| 1. Introduction |
The original descriptions of Heart Failure (HF) with preserved ejection fraction (HFpEF) date back to the mid-1980s, and for approximately a decade, studies on this subtype of HF consisted of comparative reports or case series with great heterogeneity in terms of prevalence and clinical implications.
Consequently, the most recent guidelines provided by the European Society of Cardiology for the management of acute and chronic HF indicate that 50% of patients have heart failure with reduced ejection fraction (HFrEF) and the other half suffer from HFpEF/HF. with slightly reduced ejection fraction.
In the complex scenario linking comorbidities and HFpEF, there are still many gray areas. First, whether HFpEF represents true HF or just a collection of comorbidities. Furthermore, it remains to be clarified whether distinct cardiovascular (CV) abnormalities are detectable in HFpEF and whether this syndrome can be divided into different phenotypes according to a specific grouping of distinct comorbidities.
The present review aims to elucidate the aforementioned outstanding issues by I ) reporting epidemiological data on HFpEF and comorbidities, II ) addressing the pathophysiological underpinnings of the relationship between comorbidities and HFpEF provided by studies, III ) exploring the possibility of grouping HFpEF in different phenotypes according to specific comorbidity profile. Finally, an attempt will be made to analyze the possibility of treating the underlying comorbidities on an individualized basis, as a promising approach in the therapy of this syndrome.
> 1.1 Are we facing a HFpEF tsunami in the coming decades? An epidemiological perspective.
HF represents a significant health burden worldwide and affects 1-2% of the population in developed countries. Its prevalence shows a continuous increase and the reasons behind this trend can be found in the demographic growth of the world population, the increasing proportion of elderly subjects and the improved diagnostic and therapeutic approaches that also progress the survival of patients. .
The classification of HF according to left ventricular ejection fraction (LVEF) is relatively recent and homogeneity in diagnostic evaluation was achieved only a few years ago. From several registries and population-based studies, including the Framingham Heart Study, the Strong Heart Study, and the Cardiovascular Health Study, HFpEF constitutes a large proportion (>50%) of all HF cases. In this sense, the most recent guidelines provided by the European Society of Cardiology (SEC) for the management of acute and chronic HF indicate that 50% of patients have HFrEF and the other half suffer from HFpEF/minimally reduced HFpEF.
The prevalence of risk factors that contribute to the development of HFpEF may vary among affected individuals, and they coincide synergistically to increase the risk of HF onset and progression. Although evidence on racial and ethnic differences is still limited, gender-based differences have been reported with black women experiencing higher rates of HFpEF compared to other race and sex groups.
Almost all studies have shown that advanced age and female sex are more common in HFpEF than in HFrEF.
The high prevalence of cardiovascular comorbidities and risk factors in HFpEF has been widely developed, with high blood pressure being the most prevalent condition. Coronary artery disease (CAD), although more prevalent in HFrEF, is a common condition also in HFpEF, representing a percentage of patients that ranges between 35 and 60% in epidemiological studies, and is associated with a higher risk of decreased LVEF and increased mortality.
The comorbidity burden in HFpEF also includes obesity, atrial fibrillation, diabetes mellitus, and chronic kidney disease. It is noteworthy that all the aforementioned conditions are very common in old age and the increasing percentage of elderly in the world population will be responsible for the largest predicted increase in the incidence and prevalence of HFpEF in the future.
> 1.2. Does HFpEF represent true HF or just a collection of comorbidities? Pathophysiological understanding of translational studies.
HFpEF often occurs in older female patients, who suffer with a wide range of comorbidities, ranging from hypertension and diabetes mellitus to lung disease and cancer. All of these conditions are characterized by chronic low-grade inflammation, endothelial dysfunction, cardiac fibrosis, and increased ventricular stiffness, which are key pathological features.
Systemic inflammatory and extracardiac metabolic risk factors play a critical role in the proposed “systemic microvascular paradigm” for the development of HFpEF: chronic conditions produce detrimental low-grade systemic inflammation, with increased expression of adhesion molecules in cells. microvascular, which in turn determines different degrees of systemic and cardiac inflammation. Indeed, elevated levels of circulating interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-), and circulating acute inflammatory C-reactive protein (CRP) were detected in patients suffering from HFpEF.
On the contrary, the “sterile inflammation” model , typical of HFrEF, occurs in response to cardiac remodeling due to necrosis of cardiomyocytes after ischemia.
Microvascular endothelial dysfunction represents an early marker of HFpEF, while it constitutes a late event in HFrEF. Indeed, low-grade systemic inflammation, induced by concomitant comorbidities, impairs endothelial nitric oxide (NO) production and enhances the uncoupling of endothelial nitric oxide synthase (SeON).
Importantly, endothelial dysfunction has been associated with reduced estrogen production , suggesting a possible explanation for the higher prevalence of HFpEF among postmenopausal women. Indeed, estrogens participate in the regulation of vascular tone through increased production of prostaglandins and NO, enhanced expression of ONSe, and reduced sympathetic activity.
Patients with HFrEF mainly show eccentric ventricular remodeling, determined by damage and loss of cardiomyocytes, with minimal alteration in wall thickness; In contrast, people with HFpEF generally show concentric cardiomyocyte hypertrophy, with increased ventricular wall thickness. These differences may be explained by specific peculiarities of cardiomyocytes that emerged from the comparison of cardiac biopsies from the two HF subgroups.
Increased cardiac interstitial fibrosis represents another peculiar characteristic of HFpEF, which develops in response to the activation of myofibroblasts due to oxidative stress, triggered by diabetes mellitus, aging, hypertension and pressure overload.
Finally, neurohormonal activation represents a key event in the pathophysiology of HFrEF with tremendous implications in terms of morbidity and mortality, even independently of comorbidities. Although neurohormonal hyperactivity has been reported in patients with HFpEF, it appears to be less frequent and of lesser extent than in HFrEF.
Another relevant aspect in the understanding of HFpEF refers to the presence of multiple concomitant anabolic deficits. This assumption is based on the observation, already known for two decades, that the presence of isolated and/or concomitant alterations of the main anabolic hormonal axes has a relevant impact on the natural history, morbidity and mortality of HFrEF.
> 1.3. Are cardiovascular abnormalities distinguishable in HFpEF?
A consistent body of evidence supports the possible existence of a specific pattern of cardiovascular abnormalities in HFpEF ( Figure 1 ). In 386 patients with HFpEF, a larger LV mass, greater systolic and diastolic dysfunction, more significant LA enlargement, and greater arterial stiffness were found compared with controls of the same age and sex and with the hypertensive group.
In addition to LV abnormalities, the right ventricle (RV) also plays a critical role in HFpEF in terms of risk stratification. Furthermore, progression of RV dysfunction over time is also strongly associated with worse outcomes. According to a recent study, progression of RV enlargement and systolic deterioration in HFpEF was found to be associated with a 35% increase in all-cause mortality and an 85% increase in cardiovascular mortality. In particular, changes in the structure and function of the right ventricle far exceeded those observed in the LV over time.
> 1.4. The HFpEF galaxy: phenotyping and treatment of comorbidities
One of the main unresolved issues regarding HFpEF is that the term has been used generically to define all cases of HF without approximate and easily recognizable systolic dysfunction. This phrase led over the years to label several different phenotypes as HFpEF that show great heterogeneity in clinical presentation and especially in natural history. The need to thoroughly categorize these patients stems from the failure of the vast majority of treatments used in HFrEF to equally impact the natural history of HFpEF.
The TOPCAT study used latent class analysis to group different HFpEF subgroups based on clinical presentation, serum levels of multiple biomarkers, left ventricular architecture and function, arterial stiffness, and clinical outcomes. According to this report, three main phenogroups were identified: 1) mildly symptomatic patients with evidence of LV hypertrophy and arterial stiffness; 2) elderly with atrial fibrillation, left atrial enlargement and increased serum level of biomarkers of innate immunity and vascular calcification; 3) patients with severe clinical deterioration with obesity, renal and hepatic failure and elevated levels of biomarkers of inflammatory activation.
Phenogroups 2 and 3 showed similar mortality and both reduced survival, compared to phenogroup 1. Interestingly, phenogroup 3 was associated with a more pronounced response to spironolactone in reducing the primary endpoint.
Following these premises, the need for further research is evident with the aim of even more precise phenotyping of HFpEF, in order to allow a personalized and type-specific diagnostic and therapeutic approach.
> 1.5. Randomized clinical trials in HFpEF: requiem for a funeral?
The data from the EMPEROR trial summarize the main results of the largest randomized placebo-controlled multicenter trials in this condition. The most interesting finding is the non-negligible proportion of deaths from non-cardiac causes in almost all study populations, ranging from 6 to 7%.
This was also confirmed by some registry data showing that non-cardiovascular mortality (specifically from cancer, chronic kidney disease, sepsis and respiratory disease) represents by far the most prevalent in HFpEF (62%), while it is minor importance in HFrEF. This supports the view that the main drivers of disease progression are precisely non-cardiovascular comorbidities.
A recently published trial used empagliflozin , an inhibitor of sodium-glucose cotransporter 2, a molecule originally used in the treatment of type 2 diabetes mellitus. However, clarification is needed. First, HFpEF trials differ markedly in the ejection fraction cutoff used, follow-up, and inclusion/exclusion criteria. This could have led to differences in results between these studies.
Furthermore, the primary endpoint (composite of cardiovascular death and HF hospitalization) was primarily due to the reduction in the number of hospitalizations in the empagliflozin-treated group without a significant reduction in all-cause mortality. This implies that, although this trial represents a turning point in the history of this disease, empagliflozin is only a brake on the progression of the disease without constituting a definitive cure.
2. Conclusions
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