Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.

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.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction.

Pulmonary hypertension in the setting of heart failure with preserved ejection fraction (PH-HFpEF) is a growing public health problem that is increasing in prevalence. While PH-HFpEF is defined by a high mean pulmonary artery pressure, high left ventricular end-diastolic pressure and a normal ejection fraction, some HFpEF patients develop PH in the presence of pulmonary vascular remodelling with a high transpulmonary pressure gradient or pulmonary vascular resistance. Ageing, increased left atrial pressure and stiffness, mitral regurgitation, as well as features of metabolic syndrome, which include obesity, diabetes and hypertension, are recognized as risk factors for PH-HFpEF. Qualitative studies have documented that patients with PH-HFpEF develop more severe symptoms than those with HFpEF and are associated with more significant exercise intolerance, frequent hospitalizations, right heart failure and reduced survival. Currently, there are no effective therapies for PH-HFpEF, although a number of candidate drugs are being evaluated, including soluble guanylate cyclase stimulators, phosphodiesterase type 5 inhibitors, sodium nitrite and endothelin receptor antagonists. In this review we attempt to provide an updated overview of recent findings pertaining to the pulmonary vascular complications in HFpEF in terms of clinical definitions, epidemiology and pathophysiology. Mechanisms leading to pulmonary vascular remodelling in HFpEF, a summary of pre-clinical models of HFpEF and PH-HFpEF, and new candidate therapeutic strategies for the treatment of PH-HFpEF are summarized.

Radiomics features of the cardiac blood pool to indicate hemodynamic changes in pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (PH-HFpEF).

To test the hypothesis that cine MRI-derived radiomics features of the cardiac blood pool can represent hemodynamic characteristics of pulmonary hypertension-heart failure with preserved ejection fraction (PH-HFpEF). Nineteen PH-HFpEF patients (9 male, 57.8 ± 14.7 years) and 19 healthy controls (13 male, 50.3 ± 13.6 years) were enrolled. All participants underwent a cardiac MRI scan. One hundred and seven radiomics features (7 classes) of the blood pool in the left and right ventricles/atrium (LV/RV/LA/RA) were extracted from 4-chamber cine (2D images) at the stages of systole, rapid filling, diastasis, and atrial contraction within a cardiac cycle. For PH-HFpEF patients, features acquired from LV/LA were related to the pulmonary capillary wedge pressure (PCWP); features acquired from RV/RA were related to the mean pulmonary artery pressure (mPAP) using the Pearson correlation coefficient (r). Logistic regression, receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to test the capability of radiomics features in discriminating 2 subject groups. Features acquired from different chambers at various periods present diverse properties in representing hemodynamic indices of PH-HFpEF. Multiple radiomics features blood pool were significantly related to PCWP and/or mPAP (r: 0.4-0.679, p < 0.05). In addition, multiple features of blood pools acquired at various time points within a cardiac cycle can efficiently discriminate PH-HFpEF from controls (individual AUC: 0.7-0.864). Cine MRI-derived radiomics features of the cardiac blood pool have the potential to characterize hemodynamic abnormalities in the context of PH-HFpEF.

Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease.

Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absence of specific biomarkers that can aid in the early diagnosis and management of this challenging syndrome. Currently, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are guideline-recommended biomarkers for the diagnosis and prognosis of heart failure (HF) and PH. Endothelin-1 (ET-1), vascular endothelial growth factor-D (VEGF-D), and microRNA-206 have also been recently identified as new potential circulating biomarkers for patients with PH-LHD. In this review, we aim to present the current state of knowledge of circulating biomarkers that can be used to guide future research toward diagnosis, refine specific patient phenotype, and develop therapeutic approaches for PH-LHD, with a particular focus on PH-HFpEF. Potential circulating biomarkers identified in pre-clinical models of PH-LHD are also summarized here.

Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is defined as clinical features of heart failure, ideally with biomarker evidence such as elevated plasma natriuretic peptide levels, in the setting of an ejection fraction (EF) greater than 50% and imaging evidence of diastolic left ventricular dysfunction [1,2]. In the absence of cardiac imaging or invasive hemodynamics, this is a clinical syndrome that is often indistinguishable from heart failure with reduced ejection fraction (HFrEF). HFpEF and HFrEF present with a cadre of comparable signs and symptoms including jugular venous distention, pulmonary rales on auscultation, breathlessness, orthopnea, exercise intolerance, exertional dyspnea, fatigue and peripheral edema. HFpEF accounts for at least half of all diagnoses of heart failure [1,2]. Pulmonary hypertension (PH) is a common complication of HFpEF that is linked to worse disease morbidity and mortality. In fact, mortality has been linked to increases in the intrinsic pulmonary vascular resistance in the setting of increased left ventricular end diastolic pressure, characterized hemodynamically by rises in the transpulmonary pressure gradient, pulmonary vascular resistance or diastolic pressure gradient. Despite being the most common form of PH, there are no approved therapies for the treatment of PH secondary to HFpEF. This review will summarize the hemodynamic classifications of PH in the setting of HFpEF, mechanisms of disease, the potential contribution of pulmonary vascular disease to poor outcomes in patients with HFpEF, and new approaches to therapy.

A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.

Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.