Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies

Abstract

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell–derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.

1. Introduction

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually (Chong et al., 2024). A central pathological feature linking multiple CVDs is cardiac hypertrophy, a maladaptive remodeling process that often precedes and promotes the onset of heart failure, arrhythmias, and sudden cardiac death. With aging population and persistent risk factors such as hypertension, dyslipidaemia, and lifestyle-related conditions, the prevalence of hypertrophy and its associated morbidity is steadily rising, underscoring its major clinical burden. Cardiac hypertrophy represents both a structural and molecular adaptation to chronic stress. It is one of the earliest responses of the myocardium to pressure overload, neurohormonal stimulation, and genetic alterations. Although initially compensatory, this remodeling often progresses to a maladaptive state, compromising cardiac function and increasing the risk of adverse outcomes. Hypertrophy can be classified into three clinically relevant forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible; pathological hypertrophy is triggered by prolonged hemodynamic stress, including myocardial cell stretching, often stemming from conditions such as hypertension, valvular disease, or sustained neurohumoral activation (Kavazis, 2015; Shimizu and Minamino, 2016); and hypertrophic cardiomyopathy (HCM), a primary genetic disorder linked to sarcomeric mutations (Marian and Braunwald, 2017). Distinguishing between these forms is critical, as therapeutic strategies range from lifestyle interventions and medical therapy to genetic counselling and advanced interventions. The progression from adaptive to maladaptive hypertrophy reflects a complex interplay most notably, through the renin–angiotensin system driven by oxidative stress, fibrosis, and inflammation (Oldfield et al., 2020).

Despite the availability of standard therapies such as β-blockers, ACE inhibitors, and ARBs, these treatments only alleviate symptoms and slow progression, with little capacity to reverse structural remodeling. This therapeutic limitation underscores the urgent need for innovative strategies. Advances in RNA-based therapeutics, regenerative approaches using stem cell-derived products, and precision tools such as genome editing are opening new possibilities for targeted intervention (Hou and Kang, 2012; Singh et al., 2024). This review aims to emphasize the clinical importance of distinguishing adaptive, pathological and genetic forms of cardiac hypertrophy. It critically evaluates the current treatment strategies and their limitations. It also explores the emerging multimodal therapeutic interventions that hold potential to transform precision cardiology.

2. Cardiac hypertrophy and its key mediators

Cardiac hypertrophy, defined as the enlargement of myocardial mass in response to sustained stress, is a hallmark of many cardiovascular disorders. It is driven by a complex interplay of neurohormonal, paracrine, and cellular signals that initially promote adaptation but frequently transition to maladaptive remodeling and heart failure. Two major systems dominate this process: the sympathetic nervous system (SNS) and the RAS (Fig. 1). The SNS rapidly enhances contractility and heart rate through the release of catecholamines (norepinephrine and epinephrine), while activation of the RAS leads to the generation of Ang-II, a potent effector that promotes hypertrophic, fibrotic, and inflammatory signaling (Caturano et al., 2022). Beyond these pathways, multiple mediators including endothelin-1 (ET-1), vasopressin (AVP), Serotonin (5-HT), Reactive oxygen species (ROS), Intracellular calcium overload, Inflammatory cytokines, and transforming growth factor-beta (TGF-β) contribute to the remodeling network (Neumann et al., 2023; Yang et al., 2023; Dhalla et al., 2024). Together with non-myocyte populations such as fibroblasts, endothelial cells, and immune cells, these signals coordinate structural and molecular reprogramming that shifts the heart from adaptive to pathological hypertrophy (Bazgir et al., 2023).

Fig. 1. Dual Neurohormonal Pathways Driving Cardiac Hypertrophy: Adaptive vs. Pathological Remodeling.

The schematic illustrates the distinct signaling cascades that lead to either adaptive or pathological cardiac hypertrophy. Adaptive hypertrophy, typically triggered by exercise or pregnancy is primarily mediated by activation of the sympathetic nervous system (SNS), resulting in transient myocardial thickening and preserved cardiac function. In contrast, pathological hypertrophy triggered by stress, hypertension, which is initiated by activation of the renin-angiotensin system (RAS), leading to sustained Ang-II production, which promotes ventricular wall thickening, and eventual cardiac dysfunction which is irreversible. Vasopressin, endothelin-1, serotonin and growth factors act as secondary mediators that shift between adaptive and pathological cardiac hypertrophy based on duration of activation. While transient activation of these factors during adaptive hypertrophy is reversible and does not result in lasting myocardial damage (dotted line), their sustained activation in conditions such as chronic hypertension drives the transition to pathological hypertrophy, characterized by ventricular wall thickening and impaired function (solid red line).

2.1. Role of Angiotensin-II in cardiac hypertrophy

The renin-angiotensin system (RAS) is a fundamental hormonal cascade essential for maintaining cardiovascular homeostasis, regulating vascular tone, fluid balance, and blood pressure. The classical RAS is initiated by the liver-derived precursor protein, angiotensinogen (AGT). In response to stimuli such as hypotension or hypovolemia, renin-secreted by juxtaglomerular cells in the kidney, cleaves AGT to produce Ang I, a biologically inactive decapeptide. Ang I is subsequently converted to the active octapeptide Ang II by angiotensin-converting enzyme (ACE), predominantly in the pulmonary endothelium (Bhullar and Dhalla, 2022). Ang II plays a central role in regulating heart function through its interaction with two primary subtypes of angiotensin type 1 (AT1) and type 2 (AT2) receptors. Elevated level of AngII activates AT1 receptor which may results in hypotension, increased angiotensinogen production, enhanced RAS activity, and acute pathological stimuli. Short-term (acute) increases in Ang II generally lead to physiological hypertrophy with preserved cardiac function, whereas chronic elevation causes pathological hypertrophy and progressive deterioration in cardiac performance, culminating in heart failure (Bhullar and Dhalla, 2022).

2.2. Intracellular signaling pathways in Ang II-induced cardiac hypertrophy

Among the two subtypes, AT1 receptor activation triggers several intacellular signaling pathways, including phospholipase C (PLC) protein kinase C (PKC), mitogen-activated kinases (MAPKs), and calcium signaling, all of which converge to promote protein synthesis, cardiomyocyte growth, and structural remodeling (Mori et al., 2013). Under specific conditions, AT1 receptor activates class III phosphoinositide 3- kinase (PI3K) indirectly to mediate adaptive cardiac hypertrophy through the enhancement of autophagy (Fig. 2). For instance, stimulation of AMP-activated protein kinase (AMPK), leads to phosphorylation of the scaffold protein progestin and adipoQ receptor 3 (PAQR3), which promotes the assembly of the vascular protein sorting 34 (Vps34) complex (including ATG14L and Beclin 1). This complex generates phosphatidylinositol 3-phosphate (PI3P), a critical molecule in autophagosome formation. By facilitating the clearance of damaged mitochondria and reducing ROS, this autophagy pathway supports cardiomyocyte survival and adaptive remodeling (Zhong et al., 2021). More prominently, Ang II initiates hypertrophic signaling through its binding to AT1 receptor, a G protein-coupled (GPC) receptor, which activates the Gq/11 protein. This activation stimulates Class I PI3K, leading to phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-triphosphate (PIP3), subsequently activating Akt (protein kinase B) through mammalian target of rapamycin (mTOR) signaling crucial for cardiomyocyte growth and protein synthesis. Simultaneously, PIP2 is cleaved into 2 s messengers: diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). DAG activates PKC, which regulates gene expression by phosphorylating transcription factors, while IP3 induces Ca²⁺ release from the sarcoplasmic reticulum. The rise in intracellular calcium activates Ca²⁺/calmodulin-dependent kinases and the phosphatase calcineurin, which dephosphorylates the nuclear factor of activated T-cells (NFAT), allowing its nuclear translocation and induction of hypertrophic gene transcription (Onohara et al., 2006; Bhullar and Dhalla, 2022). DAG also activates transient receptor potential canonical (TRPC) channels, particularly TRPC3 and TRPC6, contributing to membrane depolarization and further Ca²⁺ influx through L-type Ca²⁺ channels, thereby amplifying Ca²-dependent hypertrophic signaling. In parallel, Ang II also activates the secondary target MAPK pathway, a key regulator of growth, stress responses, and apoptosis.

Fig. 2. Classical and activated secondary pathways in Ang II-induced cardiac hypertrophy.

Diverging Routes to Adaptive and Pathological Remodeling. Activation of Class III PI3K- AMPK is associated with autophagy mediated adaptive hypertrophy. Whereas Angiotensin type 1 receptor activates several downstream pathways and leads to accumulation of intracellular Ca²⁺, thereby promoting the pathological hypertrophy. Angiotensin-II activation will simultaneously activate secondary targets and pathways, MAPK and other inflammatory pathways, which have distinct roles in hypertrophy and remodeling.

The MAPK cascade comprises three major branches: extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK, and each is triggered by distinct upstream kinases. The ERK1/2 pathway, typically associated with cell growth and survival, it initiates with RAS-mediated activation of rapidly accelerated fibrosarcoma (RAF), followed by sequential phosphorylation of MEK1/2 and ERK1/2. Activated ERK1/2 translocate to the nucleus to activate transcription factors involved in protein synthesis and cardiomyocyte hypertrophy. The JNK and p38 MAPK pathways are activated by cellular stress and inflammation. MEKK phosphorylates MKK4/7 to activate JNK, which acts on transcription factors such as c-Jun and ATF-2. Similarly, inflammatory signals activate MKK3/6, leading to p38 MAPK activation and transcription of proinflammatory profibrotic genes. While ERK1/2 is largely associated with adaptive hypertrophy, JNK and p38 MAPK contribute to maladaptive remodeling and cardiomyocyte apoptosis (Zhang et al., 2003). ROS also play a central role in Ang II signaling. Ang II activates NADPH oxidases (NOX), especially NOX2 and NOX4 isoforms which generate ROS that amplify redox signaling. These ROS further activate transcription factors such as NF-kB, promoting fibrotic gene expression and pathological cardiac hypertrophy (Ago and Sadoshima, 2015). Finally, additional transcription factors including STAT, Activator protein-1 (AP-1), further contribute to the transcriptional reprogramming associated with pathological hypertrophy. Table 1 provides an overview of these downstream signaling pathways and their roles in Ang II-induced cardiac remodeling.

Table 1.

Signaling pathways that contribute to cardiac hypertrophy.

Cardiac dysfunction	Pathway	Mechanism	Effects
Cardiac hypertrophy	AT1R–PLC–PKC–Ca2+–MAPK Pathway	AT1 receptor activation increases calcium and protein kinases that trigger growth signals	Promotes cell growth and gene expression, leading to hypertrophy (Zhai et al., 2005)
	Ca2+–Calcineurin–NFAT Pathway CD38 cAADPR Ca2 signaling	High calcium activates calcineurin via CD38, which sends growth proteins to the nucleus to trigger hypertrophic genes.	Drives the expression of genes involved in pathological hypertrophy (Molkentin and Dorn II, 2001; Guan et al., 2017)
	EGFR Transactivation	AT1 receptors indirectly activate the epidermal growth factor receptor and activate extracellular signal-regulated kinase.	Drives the development of cardiac hypertrophy (Zhai et al., 2006)
	NOX2/NOX4–Rac1-ROS–Redox Pathway	AT1 receptor activation increases production of ROS.	ROS activates pathological hypertrophy (Shanmugam et al., 2011; Ago and Sadoshima, 2015)
	PI3K–Akt–mTOR Pathway	ROS activates a chain of enzymes that promote protein production and cell growth.	Supports hypertrophic growth of the heart muscle (Wenzel et al., 2006)
	JAK/STAT3 pathway	Ang II triggers signaling pathways that activate growth related genes such as visfatin and BNP.	Promotes expression of hypertrophy-related genes (Chang et al., 2012)
	Wnt/β-catenin signaling	Wnt signaling blocks a brake protein (GSK3β), allowing β-catenin to promote cell growth	Encourages heart cell proliferation and hypertrophy (Blankesteijn et al., 2008)
	Mitochondrial Dysfunction & PDK4	Ang-II causes mitochondrial damage and metabolic shifts that reduce energy production	Energy imbalance leads to pathological cardiac hypertrophy (Doughan et al., 2008)
	Nrf2-Antioxidant Signaling	Oxidative stress activates Nrf2, a protective protein that increases antioxidant defences in heart cells	Reduces hypertrophy by lowering oxidative stress(Chen et al., 2019)

2.3. Counter-regulatory pathways

The AT2 receptor and Mas receptor pathways serve as critical counter-regulatory arms to the classical RAS. Collectively referred to as the non-canonical pathway, these mechanisms mediate cardioprotective effects, which oppose the deleterious effects of Ang II signaling through the AT1 receptor. This non-canonical axis includes bioactive peptides such as angiotensin 1–7, angiotensin 1–9 and alamandine. Angiotensin 1–9 activates AT2 receptor, initiating intracellular cascades that lead to nitric oxide (NO) production, contributing to vasodilation and antihypertrophic effects. Angiotensin 1–7 binds to the Mas1 receptor on vascular endothelial cells, triggering G protein-coupled signaling pathways (Fig. 3). This receptor activation leads to Akt phosphorylation, which subsequently activates endothelial nitric oxide synthase (eNOS), and increases nitric oxide (NO) bioavailability, a key mechanism in vascular relaxation and improved endothelial function. Alamandine is a heptapeptide generated through the decarboxylation of Angiotensin 1–7, binds to the Mas related G-protein coupled receptor D (MrgD). Upon receptor engagement, alamandine activates the PI3K/Akt signaling axis, leading to enhance NO production. Additionally, it stimulates AMPK, promoting metabolic homeostasis, reducing inflammation, and protecting against cardiac hypertrophic remodeling. Alamandine also activate the cAMP/PKA pathway, further supporting vasorelaxation and antifibrotic responses. Importantly, alamandine has been shown to suppress hypertrophic signaling by inhibiting ERK1/2 and p38 MAPK key components of the classical RAS cascade (Paz Ocaranza et al., 2020).

Fig. 3. Counter-Regulatory Pathways in Cardiac Hypertrophy.

Ang II binds to Angiotensin type 1 (AT1) receptor, thereby activating the pro-hypertrophic signaling, whereas counter-regulatory RAS pathway acts parallelly by activating peptides which stimulate nitric oxide production and oppose the AT1 receptor effects.

Experimental studies using hypertrophic stimuli in neonatal cardiomyocytes and H9C2 cell models have demonstrated that alamandine treatment significantly inhibits cardiomyocyte growth and reduces the expression of hypertrophy-associated genes (Liu et al., 2018b). This protective effect is partly mediated through the activation of transcription factors such as nuclear factor erythroid related factor 2 (Nrf2), which enhances antioxidant defences, mitigates oxidative stress and prevents maladaptive cardiac remodeling. This nuanced understanding of molecular signaling provides a robust foundation for therapeutic innovation. While classical pharmacological agents remain central to clinical care, their limitations, including partial reversal of cardiac remodeling and notable side effects, necessitate the development of more targeted approaches. In this context, novel strategies such as RNA-based therapy, exosome-mediated delivery, and plant-derived phytochemicals are emerging as promising tools for precision cardiology. The next section outlines the current pharmacological landscape, focusing on conventional therapies and their mechanistic roles within this evolving molecular framework.

3. Classical therapeutic options for cardiovascular disorders

Conventional pharmacotherapies, including beta blockers, statins, calcium channel blockers, and angiotensin receptor blockers (ARBs), remain central to the clinical management of cardiac hypertrophy and related cardiovascular disorders. These drugs target distinct molecular pathways to attenuate adverse remodeling, enhance myocardial function, and improve patient outcomes. Their efficacy stems from decades of clinical use and ongoing research aimed at refining dosage, reducing side effects, and improving long-term outcomes (Fig. 4). In HCM, classical therapies are primarily employed to reduce myocardial oxygen demand, alleviate left ventricular outflow tract obstruction, and control arrhythmias. In contrast, pathological hypertrophy secondary to hypertension or valvular heart disease requires treatment strategies directed at the underlying cause such as blood pressure control, valve repair or replacement, or coronary revascularization. Thus selecting the appropriate therapeutic option depends on both the etiology of hypertrophy and the overall cardiovascular risk profile of the patient.

Fig. 4. Therapeutic Strategies for Cardiac Hypertrophy.

This diagram illustrates the multimodal therapeutic approaches for managing cardiac hypertrophy.

3.1. Beta-blockers

Beta-blockers function by antagonizing beta-adrenergic receptors, primarily the beta-1 and beta-2 subtypes located in the heart. These receptors are typically activated by catecholamines such as epinephrine and norepinephrine, leading to increased heart rate, myocardial contractility, conduction velocity, and blood pressure through stimulation of renin release. By inhibiting these receptors, beta-blockers reduce sympathetic stimulation, resulting in decreased cardiac output and blood pressure (do Vale et al., 2019). Beta blockers are extensively used in clinical practice for HCM, where they help alleviate left ventricular outflow tract (LVOT) obstruction, reduce myocardial oxygen demand, improve diastolic filling and enhance overall quality of life (Pinto et al., 2025). Commonly prescribed agents include atenolol, carvedilol, metoprolol, and sotalol. A key clinical study investigated the therapeutic efficacy of metoprolol succinate in patients with obstructive hypertrophic cardiomyopathy. This randomized, double-blind, placebo-controlled crossover trial involved 29 adult patients who received either metoprolol succinate or placebo once daily for two weeks. The findings indicated that metoprolol improved heart rate and reduced left ventricular longitudinal strain (LV GLS), a marker of myocardial dysfunction suggesting a reduction in myocardial injury. Mild side effects, such as dizziness and fatigue, were reported in a subset of patients (Dybro et al., 2021). However, the effectiveness of beta-blockers varies depending on the underlying cardiovascular condition and patient demographics. For example, they are generally not considered first-line agents for managing hypertrophy in older adults due to reduced efficacy and a higher risk of adverse events. Nonetheless, in cases of obstructive HCM, beta-blockers like metoprolol remain invaluable in reducing LVOT obstruction and improving symptomatology. Thus, their use should be individualized, balancing potential benefits and risks (Vögele et al., 2017).

3.2. Statins

Statins are lipid-lowering agents that primarily function by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. In addition to reducing low-density lipoprotein cholesterol (LDL-C), statins exhibit pleiotropic effects that may influence cardiac remodeling. Specifically, they inhibit the isoprenylation of small GTP-binding proteins such as Ras-related C3 botulinum toxin substrate (Rac1) and Ras homolog gene family member A (RhoA), which are implicated in the generation of ROS and activation of pro-hypertrophic pathways (Liao, 2004). Preclinical studies have demonstrated the antihypertrophic potential of statins. For instance, a double-blind, randomized, placebo-controlled pilot trial reported that atorvastatin treatment resulted in decreased left ventricular (LV) mass and improved diastolic function (Bauersachs et al., 2007). However, other clinical trials have yielded inconsistent results. In one study involving 21 patients, atorvastatin did not significantly reverse pathological hypertrophy (Nagueh et al., 2010). Similarly, the Statin-Induced Regression of Cardiomyopathy Trial (SIRCAT), a randomized, double-blind, placebo-controlled study in HCM patients, found that atorvastatin did not lead to significant LV mass regression (Hersi et al., 2016). Taken together, these findings suggest that although statins demonstrate promising antihypertrophic effects in animal models, their translation to clinical benefit in human HCM remains limited. These inconsistencies highlight the challenges in repurposing statins for cardiac hypertrophy treatment and emphasize the need for further investigation.

3.3. Calcium channel blockers

Calcium channel blockers (CCBs) are an essential class of antihypertensive medications that exert their effects by inhibiting L-type calcium channels in vascular smooth muscle and cardiomyocytes. This inhibition reduces calcium influx, thereby lowering vascular tone and intracellular calcium levels, key contributors to pathological cardiac hypertrophy (Ruilope et al.). CCBs are classified into dihydropyridines (e.g., amlodipine) and non-dihydropyridine (e.g., verapamil, diltiazem), each with distinct cardiovascular effects. Clinical evidence supports the role of CCBs in reducing pathological hypertrophy by decreasing myocardial wall thickness and improving diastolic function. In hypertensive patients, CCBs have demonstrated superior effectiveness compared to beta blockers and diuretics(Koracevic et al., 2022). However, the utility of CCBs in HCM remains less conclusive. A recent clinical trial involving 222 asymptomatic patients with Class I HCM found no significant improvement in disease progression, functional capacity, or rates of cardiovascular hospitalization with beta-blockers or CCB therapy (Bradlow et al., 2024). Overall, CCBs play a valuable role in managing cardiac hypertrophy, through restoration of calcium homeostasis and inhibition of maladaptive remodeling. Nonetheless, they are not sufficient as monotherapy to prevent progression to heart failure, necessitating their combination with agents targeting complementary mechanisms.

3.4. Angiotensin receptor blockers

Ang II receptor blockers (ARBs) attenuate cardiac hypertrophy and fibrosis by selectively blocking the AT1 receptor thereby neutralizing the deleterious effects of Ang II on the heart (Cuspidi et al., 2008). ARBs are effective in reducing ventricular remodeling, oxidative stress, and arrhythmogenesis, making them first-line agents for treating patients with hypertensive hypertrophy. In a preclinical mouse model of -pathological hypertrophy induced by transverse aortic constriction (TAC), candesartan significantly attenuated cardiac hypertrophy and fibrosis, as evidenced by reduced ventricular wall thickness (Penicka et al., 2009). Clinical trials have also demonstrated that valsartan, compared to amlodipine, more effectively reverses pathological remodeling and oxidative stress (Yasunari et al., 2004). Commonly used ARBs, losartan, valsartan, and candesartan are frequently prescribed for patients with hypertrophic cardiomyopathy. Among these, losartan is FDA-approved for the treatment of hypertensive patients with cardiac hypertrophy (Dahlöf et al., 1998). Although ARBs are effective in managing hypertrophy related to hypertension and metabolic stress, they are generally not indicated for primary genetic forms of HCM. Together, these findings reinforce the role of ARBs as cornerstone These data support the positioning of ARBs as therapies in the pharmacologic management of pathological cardiac hypertrophy, especially when driven by systemic hypertension or volume overload.

4. Plant-based therapies for CVD

Recent research has increasingly highlighted the therapeutic potential of plant-derived phytochemicals in the management of cardiac hypertrophy. These bioactive compounds exert cardioprotective effects by reducing oxidative stress, inhibiting lipoprotein oxidation and promoting vasodilation through scavenging of free radicals. Notably, sulphur-containing phytochemicals are potent activators of Nrf2, a master regulator of antioxidant defenses (Zhao et al., 2020). Traditional Chinese medicines such as Celastrol, Qingda granule, Ginseng, and Ginkgo biloba have been extensively investigated for their cardioprotective effects. These botanicals contain diverse phytochemicals that target multiple molecular pathways involved in hypertrophic remodeling, including oxidative stress, inflammation, and fibrosis. Preclinical models of pressure overload and metabolic stress have demonstrated their ability to attenuate maladaptive hypertrophy and preserve cardiac function. also been made in clinical research.

Among these agents, Ginseng, is the most clinically investigated, with 134 registered cardiovascular trials between 2002 and 2017 (He et al., 2018). These studies examined efficacy, dosing, and safety, and preclinical work further supports its potential in reducing hypertrophy and dysfunction. However, direct evidence of ginseng’s efficacy in cardiac hypertrophy remains under active investigation. Most trials were small-scale (<100 participants), short in duration (4–12 weeks), and single-center in design. There was marked heterogeneity in trial design, including differences in ginseng species, extraction methods, formulations, and target conditions complicates data interpretation. Furthermore, only one-third of trials advanced to Phase III–IV, with the majority remaining early-phase (0–II), limiting their ability to establish robust clinical evidence. Industry involvement was relatively low, with most trials funded by nonindustrial sources, raising concerns about scalability and long-term translation. To advance phytochemicals toward clinical application, larger, rigorously designed multicenter Phase III–IV trials with standardized preparations and consistent dosing are essential. Such trials would establish robust evidence for safety and efficacy, bridging current translational gaps (He et al., 2018).

Beyond ginseng, several plant derived compounds show promise in modulating key pathogenic pathways such as the renin–angiotensin system, hypertrophy, and vascular remodeling (Shaito et al., 2020). Collectively, phytochemicals represent a cost-effective, multitargeted and potentially safer adjunct to conventional therapies. While their clinical role remains complementary at present, ongoing advances in formulation science and personalized medicine may enhance their therapeutic impact (Wang et al., 2025). Overall, plant-based therapies offer an exciting avenue for cardiovascular disease management. Continued translational research is essential to optimize their use from bench to bedside, potentially expanding the therapeutic landscape for cardiac hypertrophy and heart failure (Table 2).

Table 2.

Plant-based phytochemicals in preclinical cardiac hypertrophy.

Drug	Mechanism/Pathway	Effects	Progress
Calanus oil, Flaxseed lignans, Qingda granule	Prevents pathological heart changes by reducing interstitial collagen deposition and ROS by targeting PI3K-Akt-mTOR pathway.	Reduces cardiac hypertrophy by targeting oxidative stress and myocardial remodeling pathways.	Pre- clinical (Cheng et al., 2021; Abdellatif et al., 2023; Elsayed et al., 2023)
Amydrium sinense water extract (ASWE)	Blocks NF-κB signaling by preventing p65 nuclear translocation and degradation.	Suppresses inflammation and reverses isoproterenol-induced cardiac hypertrophy.	Pre-clinical (Wu et al., 2024)
Parkia speciosa Hassk.	Exerts antihypertrophic effect by inhibiting the MAPK and calcineurin–NFATC3 pathways.	Reduces cardiac hypertrophy and oxidative stress.	Pre-clinical (Mustafa et al., 2022)
Celastrol	Binds to STAT3, inhibiting its phosphorylation and nuclear translocation.	Reduce cardiac hypertrophy and fibrosis.	Pre-clinical (Ye et al., 2020)
Thymoquinone	Activates adaptive autophagy via the PPAR-γ/14-3-3γ signaling axis.	Decreases ROS, and hypertrophic markers to improve cardiac function.	Pre- clinical (Qiu et al., 2025)
Ginseng	Inhibits the NHE-1 mediated Ca2+ influx and calcineurin-NFAT signaling pathway.	Prevent cardiac hypertrophy and heart failure.	Preclinical/Clinical(Guo et al., 2011)
Dohongsamul-tang	Inhibits the calcineurin/NFATc4 and TGF-β/Smad2 signaling pathways.	Reduces cardiac hypertrophy and fibrosis.	Pre-clinical (Hong et al., 2024)
Astragaloside IV (AS-IV)	Reduces the expression of CCL2, inflammatory cytokine via NF-κB signaling.	Decreases the production of proinflammatory cytokines, protects the heart from hypertrophy.	Pre- clinical (Chai et al., 2024)
Nelumbo nucifera Gaertn, Resveratrol	Inhibits AT1R signaling, through downregulation of NOX2/4 and nuclear translocation factor of NF-κB.	Reduces ROS production and hypertrophic gene expression.	Pre-clinical (Cho et al., 2019; Ma et al., 2023)
Loganin	Prevents cardiac fibrosis by interstitial collagen buildup and inflammation via JAK2/STAT3 and NF-κB pathway.	Reduces hypertrophy, fibrosis and inflammation.	Pre-clinical (Xu et al., 2021)
Ginkgo biloba	Attenuates hypertrophy by activating the M2 receptor and (eNOS) pathway.	Restores the autonomic balance and prevents pathological cardiac remodeling.	Pre-clinical (Mesquita et al., 2017)

5. RNA-based therapies

Recent advancements in RNA-based therapies have opened a new era of precision medicine, offering highly specific and adaptable strategies for a wide spectrum of diseases, including cardiovascular disorders and emerging infections such as COVID-19 (Boada et al., 2021). The unprecedented success of messenger RNA (mRNA)-based vaccines during the COVID-19 pandemic has exemplified the scalability and effectiveness of RNA technologies in real-world clinical applications (Fang et al., 2022). In cardiovascular medicine, mRNAs serve therapeutic functions by encoding beneficial proteins critical for normal cardiac function. RNA-based intervention in HCM works by targeting disease-causing mutations or modulating maladaptive signaling (Carrier, 2024). In pathological hypertrophy, these strategies would likely focus on downstream pathways common to pressure or volume overload. Beyond mRNAs, non-coding RNAs (ncRNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), small Cajal body-associated RNAs (scaRNAs), transfer RNA-derived fragments (tsRNAs), and circular RNAs (circRNAs) have emerged as critical regulators and therapeutic targets in cardiac hypertrophy. It has been shown that miRNAs provide novel molecular insight and new therapeutic strategies to treat cardiovascular diseases, including HCM (Samanta et al., 2016). For instance, miR-26a-5p has been shown to inhibit cardiomyocyte hypertrophy by suppressing A disintegrin and metalloprotease (ADAM17), thereby reducing downstream pathological signaling pathways and improving cardiomyocyte function (Shi et al., 2021). Therapeutic strategies include antisense oligonucleotides (ASOs) that selectively silence pathogenic miRNAs, and miRNA mimics that restore protective ones. These approaches have shown efficacy in disease models, including primary cardiomyocyte cultures and induced pluripotent stem cell (iPSC)-derived cardiomyocytes (Laggerbauer and Engelhardt, 2022).

RNA interference (RNAi) techniques using shRNAs also provide insights into mitochondrial dysfunction. For example, silencing OPA1 in H9C2 cells has revealed mechanisms linking metabolic stress to apoptosis and energy failure in the hypertrophic state (Tu et al., 2024). Additionally, scaRNA20 plays a pivotal role in cardiomyocyte differentiation by modulating the RNA splicing machinery, offering new avenues for cardiac repair and regeneration (Perales et al., 2024). Similarly, tsRNAs have emerged as novel modulators of myocardial hypertrophy, influencing cardiac performance and potentially mediating epigenetic inheritance across generations (Shen et al., 2018). Effective delivery is a major challenge in RNA-based therapies. Advanced delivery vehicles, including lipid nanoparticles, chemically modified oligonucleotides, viral vectors, and small extracellular vesicles (sEVs) have been employed to enhance stability, tissue targeting, and bioavailability. For example, siRNAs delivered via sEVs have successfully modulated inflammatory and injury-related pathways in cardiac disease models (Katzmann et al., 2022). Recent studies have constructed competing endogenous RNA (ceRNA) networks involving lncRNAs, miRNAs, and mRNAs to map the regulatory hierarchies in hypertrophy, fibrosis, and inflammation. These networks provide a deeper understanding of post-transcriptional regulation and reveal novel therapeutic targets in heart failure and cardiac remodeling (Wang et al., 2019). A comprehensive summary and overview of major RNA-based strategies, their molecular targets, mechanisms of action, and stage of development are summarized (Table 3). Collectively, RNA therapeutics represent a paradigm shift in the management of cardiac hypertrophy, moving beyond symptom control to address the root molecular causes of disease. The calcium upregulation by percutaneous administration (CUPID) trials (CUPID-1 and CUPID-2) were phase 1/2 and phase 2b designed to assess the safety and efficacy of adeno-associated virus (AAV1)/sarcoplasmic endoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy in patients with advanced heart failure (New York Heart Association class III or IV). The trials used recombinant AAV1 vector to deliver the SERCA2a gene directly to the myocardium via intracoronary infusion. The goal is to increase the expression of SERCA2a protein in cardiomyocytes, thereby maintaining normal cardiac contractility and relaxation. CUPID Phase 1/2a results indicate a dose-dependent improvement. The Phase 2b did not meet primary endpoints (Greenberg et al., 2014, 2016). The negative results from the CUPID trials emphasize the continued need for innovative therapies in heart failure. As clinical trials progress, validation of their safety, efficacy, and optimal dosing regimens will be critical. These innovative tools have the potential to revolutionize cardiovascular therapy by enabling personalized, mechanism-based interventions that target specific pathways involved in hypertrophy, fibrosis, and cardiac dysfunction.

Table 3.

Recent advances in RNA-Based therapies for cardiac hypertrophy.

RNA			Therapeutic use	Pathway/Mechanism	Progress
Coding RNA	mRNA	Pip4k2c	Attenuates cardiac hypertrophy and fibrosis.	Inhibits mTORC1 and TGF-β1 signaling via Pip5k1a, phospho-AKT1/2/3, and phospho-Smad3.	Preclinical (Magadum et al., 2021)
		LTBP2	Knockdown reduces cardiac hypertrophy, fibrosis, and apoptosis.	Regulates NF-κB signaling and oxidative stress pathways.	Preclinical (Wang et al., 2024)
		IGF-1	Promotes cardiomyocyte survival and mediates physiological hypertrophy.	Activates IGF1-PI3K-AKT signaling pathway.	Preclinical (Bass-Stringer et al., 2021)
		YAP(mutated aYAP)	Promotes adaptive hypertrophy and survival	Downstream effector of Hippo pathway.	Preclinical (Byun et al., 2019)
		SERCA2a (ATP2A2)	Enhances cardiac contractility; reduces hypertrophy.	Regulates calcium handling via sarcoplasmic reticulum.	Clinical trials (including CUPID trials) (Lyon et al., 2020)
Non-coding RNA	miRNA	miR-1, miR-133a	Promotes anti-hypertrophic effects.	Targets and downregulates calcineurin/NFATC3, mitochondrial Ca2+ uniporter pathways	Preclinical (Dong et al., 2010; Deng et al., 2014)
		miR-10a	Promotes anti-hypertrophic effects.	Downregulates the expression of T-box5.	Preclinical (Wang et al., 2017a)
		miR- 672, miR-139-5p	Reduces cardiac hypertrophy.	Targets c-Jun expression.	Preclinical(Lu and Wu, 2018; Ming et al., 2018)
		miR- 135b	Inhibits cardiac hypertrophy	Overexpression downregulates CACNA1 mRNA.	Preclinical (Chu et al., 2018)
		miR- 142p	Inhibits cardiac hypertrophy	Overexpression inhibits SH2B1.	Preclinical (Liu et al., 2018a)
		miR- 150	Inhibits cardiac hypertrophy	Overexpression of inhibits p300.	Preclinical(Duan et al., 2013)
	lncRNA	Mhrt	Protective against CH	Antagonizes Brg1, regulates chromatin remodeling.	Pre-clinical (Mhrt-KI mice, TAC) (Xu et al., 2020)
		Chaer	Protective; inhibition prevents hypertrophy.	Blocks PRC2 binding, modulates epigenetic stress responses.	Pre-clinical (Chaer-KO mice, TAC) (Wang et al., 2016)
		DACH1	Harmful; silencing restores cardiac function	Increases SERCA2a ubiquitination, impairs calcium handling.	Pre-clinical (Ad-siRNA in mice, TAC) (Cai et al., 2019)
		Plscr4	Protective; overexpression reduces hypertrophy	Regulates miR-214/Mfn2 axis to preserve mitochondrial dynamics.	Pre-clinical (AAV9 mice, Ang-II) (Lv et al., 2018)
		SNHG1	Protective; overexpression inhibits hypertrophy	Modulates miR-15a-5p/HMGA1 axis.	Pre-clinical (pcDNA in vitro, PE) (Yan et al., 2020)
		ROR	Harmful; silencing restores cardiac function	Downregulates miR-133, activates calcineurin pathway	Pre-clinical (in vitro, PE) (Jiang et al., 2016)
	circRNA	circNfix	Inhibits CM proliferation and angiogenesis	Sponges miR-214; degrades Ybx1 to inhibit cyclins	Preclinical (Huang et al., 2019)
		MFACR	Promotes CM apoptosis post-MI	Sponges miR-652-3p; upregulates MTP18 (mitochondrial fission)	Preclinical (Wang et al., 2017b)
		circFndc3b	Promotes neovascularization post-MI	Binds FUS to activate VEGF signaling	Preclinical (Garikipati et al., 2019)
		circHIPK3	CM proliferation and survival	Sponges miR-124-3p/miR-133a; regulates Notch1	Preclinical (Si et al., 2020)
	scaRNA	scaRNA20	Regulation of cardiomyocyte differentiation.	RNA splicing	Preclinical (Perales et al., 2024)
	tRNA	tRNA	Regulators in myocardial hypertrophy and cardiac efficiency	Cardiomyocyte hypertrophic pathways	Preclinical (Shen et al., 2018)
	siRNA	siRNA	sEVs modulate cardiac inflammation by targeting key pathways	Targets inflammatory mediators and cell injury signaling pathways	Preclinical (Katzmann et al., 2022)
	shRNA	shRNA	Targets mitochondrial fusion protein OPA1	Knockdown OPA1 gene	Preclinical (Tu et al., 2024)
	ceRNA	ceRNA	Regulates gene expression related to hypertrophy, fibrosis, inflammation, programmed cell death	Systems analysis reveals key regulators of heart failure progression.	Preclinical (Wang et al., 2019)
	ASO	ASO	Silences specific miRNAs or target mRNAs to modify gene expression	ASOs or fragments may trigger RNAi, promoting mRNA degradation via RISC.	Clinical phase I (Laggerbauer and Engelhardt, 2022)

6. Stem cell therapy

Stem cell therapy has emerged as a promising approach for treating cardiovascular diseases, including cardiac hypertrophy, by promoting tissue regeneration, modulating inflammation, and enhancing vascular function. However, its clinical application remains limited due to persistent challenges such as poor retention, low survival rates, and inefficient engraftment in the hypertrophied myocardium. These limitations collectively reduce its long-term therapeutic efficacy. To overcome these limitations, exosomes- small extracellular vesicles secreted by stem cells and other cell types, have gained attention as a promising cell-free therapeutic alternative (Bei et al., 2017; Mani et al., 2023). These nano-sized vesicles encapsulate bioactive molecules, including miRNAs, proteins and lipids that mimic the paracrine effects of stem cells while minimizing risks such as immune rejection, tumorigenicity, and vascular occlusion (Jayaraman et al., 2021). For instance, engineered exosomes enriched with miR-148a or circ_0018553 have shown therapeutic efficacy in modulating hypertrophic pathways by targeting GP130 and sirtuin 2 (SIRT2), respectively (Mao et al., 2022; Hu et al., 2025). Technological advances including heart-targeting peptides and gene-editing strategies, have improved the specificity and potency of exosome-based therapies (Jayaraman et al., 2021). Together, these innovations underscore the potential of exosomes as a safe, non-cellular therapeutic modality for mitigating cardiac hypertrophy and preventing its progression to heart failure. However, standardized protocols for isolation, characterization, dosage and regulatory compliance remain to be established, representing key barriers to clinical translation. Table 4 states the ongoing clinical trial for generating patient-specific cardiomyocytes from hiPSCs, which supports the transition from population-based drug selection to precision therapy, potentially overcoming the variable and often incomplete reversal of hypertrophy seen with classical pharmacological treatments.

Table 4.

Comprehensive Summary of Ongoing clinical trials in High-risk cardiac hypertrophy The following studies are available in https://clinicaltrials.gov/.

Clinical Trial Title	Study Population	Objective	Results	Status/Phase
Factors Contributing to Increased Left Ventricle Size in Patients with Abnormally Enlarged Hearts	Individuals with sarcomeric mutations and LVH	Assess the role of IGF-I and IGFBP-3 in LV mass increase in HCM	Identified beta-cardiac myosin, alpha-tropomyosin, and cardiac troponin T mutations, linking them to HCM (Thierfelder et al., 1994; Rayment et al., 1995).	National Institutes of Health (NIH) Completed (NCT00001878)
Derivation of Human iPS Cells to Heritable Cardiac Arrhythmias	Patients and family members with inherited arrhythmias	Generate patient-specific hiPSCs and model arrhythmias	Generation of cardiomyocytes from hiPSCs for disease modeling and therapeutic testing (Expected outcome)	Johns Hopkins University Phase I (NCT02413450)
Cardiac Allograft Remodeling and Effects of Sirolimus (CAR)	Heart transplant recipients	Assess Sirolimus impact on cardiac allograft remodeling	mTOR inhibitions are associated with reduced progression of cardiac allograft vasculopathy (Expected outcome)	University of Nebraska Terminated (Phase I)
Individualized Early Risk Assessment for Heart Diseases (IndivuHeart)	Healthy volunteers (18–60 yrs)	Develop a patient-specific EHT assay for heart disease risk	The study established a platform for individualized cardiac risk assessment using hiPSC-EHTs, and classical drugs are tested in EHT (Hansen et al., 2010).	Univ. Med. Center Hamburg-Eppendorf Completed (NCT02417311)
CUPID 2: Gene Therapy in Heart Failure	Patients with heart failure	Test AAV1/SERCA2a gene therapy in heart failure	The CUPID 2 trial for AAV1/SERCA2a gene therapy in heart failure patients did not demonstrate an improvement in the clinical course (Greenberg et al., 2014).	Celladon Corp. & Duke Clinical Research Institute Phase 2b

7. Clinical application of medical devices in hypertrophic cardiomyopathy

In HCM, medical devices play a crucial role in managing disease progression and preventing adverse outcomes such as sudden cardiac death (SCD). Among these, implantable cardioverter-defibrillators (ICDs) are the gold standard for detecting life-threatening ventricular arrhythmias, delivering timely electrical shocks or pacing to restore normal rhythm (Trivedi and Knight, 2016). ICDs are particularly indicated in patients with a history of fainting, ventricular tachyarrhythmias, or a family history of SCD. For patients with end-stage heart failure secondary to longstanding hypertrophic ventricular assist devices (VADs) provide mechanical circulatory support, improving cardiac output, functional capacity, and survival (Garbade et al., 2011; Rodriguez et al., 2013). These devices may also serve as bridges to transplantation or destination therapy in ineligible transplant candidates. Additionally, cardiac resynchronization therapy (CRT) benefits HCM patients with dyssynchronous ventricular contraction and systolic dysfunction, enhancing ventricular coordination and reducing myocardial workload. The strategic integration of these devices into patient-specific treatment algorithms significantly improves quality of life, exercise tolerance, and long-term prognosis.

8. What do pre-clinical studies tell us?

Preclinical research continues to lay the foundation for innovative therapeutic strategies against cardiac hypertrophy by enabling mechanistic exploration and efficacy testing under controlled conditions. Exosome-based therapies have emerged as potent alternatives to stem cell transplantation, leveraging paracrine signaling without the complications associated with cellular therapies (Mani et al., 2023). Studies comparing delivery routes, such as intracoronary versus trans-endocardial injection, aim to optimize cellular engraftment, therapeutic retention and functional cardiac recovery (Golpanian et al., 2016; Banerjee et al., 2018). Meanwhile, RNA-based therapies offer transient, controllable gene modulation and the ability to simultaneously target multiple pathological pathways (Laina et al., 2018). These include delivery of mRNA, siRNA, and miRNA mimics or inhibitors to cardiomyocytes in animal models of hypertrophy. While promising, these therapeutic strategies remain in the preclinical phase, requiring further validation through toxicology, biodistribution, and efficacy studies before advancing to human trials. Ongoing efforts focus on optimizing formulation, improving targeting specificity, and ensuring reproducibility and scalability for eventual clinical translation.

9. Challenges in stem cell therapy

Despite encouraging preclinical outcomes, several challenges hinder the clinical translation of emerging therapies for cardiac hypertrophy. For instance, while natural product-derived compounds have shown efficacy in modulating hypertrophic signaling, they require rigorous clinical validation to confirm safety, optimal dosing, and long-term efficacy (Zhao et al., 2020). Stem cell-based therapies, though promising, face barriers such as poor engraftment, heterogeneity in patient response, immune incompatibility, and concerns regarding arrhythmogenicity. Many clinical trials have yielded modest or inconsistent outcomes, largely due to variability in cell type, delivery method, and timing of administration. Nearly two decades of research and more than 200 clinical trials have established the safety of various cell types, but their therapeutic efficacy remains debatable (Banerjee et al., 2018). Overcoming these challenges will require improved trial designs, deeper mechanistic insights, and more refined patient stratification strategies. Advances in biomaterial scaffolds, 3D bioprinting, and genome editing may further enhance the therapeutic potential of regenerative interventions.

10. Future directions

The future of cardiac hypertrophy management lies in the integration of gene editing technologies, artificial intelligence, and digital health platforms to achieve personalized, predictive, and preventive care. Tools such as CRISPR/Cas9, base editors, and prime editors are under active investigation for their ability to correct pathogenic gene mutations underlying hypertrophic conditions. Integration of machine learning (ML) and artificial intelligence (AI) is poised to revolutionize diagnostics and treatment planning. These technologies enable early risk stratification, automated image analysis, and personalized therapy optimization, thereby improving clinical outcomes and reducing healthcare costs. According to a review by Javaid et al., by 2032, cardiovascular care is expected to be fully integrated into digital health ecosystems, where ML-driven insights will guide continuous and individualized prevention strategies. Efforts are also underway to formalize preventive cardiology as a subspecialty, emphasizing early intervention, lifestyle modification, and risk-based monitoring. Future directions will prioritize the translation of preclinical findings into successful clinical interventions, grounded in precision medicine and multidisciplinary collaboration.

11. Conclusions

The management of cardiac hypertrophy is undergoing a paradigm shift—from generalized, symptom-focused interventions to multimodal, mechanism-based therapies tailored to individual molecular profiles. Innovations in stem cell biology, RNA therapeutics, natural products, medical devices, and AI-driven tools are converging to offer more durable, safe, and effective treatments. The success of this transition will hinge on sustained interdisciplinary collaboration across molecular cardiology, bioengineering, clinical sciences, and regulatory frameworks. As these novel strategies advance through the research pipeline, they promise to redefine cardiovascular care and significantly improve patient outcomes.

Glossary

AAV1

Adeno-associated Virus 1

HCM

Hypertrophic cardiomyopathy

Ang I

Angiotensin I

Ang II

Angiotensin II

AT1R

Angiotensin Type 1 Receptor

AT2R

Angiotensin Type 2 Receptor

AI

Artificial Intelligence

RAS

Renin- angiotensin system

AMPK

AMP-Activated Protein Kinase

ASO

Antisense Oligonucleotide

Class III PI3K

Class III Phosphoinositide 3-Kinase

PI3P

Phosphatidylinositol 3-phosphate

Class I PI3K

Class I Phosphoinositide 3-Kinase

PIP2

Phosphatidylinositol 4,5-bisphosphate

PIP3

Phosphatidylinositol (3,4,5)-trisphosphate

ARB

Angiotensin Receptor Blocker

ACE

Angiotensin-Converting Enzyme

CCB

Calcium converting enzyme

AVP

Arginine Vasopressin

ceRNA

Competing Endogenous RNA

circRNA

Circular RNA

DAG

Diacylglycerol

eNOS

Endothelial Nitric Oxide Synthase

EHT

Engineered heart tissue

GSK3β

Glycogen Synthase Kinase 3 Beta

ICD

Implantable Cardioverter-Defibrillator

IGFBP-3

Insulin-like Growth Factor-Binding Protein-3

IP3

Inositol 1,4,5-Trisphosphate

JAK/STAT

Janus Kinase / Signal Transducer and Activator of Transcription

LV

Left Ventricle

LVH

Left Ventricular Hypertrophy

MAPK

Mitogen-Activated Protein Kinase

Mas

Mas Receptor

ML

Machine learning

miRNA

MicroRNA

mRNA

Messenger RNA

MrgD

Mas-related G Protein-Coupled Receptor D

mTOR

Mechanistic Target of Rapamycin

NF-κB

Nuclear Factor Kappa B

NFAT

Nuclear Factor of Activated T Cells

NO

Nitric Oxide

NOX

NADPH Oxidase

PAQR3

Progestin and AdipoQ Receptor Family Member 3

PDK4

Pyruvate Dehydrogenase Kinase 4

PI3K

Phosphoinositide 3-Kinase

PKC

Protein Kinase C

PLC

Phospholipase C

pre-miRNA

Precursor microRNA

RISC

RNA-Induced Silencing Complex

RNAi

RNA Interference

ROS

Reactive Oxygen Species

sEVs

Small Extracellular Vesicles

SERCA2a

Sarco/endoplasmic reticulum calcium ATPase 1

siRNA

Small Interfering RNA

scaRNA20

Small Cajal bodies associated RNA 20

SNS

Sympathetic Nervous System

STAT

Signal Transducer and Activator of Transcription

TGF-β

Transforming Growth Factor Beta

TRPC

Transient Receptor Potential Canonical Channel

tsRNA

tRNA-derived Small RNA

VAD

Ventricular Assist Device

VEGF

Vascular Endothelial Growth Factor

YAP

Yes-Associated Protein

ASO

Anti-sense oligonucleotide

ceRNA

Competing Endogenous RNA

Data availability

No data was used for the research described in the article.