1 Introduction

Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary and/or splanchnic congestion and/or peripheral oedema. Left ventricular ejection fraction (LVEF) is the ratio of left ventricular stroke volume, which is the volume ejected from the left ventricle, to end-diastolic volume [1]. Based on LVEF, HF was classified into three EF categories, namely HF with reduced (HFrEF), mildly reduced (HFmrEF), and preserved EF (HFpEF), according to the EF ranges ≤ 40%, 41–49%, and ≥ 50%, respectively [2].

According to New York Heart Association (NYHA), HF is divided into four classes based on severity of symptoms and physical activity as follows: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations; Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations; Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results undue breathlessness, fatigue, or palpitations; Class IV: Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased. The NYHA functional classification is an independent predictor of mortality, and it is widely used in clinical practice to determine the eligibility of patients for treatment strategies [2].

HF remains a growing epidemic, affecting approximately 60 million people worldwide. HF is becoming more common, more people are suffering from it, and more hospital admissions are due to HF than ever before, both in industrialized nations like Europe and emerging nations like China [3]. An aging population and life-prolonging medical interventions to extend life after a HF diagnosis are expected to cause the prevalence of HF, which currently affects between 1 and 3% of the general adult population in some developed regions like Europe and North America, to significantly increase. HF's mortality and hospitalization rates are still high, despite improvements in the prognosis [4]. The economic burden of HF on the global health care system and economy is substantial and is even expected to increase due to the raising prevalence of the disease [5].

As a result, seeking new treatments for HF has become critically important and has remained a major priority. In order to further progress the treatment of HF and lessen the health burden associated with HF, we provide an overview of the present clinical management of HF and the most novel therapeutic developments related with interdisciplinary in current research into HF.

2 Aetiology and Pathology of HF

HF has multiple underlying causes that are not mutually exclusive but contribute to a complex disease. The aetiology of HF differs significantly between countries, with major disparities between industrialized and developing countries. Ischemic heart disease, hypertension, valvular and rheumatic heart disease, dilated cardiomyopathy, chemotherapy and radiotherapy-induced cardiomyopathy, congenital heart disease are all the causes of HF [6]. Diabetes, obesity, chronic lung disorder, inflammation or chronic infection, metabolic disease, cardiotoxic medication therapy, and alcohol abuse could also induce HF (Fig. 1) [7]. Although there is considerable geographical variation in the etiology of HF, ischemic heart disease is the leading cause of HF worldwide, with high estimates in Eastern Europe, the Middle East and South East Asia [8, 9]. Hypertension is another major cause of HF, with higher estimates in Africa compared to other regions.

Fig. 1
figure 1

The ARIC (Atherosclerosis Risk in Communities) Study revealed the correlation between the presence of risk factors and the risk of heart failure, and the corresponding strategies to reduce the risk of heart failure. Uncontrolled risk factors were defined as any of the following: hypertension with systolic blood pressure ≥ 160 mmHg; diabetes with hemoglobin A1c ≥ 8%; and BMI ≥ 35 kg/m2 [7]

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In general, HF is caused by a failure of the heart's systolic and diastolic activities, as well as an inability to expel the return blood volume from the heart, resulting in insufficient systemic blood perfusion, which triggers the proper compensatory mechanisms and eventually progresses to end-stage HF [10]. Changes in the systolic and diastolic function of the heart are influenced by a number of risk factors that induce myocardial injury, which leads to cardiac dysfunction [11].Neurohumoral activation subsequent myocardial injury plays a key role in the pathogenesis of HF. Throughthe activation of the adrenergic nervous system and of the renin–angiotensin–aldosterone system, injury and death of cardiomyocytes trigger hypertrophy of the surviving cells, resulting in fibrosis of the myocardium and gradual dilatation of the left ventricle. These changes, known as left ventricular remodeling, increase myocardial oxygen demand, which causes more myocardial damage and sets off a vicious cycle [12]. Activation of the neurohormonal system causes vasoconstriction and reduced excretion of sodium and water, resulting in fluid overload and oedema, which increases the stress on the heart. In addition, studies have demonstrated that oxidative stress contributes to the development and progression of HF [13, 14]. Increased oxidative stress causes an increase in a variety of reactive oxygen derivatives that stimulate cardiomyocyte hypertrophy, induce apoptosis, promote myocardium fibrosis, and activate inflammatory responses, as well as changes in Ca2+ regulation and activation pathways associated with electrical remodeling in HF patients. All these alterations are recognized as key elements in the development of HF [15]. Nitric oxide synthases (NOS) enzymes switch from Nitric oxide (NO) to O2− production when they become uncoupled due to depletion of the cofactor tetrahydrobiopterin. If NOS are partially uncoupled, O2− and NO may be concomitantly produced and generate peroxynitrite, which can damage the function and structure of all cellular macromolecules and further contribute to the development of heart failure through the pathway described above [16, 17]. Identifying the pathophysiological pathways that induce HF is critical for determining appropriate treatment options and generating creative ideas for HF administration.

3 Current Treatment Strategies for Patients with HF

3.1 Pharmacotherapy

Pharmacotherapy is the foundation of HFrEF treatment and should be considered before contemplating device therapy, as well as alongside non-pharmacological therapies. For the application of pharmacotherapy, HF requires a multimodal treatment regimen of multiple drug combinations as the basis of treatment for symptomatic and prognostic improvement in all patients (Table 1). Angiotensin (Ang) converting enzyme inhibitors (ACEI) or an angiotensin receptor-neprilysin inhibitor (ARNI), a beta-blockers, and an a mineralocorticoid receptor antagonists (MRA) are the drugs identified as the basis for the treatment of HFrEF and are effective in reducing mortality and improving the prognosis of patients [18]. ACEI (e.g. captopril, enalapril, lisinopril etc.) can inhibit angiotensin-converting enzyme activity, block the conversion of Ang I to Ang II, which reduces the activation of the renin–angiotensin–aldosterone system and reduces the afterload of the heart, thus relieving the symptoms of heart failure [19]. ARNI inhibit the renin–angiotensin–aldosterone system while enhancing the endogenous vasoactive peptide system to lower blood pressure and improve ventricular remodeling. A commonly used ARNI drug is sacubitril/valsartan. In the PARADIGM-HF trial, sacubitril/valsartan is superior to ACEI in reducing the risk of cardiovascular death or HF admission in patients with HFrEF and may replace ACEI to some extent [20]. Angiotensin-receptor blockers (ARB) still have a role in those who are intolerant to ACEI or ARNI. Beta-blockers (e.g. bisoprolol, carvedilol, metoprolol succinate etc.) reduce blood pressure, heart rate and myocardial oxygen consumption by blocking beta-receptors, thereby reducing circulating levels of vasoconstrictors, and improving myocardial contractile function, all of which facilitate ventricular remodeling [21]. MRA (spironolactone or eplerenone) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormones (e.g. corticosteroid and androgen) receptors, reducing sodium and water retention. In addition to its diuretic effect, MRA can reverse myocardial remodeling for the purpose of treating heart failure [22]. Conventional loop diuretics (e.g. furosemide) can act to control sodium retention in HF patients by inhibiting renal tubular sodium or chloride reabsorption. Tolvaptan, a highly selective vasopressin V2 receptor antagonist, has a draining but not sodium-draining effect and is more effective in patients with HF with hyponatremia [23]. Positive inotropic drugs include digitalis (digoxin) and non-digitalis (milrinone), which enhance myocardial contractility and improve cardiac output without increasing myocardial oxygen consumption [24].

Table 1 Main Drug classes used in patients with heart failure
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However, these traditional drugs are not sufficient for all HF patients. In the quest for improved pharmacological efficacy, a variety of non-traditional pharmaceuticals have been supplemented to the original therapies to improve HF therapy and prognosis. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g. dapagliflozin, empagliflozin) have been shown in studies to significantly reduce the risk of HF by inhibiting glucose conversion and promoting sodium excretion, thereby improving myocardial structure and function, increasing myocardial oxygen utilization, and decreasing myocardial oxidative stress and fibrosis.[25]. Thus, SGLT-2 inhibitors have been widely recommended for use in patients with HFrEF. Ivabradine is the first specific inhibitor of the funny current (If) in sinoatrial nodal tissue, slowing the heart rate by specifically inhibiting the If current. It effectively reduces the rhythm of sinoatrial node without affecting myocardial contractility or blood pressure, and has no negative inotropic effects compared to beta-blockers [26]. Ivabradine is only indicated in patients with chronic HF and its use is somewhat restricted. Soluble guanylate cyclase (sGC) stimulators (e.g. vericiguat) improve cardiomyocyte function and reduce inflammation and oxidative stress by increasing the sensitivity of sGC to endogenous nitric oxide (NO). Clinical trials have shown that administering sGC stimulators in patients with decompensated HF reduces mortality from cardiovascular causes as well as hospitalizations for HF [27].

For patients with HF combined with atrial fibrillation (AF), some specific medications are required. The combination of HF and AF significantly increases the risk of thromboembolism. Unless contraindicated, an oral, long-term anticoagulant is recommended in all patients with HF combined with AF. Direct-acting oral anticoagulants are preferred, such as rivaroxaban [28]. Beta-blockers can be used for rate control in patients with HF combined with AF [29]. Digoxin can be considered when the ventricular rate remains high, despite beta-blockers [30]. Amiodarone can be considered to reduce ventricular rate, and amiodarone is also the drug of choice for pharmacological cardioversion in patients with HF combined with AF [31].

Renal function plays an important role in heart failure and severe renal insufficiency can lead to HF. In patients with HF combined with renal dysfunction, the use of the drug requires special attention. Inhibitors of the renin–angiotensin–aldosterone system, such as ACEI, ARB and MRA, frequently induce a decline in glomerular filtration rate, but should not lead to treatment discontinuation [18]. Diuretics can be a double-edged sword for patients with HF combined with renal insufficiency. Diuretics can improve renal function by reducing renal congestion and renal venous hypertension, but the combination of multiple diuretics may also lead to acute kidney injury [32]. Therefore, in patients with HF combined with renal insufficiency, a change of diuretic may be considered, for example from classical thiazide diuretics to metolazone, indapamid or xipamid should be considered in an effort to increase diuretic efficiency [33].

Currently, there is a gap in the treatment of HFpEF, and most approved drugs for HFrEF are ineffective for HFpEF. A number of clinical trials addressing the effects of drugs on HFpEF are underway, providing possible medical evidence for the future treatment of HFpEF [34, 35]. Additionally, pharmacological treatment is only the basic treatment throughout HF. When HF progresses to severe and end-stage, there are specific types of HF that require non-pharmacological means of treatment.

3.2 Device Therapy

In addition to pharmacological treatments, a number of non-pharmacological treatments are also applied to treat patients with HF. Cardiac resynchronization therapy (CRT) has an important role to play in the treatment of asynchronized HF. CRT is able to restore the heart's contraction pattern for the appropriate amount of time, thereby not only reducing cellular, hemodynamic and structural adaptations to desynchronization, but ultimately improving functional status. CRT significantly improves the quality of life of patients with severe HF, reducing the risk of hospitalization and increasing survival [36]. The majority of patients with severe HF die as a result of sudden cardiac death caused by malignant ventricular arrhythmias, and implanted cardioverter defibrillators (ICD) are effective in rectifying potentially lethal ventricular arrhythmias. ICD is more effective than anti-arrhythmic medications in reducing the risk of sudden cardiac death in individuals with HF.[37]. Among patients with NYHA class II or III HF, a wide QRS (part of electrocardiographic wave) complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure [38].

Additionally, atrioventricular nodal ablation with the implantation of a CRT device is reasonable patients with HF combined with AF if a rhythm control strategy fails or is not desired and ventricular rates remain rapid despite medical therapy [39]. Compared to drug therapy, catheter ablation significantly reduces mortality in patients with HF combined with AF [40].

In patients with heart failure with severe renal insufficiency, progression to the uremic stage is when drugs such as diuretics are not effective and dialysis is required. Dialysis not only relieves the symptoms of renal insufficiency, but also provides relief for HF [41].

3.3 Mechanical Circulatory Support

Mechanical circulatory support (MCS) can improve survival and symptoms of patients with advanced HF. Short-term MCS devices are indicated to reverse critical endorgan hypoperfusion and hypoxia in the setting of cardiogenic shock. Short-term MCS devices include intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), TandemHeart and Impella. Short-term MCS should be used in patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles 1 or 2 as a bridge to decision (BTD), bridge to recovery (BTR), bridge to bridge (BTB) for either long-term MCS or urgent heart transplantation [42]. Some patients with HF do not respond well to standard treatment and develop advanced HF requiring treatment with a left ventricular assist device (LVAD). LVAD are blood pumps that provide power to introduce blood flow from the left atrium or left ventricle into the assisted pump body, which drives blood flow into the aorta and completely replaces the left heart pumping function. Implantation of a LVAD can improve survival in patients with worsening HF, awaiting heart transplantation, and can also be used to improve quality of life in patients with advanced HF who are not candidates for transplantation. Over the past decade, short- and medium-term survival rates for HF patients after LVAD implantation have improved, significantly outperforming drug therapy [43]. For many patients with HF, the main determinant of clinical symptoms and impaired cardiac function is elevated left atrial pressure. The interatrial shunt device treats chronic HF by directly reducing left atrial overload through an atrial left-to-right shunt, without significantly reducing cardiac output or causing complications such as pulmonary hypertension. The interatrial shunt device is effective in the treatment of patients with chronic HF, but more clinical evidence is needed to further demonstrate the extent of benefit to patients with HF [44]. In the absence of restrictions, heart transplantation is still the gold standard for the treatment of advanced HF. However, the widespread clinical application of heart transplantation is still limited by high surgical risks, few sources of heart donors, and high surgical costs.

Thus, most clinical treatment including pharmacological therapy, associated device therapy, interventional therapy, and end-stage surgical related therapy could reduce the symptoms of HF and improve the life quality of patients in some extent, while the prevention for the progression of HF together with the reduction of health and financial burden for patients with HF still need to further explored. A large amount of new research is being undertaken all over the world to further investigate strategies and tactics for improving the prognosis of patients with HF.

4 Emerging Interdisciplinary Treatment Strategies for HF

Multidisciplinary intersection facilitates exploration of new ways to treat heart failure (Fig. 2).

Fig. 2
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Emerging interdisciplinary (i.e. stem cells, exosomes, biomaterials, nanotechnology, etc) may promote the progressive treatment of heart failure in the future

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4.1 Stem Cells

The use of stem cells to stimulate myocardial healing is regarded to be a new approach to the treatment of HF. Induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) and skeletal muscle myogenic cells have been extensively investigated for use in cardiac disease, with the aim of repairing the heart at the cellular level. Among these, iPSCs and ESCs are candidates for myocardial regeneration because of their ability to self-renew and their potential to differentiate into various cell types such as cardiomyocytes [45]. Cardiomyocytes derived from iPSCs have the practical properties of cardiomyocytes such as contractility, spontaneous beating and ion channel expression. Transplantation of iPSCs-derived cardiomyocytes is expected to improve cardiac function through both mechanistic contribution to cardiac contraction and trophic effects. The feasibility of repairing the injured heart by transplantation of iPSCs-derived cardiomyocytes has been demonstrated in animal models [46]. The first clinical transplantation of cardiac progenitor cells derived from human ESCs has been reported. The patient showed significant improvement in cardiac function 3 months after transplantation, demonstrating the feasibility of transplanting human ESCs-derived cardiac progenitor cells for the treatment of ischemic HF [47]. Considering the similarities between cardiomyocytes derived from human ESCs and cardiomyocytes derived from iPSCs, the platform developed using human ESCs should also be applicable to human iPSCs [48]. There has been ongoing interest in the potential of skeletal muscle myogenic cells to treat patients with HF. Skeletal muscle myogenic cells are derived from skeletal muscle progenitor cells and have regenerative capacity. Skeletal muscle myogenic cells can be transplanted into a damaged heart to reduce ventricular antagonistic repair, reduce interstitial fibrosis and increase cardiac function. Follow-up of patients transplanted with skeletal muscle myogenic cells showed a gradual improvement in clinical symptoms and cardiac function, and a decrease in the incidence of HF [49]. Paracrine mechanisms play an important role in cell therapy. Mesenchymal stromal cells from different sources (i.e. adipose, bone marrow) and cardiac stromal cells can secrete biologically active substances, including cytokines, extracellular vesicles, etc., which play the therapeutic role in injured heart. However, more clinical data is needed to support stem cell-based treatments for HF, and the optimal cell type and dosage for stem cell therapy needs to be further defined.

4.2 Exosomes

Exosomes are common membrane-bound nanovesicles containing various biomolecules such as lipids, proteins and nucleic acids. Exosomes contain an array of membrane-associated protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosomes are secreted extracellularly by cells, are taken up by target cells, deliver biological information to the target cells and regulate signaling pathways [50]. Exosomes play a key role in the pathophysiology of cardiovascular disease. All major cardiac cell types, including cardiomyocytes, endothelial cells, and fibroblasts, release exosomes that modulate cellular functions. acting as mediators of messages between cells [51]. Studies have shown that stem cells exert therapeutic effects through the paracrine function of exosomes and demonstrate the unique therapeutic function of exosomes [52, 53]. Exosomes and their cargo underlie the mechanism of action of iPSCs-derived cardiomyocytes in rescuing damaged cardiomyocytes against apoptosis, necrosis, inflammation, remodeling and fibrosis in infarcted myocardium, providing unique insights into the therapeutic potential of endogenous exosomes derived from their own iPSC derivatives [54]. During cardiac injury, exosomes can be introduced exogenously to promote myocardial repair through their anti-apoptotic, pro-angiogenic and proliferative effects to achieve individualized treatment. Due to their bilayer membrane and nanoscale size, exosomes protect their carriers from complement fixation or macrophage clearance or damage, thereby prolonging their circulating half-life and increasing their biological activity [55]. Thus, exosomes can be used as drug delivery vesicles for the treatment of HF. Exosomes can selectively target specific types of cells and have the potential to provide precision medicine for HF [56]. It was found that the distribution of subsequent therapeutic exosomes in the heart was successfully and effectively improved by pre-blocking the endocytosis of exosomes by macrophages. The established two-step exosome delivery strategy (blocking the uptake of exosomes first followed by delivery of therapeutic exosomes) will be a promising method for targeted therapy [57]. Overall, exosomes overcome the potential toxicity, immunogenicity and inability to penetrate barriers of artificial drug carriers to target drug delivery to specific tissues of the heart, offering a new strategy for the precise treatment of HF patients.

4.3 Biomaterials

Biomaterials offer a possibility to prevent and treat HF after myocardial infarction, and tissue engineering strategies using biomaterials have been explored. The goal of tissue engineering is to mitigate the critical shortage of donor organs via in vitro fabrication of functional biological structures. Classical tissue engineering has been used in the treatment of a wide range of diseases, replacing tissue or organs that have been damaged, to the benefit of many patients [58]. For the myocardium, cardiac patch is a block of living tissue that has been engineered in the laboratory to function as close to natural myocardial tissue. Heart patches made from biomaterials are used to replace diseased or damaged native ventricular myocardium, showing good results in animal models [59]. Heart patches show promise of being able to stop the enlargement and remodeling of damaged heart muscle, improve heart function and prevent HF caused by heart muscle damage [46]. Injectable biomaterial scaffolds are also a novel strategy for biological tissue engineering to promote endogenous regeneration of the heart. Injectable scaffolds are delivered via catheters, allowing the material to be delivered directly to the site of injury within the heart. Initially, injectable biomaterial scaffolds carried cells for delivery to the injured heart muscle, in a somewhat similar way to heart patches. It has now been found that some of the biomaterial itself has a role in preventing left ventricular remodeling. In addition to cells, injectable materials can be used to deliver other therapeutic agents such as growth factors and genes to further improve heart function and cell survival [60]. 3D bioprinting is a promising technique for cardiac tissue engineering owing to its ability to print heterogeneous structures and make full use of advanced achievements in cell and material engineering fields [61]. Many intricate structures have recently been bioprinted by printing that mimics the macroscopic anatomical heart. For example, A tri-leaflet heart valve, a neonatal-scale collagen heart, and a human cardiac ventricle model were printed. It is shown that the use of 3D bioprinting in cardiac tissue engineering offers new strategies for the repair of cardiac defects [62]. Biomaterials can repair damaged myocardium and, to some extent, end the progression of HF after myocardial infarction, overcoming the limitations of conventional treatment.

4.4 Nanotechnology

In recent years, nanotechnology has been developing very rapidly in the field of cardiovascular diseases. Nanotechnology is an emerging and dynamic multidisciplinary field involving atomic and molecular structures that exhibit unique mechanical, electrical, catalytic, thermal, magnetic and imaging properties. Exploring its application in the medical field has been a major topic of study due to its material qualities, and nanomedicine has emerged [63]. Nanotechnology has unique advantages in the diagnosis and treatment of disease [64]. Targeted nanoparticles are designed to specifically bind to the desired protein, attach to the desired biomarker, and detect the onset of heart failure at a very early stage with sensitivity and accuracy. This increases the chances of successful treatment and a potential cure, resulting in a better prognosis for patients [65]. Nanotechnology allows for the effective delivery of specific biomolecules to a target location without exposing healthy cells and the ability to deliver therapeutic molecules to specific diseased tissues across difficult barriers. It was shown that delivery of the adenoviral S100A1 gene normalized S100A1 protein expression in a post-infarction rat model of HF and reversed contractile dysfunction of failing myocardium in vitro and in vivo. Gene transfer via nanotechnology to restore S100A1 protein levels in failing myocardium may be a new therapeutic strategy for the treatment of HF [66]. In animal experiments, it was found that cardiomyocytes are able to internalize and transport nanomaterials to the perinuclear region and that this process is non-toxic. Furthermore, the trials demonstrate the viability of nanotechnology-based pharmaceutical, protein, and genetic material delivery to the failing myocardial, providing a basis for nanotechnology in the treatment of HF.[67]. Nanotechnology allows for the effective delivery of specific biomolecules to a target location without exposing healthy cells and the ability to deliver therapeutic molecules to specific diseased tissues across difficult barriers. It was shown that delivery of the adenoviral S100A1 gene normalized S100A1 protein expression in a post-infarction rat model of HF and reversed contractile dysfunction of failing myocardium in vitro and in vivo. Gene transfer via nanotechnology to restore S100A1 protein levels in failing myocardium may be a new therapeutic strategy for the treatment of HF [68]. Nanotechnology will have a profound impact on the treatment of HF. Targeted delivery of nanoparticle-encapsulated drugs will circumvent many of the limitations of conventional therapies by increasing the concentration of effective drugs at the intended site of action and reducing systemic doses and adverse side effects. However, the biocompatibility, toxicity, and tissue-organ targeting of nanotransporters are still challenge to be solved in the future.

5 Conclusions

In conclusion, heart failure is a multi-cause disease with complicated pathophysiological pathways, and its incidence is increasing. Treatment of HF remains critical to reducing mortality rates. Traditional treatments still play a role, but they are no longer adequate for the management of heart failure. The prevention and treatment of heart failure necessitates a multidisciplinary and multifaceted approach. The therapy of heart failure is continually developing, with molecular, cellular, biomaterial, and genetic studies investigating treatment routes. However, in order to develop a comprehensive treatment strategy, a large number of high-quality basic experiments and clinical research will be required in the future to justify their safety and efficacy.