Although serum BNP and N-terminal pro-BNP are used conventionally for heart failure diagnosis, a high or low level of serum BNP is not a definite indicator of the presence or absence of heart failure, respectively.¹⁸ Hence, various other potential biomarkers have been investigated for this purpose.

Carbohydrate antigen 125 (CA 125), also known as mucin 16, is a glycoprotein that is used in cancer diagnosis, especially ovarian cancer.²⁹ Recent evidence has indicated an elevation of CA 125 serum levels in congestion and inflammation in the body. In a clinical trial, Núñez et al.³⁰ reported that high levels of CA 125 were directly correlated with symptoms of heart failure as well as clinical outcomes, including hospital readmission and death. This highlights the importance of CA 125 in prognostication and risk stratification for patients with heart failure.

Another investigated biomarker for heart failure is soluble ST2 from the interleukin-1 receptor family. It is an indicator of mechanical stress and fibrosis in cardiomyocytes. Riccardi et al.³¹ highlighted that, unlike serum BNP biomarkers, soluble ST2 shows lower variations with age, sex, and some physiological processes in the body, allowing for the establishment of a constant threshold for diagnosis. In a randomized controlled trial,³² patients with HFrEF after acute decompensation were stratified into two groups to receive soluble ST2-guided therapy and standard therapy, respectively. After 6 months, compared to standard therapy, soluble ST2-guided therapy improved left ventricular ejection fraction (LVEF) and patients’ quality of life and reduced the incidence of poor clinical outcomes.

Furthermore, Galectin-3 is a proven indicator of fibrosis and anatomical remodeling. Galectin-3 has been found to be reflective of the early stages of inflammatory processes in the body, and this could aid the development of therapeutic agents at this stage of pathogenesis.³³ However, the expression of Galectin-3 is not specific to the heart; it has been found to be elevated in other inflammatory diseases, including autoimmune and neurodegenerative diseases.³⁴

Other biomarkers that are being utilized/investigated for their potential roles in the pathogenesis of heart failure include procalcitonin,³⁵ neutrophil gelatinase-associated lipocalin,³⁶ and mid-regional pro-atrial natriuretic peptide.¹⁸

GLS, measured through echocardiography, tracks muscle movement to assess the contractility of the heart in the longitudinal direction during each cardiac cycle.³⁷ This is particularly important for the diagnosis of HFpEF. The Copenhagen City Heart Study, a longitudinal study with an average follow-up period of 11 years, found that low GLS was significantly associated with the incidence of heart failure, among other cardiovascular diseases. Findings from the study highlighted the roles of GLS in the determination of long-term risk cardiovascular diseases.³⁷

AI has revolutionized various fields in health management; AI-based advancements in medicine include robot-assisted surgery, machine learning models for disease prediction and treatment planning, as well as AI-based drug discovery and development.³⁸ An example of these advancements in heart failure management is the AI-Clinical Decision Support System, a machine learning innovation that assists physicians in the diagnosis of heart failure.³⁹ The system uses patients’ information, such as physical evaluation results, echocardiographic findings, and findings from other tests, to predict heart failure diagnosis and the associated ejection fraction. The system showed a 98% concordance rate with heart failure specialists. Furthermore, machine learning models have also been developed for risk stratification⁷ and prediction of treatment outcomes⁴⁰ in patients with heart failure.

Pharmacological agents for the management of heart failure have accumulated over the years. An example of new drug classes used for heart failure management is sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Although originally developed for the management of type 2 diabetes, SGLT-2 inhibitors have been shown to reduce the risk of death and hospitalization in patients with heart failure regardless of the presence or absence of comorbidity with diabetes.⁴¹ The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure⁴¹ and Empagliflozin in Heart Failure (EMPEROR)⁴² trials are notable for the assessment of the impacts of dapagliflozin and empagliflozin, respectively, on cardiovascular outcomes.

The favorable outcomes of the drugs, as reported in these trials, prompted the inclusion of the drugs in the list of drugs used for heart failure management. SGLT-2 inhibitors, alongside three other traditional drug classes—beta-blockers, angiotensin receptor blockers + angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists—are known as the foundational drugs for heart failure. Recent international guidelines for heart failure management, including the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure¹⁷ and the 2022 AHA/ACC/HFSA guideline for the management of heart failure,¹⁰ recommend the use of these drugs. Although previous treatment guidelines encouraged stepwise inclusion and up-titration of doses of these drugs based on the severity of heart failure, newer guidelines now recommend starting all four foundational drugs as soon as possible for patients.⁴³ The rationale for this is that the drug classes act by different mechanisms, and together, they elicit an additive response.⁴⁴ Notwithstanding, the peculiar characteristics and tolerance of each patient must be considered when introducing these drugs.⁴⁵

Various other drugs have been evaluated for heart failure management, including omecamtiv mecarbil, which belongs to the cardiac myosin activators class and acts directly on cardiac muscle to improve contractility and systolic function.⁴⁶ The Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure trial investigated omecamtiv mecarbil and reported a slightly lower incidence of adverse events with omecamtiv mecarbil compared to placebo.⁴⁶ While this is promising, further research efforts are needed to substantiate this finding.

Another example of a novel drug for heart failure management is vericiguat. Vericiguat is a soluble guanylate cyclase stimulator that causes vasodilation and improves blood flow.⁴⁷ The Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction trial reported a modest reduction in the incidence of death and hospitalization in patients with heart failure who were administered vericiguat for approximately 11 months compared to those who received the placebo.⁴⁷

Heart rate is a proven prognostic factor of heart failure, and elevated resting heart rate is associated with poor outcomes. Increased heart rate is a common finding in patients with heart failure, as the reduced heart function induces a compensatory mechanism that results in tachycardia.⁴⁸ While beta-blockers are used to manage increased heart rate, lack of selectivity causes other unfavorable cardiovascular outcomes.⁴⁹ Ivabradine is a selective inhibitor of I_f current in the sinoatrial node, slowing down the heart rate and reducing cardiac workload. The SHIFT trial assessed treatment outcomes associated with ivabradine in comparison with placebo in patients with heart failure who had elevated heart rates ≥70 beats per minute and LVEF ≤35%.⁵⁰ Ivabradine resulted in an 18% reduction in the risk of cardiovascular death or hospital admission for worsening heart failure. Therefore, ivabradine is used clinically in heart failure therapy that requires heart rate reduction.

Given that obesity is a common risk factor for heart failure, especially in patients with preserved ejection fraction, novel weight-loss medications have been investigated for their roles in the management of HFpEF. Glucagon-like peptide-1 agonists are a class of drugs used in managing type 2 diabetes and weight management, and medications from this drug class have been evaluated for heart failure therapy.⁵¹ Notable examples of these assessments are the STEP-HFpEF and SUMMIT trials. The STEP-HFpEF trial focused on semaglutide; in addition to causing higher reductions in body weight compared to placebo (13.3% vs. 2.6%), semaglutide increased the Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-CSS) of patients (16.6 vs. 8.7 points), indicating fewer symptoms of heart failure and better quality of life.⁵² Likewise, the SUMMIT trial demonstrated that tirzepatide use resulted in a lower incidence of cardiovascular deaths or worsened heart failure (9.9% vs. 15.3%) and increased KCCQ-CSS (19.5 vs. 12.7 points).⁵³ These findings emphasize the importance of semaglutide and tirzepatide in the long-term management of HFpEF.

Heart failure due to valvular disease has also received considerable research attention in recent years. The MITRA-FR and the COAPT are important trials that assessed the impact of the catheter-based device (MitraClip) procedure on the management of mitral valve regurgitation in patients with reduced left ventricular ejection.^54,55 The patients included in the study were those who remained symptomatic after the maximum doses of pharmacological treatments. The procedure, also known as the mitral transcatheter edge-to-edge repair, used the MitraClip to repair the mitral valve. The MITRA-FR trial, which included patients with severe mitral regurgitation, reported no significant difference in the incidence of death and hospitalization between patients who underwent the procedure + standard treatment and those who received only standard treatment.⁵⁴ However, the COAPT trial, which included patients with moderate-to-severe mitral regurgitation, reported a lower incidence of hospitalization and mortality in the experimental group.⁵⁵

Despite the progress made in the pharmacological treatment of heart failure in recent years, considerable limitations still exist, including lack of drug specificity, patient nonadherence to medication regimen, and the need for continuous modulation of pathophysiological pathways. The use of medical devices aims to address some of these limitations.

Given the need for continuous monitoring of patient’s physiological parameters, the CHAMPION trial investigated the use of a remote pulmonary artery pressure monitoring device (CardioMEMS) in the management of patients with heart failure. The control group received standard care alone.²⁸ In addition to improving symptoms, CardioMEMS reduced the rate of hospitalization in the group whose care was managed based on pulmonary artery pressure measurements from the device. The device is a wireless implantable hemodynamic monitoring system that uses radiofrequency signals to transmit measurements to healthcare providers. This device is FDA-approved and is included in the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.¹⁰

The implantable cardioverter defibrillator (ICD) is used in patients who are prone to life-threatening arrhythmias, and it delivers shock to the heart (like a conventional defibrillator) to reset heart rhythm. ICD reduces the risk of sudden cardiac death and all-cause mortality in patients with heart failure.⁵⁶ Similar to this, the Baroreflex Activation Therapy for Heart Failure trial reported that the inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system caused by the implantable Barostim NEO system improved symptoms of heart failure.⁵⁷ The authors indicated that the system improved the exercise capacity and patients’ quality of life. Subsequently, the device was approved in 2019 by the FDA for patients who continued to exhibit symptoms despite pharmacological treatments.

Similar to the use of ICDs, cardiac resynchronization therapy (CRT) involves the implantation of a biventricular pacemaker, which delivers electrical signals to the two ventricles to synchronize their contractions and improve cardiac function.⁵⁸ This is a long-term management approach for heart failure, and evidence supporting its use is available in the literature. Moss et al.⁵⁹ compared the efficacy of CRT+ICD against ICD alone in patients with cardiomyopathy and an ejection fraction of ≤30%, reporting that CRT+ICD reduced the incidence of all-cause mortality or heart failure events (17.2% vs. 25.3%). An alternative to this approach is bundle branch pacing, which targets the part of the heart responsible for propagating electrical signals from atrioventricular nodes to the ventricles. Hence, in patients with ventricular dysfunction due to the left bundle branch block, the left bundle branch may be targeted to synchronize ventricular contraction and improve cardiac function. This is known as left bundle branch pacing, and it is associated with better electrical resynchronization in this patient group.⁶⁰

In severe heart failure or cardiogenic shock, mechanical circulatory support devices are critical to sustain cardiac and respiratory functions and ensure continuous organ perfusion. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) device is a common example of such devices and is used in the acute management of cardiogenic shock.⁶¹ Cannulas from the device are introduced into the patient’s body through a major vein and artery. Subsequently, the machine provides oxygenation to the blood and removes carbon dioxide. The EURO SHOCK trial, while challenged by the COVID-19 pandemic, reported that VA-ECMO reduced all-cause mortality in patients who received the procedure (43.8% vs. 61.1%) compared to those who received standard treatment.⁶² However, the study also reported increased bleeding complications in those who received VA-ECMO. Similarly, the DanGer Shock trial assessed the use of a percutaneous microaxial flow pump, another acute mechanical circulatory support device that provides left ventricular support but relies on optimal functioning of the right side of the heart.⁶³ This device also reduced all-cause mortality but was associated with increased adverse events. Overall, these devices provide life-preserving outcomes, but treatment plans must encompass the prevention of adverse events.

Furthermore, in heart failure caused by left ventricle failure, also known as left-sided heart failure, a left ventricle assist device (LVAD) may be required. A series of LVAD devices have been researched, notable of which is the HeartMate series: HeartMate I (pusher-plate pump), HeartMate II (axial-flow pump), and HeartMate 3 (centrifugal-flow pump).⁶⁴ Each new HeartMate was designed to correct the limitations of the previous ones and provide improved outcomes. HeartMate 3 is the latest in the series, and it is a fully magnetically levitated centrifugal-flow LVAD. In the final report of the MOMENTUM 3 trial published in 2019, HeartMate 3 was reported to be superior to HeartMate II in terms of reduced frequency of pump replacement, reduced reoperation rates, and lower incidence of stroke or bleeding.⁶⁵

Other medical device-based heart failure therapies include the use of pacemakers, cardiac contractility modulation, and the use of intra-aortic balloon pumps.⁶⁶ While these may be considered classical treatment approaches, many of them have received evidence-based improvements over the last decade.

Heart transplantation is a curative treatment for end-stage heart failure, and it improves the functional status of patients and their quality of life. This approach commenced many decades ago, but it has seen improvement in recent years. Challenges of cardiac transplantation included a limited pool of donors, graft rejection, and short survival rates.⁶⁷ To address this, studies have evaluated novel drugs to suppress the sensitization of recipients to the newly transplanted organs. Consequently, novel targeted monoclonal antibody drugs, including tocilizumab, clazakizumab, eculizumab, and daratumumab, have been researched to provide pharmacological desensitization, prevent organ rejection, and enhance survival.⁶⁸

Previously, individuals with viral infections such as hepatitis C, human immunodeficiency virus, and the severe acute respiratory syndrome coronavirus 2 were ineligible to be organ donors. There were concerns about transmission of the infection to the recipients as well as the rapid proliferation of the virus due to the immunosuppressive state after organ transplantation. However, given advances in the management of these conditions and promising reports of curative therapies, various organ transplant societies are starting to accept the transplantation of organs from infected individuals.⁶⁹ In such cases, the non-infected recipient received prophylaxis treatment perioperatively to reduce the risk of transmission and the development of infection.⁶⁹

Moreover, research efforts are underway on the transplantation of organs from animals to humans—xenotransplantation. Previous efforts in this regard led to an antigenic response in humans; however, the advances in the field of gene editing have made it possible to delete genes that could cause an antigenic response from the animal. Griffith et al.⁷⁰ reported the transplantation of a heart from a genetically modified pig. The patient survived for 2 months. However, on post-mortem clinical assessments, the observed changes were not consistent with typical rejection reactions; research is ongoing to determine the cause of structural abnormalities found in the organ. Notwithstanding, findings from studies such as this can serve as reference points for future research in xenotransplantation.

Structural remodeling and formation of scar tissues are critical pathological manifestations in heart failure; hence, research efforts are underway on the use of regenerative cells to repair damaged cardiac tissue and improve symptoms. The CCTRN CONCERT-HF trial combined bone marrow mesenchymal stromal cells and c-kit positive cardiac cells as a regenerative treatment for heart failure secondary to ischemic heart disease.⁷¹ The participants underwent transendocardial injection of the regenerative cells and were monitored for up to 1 year. Findings from the study demonstrated improved clinical outcomes and reduced incidence of adverse events with the regenerative treatment. However, no observable changes were found in the structure or function of the left ventricle; hence, the authors concluded that the observed outcomes could be due to systemic or paracrine cellular mechanisms rather than direct repair in the cardiomyocytes.

Other regenerative cells are being investigated for heart failure management, and promising outcomes have been reported.^72,73 The ultimate goal of the research efforts in this area is to enhance regenerative ability in the heart tissues, thereby promoting cellular repair and resolution of symptoms of heart failure.

Gene therapies, including the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based approaches, offer promising potential in the management of heart disease by targeting disease-specific mutations that are associated with cardiomyopathy.⁷⁴ Genome editing mechanisms have been used to prepare genetic models of heart disease to enable the identification of genetic defects. Furthermore, the identified mutations have aided the development of CRISPR/Cas 9 genetic material, which can be introduced into the heart to excise mutations and promote gene correction.⁷⁵

Yin et al.⁷⁶ recently developed echogenic liposomes for the delivery of CRISPR/Cas9 complexes into rat heart models; this study recorded successful gene editing, holding promise for application in humans. Zinc finger nucleases and transcription activator-like effector nucleases, among others, are other genome editing approaches that have been investigated.⁷⁴

However, various challenges have been highlighted, including delivery and targeting systems, immune response, and off-target effects. Additionally, ethical concerns exist regarding the use of gene editing in humans due to limited information on the possible adverse effects.⁷⁵

Similar to the diagnosis of heart failure, management strategies for heart failure have also benefited from the advent of AI-based innovations. Through a retrospective analysis, Ayers et al.⁷⁷ designed a machine learning model to predict 1-year survival after heart transplantation in adult patients. The study reported improved performance in a machine learning model that combined deep neural networks, logistic regression, AdaBoost, and random forest algorithms compared to the performance of the individual algorithms. The models used preoperative parameters, making them potentially important in designing eligibility criteria for patients undergoing transplants and predicting which patients are more likely to have better outcomes.

Likewise, Kianmehr et al.⁷⁸ utilized a machine learning model to evaluate the impact and interactive effect of multiple therapies for different comorbidities—hypertension and type 2 diabetes—on the risk of heart failure. The author reported that baseline diastolic blood pressure impacted glycemic control: a high risk of heart failure was observed in patients undergoing intensive hypoglycemic treatment who had low baseline diastolic pressure (45–69 mmHg) compared to those who had moderate or high baseline diastolic pressure.

The utilization of AI in heart failure management aims to ensure that management approaches are tailored to patient needs and that treatment efforts result in maximal efficacy with minimal adverse effects.⁷⁷ However, the importance of physician-supervised health management cannot be overemphasized; hence, it is essential that AI systems are designed to support clinicians in clinical decision-making rather than replace them. The novel treatment strategies are summarized in Figure 3.