-1 signaling, causing cardiac nitrosative and oxidative stress (49). A series of studies investigating the effects of NO blockade in pulmonary circulation have shown that endothelium-derived NO mediates basal PV tone and dilation to endothelium-dependent stimuli (50). In healthy humans, systemic infusion of acetylcholine, a NO synthase agonist, increases local pulmonary blood flow, whereas infusion of a NO synthase inhibitor decreases pulmonary blood flow (50). Decreased NO bioavailability is observed in patients with HFpEF, which may explain the impaired vasodilation response to acetylcholine stimulation in the coronary capillary bed (51). Endothelial-derived NO also inhibits smooth muscle proliferation and hypertrophy along with PGI2, preventing platelet aggregation and adhesion (52). Pressure-induced cyclic stretch, previously described as a contributor to wall stress, also participates by increasing endothelial NO synthase phosphorylation in human umbilical vein endothelial cells, which increases IL-6 and cytokine release (53). Despite decreased NO bioavailability being a longstanding paradigm in the pathogenesis of PH-HFpEF, the clinical utility of this mechanism necessitates further study. Several recent trials have called into question the link between NO bioavailability and the pathogenesis of PH-HFpEF (1), and recent trials of agents targeting deficient NO signaling did not improve symptoms or outcomes (54–56). Thus, the therapeutic role of NO necessitates further study.

Increased Endothelin-1 and Mortality

In PH-HFpEF, LA hypertension causes pulmonary edema, which further activates endothelin-1 (ET-1) expression and decreases NO and BNP activity (57). Chowdhury et al. (58) investigated the potential role of ET-1 in the pathogenesis of PH-HFpEF and demonstrated that ET-1 is predictive of 1-year HF hospitalization in patients with HFpEF. Increasing ET-1 levels were also associated with long-term mortality and worsening PV remodeling in PH-HFpEF (58). Specifically, higher ET-1 from wedge samples (ET-1 produced in the pulmonary vasculature) was associated with PH, elevated PVR, and increased risk of hospitalization (58). Other studies have also demonstrated elevated ET-1 in patients with cpc-PH, implicating ET-1 as a potential contributor to and prognostic biomarker for the development of cpc-PH (59). Obokata et al. (57) also demonstrated elevated ET-1 and adrenomedullin, a counterregulatory neurohormone in patients with HFpEF; these data are consistent with the hypoxia-induced upregulation of the pulmonary endothelial mechanisms that contribute to the transition from ipc-PH to cpc-PH. Reactive oxygen species (ROS) production has also been shown to increase ET-1 release in human umbilical vein endothelial cells, further suggesting the role of endothelial cell factors influencing intimal thickness and remodeling (53). ET-1 may also be a potential therapeutic target, with studies demonstrating that dual inhibition of ET-1 receptors improved HFpEF by reducing adverse cardiac hypertrophy and PV remodeling (60). These data strongly suggest that ET-1 potentiates endothelial dysfunction and vasoconstriction via lipid peroxidation and oxidation; however, trials have not shown favorable outcomes (41). Unfortunately, PH-HFpEF treatment guidelines also strongly recommend against using PAH therapies outside of clinical trials (24).

METABOLIC SYNDROME AND INFLAMMATION

The lack of human HF PV tissue poses a significant shortcoming to PH-HFpEF research. Without molecular mechanisms, it is difficult to profile diagnostic markers that may be causing inflammatory processes in PH-HFpEF. Decreased NO bioavailability and impaired NO-mediated relaxation has been directly linked to ROS from metS-induced systemic inflammation; indeed, this can impair contractility of cardiomyocytes and deteriorate diastolic function (61). Multiple studies have demonstrated how intramyocardial lipid accumulation in patients with metS contributes to diastolic dysfunction, which, acting in concert with HFpEF, progresses to PH-HFpEF (62). Lai et al. (63) induced PH-HFpEF in a metS model of double-leptin receptor defect; interestingly, PH-HFpEF in early stages was responsive to nitrite and metformin treatment, but PH-HFpEF in later stages, likely progressed to cpc-PH, was not treatable with nitrite and metformin. This suggests additional deleterious processes other than NO bioavailability contributing to cpc-PH.

Here, we describe the utility of preliminary animal models of metS and PH-HFpEF that have been proposed to contribute to PH-HFpEF pathogenesis (Fig. 3). Elevated circulating inflammatory biomarkers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are more pronounced in HFpEF than HFrEF, suggesting unique inflammatory signaling substantiating the comorbidity-inflammation paradigm in HFpEF (66). Several inflammatory biomarkers have been found to be better predictors of HFpEF severity and outcomes than natriuretic peptides, with endomyocardial biopsies from patients with HFpEF showing inflammatory cell infiltration correlating with diastolic dysfunction (67).

Figure 3. Metabolic syndrome-induced pulmonary hypertension (PH)-heart failure (HF) with preserved ejection fraction (PH-HFpEF) in experimental animal models. PH-HFpEF has been strongly associated with features of metabolic syndrome (metS), including hyperglycemia, adiposity, and insulin resistance. Many studies have explored the association of metS with PH-HFpEF, specifically via the use of animal models. Ranchoux et al. (64) developed a metS rat model through a high-fat diet and olanzapine-induced hyperglycemia and diastolic dysfunction via supracoronary aortic banding. This rat model developed features of PH-HFpEF. Anti-IL-6 antibodies and metformin treatment reversed features of PH, such as pulmonary vascular (PV) remodeling. Meng et al. (65) demonstrated how a metS model via a high-fat diet induced features of PH-HFpEF; no treatment modality was used in this study to reverse the adiposity. Lai et al. (63) studied how pulmonary endothelial injury in leptin receptor-deficient obese mouse model of metS induced PH-HFpEF features. Treatment with nitrite and metformin reversed the features of metS, including hyperglycemia and glucose intolerance, and increased adiponectin levels, a key protector of metabolic and vascular diseases. However, more severely affected PH-HFpEF rats, likely progressed to pre- and postcapillary PH (cpc-PH), did not benefit from nitrite or metformin treatment, suggesting the need for early mets therapeutic intervention as nitric oxide (NO) bioavailability may play a less predominant role in cpc-PH pathogenesis in HFpEF. EF, ejection fraction; LV, left ventricle; LVEF, left ventricle ejection fraction; RVSP, right ventricular systolic pressure; PVR, pulmonary vascular resistance. Figure was created with a licensed version of BioRender.com.

Interleukin-6

Elevation of proinflammatory cytokine interleukin-6 (IL-6) has been shown to experimentally increase PA smooth muscle cell (PASMC) proliferation through STAT3 (signal transducer and activator of transcription 3) activation (68). This proinflammatory state also induces insulin resistance by increasing free fatty acid (FFA) concentration and interfering with the anti-inflammatory effect of insulin. Insulin has been studied to suppress NF-κB binding activity, ROS generation, and other proinflammatory transcription factors (69). Therefore, insulin resistance, as seen in type 2 diabetes, can induce a proinflammatory state and further increase IL-6. Ranchoux et al. (64) developed a PH-HFpEF rat model via olanzapine-induced hyperglycemia, high-fat diet-induced metS, and supracoronary aortic banding-induced diastolic dysfunction. Interestingly, only the rats with both metS and diastolic dysfunction displayed an increase in PVR and adverse PV remodeling, reflecting pathophysiological characteristics of PH-HFpEF (64). This combination of diastolic dysfunction and metS also induced a significant proinflammatory state via increased expression of IL-6. In fact, reducing IL-6 by anti-IL-6 antibodies and metformin reversed PV remodeling (64). This study strongly emphasizes the deleterious combination of metS- and diastolic dysfunction-induced PH-HFpEF through activation of the IL-6/STAT3 pathway as a key mechanism of PV remodeling.

Diabetes-Related Metabolic Cardiomyopathy

Metabolic cardiomyopathy has been demonstrated to result from metS diseases, such as obesity and type 2 diabetes. This remodeling predisposes structural and functional changes that lead to HFpEF. A key player in this process are sirtuins, which are molecules that maintain metabolic homeostasis by regulating fatty acid metabolism and mitochondrial function, both maladaptations that have been linked with HFpEF (70). In fact, the beneficial effects of sodium glucose transporter-2 inhibitors in HFpEF have been suggested to be due to restoration of sirtuin-1 (SIRT1) activity (71). Costantino et al. (70) demonstrated that dietary supplementation with recombinant SIRT1 preserved cardiac function and restored cardiac lipidome remodeling in murine models of metabolic cardiomyopathy, reducing incidence of HFpEF.

Lipotoxicity

Obesity has a central role in the development of HFpEF. A causal link between adiposity and mediators of inflammation has been recognized through a mechanism known as “lipotoxicity” (72). Lipotoxicity suggests that lipid accumulation from nonadipose organs results in oxidative stress, mitochondrial dysfunction, and apoptosis, leading to skeletal muscle insulin resistance, pancreatic β-cell dysfunction, and nonalcoholic fatty liver disease in metS (72). Ranchoux et al. (64) demonstrated a direct correlation between ectopic adipose tissue accumulation and PH severity in animals with metS and diastolic dysfunction. In addition, the association between metS adiposity and PH-HFpEF was established via the development of a mouse model on high-fat diet (65). This mouse model demonstrates several clinical features of PH-HFpEF, including elevated RV systolic pressure, LV end diastolic pressure, preserved LVEF, and biventricular hypertrophy (65). Specifically, leptin is a molecule made from fat cells directly related to adiposity that is closely associated with metS and diastolic function (73). Prior studies have activated the leptin/leptin receptor axis, which contributes to PASMC proliferation and abnormal macrophage activation (74).

Regulatory T Cells/T Helper 17 Cell Balance

It has been well established that cpc-PH attributed to HFpEF mimics the etiology of WHO Group I PAH (17, 75); in fact, research has also demonstrated how ET-1 receptor antagonization resulted in a significant reduction of PVR and improved exercise capacity in both cpc-PH attributed to HFpEF and PAH (42). Therefore, examining the inflammatory mechanisms in PAH may elucidate the pathogenesis of cpc-PH.

Equilibrium and homeostasis of the immune response in WHO Group I PAH has been shown to primarily involve T helper 17 (Th17), regulatory T (Treg), and cytotoxic T (Tc) cells (76). Although Th and Tc cells produce a proinflammatory response, Treg cells produce an anti-inflammatory response. Human and animal models have shown that the imbalance of Treg:Th17 ratio correlates with PAH disease severity (76). Treg cells and their anti-inflammatory byproducts regulate growth and hypertrophy of the vasculature and smooth muscle cells under inflammatory conditions via suppressing the Akt/ERK pathway, which is the pathway responsible for triggering cell growth, survival, and motility (77). Through this pathway, Treg cells have suppressive effects on collagen and fibroblasts and control ventricular remodeling, preventing development of RV hypertrophy (78). In addition, Treg dysfunction has been directly shown to increase PAH progression via decreasing inflammatory effects (79). Treg dysfunction could also explain the RV maladaptive remodeling in cpc-PH. Treg:Th17 imbalance has been demonstrated to exist in patients with chronic HFpEF in the study by Li et al. (80), but these results were also seen in patients with HFrEF.

Macrophage Proliferation

Agrawal et al. (81) demonstrated that as early as 2 wk of exposure to NG-nitro-l-arginine methyl ester/high-fat diet, mice develop PH-HFpEF features, including preserved CO, diastolic dysfunction, weight gain, increased PVR, RV systolic pressure, RV mass, and histological PV remodeling. The same model exposed to clodronate (to deplete monocytes and macrophages) demonstrated less weight gain, near normal RV systolic pressure, normal RV mass, and decreased PV remodeling (81). Studying the cytokine profile further, the study inhibited IL-1B to yield the same changes, emphasizing the unique and specific role of myeloid produced IL-1B in small vessel muscularization (81). These results suggest the role of circulating myeloid cells that migrate to the lungs and contribute to PH and RV dysfunction in PH-HFpEF. In addition, galectin-3, a lectin expressed by activated cardiac macrophages, has also been shown to be associated with adverse LV remodeling, cardiomyocyte hypertrophy, and myocardial fibrosis (82). In fact, galectin-3 has been shown to be an independent prognostic marker in humans with PH-HFpEF (83).

Metabolic Interventions

Many of the current treatments that exist for PH-HFpEF rely on treating comorbid metS. As previously discussed, anti-IL-6-antibodies, metformin, and nitrite provide promising results in animal models of PH-HFpEF (63, 65). The role of metformin in PV remodeling is interesting. Metformin treatment has been shown to improve PH-LHD, either by inhibiting leptin secretion or by inhibiting aromatase/estrogen synthesis (64, 84). Metformin failed to reverse PV remodeling in mice with SuHx (combined exposure of hypoxia and vascular endothelial growth factor receptor antagonist)-induced PAH, although treatment prevented development of PAH in hypoxia models (84). Many patients with PAH present with signs of insulin resistance and glucose intolerance sans obesity and type 2 diabetes that are more prevalently seen in PH-HFpEF; therefore, the divergent responses to early animal clinical trials suggest preferentially beneficial treatment of PH-HFpEF, with limited treatment efficacy for PAH (84). Antidiabetic agents such as sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists are currently included in the guideline-directed medical therapy for HFpEF (18). Recent trials with Semaglutide exhibited reduced symptoms, improved exercise function, and induced greater weight loss in patients with HFpEF and obesity (85). Although promising, their role in the treatment of PH-HFpEF entails further study.

NOVEL MECHANISMS OF PH-HFpEF: POLYUNSATURATED FATTY ACIDS IN REGULATING CARDIOVASCULAR INFLAMMATION AND REMODELING

Polyunsaturated fatty acids (PUFA), arachidonic acids (AA), and their metabolites play an important role in regulating complex cardiovascular functions under physiological and pathological conditions. O’Sullivan et al. (86) recently demonstrated how in the nonfasting state, HFpEF hearts transition to complex lipid generation correlating with increasing PA pressures. Furthermore, Jovanovic et al. (87) examined the human plasma lipidome in patients with HFpEF to discover significant correlation between smoking status and individual long-chain fatty acid lipid species (despite no difference between disease and control groups), and significant differences between distinct lipid species and echocardiographic parameters in HFpEF. Although the group could not conclude significant associations between lipidomic parameters and HFpEF, limited by their sample size, the study suggests a complex, nonlinear relationship between lipid metabolism and disease progression that entails further study (87). Indeed, our group has also noted several potential mechanistic links between these inflammatory mediators and PH-HFpEF, including discovering multiple PUFA metabolites significantly predictive of ipc-PH, cpc-PH, and no PH, and metabolites that predicted all cause hospitalization and mortality (88, 89). In this section, we review novel aspects of PUFA lipid mediators and potential links to the adverse PV remodeling and RV dysfunction seen in cpc-PH attributable to HFpEF, as outlined in Table 3.

Table 3. Suggested role of oxylipins in PH-HFpEF

PH Hallmarks Oxidized Lipids	Effect	References	
Vascular remodeling			
 COX-derived PGE2	Mediates neointimal hyperplasia via cyclic stretch upregulation of COX-2	(38)	
 CYP-derived EET	Protects against myocardial structural and metabolic remodeling	(90)	
Apoptosis			
 LOX-derived 15-HETE	Activates SIRT1 to protect against PASMC apoptosis	(70, 91)	
 LOX-derived maresins	Improves RV systolic pressure by inhibiting the AKT/Erk pathway and improving Treg/Th17 imbalance	(92)	
Vasoconstriction			
 COX-derived PGI2	Reduces PASP by promoting pulmonary artery relaxation and improves RV hypertrophy and PV intimal wall thickening	(93)	
 COX-derived TXA2	Antagonizes PGI2 actions and acts synergistically with serotonin with mitogenic effect on PASMCs	(94)	
Inflammation			
 COX-derived TXA2	Stimulates platelet aggregation		
 LOX-derived LXA4	Improves RV systolic pressure by decreasing IL-10 and ROS generation in vascular endothelial cells to improve RV systolic pressure	(95, 96)	
 CYP-derived EET	Decreases TGF-β profibrotic activity	(97)	
 LOX-derived D-series resolvins	Suppresses neutrophil migration and cytokine production by activating innate immunity and promoting phagocytotic activity in macrophages	(98)	
COX, cyclooxygenase; EET, epoxyeicosatrienoic acid; 15-HETE, 15-hydroxyeicosatetraenoic acid; IL-10, interleukin-10; ROS, reactive oxygen species; LOX, lipoxygenase; LXA4, lipoxin A4; PASMCs, pulmonary arterial smooth muscle cells; PASP, pulmonary artery systolic pressure; PGE2, prostaglandin E2; PGI2, prostacyclin; PH-HFpEF, pulmonary hypertension in the setting of heart failure with preserved ejection fraction; PV, pulmonary vascular; ROS, reactive oxygen species; RV, right ventricular; SIRT1, sirtuin1; TGF-β, transforming growth factor-β; Treg/Th17, regulatory T cells/T helper 17 cells; TXA2, thromboxane A2.

N-3 (omega-3) PUFAs have been found to be effective in reducing ischemic heart disease, atrial and ventricular arrhythmia, hypertension, peripheral artery disease, and HF; furthermore, a study carried out by Hassan and Hanachi group showed that a n-3 PUFA rich diet can decrease likelihood of developing metS (99). Almost all lipid mediators derived from n-3 PUFA are proresolutory mediators of inflammation. Conversely, n-6 (omega-6) PUFAs, such as AA, are precursors to primarily proinflammatory mediators, with studies demonstrating higher intakes of n-6 PUFA associated with increased IL-6 and CRP (100). Increase in n-6:n-3 ratio is seen in chronic inflammatory diseases, such as cardiovascular disease, obesity, inflammatory bowel disease, and nonalcoholic fatty liver disease. AA and its metabolites are the most studied and emphasized in relevance to cardiovascular biology. Generally, AA metabolism by cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome-P450 (CYP) enzymes leads to mediators of proinflammation. These enzymes can then generate a vast spectrum of oxidized lipid mediators, generally referred to as “oxylipins” to mediate inflammatory processes and disease (Fig. 4). Although AA-derived oxylipins are primarily proinflammatory, they can also be anti-inflammatory or proresolutory. Almost all proresolution lipid mediators are derived from the LOX pathway, with leukotrienes (LTs; e.g., LTB4) as an exception. COX, LOX, and CYP enzymes also metabolize n-3 PUFAs to generate proresolutory and anti-inflammatory oxylipins such as eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA).

Figure 4. Role of inflammatory lipid homeostasis in pulmonary hypertension (PH)-heart failure (HF) with preserved ejection fraction (PH-HFpEF). Diagram shows the balance of inflammatory lipid mediator homeostasis that is needed to prevent progression to PH-HFpEF. The comorbidities present with HFpEF establish a baseline state of chronic low-grade inflammation, defined by IL-6 activation, macrophage and neutrophil proliferation, and imbalance of regulatory T cells (Treg)-to-T helper cells (Treg:Th17) ratio. This chronic inflammatory state can be characterized and enhanced by the imbalance of anti-inflammatory lipid metabolites with proresolutory metabolites and proinflammatory metabolites. In a state where the balance is tipped toward proinflammatory lipid metabolism, we predict that this can further increase proliferation of immune cells and cytokines, antibodies, soluble mediators, fibroblasts, and reactive oxygen species (ROS), predisposing to a complex state of the deleterious pre- and postcapillary PH (cpc-PH) in patients with HFpEF. Conversely, we predict that the predominance of proresolutory metabolites can protect against this state, as seen in patients with compensated HFpEF who do not develop cpc-PH or develop isolated postcapillary PH (ipc-PH). PGE1, prostaglandin E1; PGI2, prostacyclin; LXA4, lipoxin A4; LXB4, lipoxin B4; LTB4, leukotriene B4; NO, nitric oxide; ROS, reactive oxygen species; RV, right ventricular. Figure was created with a licensed version of BioRender.com.

Cyclooxygenase

Differentiation of fibroblasts into proinflammatory myofibroblasts is a critical mechanism in arterial fibrosis that characterizes the irreversible remodeling of cpc-PH. Cyclic stretch has been shown to increase the expression of fibroblast growth factors in PASMCs, and upregulate cyclooxygenase (COX)-2 (38). COX-2 derived prostaglandin-E2 (PGE2) has been demonstrated to play a role in neointimal hyperplasia, as targeted deletion of PGE1 receptors in vascular smooth muscle cells directly impacts vascular remodeling in mice (93). PGI2 has been shown to reduce PASP by promoting PA relaxation, and current treatment for PAH remains PGI2 analogs, such as iloprost, treprostinil, and epoprostenol. In fact, even in patients with HFpEF, preliminary results show that inhaled iloprost favorably improves myocardial performance during exercise by improving RV systolic function (101). In patients with PH-HFpEF, treprostinil has also been suggested as an early treatment for mild metS-associated PH-HFpEF, with similar effects as metformin (102). Past studies have shown how treatment with PGE1 via epoprostenol reduces the maladaptive vascular remodeling in the lungs and heart, and improves RV hypertrophy and intimal wall thickening via potent alveolar vasodilation in rat models of PH (103). COX-derived PGE1 and PGE2 have also been used to treat postoperative PH (e.g., mitral valve replacement or open-heart surgery) and improve ventricular function and survival in PH secondary to HF (103).

Proinflammatory COX-derived thromboxane A2 (TXA2) is a potent stimulus for platelet aggregation, directly antagonized by the actions of PGI2. The imbalance between the release of TXA2, a vasoconstrictor, and PGI2, a vasodilator, may contribute to the development of cpc-PH. Although data regarding the ability of TXA2 to stimulate PASMC proliferation are inconsistent, it has been shown that the presence of serotonin is synergistic with TXA2 production, with a possible mitogenic effect on PASMCs (94). These changes in blood vessel walls can lead to reduced diameter of pulmonary arteries, and over time, right HF.

Lipoxygenase

Lipoxygenase (LOX)-derived 15-hydroxyeicosatetraenoic acids (15-HETE) plays a significant role in hypoxic PAH via vascular remodeling and proliferation of PASMCs through the protein kinase C signal transduction pathway (104). Although 15-HETE has not been directly studied in association with PH-LHD, studies have demonstrated that 15-HETE promotes SIRT1 levels in PASMCs (91). SIRT1 has been previously demonstrated as a key player in HFpEF pathogenesis (70). SIRT1 also mediates 15-HETE-induced PASMC proliferation during hypoxia and normoxia, protecting PASMC apoptosis and remodeling (91). Further study regarding 15-HETE and vascular remodeling in PH-HFpEF is necessary, as this mechanism can constitute a new therapeutic foundation.

Lipoxin A4 (LXA4) and LXB4 attenuate the inflammatory response by leading to downstream production of IL-10, a regulatory cytokine, which can further reduce adhesion and aggregation of neutrophils (95). LXA4 demonstrates atheroprotective effects via impairing production of proinflammatory cytokines, inhibiting neutrophil chemotaxis, and activating the proresolving functions of macrophages (105). In addition, studies have demonstrated that LXA4 suppresses NADPH-oxidase mediated ROS generation in vascular endothelial cells (105). The cardioprotective nature of statins can also be partly attributable to LXA4; cholesterol reducing medications such as HMG-CoA reductase inhibitors atorvastatin and simvastatin have been shown to increase the myocardial content of LXA4 (96). LOX metabolism of n-3 DHA can produce proresolutory maresins and D-series resolvins. Resolvins attenuate ROS generation, inhibit cytokine release, stimulate macrophages to phagocytose neutrophils, and disrupt TX-mediated platelet aggregation (98). Our group has specifically identified maresin-1 as a key lipid metabolite predictive of cpc-PH in HFpEF (88). Maresin-1 suppresses neutrophil migration and cytokine production by activating Tc, Th1, and Treg cells, and promoting phagocytotic activity in macrophages. Maresin-1 has also been shown to improve Treg:Th17 imbalance in rheumatoid arthritis, an imbalance that has been suggested to propagate HFpEF (80, 92). Maresin-1 intervention has been shown to reverse PAH in mice by decreasing RV systolic pressure and RV dysfunction through inhibiting the AKT/Erk pathway, the pathway responsible for PV remodeling (106). This demonstrates that maresin-1 may have a potent therapeutic effect in the cpc-PH component of HFpEF.

Cytochrome-P450

Produced primarily in the endothelium and myocardium, CYP-generated epoxyeicosatrienoic acids (EETs) function as anti-inflammatory mediators by reducing systemic hypertension and promoting angiogenesis. EETs function as microcirculatory vasodilators in arteries, and low levels are associated with endothelial dysfunction and decreased NO bioavailability (90). Animal models of cardiac hypertrophy and HFpEF display low-cardiomyocyte EET level, suggesting the protective effect of EETs against myocardial structural and metabolic remodeling (90). Finally, cardiac fibrosis is a primary pathological change in HFpEF leading to diastolic dysfunction; indeed, EETs relieve the differentiation of cardiac fibroblasts into myofibroblasts via inhibition of transforming growth factor-β (TGF-β), which has been shown as the key transformation in cpc-PH (38, 97, 107). Recent studies also demonstrated how EETs reduce PH and lung ischemia-reperfusion injury in rats with PH-LHD (108). EETs pose as promising candidates for treating PH-HFpEF.

Quantifying PUFA Metabolites for Prognostic Scoring of PH-HFpEF

Given the immense biological diversity of PUFA-derived oxygenated metabolites that carry potential for significant clinical utility, there is a need for a sensitive, selective, reliable, and accurate assay system to assess lipid species quantitatively and qualitatively. Lipid chromatography mass spectroscopy (LC-MS) is the method of choice to quantify the hundreds of metabolites and create a risk stratification score based on the contribution of each molecule to the severity of PH-HFpEF progression. LC-MS is a reliable analytical platform for mediator lipidomic assays with detection limits even below their physiological activities (in the subpicogram range). Given that certain PUFA metabolites partake in anti-inflammatory, proinflammatory, and proresolutory processes, it is possible to stratify a risk and severity score from populations with PH-HFpEF and potentially detect early prognostic and diagnostic biomarkers for early development of PH without the need for invasive RHC.

CONCLUSION

Development of PH in HFpEF is a significant prognostic indicator of increased short- and long-term mortality risk. The prevalence of HFpEF increases with age and is strongly associated with female gender and chronic metS encompassing obesity, type 2 diabetes mellitus, hypertension, pulmonary disease, and liver disease; therefore, it is likely that patients with HFpEF sustain a chronic, low-grade inflammatory state. We suggest that the inflammatory state activates neurohormonal mediators, adaptive immunity, and PUFA-generated lipid enzymatic metabolism, which leads to PV remodeling, pulmonary vasoconstriction, and RV diastolic dysfunction. These changes finally contribute to cpc-PH progression and subsequent clinical worsening. Elucidating the critical knowledge gaps in pathophysiology is essential to discovering new pharmacological strategies targeting noncardiac biomarkers to improve PH-HFpEF outcomes. Quantitative and qualitative lipidomics analysis opens a new frontier in the pathophysiology of HFpEF and holds significant promise for diagnostic and therapeutic advancements in PH-HFpEF.

GRANTS

This work was supported by the Adela and Alfred Mundt Foundation for Heart Failure Research (to S.J.K.); National Heart, Lung, and Blood Institute Grant HL-137004 (to D.J.K. and S.T.H.); the David and Helen Boone Foundation Research Fund (to D.J.K.); and the University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center (to D.J.K. and S.T.H.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

V.A., D.J.K., and S.J.K. conceived and designed research; V.A. prepared figures; V.A., R.V., R.G., D.J.K., and S.J.K. drafted manuscript; V.A., R.V., P.D., S.T.H., R.G., K.R.M., D.J.K., and S.J.K. edited and revised manuscript; V.A., R.V., P.D., S.T.H., R.G., K.R.M., D.J.K., and S.J.K. approved final version of manuscript.

ACKNOWLEDGMENTS

We thank Amanda Faye Lipsey at Amanda Faye Consulting for editorial assistance.
==== Refs
REFERENCES

1. Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, Blaxall BC, Agarwal R, Chirinos JA, Collins S, Deo RC, Gladwin MT, Granzier H, Hummel SL, Kass DA, Redfield MM, Sam F, Wang TJ, Desvigne-Nickens P, Adhikari BB. Research priorities for heart failure with preserved ejection fraction: National Heart, Lung, and Blood Institute Working Group Summary. Circulation 141 : 1001–1026, 2020. doi:10.1161/CIRCULATIONAHA.119.041886. 32202936
2. Brittain EL, Thenappan T, Huston JH, Agrawal V, Lai YC, Dixon D, Ryan JJ, Lewis EF, Redfield MM, Shah SJ, Maron BA; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Stroke Council. Elucidating the clinical implications and pathophysiology of pulmonary hypertension in heart failure with preserved ejection fraction: a call to action: a science advisory from the American Heart Association. Circulation 146 : e73–e88, 2022. doi:10.1161/CIR.0000000000001079. 35862198
3. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145 : e876–e894, 2022. doi:10.1161/CIR.0000000000001062. 35363500
4. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14 : 591–602, 2017. doi:10.1038/nrcardio.2017.65. 28492288
5. Prausmüller S, Weidenhammer A, Heitzinger G, Spinka G, Goliasch G, Arfsten H, Abdel Mawgoud R, Gabler C, Strunk G, Hengstenberg C, Hulsmann M, Bartko PE, Pavo N. Obesity in heart failure with preserved ejection fraction with and without diabetes: risk factor or innocent bystander? Eur J Prev Cardiol 30 : 1247–1254, 2023. doi:10.1093/eurjpc/zwad140. 37210596
6. Ho JE, Enserro D, Brouwers FP, Kizer JR, Shah SJ, Psaty BM, Bartz TM, Santhanakrishnan R, Lee DS, Chan C, Liu K, Blaha MJ, Hillege HL, van der Harst P, van Gilst WH, Kop WJ, Gansevoort RT, Vasan RS, Gardin JM, Levy D, Gottdiener JS, de Boer RA, Larson MG. Predicting heart failure with preserved and reduced ejection fraction: the International Collaboration on Heart Failure Subtypes. Circ Heart Fail 9 : e003116, 2016. doi:10.1161/CIRCHEARTFAILURE.115.003116. 27266854
7. Wagner JUG, Dimmeler S. Cellular cross-talks in the diseased and aging heart. J Mol Cell Cardiol 138 : 136–146, 2020. doi:10.1016/j.yjmcc.2019.11.152. 31783034
8. Upadhya B, Stacey RB, Kitzman DW. Preventing heart failure by treating systolic hypertension: what does the SPRINT add? Curr Hypertens Rep 21 : 9, 2019. doi:10.1007/s11906-019-0913-3. 30659372
9. Galie N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J 53 : 1802148, 2019. doi:10.1183/13993003.02148-2018. 30552088
10. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 53 : 1119–1126, 2009. doi:10.1016/j.jacc.2008.11.051. 19324256
11. Salamon JN, Kelesidis I, Msaouel P, Mazurek JA, Mannem S, Adzic A, Zolty R. Outcomes in World Health Organization group II pulmonary hypertension: mortality and readmission trends with systolic and preserved ejection fraction-induced pulmonary hypertension. J Card Fail 20 : 467–475, 2014. doi:10.1016/j.cardfail.2014.05.003. 24858070
12. Stolfo D, Lund LH, Benson L, Hage C, Sinagra G, Dahlstrom U, Savarese G. Persistent high burden of heart failure across the ejection fraction spectrum in a nationwide setting. J Am Heart Assoc 11 : e026708, 2022. doi:10.1161/JAHA.122.026708. 36326055
13. Rezaee ME, Nichols EL, Sidhu M, Brown JR. Combined post- and precapillary pulmonary hypertension in patients with heart failure. Clin Cardiol 39 : 658–664, 2016. doi:10.1002/clc.22579. 27768231
14. Opitz CF, Hoeper MM, Gibbs JS, Kaemmerer H, Pepke-Zaba J, Coghlan JG, Scelsi L, D'Alto M, Olsson KM, Ulrich S, Scholtz W, Schulz U, Grünig E, Vizza CD, Staehler G, Bruch L, Huscher D, Pittrow D, Rosenkranz S. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol 68 : 368–378, 2016. doi:10.1016/j.jacc.2016.05.047. 27443433
15. Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail 4 : 257–265, 2011. doi:10.1161/CIRCHEARTFAILURE.110.958801. 21411741
16. Fayyaz AU, Edwards WD, Maleszewski JJ, Konik EA, DuBrock HM, Borlaug BA, Frantz RP, Jenkins SM, Redfield MM. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 137 : 1796–1810, 2018. doi:10.1161/CIRCULATIONAHA.117.031608. 29246894
17. Assad TR, Hemnes AR, Larkin EK, Glazer AM, Xu M, Wells QS, Farber-Eger EH, Sheng Q, Shyr Y, Harrell FE, Newman JH, Brittain EL. Clinical and biological insights into combined post- and pre-capillary pulmonary hypertension. J Am Coll Cardiol 68 : 2525–2536, 2016. doi:10.1016/j.jacc.2016.09.942. 27931609
18. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 136 : e137–e161, 2017. doi:10.1161/CIR.0000000000000509. 28455343
19. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Radegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 43 : 3618–3731, 2022 [Erratum in Eur Heart J 44: 1312, 2023]. doi:10.1093/eurheartj/ehac237. 36017548
20. Pellegrini P, Rossi A, Pasotti M, Raineri C, Cicoira M, Bonapace S, Dini FL, Temporelli PL, Vassanelli C, Vanderpool R, Naeije R, Ghio S. Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure. Chest 145 : 1064–1070, 2014. doi:10.1378/chest.13-1510. 24356904
21. Cahill TJ, Pibarot P, Yu X, Babaliaros V, Blanke P, Clavel MA, Douglas PS, Khalique OK, Leipsic J, Makkar R, Alu MC, Kodali S, Mack MJ, Leon MB, Hahn RT. Impact of right ventricle-pulmonary artery coupling on clinical outcomes in the PARTNER 3 trial. JACC Cardiovasc Interv 15 : 1823–1833, 2022. doi:10.1016/j.jcin.2022.07.005. 36137685
22. 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 305 : H1373–H1381, 2013. doi:10.1152/ajpheart.00157.2013. 23997100
23. Dong Y, Pan Z, Wang D, Lv J, Fang J, Xu R, Ding J, Cui X, Xie X, Wang X, Chen Md Y, Guo X. Prognostic value of cardiac magnetic resonance-derived right ventricular remodeling parameters in pulmonary hypertension: a systematic review and meta-analysis. Circ Cardiovasc Imaging 13 : e010568, 2020. doi:10.1161/CIRCIMAGING.120.010568. 32673506
24. Vachiéry JL, Tedford RJ, Rosenkranz S, Palazzini M, Lang I, Guazzi M, Coghlan G, Chazova I, De Marco T. Pulmonary hypertension due to left heart disease. Eur Respir J 53 : 1801897, 2019. doi:10.1183/13993003.01897-2018. 30545974
25. Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest 139 : 988–993, 2011. doi:10.1378/chest.10-1269. 20864617
26. Inampudi C, Silverman D, Simon MA, Leary PJ, Sharma K, Houston BA, Vachiéry JL, Haddad F, Tedford RJ. Pulmonary hypertension in the context of heart failure with preserved ejection fraction. Chest 160 : 2232–2246, 2021. doi:10.1016/j.chest.2021.08.039. 34391755
27. Miller WL, Mahoney DW, Enriquez-Sarano M. Quantitative Doppler-echocardiographic imaging and clinical outcomes with left ventricular systolic dysfunction: independent effect of pulmonary hypertension. Circ Cardiovasc Imaging 7 : 330–336, 2014. doi:10.1161/CIRCIMAGING.113.001184. 24488981
28. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M.; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37 : 67–119, 2016. doi:10.1093/eurheartj/ehv317. 26320113
29. Robbins IM, Hemnes AR, Pugh ME, Brittain EL, Zhao DX, Piana RN, Fong PP, Newman JH. High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ Heart Fail 7 : 116–122, 2014. doi:10.1161/CIRCHEARTFAILURE.113.000468. 24297689
30. van de Bovenkamp AA, Wijkstra N, Oosterveer FPT, Vonk Noordegraaf A, Bogaard HJ, van Rossum AC, de Man FS, Borlaug BA, Handoko ML. The value of passive leg raise during right heart catheterization in diagnosing heart failure with preserved ejection fraction. Circ Heart Fail 15 : e008935, 2022. doi:10.1161/CIRCHEARTFAILURE.121.008935. 35311526
31. Adir Y, Guazzi M, Offer A, Temporelli PL, Cannito A, Ghio S. Pulmonary hemodynamics in heart failure patients with reduced or preserved ejection fraction and pulmonary hypertension: Similarities and disparities. Am Heart J 192 : 120–127, 2017. doi:10.1016/j.ahj.2017.06.006. 28938958
32. Del Punta L, De Biase N, Armenia S, Di Fiore V, Maremmani D, Gargani L, Mazzola M, De Carlo M, Mengozzi A, Lomonaco T, Galeotti GG, Dini FL, Masi S, Pugliese NR. Combining cardiopulmonary exercise testing with echocardiography: a multiparametric approach to the cardiovascular and cardiopulmonary systems. Eur Heart J Imaging Methods Pract 1 : qyad021, 2023. doi:10.1093/ehjimp/qyad021.39044798
33. Lin K, Sarnari R, Pathrose A, Gordon DZ, Blaisdell J, Markl M, Carr JC. Cine MRI characterizes HFpEF and HFrEF in post-capillary pulmonary hypertension. Eur J Radiol 139 : 109679, 2021. doi:10.1016/j.ejrad.2021.109679. 33819807
34. Bers DM. Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction. Annu Rev Physiol 76 : 107–127, 2014. doi:10.1146/annurev-physiol-020911-153308. 24245942
35. Packer M, Lam CSP, Lund LH, Redfield MM. Interdependence of atrial fibrillation and heart failure with a preserved ejection fraction reflects a common underlying atrial and ventricular myopathy. Circulation 141 : 4–6, 2020. doi:10.1161/CIRCULATIONAHA.119.042996. 31887078
36. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation 125 : 289–297, 2012. doi:10.1161/CIRCULATIONAHA.111.051540. 22131357
37. Leopold JA. Pulmonary venous remodeling in pulmonary hypertension: the veins take center stage. Circulation 137 : 1811–1813, 2018. doi:10.1161/CIRCULATIONAHA.118.033013. 29685930
38. Allen BJ, Frye H, Ramanathan R, Caggiano LR, Tabima DM, Chesler NC, Philip JL. Biomechanical and mechanobiological drivers of the transition from postcapillary pulmonary hypertension to combined pre-/postcapillary pulmonary hypertension. J Am Heart Assoc 12 : e028121, 2023. doi:10.1161/JAHA.122.028121. 36734341
39. Zhang LL, Chen GH, Tang RJ, Xiong YY, Pan Q, Jiang WY, Gong ZT, Chen C, Li XS, Yang YJ. Levosimendan reverses cardiac malfunction and cardiomyocyte ferroptosis during heart failure with preserved ejection fraction via connexin 43 signaling activation. Cardiovasc Drugs Ther (2023). Epub ahead of print. doi:10.1007/s10557-023-07441-4. 36881213
40. Burkhoff D, Borlaug BA, Shah SJ, Zolty R, Tedford RJ, Thenappan T, Zamanian RT, Mazurek JA, Rich JD, Simon MA, Chung ES, Raza F, Majure DT, Lewis GD, Preston IR, Rich S. Levosimendan improves hemodynamics and exercise tolerance in PH-HFpEF: results of the randomized placebo-controlled HELP trial. JACC Heart Fail 9 : 360–370, 2021. doi:10.1016/j.jchf.2021.01.015. 33839076
41. Ovchinnikov A, Potekhina A, Belyavskiy E, Ageev F. Heart failure with preserved ejection fraction and pulmonary hypertension: focus on phosphodiesterase inhibitors. Pharmaceuticals (Basel) 15 : 1024, 2022. doi:10.3390/ph15081024. 36015172
42. Caravita S, Faini A, Carolino D'Araujo S, Dewachter C, Chomette L, Bondue A, Naeije R, Parati G, Vachiery JL. Clinical phenotypes and outcomes of pulmonary hypertension due to left heart disease: role of the pre-capillary component. PLoS One 13 : e0199164, 2018. doi:10.1371/journal.pone.0199164. 29920539
43. Townsley MI, Fu Z, Mathieu-Costello O, West JB. Pulmonary microvascular permeability. Responses to high vascular pressure after induction of pacing-induced heart failure in dogs. Circ Res 77 : 317–325, 1995. doi:10.1161/01.res.77.2.317. 7614719
44. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol 17 : 559–573, 2020. doi:10.1038/s41569-020-0363-2. 32231333
45. Boerrigter B, Trip P, Bogaard HJ, Groepenhoff H, Oosterveer F, Westerhof N, Vonk Noordegraaf A. Right atrial pressure affects the interaction between lung mechanics and right ventricular function in spontaneously breathing COPD patients. PLoS One 7 : e30208, 2012. doi:10.1371/journal.pone.0030208. 22272306
46. Blann AD, Woywodt A, Bertolini F, Bull TM, Buyon JP, Clancy RM, Haubitz M, Hebbel RP, Lip GY, Mancuso P, Sampol J, Solovey A, Dignat-George F. Circulating endothelial cells. Biomarker of vascular disease. Thromb Haemost 93 : 228–235, 2005. doi:10.1160/TH04-09-0578. 15711737
47. Ramadhiani R, Ikeda K, Miyagawa K, Ryanto GRT, Tamada N, Suzuki Y, Hirata K, Emoto N. Endothelial cell premature senescence exacerbates pulmonary arterial hypertension through contact-mediated interaction with vascular smooth muscle cells. Eur Heart J 41 : ehaa946.2234, 2020. doi:10.1093/ehjci/ehaa946.2234.
48. Sanders-van Wijk S, Tromp J, Beussink-Nelson L, Hage C, Svedlund S, Saraste A, Swat SA, Sanchez C, Njoroge J, Tan RS, Fermer ML, Gan LM, Lund LH, Lam CSP, Shah SJ. Proteomic evaluation of the comorbidity-inflammation paradigm in heart failure with preserved ejection fraction: results from the PROMIS-HFpEF study. Circulation 142 : 2029–2044, 2020. doi:10.1161/CIRCULATIONAHA.120.045810. 33034202
49. Schiattarella GG, Altamirano F, Tong D, French KM, Villalobos E, Kim SY, Luo X, Jiang N, May HI, Wang ZV, Hill TM, Mammen PPA, Huang J, Lee DI, Hahn VS, Sharma K, Kass DA, Lavandero S, Gillette TG, Hill JA. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568 : 351–356, 2019. doi:10.1038/s41586-019-1100-z. 30971818
50. Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 4 : 302–312, 2010. doi:10.2174/1874192401004010302. 21339899
51. Mesquita T, Lin YN, Ibrahim A. Chronic low-grade inflammation in heart failure with preserved ejection fraction. Aging Cell 20 : e13453, 2021. doi:10.1111/acel.13453. 34382743
52. Radomski MW, Palmer RM, Moncada S. An l-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 87 : 5193–5197, 1990. doi:10.1073/pnas.87.13.5193. 1695013
53. Hu Z, Xiong Y, Han X, Geng C, Jiang B, Huo Y, Luo J. Acute mechanical stretch promotes eNOS activation in venous endothelial cells mainly via PKA and Akt pathways. PLoS One 8 : e71359, 2013. doi:10.1371/journal.pone.0071359. 23977025
54. Dachs TM, Duca F, Rettl R, Binder-Rodriguez C, Dalos D, Ligios LC, Kammerlander A, Grünig E, Pretsch I, Steringer-Mascherbauer R, Ablasser K, Wargenau M, Mascherbauer J, Lang IM, Hengstenberg C, Badr-Eslam R, Kastner J, Bonderman D. Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial. Eur Heart J 43 : 3402–3413, 2022. doi:10.1093/eurheartj/ehac389. 35909264
55. Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J Jr, Parker J, Seferovic JP, Wilson P, Mittleman RS, Profy AT, Konstam MA. Effect of praliciguat on peak rate of oxygen consumption in patients with heart failure with preserved ejection fraction: The CAPACITY HFpEF randomized clinical trial. JAMA 324 : 1522–1531, 2020. doi:10.1001/jama.2020.16641. 33079154
56. Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, Hernandez AF, O'Connor CM, Pieske B, Ponikowski P, Shah SJ, Solomon SD, Voors AA, She L, Vlajnic V, Carvalho F, Bamber L, Blaustein RO, Roessig L, Butler J; VITALITY-HFpEF Study Group. Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial. JAMA 324 : 1512–1521, 2020 [Erratum in JAMA 325: 494, 2021]. doi:10.1001/jama.2020.15922. 33079152
57. Obokata M, Kane GC, Reddy YNV, Melenovsky V, Olson TP, Jarolim P, Borlaug BA. The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction. Eur Heart J 40 : 3707–3717, 2019. doi:10.1093/eurheartj/ehz626. 31513270
58. Chowdhury MA, Moukarbel GV, Gupta R, Frank SM, Anderson AM, Liu LC, Khouri SJ. Endothelin 1 is associated with heart failure hospitalization and long-term mortality in patients with heart failure with preserved ejection fraction and pulmonary hypertension. Cardiology 143 : 124–133, 2019. doi:10.1159/000501100. 31514181
59. Meoli DF, Su YR, Brittain EL, Robbins IM, Hemnes AR, Monahan K. The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension. Pulm Circ 8 : 2045893217745019, 2018. doi:10.1177/2045893217745019. 29251543
60. Valero-Munoz M, Li S, Wilson RM, Boldbaatar B, Iglarz M, Sam F. Dual endothelin-A/endothelin-B receptor blockade and cardiac remodeling in heart failure with preserved ejection fraction. Circ Heart Fail 9 : e003381, 2016. doi:10.1161/CIRCHEARTFAILURE.116.003381. 27810862
61. Bitar MS, Wahid S, Mustafa S, Al-Saleh E, Dhaunsi GS, Al-Mulla F. Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. Eur J Pharmacol 511 : 53–64, 2005. doi:10.1016/j.ejphar.2005.01.014. 15777779
62. Wei J, Nelson MD, Szczepaniak EW, Smith L, Mehta PK, Thomson LE, Berman DS, Li D, Bairey Merz CN, Szczepaniak LS. Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women. Am J Physiol Heart Circ Physiol 310 : H14–H19, 2016. doi:10.1152/ajpheart.00612.2015. 26519031
63. Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 133 : 717–731, 2016. doi:10.1161/CIRCULATIONAHA.115.018935. 26813102
64. Ranchoux B, Nadeau V, Bourgeois A, Provencher S, Tremblay E, Omura J, Coté N, Abu-Alhayja'a R, Dumais V, Nachbar RT, Tastet L, Dahou A, Breuils-Bonnet S, Marette A, Pibarot P, Dupuis J, Paulin R, Boucherat O, Archer SL, Bonnet S, Potus F. Metabolic syndrome exacerbates pulmonary hypertension due to left heart disease. Circ Res 125 : 449–466, 2019. doi:10.1161/CIRCRESAHA.118.314555. 31154939
65. Meng Q, Lai YC, Kelly NJ, Bueno M, Baust JJ, Bachman TN, Goncharov D, Vanderpool RR, Radder JE, Hu J, Goncharova E, Morris AM, Mora AL, Shapiro SD, Gladwin MT. Development of a mouse model of metabolic syndrome, pulmonary hypertension, and heart failure with preserved ejection fraction. Am J Respir Cell Mol Biol 56 : 497–505, 2017. doi:10.1165/rcmb.2016-0177OC. 28118022
66. DuBrock HM, AbouEzzeddine OF, Redfield MM. High-sensitivity C-reactive protein in heart failure with preserved ejection fraction. PLoS One 13 : e0201836, 2018. doi:10.1371/journal.pone.0201836. 30114262
67. Sciarretta S, Ferrucci A, Ciavarella GM, De Paolis P, Venturelli V, Tocci G, De Biase L, Rubattu S, Volpe M. Markers of inflammation and fibrosis are related to cardiovascular damage in hypertensive patients with metabolic syndrome. Am J Hypertens 20 : 784–791, 2007. doi:10.1016/j.amjhyper.2007.01.023. 17586414
68. Weiss TW, Arnesen H, Seljeflot I. Components of the interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness. Metabolism 62 : 1008–1013, 2013. doi:10.1016/j.metabol.2013.01.019. 23428306
69. Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86 : 3257–3265, 2001. doi:10.1210/jcem.86.7.7623. 11443198
70. Costantino S, Mengozzi A, Velagapudi S, Mohammed SA, Gorica E, Akhmedov A, Mongelli A, Pugliese NR, Masi S, Virdis A, Hülsmeier A, Matter CM, Hornemann T, Melina G, Ruschitzka F, Luscher TF, Paneni F. Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy. Cardiovasc Diabetol 22 : 312, 2023. doi:10.1186/s12933-023-02057-2. 37957697
71. Packer M. Cardioprotective effects of Sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. Circ Heart Fail 13 : e007197, 2020. doi:10.1161/CIRCHEARTFAILURE.120.007197. 32894987
72. Leggat J, Bidault G, Vidal-Puig A. Lipotoxicity: a driver of heart failure with preserved ejection fraction? Clin Sci (Lond) 135 : 2265–2283, 2021. doi:10.1042/CS20210127. 34643676
73. Faxén UL, Hage C, Andreasson A, Donal E, Daubert JC, Linde C, Brismar K, Lund LH. HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin. Int J Cardiol 228 : 709–716, 2017. doi:10.1016/j.ijcard.2016.11.194. 27886615
74. Huertas A, Tu L, Thuillet R, Le Hiress M, Phan C, Ricard N, Nadaud S, Fadel E, Humbert M, Guignabert C. Leptin signalling system as a target for pulmonary arterial hypertension therapy. Eur Respir J 45 : 1066–1080, 2015. doi:10.1183/09031936.00193014. 25745038
75. Naeije R, Gerges M, Vachiery JL, Caravita S, Gerges C, Lang IM. Hemodynamic phenotyping of pulmonary hypertension in left heart failure. Circ Heart Fail 10 : e004082, 2017. doi:10.1161/CIRCHEARTFAILURE.117.004082. 28912263
76. Qiu H, He Y, Ouyang F, Jiang P, Guo S, Guo Y. The role of regulatory T cells in pulmonary arterial hypertension. J Am Heart Assoc 8 : e014201, 2019. doi:10.1161/JAHA.119.014201. 31771439
77. Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, Scerbavicius R, Burns N, Cool C, Wood K, Parr JE, Boackle SA, Voelkel NF. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med 175 : 1280–1289, 2007. doi:10.1164/rccm.200608-1189OC. 17413127
78. Chu Y, Xiangli X, Xiao W. Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice. Mol Med Rep 11 : 3181–3187, 2015. doi:10.3892/mmr.2014.3106. 25523119
79. Voelkel NF, Tamosiuniene R, Nicolls MR. Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14 : 939–951, 2016. doi:10.1080/14779072.2016.1180976. 27096622
80. Li N, Bian H, Zhang J, Li X, Ji X, Zhang Y. The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. Clin Chim Acta 411 : 1963–1968, 2010. doi:10.1016/j.cca.2010.08.013. 20713031
81. Agrawal V, Kropski JA, Gokey JJ, Kobeck E, Murphy MB, Murray KT, Fortune NL, Moore CS, Meoli DF, Monahan K, Ru Su Y, Blackwell T, Gupta DK, Talati MH, Gladson S, Carrier EJ, West JD, Hemnes AR. Myeloid cell derived IL1β contributes to pulmonary hypertension in HFpEF. Circ Res 133 : 885–898, 2023. doi:10.1161/CIRCRESAHA.123.323119. 37929582
82. Edelmann F, Holzendorf V, Wachter R, Nolte K, Schmidt AG, Kraigher-Krainer E, Duvinage A, Unkelbach I, Düngen HD, Tschöpe C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Stough WG, Pieske BM. Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial. Eur J Heart Fail 17 : 214–223, 2015. doi:10.1002/ejhf.203. 25418979
83. Mazurek JA, Horne BD, Saeed W, Sardar MR, Zolty R. Galectin-3 levels are elevated and predictive of mortality in pulmonary hypertension. Heart Lung Circ 26 : 1208–1215, 2017. doi:10.1016/j.hlc.2016.12.012. 28242288
84. Goncharov DA, Goncharova EA, Tofovic SP, Hu J, Baust JJ, Pena AZ, Ray A, Rode A, Vanderpool RR, Mora AL, Gladwin MT, Lai YC. Metformin therapy for pulmonary hypertension associated with heart failure with preserved ejection fraction versus pulmonary arterial hypertension. Am J Respir Crit Care Med 198 : 681–684, 2018. doi:10.1164/rccm.201801-0022LE. 29727194
85. Kosiborod MN, Abildstrom SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Lelonek M, Melenovsky V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, Van der Meer P, von Lewinski D, Wolf D, Petrie MC; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 389 : 1069–1084, 2023. doi:10.1056/NEJMoa2306963. 37622681
86. O’Sullivan JF, Li M, Koay YC, Wang XS, Guglielmi G, Marques FZ, Nanayakkara S, Mariani J, Slaughter E, Kaye DM. Cardiac substrate utilization and relationship to invasive exercise hemodynamic parameters in HFpEF. JACC Basic Transl Sci 9 : 281–299, 2024. doi:10.1016/j.jacbts.2023.11.006. 38559626
87. Jovanovic N, Foryst-Ludwig A, Klose C, da Conceicao CR, Alasfar L, Birkner T, Forslund SK, Kintscher U, Edelmann F. An altered plasma lipidome-phenome network characterizes heart failure with preserved ejection fraction. ESC Heart Fail. In press. doi:10.1002/ehf2.14654. 38243357
88. Aradhyula V. A novel lipidomics approach to predicting pulmonary hypertension in human heart failure. Translation 11 , 2023. doi:10.46570/utjms.vol11-2023-639.
89. Faleel D, Elzanaty A, Aradhyula V, Vyas R, Dube P, T. Haller S, Gupta R, J. Kennedy D, J. Khouri S. Machine learning analysis of identifies polyunsaturated fatty acid metabolites predictive of adverse outcomes in heart failure with preserved ejection fraction patients. Translation 11 , 2023. doi:10.46570/utjms.vol11-2023-951.
90. Zhang M, Shu H, Chen C, He Z, Zhou Z, Wang DW. Epoxyeicosatrienoic acid: A potential therapeutic target of heart failure with preserved ejection fraction. Biomed Pharmacother 153 : 113326, 2022. doi:10.1016/j.biopha.2022.113326. 35759865
91. Li F, You Y, Zhu H. 15-HETE protects pulmonary artery smooth muscle cells against apoptosis via SIRT1 regulation during hypoxia. Biomed Pharmacother 108 : 325–330, 2018. doi:10.1016/j.biopha.2018.07.166. 30227325
92. Jin S, Chen H, Li Y, Zhong H, Sun W, Wang J, Zhang T, Ma J, Yan S, Zhang J, Tian Q, Yang X, Wang J. Maresin 1 improves the Treg/Th17 imbalance in rheumatoid arthritis through miR-21. Ann Rheum Dis 77 : 1644–1652, 2018. doi:10.1136/annrheumdis-2018-213511. 30045854
93. Zhang J, Zou F, Tang J, Zhang Q, Gong Y, Wang Q, Shen Y, Xiong L, Breyer RM, Lazarus M, Funk CD, Yu Y. Cyclooxygenase-2-derived prostaglandin E(2) promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor. Circ Res 113 : 104–114, 2013. doi:10.1161/CIRCRESAHA.113.301033. 23595951
94. Maclean MMR. The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series). Pulm Circ 8 : 2045894018759125, 2018. doi:10.1177/2045894018759125. 29468941
95. Wu J, Ding DH, Li QQ, Wang XY, Sun YY, Li LJ. Lipoxin A4 regulates lipopolysaccharide-induced BV2 microglial activation and differentiation via the notch signaling pathway. Front Cell Neurosci 13 : 19, 2019. doi:10.3389/fncel.2019.00019. 30778288
96. Campos-Estrada C, Liempi A, González-Herrera F, Lapier M, Kemmerling U, Pesce B, Ferreira J, López-Muñoz R, Maya JD. Simvastatin and benznidazole-mediated prevention of Trypanosoma cruzi-induced endothelial activation: role of 15-epi-lipoxin A4 in the action of simvastatin. PLoS Negl Trop Dis 9 : e0003770, 2015. doi:10.1371/journal.pntd.0003770. 25978361
97. Cao J, Tsenovoy PL, Thompson EA, Falck JR, Touchon R, Sodhi K, Rezzani R, Shapiro JI, Abraham NG. Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway. Prostaglandins Other Lipid Mediat 116–117 : 76–86, 2015. doi:10.1016/j.prostaglandins.2015.01.002. 25677507
98. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447 : 869–874, 2007. doi:10.1038/nature05877. 17568749
99. Delavar MA, Lye MS, Khor GL, Hassan ST, Hanachi P. Dietary patterns and the metabolic syndrome in middle aged women, Babol, Iran. Asia Pac J Clin Nutr 18 : 285–292, 2009. 19713190
100. de Batlle J, Sauleda J, Balcells E, Gomez FP, Méndez M, Rodriguez E, Barreiro E, Ferrer JJ, Romieu I, Gea J, Antó JM, Garcia-Aymerich J; PAC-COPD Study Group. Association between Omega3 and Omega6 fatty acid intakes and serum inflammatory markers in COPD. J Nutr Biochem 23 : 817–821, 2012. doi:10.1016/j.jnutbio.2011.04.005. 21889886
101. Huang CY, Lee JK, Chen ZW, Cheng JF, Chen SY, Lin LY, Wu CK. Inhaled prostacyclin on exercise echocardiographic cardiac function in preserved ejection fraction heart failure. Med Sci Sports Exerc 52 : 269–277, 2020. doi:10.1249/MSS.0000000000002145. 31479003
102. Wang L, Halliday G, Huot JR, Satoh T, Baust JJ, Fisher A, Cook T, Hu J, Avolio T, Goncharov DA, Bai Y, Vanderpool RR, Considine RV, Bonetto A, Tan J, Bachman TN, Sebastiani A, McTiernan CF, Mora AL, Machado RF, Goncharova EA, Gladwin MT, Lai YC. Treatment with treprostinil and metformin normalizes hyperglycemia and improves cardiac function in pulmonary hypertension associated with heart failure with preserved ejection fraction. Arterioscler Thromb Vasc Biol 40 : 1543–1558, 2020. doi:10.1161/ATVBAHA.119.313883. 32268788
103. Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH. Prostaglandins in severe congestive heart failure. Relation to activation of the renin–angiotensin system and hyponatremia. N Engl J Med 310 : 347–352, 1984. doi:10.1056/NEJM198402093100603. 6361570
104. Jiang J, Wang S, Wang Z, Ma J, Liu S, Li W, Zhu D. The role of ERK1/2 in 15-HETE-inhibited apoptosis in pulmonary arterial smooth muscle cells. J Recept Signal Transduct Res 31 : 45–52, 2011. doi:10.3109/10799893.2010.512013. 20822476
105. Wu Y, Zhai H, Wang Y, Li L, Wu J, Wang F, Sun S, Yao S, Shang Y. Aspirin-triggered lipoxin A4 attenuates lipopolysaccharide-induced intracellular ROS in BV2 microglia cells by inhibiting the function of NADPH oxidase. Neurochem Res 37 : 1690–1696, 2012. doi:10.1007/s11064-012-0776-3. 22552474
106. Li H, Li X, Hao Y, Wu C, Fu Y, Su N, Chen H, Ying B, Wang H, Su L, Cai H, He Q, Cai M, Sun J, Lin J, Scott A, Smith F, Huang X, Jin S. Maresin 1 intervention reverses experimental pulmonary arterial hypertension in mice. Br J Pharmacol 179 : 5132–5147, 2022. doi:10.1111/bph.15906. 35764296
107. Li X, Chu G, Zhu F, Zheng Z, Wang X, Zhang G, Wang F. Epoxyeicosatrienoic acid prevents maladaptive remodeling in pressure overload by targeting calcineurin/NFAT and Smad-7. Exp Cell Res 386 : 111716, 2020. doi:10.1016/j.yexcr.2019.111716. 31734152
108. Ding Y, Tu P, Chen Y, Huang Y, Pan X, Chen W. CYP2J2 and EETs protect against pulmonary arterial hypertension with lung ischemia-reperfusion injury in vivo and in vitro. Respir Res 22 : 291, 2021. doi:10.1186/s12931-021-01891-w. 34774051
