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Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

ABSTRACT: Approximately 50% of patients with symptoms and signs of heart failure have a left ventricular ejection fraction (LVEF) ?50% and are often simply referred to as 'heart failure with preserved EF', 'HFpEF'. Many of such patients have HF secondary to specific cardiac conditions (i.e., valvular or pericardial disease) in which the symptoms and signs occur despite the LVEF being preserved due to diastolic dysfunction secondary to the underlying disease (secondary HFpEF), differently from those HFpEF patients in which the impaired LV filling is due to a primary diastolic dysfunction (primary HFpEF). When primary HFpEF patients are properly diagnosed, they appear to have a milder form of HF with a lower cardiovascular mortality compared with HFrEF and secondary HFpEF population, but a risk of HF hospitalization that is significantly higher than patients with similar cardiovascular risk factors but without the diagnosis of HFpEF. We herein review the diagnostic approach to HFpEF and present a differential diagnosis of HFpEF in a primary and secondary form.

SUBMITTER: Del Buono MG

PROVIDER: S-EPMC6608585 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

Del Buono Marco Giuseppe MG Buckley Leo L Abbate Antonio A

The American journal of cardiology 20180803 9

Approximately 50% of patients with symptoms and signs of heart failure have a left ventricular ejection fraction (LVEF) ≥50% and are often simply referred to as 'heart failure with preserved EF', 'HFpEF'. Many of such patients have HF secondary to specific cardiac conditions (i.e., valvular or pericardial disease) in which the symptoms and signs occur despite the LVEF being preserved due to diastolic dysfunction secondary to the underlying disease (secondary HFpEF), differently from those HFpEF ...[more]

PMID: 30220416

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Project description:Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart.

Project description:Rationale: Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are crucial elements in the pathogenesis of hypertension-induced cardiac remodeling. The C-X-C chemokine receptor 4 (CXCR4) is a critical regulator of the macrophage-mediated immune response. Nevertheless, the contribution of CXCR4 to macrophage phenotype and function during the progression of HFpEF remains unclear. Herein, we aimed to determine the role of macrophagic CXCR4 in heart failure with preserved ejection fraction (HFpEF). Methods: As a HFpEF model, wild type mice and myeloid-specific CXCR4 deficiency mice were subjected to pressure overload for 30 days to assess the function of macrophagic CXCR4 on cardiac function. Medium from macrophages was used to treat cardiac fibroblasts to study macrophage-to-fibroblast signaling. Results: We found circulatory CXCR4+ immune cells, mainly monocytes, markedly increased in HFpEF patients with hypertension. In the experimental HFpEF mice model, macrophages but not neutrophils represent the main infiltrating inflammatory cells in the heart, abundantly expressing CXCR4. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in the heart of HFpEF mice, thus ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, transcriptomic profiling data revealed that CXCR4 loss in macrophages exhibited a decreased transcriptional signature associated with the regulation of inflammatory response. Notably, CXCR4 significantly augmented chemokine (C‑X‑C) motif ligand (CXCL3) expression, which at least partly contributed to fibrosis by promoting myofibroblast differentiation. Mechanistically, the increased production of pro-inflammatory cytokines in CXCR4 expressed macrophages could be attributed to the suppression of the peroxisome proliferator-activated receptor γ (PPARγ) activity. Conclusions: Collectively, our data supported that the infiltration of CXCR4+ macrophages in the heart exacerbates hypertension-induced diastolic function by promoting pro-inflammatory cytokines production and thus may serve as a potential therapeutic target for hypertension-induced HFpEF.

Dataset Information

Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

Publications

Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

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