Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is an increasingly frequent form and is estimated to be the dominant form of HF. On the other hand, HFpEF is a syndrome with systemic involvement, and it is characterized by multiple cardiac and extracardiac pathophysiological alterations. The increasing prevalence is currently reaching epidemic levels, thereby making HFpEF one of the greatest challenges facing cardiovascular medicine today. Compared to HF with reduced ejection fraction (HFrEF), the medical attitude in the case of HFpEF was a relaxed one towards the disease, despite the fact that it is much more complex, with many problems related to the identification of physiopathogenetic mechanisms and optimal methods of treatment. The current medical challenge is to develop effective therapeutic strategies, because patients suffering from HFpEF have symptoms and quality of life comparable to those with reduced ejection fraction, but the specific medication for HFrEF is ineffective in this situation; for this, we must first understand the pathological mechanisms in detail and correlate them with the clinical presentation. Another important aspect of HFpEF is the diversity of patients that can be identified under the umbrella of this syndrome. Thus, before being able to test and develop effective therapies, we must succeed in grouping patients into several categories, called phenotypes, depending on the pathological pathways and clinical features. This narrative review critiques issues related to the definition, etiology, clinical features, and pathophysiology of HFpEF. We tried to describe in as much detail as possible the clinical and biological phenotypes recognized in the literature in order to better understand the current therapeutic approach and the reason for the limited effectiveness. We have also highlighted possible pathological pathways that can be targeted by the latest research in this field.

Heart Failure with Preserved Ejection Fraction: How to Deal with This Chameleon

“…Microvascular dysfunction, oxidative stress, inflammation, and senescence have been proposed as etiological factors of HFpEF [ 5 ].…”

“…Alterations in growth signaling pathways, including insulin-like growth factor-1 (IGF-1), have also been reported in the absence of CVD, confirming the direct relationship between senescence and HFpEF [ 8 ]. Circulating molecules such as the vascular endothelial growth factor, IL-1, IL-8 cytokines, matrix metalloproteinase, and the plasminogen activator inhibitor (PAI)-1 have been recognized as being involved in the mechanisms sustaining inflammation and oxidative stress tissue remodeling [ 5 ]. This secretory pattern has been hypothesized to promote the development of HFpEF [ 5 , 9 ].…”

“…Circulating molecules such as the vascular endothelial growth factor, IL-1, IL-8 cytokines, matrix metalloproteinase, and the plasminogen activator inhibitor (PAI)-1 have been recognized as being involved in the mechanisms sustaining inflammation and oxidative stress tissue remodeling [ 5 ]. This secretory pattern has been hypothesized to promote the development of HFpEF [ 5 , 9 ]. Indeed, inflammation has been proposed to be a leading etiological factor of HFpEF [ 9 ].…”

Global longitudinal strain as a predictor of risk in patients with heart failure with preserved ejection fraction: A deserved role?

“…Comparatively, HFpEF patients tend to be female, elderly, and commonly have associated comorbidities such as hypertension, diabetes, obesity, chronic renal failure, and atrial fibrillation, in contrast to those with HFrEF. 2 Despite the increasing prevalence and poor prognosis associated with HFpEF, identifying patients who will experience unfavourable outcomes within this heterogeneous group remains exceedingly difficult. Beyond LVEF, a prompt and accurate diagnosis is therefore a key challenge for improving the prognosis of these patients.…”

“…The aetiology of this pathophysiology remains unclear, multifactorial and related to systemic inflammation leading to endothelial dysfunction, microvascular dysfunction and general oxidative stress. 2 Microvascular dysfunction contributes significantly to structural and functional alterations. 13,14 Numerous studies have shown that HFpEF should not be regarded as a single entity but rather as a heterogeneous spectrum comprising various epidemiological, clinical, biomarker, and prognostic profiles within the population.…”