Pathophysiological mechanisms of HI in HFpEF

The chronic HI characteristic of IR, while on the one hand playing a positive role in attempting to maintain blood sugar within a normal range, unfortunately, on the other hand, plays a very negative role in relation to the cardiovascular system [14, 18, 31]. Below, we will see why. The insulin IGF-1-PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca²⁺ handling through the effects of the protein kinase Akt [32]. However, in IR conditions, while the PI3K pathway functions poorly, the mitogen-activated protein kinase (MAPK) pathway is little or not at all altered, so that increased levels of circulating insulin hyperstimulate this pathway, causing significant alterations in cardiocirculatory homeostasis. In this regard, it should be noted that in conditions of IR, high levels of circulating insulin, in addition to controlling carbohydrate metabolism, cause reduced secretion of nitric oxide (NO) at the vascular level. At the same time, they cause an increase in endothelin-1 (ET-1) secretion. For this reason, there is an imbalance in vascular homeostasis in the vasoconstrictive sense. ET-1 is a peptide hormone that acts through specific receptors to activate the MAPK pathway, regulating physiological processes such as vasoconstriction and vascular remodeling, but also pathophysiological processes such as tumor progression. In summary, MAPK is the cellular signaling mechanism, while ET-1 is an external signal that activates this pathway. Together, these effects lead to endothelial dysfunction and atherosclerosis [31].

HI has also been found to be associated with increased activity of the sympathetic nervous system. In fact, it has been shown that increased levels of insulin lead to increased secretion of norepinephrine. This also stimulates vasoconstriction. Furthermore, insulin receptors have been demonstrated in the renal tubules. Overstimulation of these renal receptors in the tubules leads to increased reabsorption of sodium and water, resulting in an expansion of blood volume (hypervolemia). Insulin and the renin-angiotensin-aldosterone system (RAAS) are closely linked, with IR hyperactivating the RAAS, and in turn, the RAAS worsening IR. This negative feedback loop contributes to cardiovascular disease, hypertension, and type 2 diabetes, as angiotensin II (a component of the RAAS) impairs insulin signaling, induces inflammation, and causes vasoconstriction [33]. All these associated mechanisms may significantly contribute to the development of some forms of hypertension, actually classified as essential or primary hypertension (Figure 1).

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Figure 1. Hyperinsulinemia associated with insulin resistance through various mechanisms causes hypertension with consequent concentric remodeling of LV, which, in the long term, may facilitate the development of HFpEF. ↑: increased; ↓: decreased; LV: left ventricle; RAAS: renin-angiotensin-aldosterone system; HFpEF: heart failure with preserved ejection fraction.

Insulin itself, via the MAPK pathway and through its binding to the IGF receptor, stimulates cell growth at various levels, but for our purposes, we are particularly interested in the stimulation of growth in endothelial cells, vascular smooth muscle cells, and cardiomyocytes [34, 35]. In addition, HI also promotes the deposition of intramyocardial and epicardial adipose tissue, promoting atherosclerosis on the one hand and myocardial hypertrophy on the other [36–38]. In IR conditions, the myocardium also becomes less responsive to insulin, impairing its ability to use glucose for energy. This leads to the heart relying more heavily on fatty acids, causing cellular stress, mitochondrial dysfunction, and oxidative damage, which can contribute to HF over time [38, 39]. Other factors like inflammation, lipotoxicity, and impaired calcium handling further contribute to cardiac dysfunction [40, 41]. It has been demonstrated that all these pathological mechanisms triggered simultaneously by HI associated with IR produce, both directly and indirectly, through the triggering of arterial hypertension, an increase in LV mass, also due to an increase in intramyocardial and epicardial fat, with concentric LV remodeling, increased myocardial fibrosis, and diastolic dysfunction. All of this ultimately leads to the development and/or worsening of HFpEF over time, if already present [42] (Figure 2). However, the relationship between IR/HI and HF should not be considered unidirectional since HF may also contribute to IR development, creating a self-perpetuating vicious circle [43].

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Figure 2. It schematically shows the epidemiological data and the possible clinical implications existing between IR and HFpEF. CV: cardiovascular; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LV: left ventricle.

Based on the above, we believe that it would be useful to identify individuals with IR both before they develop HF and during the course of HF in order to attempt to prevent or, at least, slow down the negative progression of HF, including through interventions designed to counteract IR.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)

GLP-1 RAs have been shown to improve IR through mechanisms other than just reducing body weight and obesity [55]. In fact, they have been shown to reduce IR many weeks before having an effect on body weight reduction [55]. These substances can increase insulin sensitivity and, therefore, circulating insulin levels by reducing inflammation and oxidative stress and increasing the expression of glucose transporters in insulin-dependent tissues, even though, in the first instance, they would directly stimulate pancreatic beta cells to produce more insulin and inhibit glucagon secretion [56–58]. In addition to their effectiveness in treating type 2 diabetes and obesity, GLP-1 RAs have demonstrated clear cardiovascular benefits in the treatment of HFpEF [59, 60]. It appears that they act both indirectly, through weight loss and systemic metabolic improvement, and directly on the myocardium, although the presence of functional GLP-1 receptors in the myocardium (except in the atrial myocardium and sinoatrial node) is uncertain [61]. Experimental studies in animals have shown that GLP-1 increases myocardial glucose utilization, shifting fatty acid metabolism towards carbohydrate oxidation [62]. In addition, GLP-1 receptors are expressed in endothelial cells, and activation of these GLP-1 receptors improves endothelial function by increasing NO availability, resulting in reduced arterial resistance [63]. In animal models, GLP-1 RAs have also inhibited myocardial fibrosis and reduced LV hypertrophy [64]. However, most of these beneficial mechanisms of GLP-1 RAs could be partly explained by the fact that they improve IR and, consequently, the insulin required for good glycemic control is reduced [55, 65]. We have seen that higher circulating insulin levels associated with IR can trigger those harmful mechanisms that may be counteracted by GLP-1 RA therapy.

Metformin

Metformin belongs to the class of biguanides, drugs known to lower blood sugar through a beneficial effect of reducing IR and circulating insulin levels. It has been around for over 60 years and is still the drug recommended by US and European guidelines as the first-line treatment for type 2 diabetes, which is the form of diabetes resulting from IR [66, 67]. Metformin counteracts IR by decreasing glucose production in the liver and intestinal glucose absorption. In addition, it increases insulin sensitivity and glucose transport into cells by increasing the expression and translocation of glucose transporter 4 (GLUT4) [67, 68]. This is achieved through the activation by metformin of the enzyme AMP-activated protein kinase (AMPK), which in turn stimulates GLUT4 activity [69, 70]. Through these insulin sensitization mechanisms, metformin is able to reduce the chronically elevated circulating levels of insulin in conditions of IR [70].

Some studies show that treatment with metformin is associated with a lower risk of hospitalizations for all causes and HF-related hospitalizations. In addition, some meta-analyses have shown a significant reduction in all-cause mortality in diabetic patients with HF treated with metformin compared to other antidiabetic drugs [71, 72]. The risk of lactic acidosis associated with metformin in patients with HF has been downplayed, mainly affecting patients with specific associated conditions (severe kidney or liver disease, excessive alcohol consumption, dehydration) [73, 74]. Metformin is currently being studied for its potential role in the treatment of HFpEF, mainly because many patients with this condition also have type 2 diabetes, and metformin could be beneficial in these patients by counteracting IR and reducing the HI associated with it and, therefore, the cardiovascular damage caused by this condition (DANHEART; H-HeFT and Met-HeFT; ClinicalTrials.gov ID NCT03514108; CARMET; ClinicalTrials.gov ID NCT01690091).

Other potential agents

Physiology of the GH/IGF-1 axis in the cardiovascular system

GH is secreted by the anterior pituitary in a pulsatile fashion and stimulates hepatic production of IGF-1, the main mediator of its anabolic and metabolic effects. The GH/IGF-1 axis is tightly regulated by hypothalamic hormones, nutritional status, sleep, physical activity, and several metabolic signals, including insulin and adipokines.

Both GH and IGF-1 exert relevant actions on the cardiovascular system. GH receptors and IGF-1 receptors are expressed in cardiomyocytes, cardiac fibroblasts, and vascular cells, including endothelial and vascular smooth muscle cells. Experimental and human data indicate that physiological activation of this axis promotes adaptive cardiac hypertrophy, improves myocardial contractility and calcium handling, enhances endothelial NO production, and exerts anti-apoptotic and anti-inflammatory effects. Castellano et al. [9] and Arcopinto et al. [11] have comprehensively reviewed how GH/IGF-1 signaling modulates LV growth, systolic function, and vascular tone in both normal and failing hearts.

More recent work by Higashi et al. [15] and Werner [35] has highlighted that IGF-1 also improves endothelial function, mitochondrial integrity, and oxidative stress resistance, suggesting a broader vasculoprotective and cardioprotective role.

In physiological conditions, therefore, the GH/IGF-1 axis supports cardiac performance and vascular homeostasis. Both deficiency and excess, however, as well as alterations in IGF-1 bioavailability, are associated with adverse cardiac remodeling and an increased risk of HF [81].

GH/IGF-1 deficiency and HF

Adult growth hormone deficiency (GHD) provides a natural model of chronic impairment of GH/IGF-1 signaling. Patients with GHD typically present with increased visceral adiposity, dyslipidemia, endothelial dysfunction, and reduced exercise capacity—a phenotype that overlaps with cardiometabolic HF. Cardiac imaging studies have shown that adults with GHD have reduced LV mass, impaired systolic and diastolic function, and lower stroke volume compared with age- and sex-matched controls [82–84].

Cardiac magnetic resonance and echocardiographic data consistently indicate that LV mass index in adult-onset GHD lies at or below the lower limit of normal, and that one year of GH replacement increases LV mass, wall thickness, and stroke volume, while improving global longitudinal strain and exercise tolerance [85, 86].

These findings support the concept that physiological GH/IGF-1 signaling is required to maintain adequate myocardial structure and performance.

Beyond “overt” GHD, several observational studies have linked low circulating IGF-1 levels in the general population with a higher risk of incident cardiovascular disease and HF [86, 87]. A large prospective cohort showed a non-linear association between IGF-1 and cardiovascular events, with both low and high IGF-1 concentrations associated with increased risk, suggesting the existence of an “optimal” IGF-1 range for cardiovascular health [81].

A recent meta-analysis focusing on IGF-1 and HF reported that reduced IGF-1 levels are frequently observed in HF patients and are associated with higher HF incidence and HF-related mortality [88].

Mechanistically, low IGF-1 may contribute to HF through several pathways: a) the loss of anti-apoptotic signaling in cardiomyocytes, with increased susceptibility to oxidative stress and neurohormonal activation; b) impaired endothelial function and reduced NO bioavailability, which favor microvascular dysfunction and increase ventricular afterload; c) worsened skeletal muscle function and sarcopenia, further limiting exercise capacity and promoting the HF frailty phenotype [88].

These alterations are particularly relevant in HFpEF, where concentric LV remodeling, diastolic dysfunction, microvascular inflammation, and peripheral limitations to exercise play a major pathophysiological role. In this setting, low-normal IGF-1 levels may act synergistically with IR, visceral obesity, and systemic inflammation to promote the so-called “metabolic HFpEF” phenotype.

GH resistance and altered IGF-1 bioavailability in chronic HF

In HF, both hepatic and peripheral resistance to GH is possible. The first is characterized by reduced hepatic IGF-1 production following GH stimulation, with a reduction of the effects of IGF-1 on growth, anabolism, and feedback regulation of GH. While the second is characterized by deficient effects directly on GH at the peripheral level, independently of IGF-1, such as those on metabolism, body composition, cardiovascular function, and cellular growth [89].

Several studies have described a state of acquired GH resistance in advanced HF, with normal or increased circulating GH levels but relatively low or inappropriately normal IGF-1 concentrations [11].

This pattern resembles other catabolic states such as chronic kidney disease, malnutrition, and cachexia, in which inflammatory cytokines, hepatic dysfunction, and alterations in GH receptor signaling blunt the IGF-1 response to GH [90, 91].

The severity of HF is associated with progressive blunting of GH/IGF-1 activity, with lower IGF-1 levels correlating with more advanced symptoms, reduced exercise capacity, and worse prognosis [92].

Both low IGF-1 and excessive IGF-1 (as in acromegaly) are linked to a higher HF risk.

Several mechanisms may explain GH resistance in HF: a) the systemic inflammation and elevated cytokines (e.g., TNF-α, IL-6) downregulate GH receptors and post-receptor signaling in the liver and peripheral tissues; b) the hepatic congestion and dysfunction reduce IGF-1 synthesis and alter IGF-binding protein (IGFBP) profiles, limiting free, bioactive IGF-1; c) the neurohormonal activation and chronic sympathetic hyperactivity further perturb GH secretion patterns and IGF-1 production [93–96].

These alterations contribute to a vicious circle: reduced GH/IGF-1 signaling promotes skeletal muscle wasting, reduced peak VO₂, impaired myocardial energetics, and progressive decline in functional capacity, which in turn worsens HF outcomes [11]. HF patients who should be screened for GH/IGF-1 abnormalities are those with severe disease, poor functional capacity, high mortality risk, or specific conditions like polytransfused patients, as low IGF-1 levels often signal worse outcomes, making screening useful for prognosis and potentially guiding therapy [97]. Because insulin and IGF-1 share the PI3K/Akt signaling cascade, disturbances in one system directly affect the activity of the other. In HF, systemic IR inhibits PI3K/Akt signaling, reduces hepatic IGF-1 synthesis, alters IGF-binding protein profiles, and impairs IGF-1 receptor phosphorylation [88, 98]. As a result, even normal GH secretion leads to insufficient IGF-1 bioactivity (“GH resistance”). Conversely, reduced IGF-1 signaling worsens glucose uptake, inflammation, and skeletal muscle catabolism, thereby exacerbating IR. This bidirectional interaction creates a vicious cycle that amplifies endothelial dysfunction, myocardial fibrosis, impaired energetics, and the progression of both HFpEF and HFrEF.

GH/IGF-1 excess: lessons from acromegaly

Acromegaly, characterized by chronic GH and IGF-1 excess, represents the opposite extreme of GH/IGF-1 derangement. Patients with uncontrolled acromegaly often develop a specific acromegalic cardiomyopathy, initially characterized by concentric LV hypertrophy and increased cardiac output, and later progressing to diastolic dysfunction, systolic impairment, and, in a minority of patients, overt HF [99].

Histological and imaging studies describe myocyte hypertrophy, interstitial fibrosis, and microvascular changes, with impaired diastolic relaxation and, in advanced stages, reduced EF. The adequate biochemical control of acromegaly (normalization of GH and IGF-1 levels) can lead to partial regression of LV hypertrophy and improvement in diastolic function, especially when treatment is initiated in earlier disease stages [100, 101].

Recent epidemiological data suggest that, after adjusting for disease control and classical cardiovascular risk factors, the risk of HF in acromegaly may approach that of the general population, reinforcing the concept that duration and degree of hormonal excess are critical determinants of cardiac outcomes [102].

Nevertheless, acromegaly clearly illustrates that chronic, marked GH/IGF-1 excess can be deleterious for the heart, promoting pathological hypertrophy and HF in susceptible individuals.

Taken together, data from GHD and acromegaly support a U-shaped relationship between IGF-1 and cardiovascular risk, in line with large population cohorts: both insufficient and excessive IGF-1 signaling may predispose to HF.