Emerging therapies targeting cardiovascular risk factors to prevent or delay the onset of heart failure

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors

SGLT-2 primarily functions in the kidney, where it reabsorbs filtered glucose. By inhibiting SGLT-2, the reabsorption of glucose is reduced, resulting in increased glucose clearance through urination, which lowers blood glucose levels.^[21] These novel oral hypoglycemic drugs, specifically empagliflozin, canagliflozin, and dapagliflozin, represent significant breakthroughs in the realm of cardioprotective and nephroprotective anti-diabetic drugs. They have demonstrated remarkable class-effect outcomes, reducing CV and all-cause mortality, hospitalizations due to HF, and the progression of diabetic nephropathy.^[22]

Although the primary focus of clinical studies involving SGLT-2 inhibitors was glucose control, secondary endpoints and safety outcomes included the effects on BP and weight. For instance, the EMPA-REG OUTCOME trial was the first to reveal a reduction in CV mortality among high-risk patients with type 2 diabetes treated with empagliflozin. This study showed a clinically significant reduction in 24-h SBP and DBP decreased by 4.2 and 1.7 mmHg, respectively, in individuals taking 25 mg of empagliflozin daily compared to a placebo after 12 weeks of treatment. A smaller, yet significant, reduction in BP was observed in those using the lower dose of empagliflozin (10 mg).^[22,23] In addition, a meta-analysis of 45 placebo-controlled studies demonstrated a mean SBP reduction of −3.77 mmHg (95% confidence interval [CI] −4.65–−2.90). In six active-controlled studies, the mean change was −4.45 mmHg (95% CI −5.73–−3.18) compared to other agents. Among 16 studies, the mean change from baseline in DBP was −1.75 mmHg (95% CI −2.27–−1.23), with the six active-controlled studies suggesting a mean change of −2.01 mmHg (95% CI −2.62–−1.39) compared to other agents.^[24] In summary, SGLT-2 inhibitors exert a more pronounced effect on daytime BP compared to nighttime, and their BP-lowering efficacy is comparable to that of low-dose thiazide diuretics, with a change from baseline in 24-h SBP of −3.62 mmHg (95% CI −4.29, −2.94) for SGLT-2 inhibitors and −3.46 mmHg (95% CI −6.15, −0.77) for low-dose hydrochlorothiazide (12.5 mg), while the change from baseline in 24-h DBP averaged −1.70 mmHg (95% CI −2.13, −1.26) for SGLT-2 inhibitors and −2.23 mmHg (95% CI −4.34, −0.12) for low-dose hydrochlorothiazide.^[25] While the mechanisms behind SGLT-2 inhibitors’ BP-lowering effects involve natriuresis and osmotic diuresis, they are not yet fully elucidated.^[26]

RAAS

The primary action of the mineralocorticoid steroid hormone aldosterone is mediated through the mineralocorticoid receptor (MR). Its core function involves maintaining the balance of sodium and potassium, which plays a pivotal role in BP regulation. Consequently, an imbalance in aldosterone levels can result in the progression of heart and kidney diseases by elevating oxidative stress, inflammatory mediators, and fibrotic factors. Extensive clinical trials have confirmed the effectiveness and safety of steroidal MR antagonists (MRAs), such as spironolactone and eplerenone, in reducing BP in individuals with resistant hypertension. However, the use of these drugs is limited due to the increased risk of developing hyperkalemia. As a result, there is a pressing need to develop innovative non-steroidal dihydropyridine compounds to mitigate the adverse effects of steroidal antagonists.^[27]

Non-steroidal MRAs demonstrate a high degree of selectivity and enhanced affinity for MR, without interfering with progesterone and androgen receptors. They exhibit greater potency and a longer half-life compared to eplerenone and without the anti-androgenic effects observed with spironolactone.^[22] Among these non-steroidal MRAs, finerenone stands out as the most advanced candidate with a comprehensive global clinical development program. Finerenone, a dihydronaphthyridine-based compound, exhibits a remarkable selectivity for MR over other steroid hormone receptors with a high binding affinity (IC₅₀: 18 nM).^[28] Its distinct binding mode to MR-ligand-binding domain (LBD) as a “bulky” antagonist induces a unique MR-LBD conformational change, including the protrusion of Helix 12. This binding leads to an unstable receptor-ligand complex and the prevention of transcriptional coregulator recruitment, which, in turn, triggers a ligand-specific antagonistic effect on target genes. These unique characteristics potentially explain the differential clinical responses observed with finerenone.^[27,28]

Clinical trials involving finerenone have been conducted in patients with CKD, diabetes, and HFHF. Clinical trials involving finerenone have been conducted in patients with CKD, diabetes, and HFHF. Notably, in the Phase II ARTS-HF trial, among patients with HFrEF and coexisting type 2 diabetes mellitus (T2DM) or CKD, treatment with finerenone demonstrated a similar reduction in NT-proBNP compared to eplerenone. Importantly, a significant reduction in the composite of all-cause mortality, CV hospitalization, or emergency HF presentation was observed in patients receiving a dosage of 10–20 mg of finerenone compared to eplerenone. This outcome was particularly remarkable, although the trial was not specifically designed or powered to assess this endpoint.^[29] Finerenone also exhibited superior results in randomized clinical trials for individuals with worsening chronic cardiac and renal conditions compared to eplerenone, reducing cardiac hypertrophy and proteinuria significantly. In addition, Finerenone demonstrated slight impacts on BP, showing average SBP alterations of −3.0 mm Hg at month 1 and −2.1 mm Hg at month 12 compared to −0.1 mm Hg at month 1 and 0.9 mm Hg at month 12 observed with the placebo.^[30] The development of finerenone represents a critical advancement in the use of non-steroidal MRAs for hypertension.^[27]

Two other non-steroidal MRA compounds are making strides: esaxerenone, which has been approved for the treatment of arterial hypertension in Japan, and apararenone, which is currently undergoing clinical trials.^[27,31] Esaxerenone is characterized by its high affinity (IC₅₀: 3.7 nM) and exceptional selectivity for MR, with a more than 1000-fold higher selectivity compared to glucocorticoid, progesterone, or androgen receptors. It recently showed promising results in a phase III randomized controlled trial (ESAX-HTN) when compared to eplerenone, demonstrating safety and efficacy in managing hypertension. It also displayed protective effects on the heart and kidneys in hypertensive rats induced by deoxycorticosterone acetate salt, surpassing the results achieved by spironolactone or eplerenone.^[22,31] Furthermore, esaxerenone exhibited substantial antihypertensive and renal-protective effects by inhibiting renal inflammatory and oxidative stress pathways, significantly decreasing SBP from 187 ± 6 to 131 ± 4 mmHg.^[32] It was also shown to bind to MR, thereby preventing aldosterone binding and MR activation.^[33] The results of a long-term phase III clinical trial indicated that esaxerenone can effectively achieve target BP levels either as a monotherapy or in combination with other antihypertensive drugs.^[32]

In addition, two more non-steroidal MRAs, AZD9977 (AstraZeneca; Phase I), and KBP-5074 (KBP Biosciences; Phase II), have entered clinical trials. AZD9977 is a novel drug designed to counter the harmful effects of aldosterone and cortisol in non-epithelial tissues while having minimal impact on electrolyte balance in kidney epithelial cells. This tissue-specific modulation suggests that AZD9977 could offer protection against the progression of CV and renal diseases in patients with HFpEF, CKD, or both, without the risk of hyperkalemia associated with steroidal MRAs such as spironolactone and eplerenone.^[34] On the other hand, KBP-5074 has demonstrated a significant reduction in SPB in patients with uncontrolled hypertension, with a change in SBP from baseline to day 84 of −15.9 mm Hg in the 0.5 mg cohort and −11.5 mm Hg in the 0.25 mg cohort compared to −5.3 mm Hg in the placebo cohort. In addition, KBP-5074 exhibited a positive impact on urine albumin-to-creatinine ratio reduction in adults with type 2 diabetes and albuminuria, all without inducing serious adverse events related to hyperkalemia.^[35,36] These new therapeutic options, including KBP-5074 and AZD9977, may offer a safe approach to controlling hypertension in individuals with hypertension-related complications, without the need for potassium-lowering agents. Without a doubt, research in this field has the potential to significantly contribute to the future development of safe and effective non-steroidal MRAs.

Natriuretic peptide and neprilysin (NEP)

Neurohormonal regulatory mechanisms play a significant role in shaping the pathways leading to HF, primarily acting through three central systems: the autonomic nervous system, the RAAS, and the natriuretic peptide system (NPS).^[37] NEP, a zinc-dependent metallopeptidase, has gained recognition as a crucial player in this neurohormonal regulation.^[38] It is responsible for breaking down atrial natriuretic peptide, brain natriuretic peptide, bradykinin, and NPS.^[22] Consequently, a NEP inhibitor (NEPi) prevents the degradation of vasoactive peptides, including bradykinin, calcitonin gene-related peptide, adrenomedullin, and endothelin-1. NEPi’s beneficial effects encompass vasodilation, enhanced diuretic action, natriuresis, reduced sympathetic activity, and the long-term promotion of anti-inflammatory, antifibrotic, and antihypertrophic effects on cardiomyocytes in vitro.^[31] Nevertheless, NEPi alone cannot fully replace existing therapies due to a lack of safety and efficacy data. However, clinical trials have demonstrated the improved prognosis of HF patients and BP reduction in those with uncontrolled hypertension when treated with angiotensin receptor-neprilysin inhibitors (ARNI).^[39]

Omapatrilat, the first dual angiotensin converting enzyme (ACE)–neprilysin inhibitor, initially showed significant BP reduction compared to ACE inhibitor monotherapy. However, its synergistic inhibition of bradykinin breakdown led to an increased risk of angioedema, prompting the discontinuation of further research into this drug class.^[21] To address this issue, researchers developed LCZ696, a dual ARNI that combines sacubitril and valsartan. LCZ696 has emerged as a treatment for HFrEF. The innovative concept underlying NEP inhibition in HF shifts from complete neurohormonal inhibition to a modulation approach. Sacubitril/valsartan promotes vasodilation, reduces blood volume, and enhances sodium and water excretion through the kidneys by decreasing aldosterone production through its angiotensin receptor blocker-based effects. These mechanisms lead to lowered BP primarily due to reduced blood volume and natriuresis. Sacubitril/valsartan helps balance the neurohormonal environment, offering early relief of HF signs and symptoms and long-term improvements in left ventricular remodeling. These neurohormonal benefits translate into a reduction in major modes of death in HFrEF, including sudden cardiac death and worsening HF.^[37] In 2015, the United States Food and Drug Administration (USFDA) approved LCZ696 for the treatment of CV disorders, and it was found to be superior to the angiotensin receptor blocker enalapril in cardioprotection. Ilepatril (AVE 7688) VPi is currently undergoing a phase 3 clinical trial.^[31]

Endothelin receptor (ETR) endothelin pathway

Endothelin, a 21-amino acid peptide, is generated by the vascular endothelium from a 39-amino acid precursor called big endothelin. This conversion is facilitated by an enzyme known as endothelin-converting enzyme located on the endothelial cell membrane.^[40] Endothelin serves as a potent vasoconstrictor and smooth muscle mitogen and operates through endothelin A and endothelin B receptors.

Patients with pulmonary arterial hypertension (PAH) exhibit overexpression of endothelin in their lungs and plasma.^[41] Endothelin receptor antagonists (ERAs) are a class of potent vasodilators and antimitotic agents capable of specifically dilating and remodeling the pulmonary arterial system. Two types of ETRs are involved: endothelin type A receptors (ETAR) primarily found on vascular smooth muscle cells, promoting vasoconstriction by increasing intracellular calcium, and endothelin type B receptors (ETBR) located on endothelial cells, which stimulate the release of vasodilating agents such as NO and prostacyclin.^[41] Therefore, either selectively blocking ETAR alone or non-selectively blocking both ETAR and ETBR together can dilate pulmonary vessels.

Numerous clinical studies have demonstrated that blocking the endothelin system reduces BP in patients with mild-to-moderate hypertension and even in those with resistant hypertension.^[42] At present, a variety of ETR antagonists (ETRAs) have been developed and can be categorized into three groups based on their functions: selective ETAR antagonists such as darusentan and ambrisentan, non-selective ETRAs such as bosentan and macitentan, and selective ETBR antagonists.^[26] Bosentan, the oldest of the ERAs, has been authorized since 2001. While short-term studies have shown improvements in clinical symptoms in patients with PAH, hemodynamics, and time to clinical worsening, the COMPASS-2 study indicated no significant effect in patients already treated with sildenafil. [40] Darusentan, a selective ETAR antagonist, was explored for its use in resistant hypertension, but results were discouraging as the predetermined coprimary endpoints were not achieved, primarily due to BP measurement methodologies. However, a multicenter, randomized, and double-blind study revealed that darusentan dose-dependently reduced BP in patients with essential hypertension.^[22,26] Ambrisentan, a selective ERA antagonist, was found to improve various aspects of patient well-being when administered as monotherapy, and its combination with tadalafil showed favorable effects on exercise capacity and long-term outcomes compared to monotherapy with either substance.^[41] No known hepatotoxic effects or clinically relevant drug interactions have been associated with ambrisentan. Macitentan, a novel dual ETAR/ETBR antagonist, demonstrated significant reductions in mean arterial pressure and mean pulmonary artery pressure, surpassing bosentan in hypertensive rats and pulmonary hypertensive bleomycin-treated rats.^[22] In the SERAPHIN study, macitentan showed favorable effects in patients with PAH, both when used as monotherapy and in combination with other PAH medications, primarily sildenafil.^[43]

Aprocitentan (ACT-132577), a new dual ETA/ETB antagonist, significantly inhibits the binding of ET-1 to both ETAR and ETBR. In a phase 2 dose-finding study in hypertension patients, aprocitentan, administered as monotherapy at doses ranging from 10 mg to 25 mg, provided the most favorable profile by effectively lowering BP with low rates of fluid retention.^[44] In the phase 3 precision study, patients with resistant hypertension receiving standardized antihypertensive treatment, including a diuretic, showed that the addition of aprocitentan led to reductions in both standardized automated office and 24-h ambulatory BP compared to a placebo after four weeks of initial treatment. Aprocitentan demonstrated a significant decrease in SBP in comparison to the placebo, registering a mean change of −15.3 mmHg for the 12.5 mg dose, −15.2 mmHg for the 25 mg dose, and −11.5 mmHg for the placebo.^[44] These findings suggest that targeting ETRs may have therapeutic effects in the treatment of hypertension.

New medication development

Newer drugs have been developed to better manage DM. The addition of a new DM medication does not diminish the need of making dietary changes and improving physical exercise. However, if the usage of first-line treatments (e.g., metformin), adjustments to one’s diet, and exercise are insufficient to get one into adequate blood sugar management, then using one of the new medications can prevent or lessen the issues that emerge when one lives with diabetes. These newer medications include dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-receptor agonists (GLP-1RAs), and SGLT-2 inhibitor.

Continuous glucose monitoring

Effective glucose monitoring is the cornerstone for mitigating acute and chronic complications, reducing disability, and preventing premature mortality in individuals with DM.^[71] Maintaining proper glycemic control in diabetic patients significantly reduces the risk of developing CV conditions, including HF, as a consequence of DM as a risk factor. Conventionally, monitoring glycemic levels has relied on the average of HbA1c levels over 2–3 months. However, HbA1c may not be a suitable marker for patients with abnormal hemoglobin, end-stage renal illness, or chronic liver disease.^[61] In addition, HbA1c cannot predict daily fluctuations in glucose levels, such as episodes of hypoglycemia.^[72] Therefore, patients are required to perform self-monitoring of blood glucose (SMBG) to assess daily variations in blood glucose, set individualized glycemic targets, and tailor their DM management accordingly.^[72] However, SMBG has limitations in providing a comprehensive overview of blood glucose patterns and detecting hyperglycemic events.^[73] To address these limitations, CGM with wearable devices has emerged as a method for customizing treatment plans with the aim of enhancing glycemic control.^[74] Patients with DM who utilize CGM experience more substantial reductions in Hb1Ac, body weight, caloric intake, and exhibit greater adherence to dietary and physical activity recommendations compared to those using standard SMBG.^[75] These improvements contribute to a reduction in the risk of complications that may lead to HF.

The daily glucose data generated by CGM enable patients to comprehend the connections between self-care, medication adherence, nutrition, physical activity, and glycemic management.^[74] CGM empowers patients to monitor their glucose levels, make informed decisions about medical consultations, track their dietary choices, identify abnormal readings, and determine the factors causing them, allowing for timely adjustments. Clinicians and nutritionists, in turn, utilize CGM information to optimize medication and nutrition-based interventions and educate patients on self-care practices, aided by clear and patient-friendly summaries of glucose patterns and profiles.^[72] In comparison, routine blood glucose measurement methods, such as HbA1c tests and patient SMBG, lack the ability to capture glucose fluctuations.^[72]

Bionic pancreas

The use of insulin pumps, including commercially available hybrid closed-loop systems that offer partial automation of insulin delivery, typically involves inputting various parameters such as basal rates, insulin-sensitivity factors, carbohydrate-to-insulin ratios, total daily insulin doses, or a combination of these factors.^[76] At mealtimes, insulin doses are determined by the user entering the number of grams of carbohydrates in the meal, and effective treatment may depend on user-initiated correction doses for hyperglycemia.^[65] These systems may also require a warm-up period during which the user’s insulin dosing data is incorporated before full automation can begin.^[76]

In contrast, the iLet bionic pancreas developed by Beta Bionics operates differently. It does not rely on the patient’s previous insulin regimen, such as basal and bolus dose settings. Instead, it is initialized solely based on the patient’s body weight. This bionic pancreas fully automates the calculation and delivery of all required insulin doses immediately after inputting body-weight data, without the need for a warm-up period.^[76] A multicenter randomized trial led by Russell et al. assessed the use of a bionic pancreas in individuals with type 1 diabetes. The trial showed that using the bionic pancreas in an insulin-only configuration was associated with reduced levels of Hb1Ac, lower mean glucose levels, an additional 2.6 h/day spent within the target glucose range, and less time spent in a hyperglycemic state, all without an increase in the incidence of hypoglycemia.^[76] Notably, this device has received approval from the USFDA and is currently being used by some individuals with type 1 diabetes. Based on the promising results from Russell’s research and his team, the beta bionic pancreas is a promising tool that can help reduce the risk of HF associated with diabetes as a risk factor.

Stem cell therapy

Therapeutic approaches for controlling hyperglycemia in DM, such as exogenous insulin and other hypoglycemic medications, have limitations as they only delay the onset of diabetes-related complications and do not replicate the natural secretion of insulin, leading to unstable glucose levels and disruptions in patients’ daily lives.^[77]

Stem cells are characterized by their unique ability to undergo self-renewal, generating additional cells, and providing daughter cells that can differentiate into specific cell lineages.^[78] With immunomodulatory properties, the capacity to differentiate into specialized cells, and the potential for regeneration, stem cells present a promising and novel therapeutic avenue for addressing diabetes and its complications.^[77] These unspecialized cells possess the remarkable capability of both self-renewal and differentiation into mature cells with specific functions.^[79] Stem cells exhibit the capacity to differentiate into various cell types, including heart muscle cells, making them a viable treatment option. They can be categorized based on their origin, with common sources including bone marrow, adipose tissue, or even the cardiac tissue itself.^[78]

In a study conducted by Bhansali et al., stem cells were harvested from autologous bone marrow retrieved through the posterior superior iliac spine route under local anesthesia.^[79] These stem cells were then injected into the gastroduodenal artery using a 5F catheter navigated through the transfemoral route.^[79] The study’s primary endpoints after 6 months of stem cell transplantation (SCT) included a 50% reduction in insulin requirement and an improvement in glucagon-stimulated C-peptide levels.^[79] The results demonstrated that SCT reduced the daily insulin dosage needed by 70% of patients after just one treatment, improved glucagon-stimulated C-peptide levels, and lowered HbA1c by 1.1%.^[79] Numerous other studies have reported successful outcomes with stem cell therapy in diabetes management, indicating its potential to rejuvenate the pancreas’s natural insulin production. Administered in the early stages, stem cell therapy may reverse dependency on medications and insulin, consequently reducing the risk of diabetes-related complications, including HF.

Gene therapy

Gene therapy, a nascent field of medical research, focuses on manipulating human cells’ genetic material to treat or potentially cure specific diseases. This approach involves repairing or replacing faulty genetic material within the body.

In the context of type 1 diabetes, researchers are reprogramming alternative cells to perform the functions of beta cells, including insulin production. Using an adeno-associated viral (AAV) vector, researchers like Xiao et al. in 2018 transferred two proteins, pancreatic and duodenal homeobox 1, and musculoaponeurotic fibrosarcoma (MAF) basic leucine zipper transcription factor A, to a mouse’s pancreas. This intervention transformed alpha cells to function similarly to beta cells, leading to normal blood sugar levels in mice for up to 4 months after gene therapy, all without the need for immunosuppressive drugs that restrict or halt immune system activity.^[80] Although there are limited studies, primarily focusing on in vivo experiments, exploring the use of gene therapy for managing type 1 diabetes, its potential contribution to preventing HF complications in diabetes remains uncertain due to its early stages of development.

The use of mechanical circulatory support (MCS) devices

Heart transplantation is considered the definitive treatment for individuals with refractory end-stage HF, the demand for donor hearts exceeds availability. Consequently, MCS has become crucial in treating patients with end-stage HF.^[83]

In the 1960s, Drs. Michael DeBakey and Frank Spencer recognized the benefits of cardiopulmonary bypass (CPB) extending beyond the operating theater into the post-surgical recovery period. Resting the heart on CPB for extended periods allowed for ventricular function recovery in patients with cardiogenic shock.^[84] VADs, a type of MCS device, have shown significant positive impacts in HF management. Various types of VADs include the left VAD (commonly fixed at the left side of the heart to pump oxygenated blood to the body), right VAD (pumping deoxygenated blood from the right side of the heart to the lungs), biventricular assist device (supporting both sides of the heart), and pediatric VAD (used for individuals ranging from newborns to young adults). The implantation of VADs into the hearts of patients requiring this device involves close monitoring to ensure proper functionality before hospital discharge.

Positive experiences with adult MCS suggest that, for appropriate pediatric-age patients not expected to rapidly recover sufficient ventricular function or facing prolonged transplantation waiting times, implantable VADs provide the most beneficial form of chronic mechanical support.^[85] Complications associated with MCS, such as infection, bleeding, and thrombosis, have been reported.^[83] While these complications are not universal in every VAD procedure, further studies are necessary to explore ways to prevent or manage them if they arise. At present, VADs serve as life-saving interventions for HF patients.

Gene therapy

In the context of gene therapies for HF, various transgenes with specific intended impacts are considered, including the regulation of intracellular calcium. This involves the introduction of genes that encode proteins crucial for cardiac function or the silencing of genes that contribute to disease progression. For example, a study published in the journal Circulation Research demonstrated that gene therapy targeting the SERCA2a gene, which plays a key role in regulating calcium ion balance in cardiac cells, has shown improvement in heart function among HF patients.^[111] SERCA2a serves as a calcium cycling regulator within the heart, primarily function involves facilitating the relaxation of cardiac muscle by sequestering calcium ions in the sarcoplasmic reticulum. This regulatory mechanism is fundamental in maintaining the balance of calcium levels, a key factor in the contraction and relaxation cycles of cardiac muscle.^[112] Despite promising results in early trials, further research is essential to fully comprehend the safety and efficacy of these approaches.

A significant characteristic of chronic HF is the dysfunction of the β-adrenergic receptor (βAR), with G-protein-coupled receptor kinase 2 (GRK-2) playing a disruptive role. This disturbance leads to the downregulation of βARs and a diminished contractile response to adrenergic agonists, both characteristic of chronic HF.^[112,113] The β-Adrenergic receptor kinase c-terminal peptide (βARKct), inhibiting endogenous βARK1, has shown promise in preserving cardiac function and delaying HF progression through GRK-2 inhibition.^[103] Thus, βARKct when overexpressed improved left ventricular contractility and delays HF progression through GRK-2 inhibition.^[114] βARKct cardiac gene transfer contributes to the preservation of cardiac function, demonstrating improvements in the left ventricular contractility in both rodent and large animal models.

Researchers are exploring the use of viral vectors as a means to deliver therapeutic genes directly into heart cells. Viruses can undergo modification to carry the desired genes, serving as efficient carriers for targeted delivery to specific cells. In the early stages, predominantly adenoviral and γ-retroviral vectors were employed. However, recent technical advancements have facilitated the large-scale production of AAV and lentiviral vectors. As of now, adenoviruses and AAVs stand out as the primary viral vectors utilized in clinical trials related to cardiac interventions.^[115] Once introduced into the cells, these therapeutic genes possess the capability to rectify faulty genes or provide additional copies of a healthy gene, compensating for the defective counterpart. This approach holds significant promise for addressing the root causes of genetic abnormalities associated with HF. In addition to viral vector-based strategies, there is considerable excitement surrounding RNA-based therapies. This innovative approach involves targeting RNA molecules implicated in HF to develop treatments that specifically tackle the underlying genetic abnormalities. By focusing on RNA, scientists aim to modulate gene expression in a more targeted and precise manner. This avenue not only presents a promising therapeutic approach but also holds the potential for tailoring treatment plans to individual patients, paving the way for personalized and more effective interventions.

Despite the great promise gene therapies hold for HF, substantial challenges exist in translating these therapies to human patients.^[111] A major obstacle lies in delivering therapeutic genes efficiently and safely to heart cells. Researchers are actively investigating various delivery methods to optimize gene transfer and minimize the risk of adverse effects. In addition, long-term safety and effectiveness studies are crucial to ensuring the viability of these therapies in clinical practice, addressing potential severe host immune responses, and determining the optimal timing of administration.

Stem cell therapy

In the realm of HF, stem cell therapy involves utilizing these cells to repair and regenerate damaged myocardial tissue, exhibiting promise in regenerating functional heart muscle within degenerated and scarred myocardium.^[116,117]

Clinical trials have demonstrated the safety and efficacy of stem cell therapy, leading to its integration into mainstream heart health care. Initial trials, dating back to 2002, targeted the treatment of ischemic HF using stem cells. Key randomized clinical trials such as STAMI, RE. PAIR-AMI, and TOP CARE-CH. D reported conflicting data on stem cell advantages for cardiac function in 2006. However, subsequent trials like STAR-HEAR.T, BOOST, SC. IPIO, ĊADUCEÚS, ŖEGEÑT, and Focus HF demonstrated the positive impact of stem cells on remodeling and the function of ischemic myocardium.^[118] For instance, the Focus-HF trial revealed that intramyocardial transplantation of autologous bone marrow mononuclear cells improved QoL and exercise capacity in patients with ischemic HF, attributing these effects to enhanced perfusion of the ischemic myocardium. Similarly, the application of CD34+ stem cells directly into the myocardium of patients with refractory angina demonstrated significant reductions in both the frequency and duration of anginal episodes, as highlighted by Vrtovec et al. in 2013.^[119] In the SCIPIO trial, the intracoronary infusion of cardiac stem cells was investigated in patients with ischemic HF who had experienced an acute MI. The results of this trial indicated a notable reduction in infarct size and an improvement in the left ventricular function, underscoring the positive impact of intracoronary stem cell infusion in post-MI patients with HF.

Stem cell therapy for HF has shown promise in both pre-clinical research and early clinical trials, with the first approach aiming to prevent additional damage to the heart post-heart attack, while the second concentrates on fostering the growth of new, healthy heart tissue.^[116] Recent advancements highlight the potential of mesenchymal stem cell (MSC) transplantation in impeding further cardiac damage post-MI and promoting the regeneration of functional heart muscle. MSCs, derived from sources such as bone marrow or adipose tissue, release cytokines, and growth factors that activate endogenous repair mechanisms, expediting the healing process. Moreover, MSCs can differentiate into cardiomyocytes when introduced into the murine myocardium, presenting an alternative treatment avenue for individuals with HF.^[78,120] Notably, even allogeneic MSCs appear to be non-immunogenic and non-inflammatory, enhancing their appeal as a potential therapeutic option.^[121] In addition to MSCs, induced pluripotent stem cells (iPSCs) have emerged as a promising tool for improving heart function post-MI. iPSCs are adult cells that undergo reprogramming to attain a pluripotent state, allowing them to differentiate into heart cells. This innovative technology leverages the patient’s own cells, thereby reducing the risk of rejection or immune-related complications. However, further research is essential to comprehensively understand the mechanisms and refine the delivery methods of stem cell therapy for HF. Ongoing investigations are crucial for advancing the therapeutic potential of these regenerative approaches and establishing their place in the clinical management of HF.

While stem cell treatments offer exciting possibilities, challenges remain, particularly in ensuring the survival and integration of transplanted stem cells within heart tissue. Scientists are actively exploring strategies such as tissue engineering and biomaterial scaffolds to enhance cell retention and integration. In addition, refining the timing and delivery methods of stem cell treatments is crucial for maximizing their therapeutic effects.

Personalized medicine

Precision medicine, also known as personalized medicine, is increasingly influential in the realm of HF prevention and treatment, with recent advancements in medical therapies, monitoring technologies, and device interventions reshaping HF management.^[104] While HF remains a formidable and progressive condition, especially in Sub-Saharan Africa, where a substantial burden exists, advanced treatments such as heart transplantation and artificial heart blood pumps face constraints related to cost, organ availability, and associated risks^[122] presenting challenges in determining the most suitable treatment for individual patients. Precision medicine emerges as a solution by analyzing an individual’s genetic makeup, lifestyle, and medical history to tailor treatment plans, addressing specific risk factors, and optimizing outcomes.^[114]

Precision medicine for HF seeks to personalize treatment strategies based on individual characteristics, including genetic profiles, comorbidities, and responses to prior treatments. Utilizing cutting-edge molecular technologies such as genomics, proteomics, transcriptomics, metabolomics, and phenomics, combined with environmental and lifestyle factors, precision medicine identifies patient groups with similar disease profiles likely to benefit from targeted therapies.^[123] This approach involves synthesizing extensive data collected through various methods to deeply characterize patient populations, with the primary goal of determining optimal care for individuals based on their unique profiles, moving away from reliance on population averages. The strength of precision medicine lies in its ability to synthesize rapidly evolving datasets, including information from clinical assessments, imaging, laboratory testing, next-generation sequencing (NGS), metabolomic and proteomic studies, as well as historical health record data.^[124] Leveraging advanced systems biology and network analytical methods allows the discovery of new and unbiased relationships between health and disease factors within this expansive dataset.

In the context of HF, precision medicine holds three potential applications. First, it seeks to uncover the genetic basis of common HF causes such as CHD and CMP. Second, it aims to develop risk-stratification models for guiding counseling and therapeutic interventions, utilizing genetics to inform therapy choices based on predicted responses. Third, precision medicine focuses on identifying new targets for biological or pharmacological therapies, potentially repurposing existing medications or discovering new ones targeted at dysregulated pathways causing different forms of HF. This personalized approach allows for more precise and targeted disease management, potentially improving outcomes and enhancing the QoL for HF patients.

Recent advancements in precision medicine and advanced analytics have offered insights into the molecular pathways involved in HF, particularly distinguishing between patient groups with reduced and preserved ejection fraction. NGS has emerged as a powerful tool, uncovering novel gene targets across various medical fields and increasingly becoming financially feasible as a diagnostic modality. In contrast to genotyping panels, NGS provides the opportunity to discover not only novel mutations but also compound mutations that may collaborate to modify HF phenotypes and disease severity.^[123] This technology holds the potential to revolutionize HF diagnosis and treatment, offering a more tailored and effective approach to managing this complex condition.

In addition to predictive and prognostic techniques, precision medicine can play a pivotal role in identifying potential responders to therapy before treatment initiation, particularly in the field of pharmacogenetics. Beta-blockers, extensively studied in pharmacogenomics for HF, exemplify this approach.^[125] A notable example is the exploration of the Arg389Gly variant in the gene encoding the β1-adrenergic receptor (ADRB1). Pharmacological studies have revealed that receptors with the Arg389 variant exhibit greater basal and agonist-stimulated activity compared to those with the Gly389 variant. This difference in receptor activity has translated into significant mortality benefits for HF patients. Research has shown that patients homozygous for the ADRB1 Arg389 variant experienced a substantial 38% reduction in mortality when treated with bucindolol therapy, while Gly389 carriers did not derive a comparable benefit from the same treatment.^[125,126] Studies have also shed light on RAAS-modifying drugs, specifically the variation in survival benefits associated with both endogenous ACE levels and the efficacy of ACE inhibition. These approaches have provided new insights into the role of genetic variation in predicting the severity of ventricular remodeling in CMP and CHD.^[123]

The exploration of pharmacogenetics in HF illuminates the potential for a more personalized and effective therapeutic approach. By identifying genetic variants and their impact on the response to specific medications, health-care providers can make informed decisions about treatment plans that are more likely to benefit individual patients, enhancing the overall effectiveness of HF management and minimizing the risk of adverse reactions.

Precision medicine is poised to transform the future of CVD management due to the gradual onset and complex nature of these conditions. Despite its potential, the field is still evolving, with many necessary technologies in early stages. Limited research, hindered by ethical and social issues, along with considerations of cost-effectiveness and test availability, may impact the broader adoption of precision medicine in clinical practice.^[127]