Cardiac Memory and Remodeling as dual Pathways of Cardiac Adaptation and Disease; A Natural Approach to Enhancing Cardiac Memory and Preventing Remodeling

Cardiac Memory and Remodeling as dual Pathways of Cardiac Adaptation and Disease; A Natural Approach to Enhancing Cardiac Memory and Preventing Remodeling | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 May 2025 V1 Latest version Share on Cardiac Memory and Remodeling as dual Pathways of Cardiac Adaptation and Disease; A Natural Approach to Enhancing Cardiac Memory and Preventing Remodeling Author : Mohamed Ahmed [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174823396.62816093/v1 303 views 107 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Cardiac memory and remodeling represent two interrelated distinct electrophysiological and structural processes that underlie both adaptive and maladaptive responses of the heart to stress. While cardiac memory involves persistent alterations in repolarization patterns following abnormal activation, cardiac remodeling encompasses molecular, cellular, and architectural changes that can ultimately lead to heart failure and arrhythmia. Recent scientific interest has turned toward the potential of natural or herbal remedies to modulate these processes. Several plant-derived compounds---such as flavonoids, saponins, alkaloids, and polyphenols from herbs like Green tea, Nigella sative, Hypericum perforatum, Ginkgo biloba, Cinnamon, Hawthorn, Bacopa monnieri, and Curcuma longa, have shown promising effects in preserving electrical stability and preventing pathological remodeling. These botanicals may act by stabilizing calcium and potassium ion channels, reducing oxidative stress, improving mitochondrial function, and attenuating pro-fibrotic signaling cascades. This review explores the dual nature of cardiac memory and remodeling as both compensatory and pathological pathways, and discusses how these natural remedies may enhance cardiac memory for therapeutic benefit while inhibiting deleterious remodeling processes. Cardiac Memory and Remodeling as dual Pathways of Cardiac Adaptation and Disease; A Natural Approach to Enhancing Cardiac Memory and Preventing Remodeling Mohamed Ahmed [email protected] Faculty of Veterinary Medicine, Cairo University Department of Pharmacology Address: Giza 12918, badrachin main street Tel:+201150325445 Cardiac memory and remodeling represent two interrelated distinct electrophysiological and structural processes that underlie both adaptive and maladaptive responses of the heart to stress. While cardiac memory involves persistent alterations in repolarization patterns following abnormal activation, cardiac remodeling encompasses molecular, cellular, and architectural changes that can ultimately lead to heart failure and arrhythmia. Recent scientific interest has turned toward the potential of natural or herbal remedies to modulate these processes. Several plant-derived compounds—such as flavonoids, saponins, alkaloids, and polyphenols from herbs like Green tea, Nigella sative, Hypericum perforatum, Ginkgo biloba, Cinnamon, Hawthorn, Bacopa monnieri, and Curcuma longa, have shown promising effects in preserving electrical stability and preventing pathological remodeling. These botanicals may act by stabilizing calcium and potassium ion channels, reducing oxidative stress, improving mitochondrial function, and attenuating pro-fibrotic signaling cascades. This review explores the dual nature of cardiac memory and remodeling as both compensatory and pathological pathways, and discusses how these natural remedies may enhance cardiac memory for therapeutic benefit while inhibiting deleterious remodeling processes. Keywords: Cardiac memory, Cardiac remodeling, Ion channel modulation, Oxidative stress, Mitochondrial function, Anti-fibrotic pathways, and Herbal remedies. Introduction The heart exhibits remarkable plasticity in response to physiological and pathological stimuli, primarily through two interconnected adaptive processes: cardiac memory and cardiac remodeling. Cardiac memory, first observed as a T-wave alteration following transient ventricular pacing, refers to the heart’s capacity to ”remember” abnormal electrical activation and retain changes in repolarization patterns even after normal conduction is restored [1]. Cardiac memory is not merely a transient change in electrocardiographic (ECG) patterns such as T-wave inversion or altered repolarization following abnormal ventricular activation, but rather reflects deeper molecular and structural adaptations within the myocardium. These adaptations persist even after normal electrical activation is restored, indicating that the heart undergoes long-term cellular remodeling in response to prior electrical activity [2-4]. In contrast, cardiac remodeling encompasses a spectrum of structural and functional myocardial alterations—ranging from myocyte hypertrophy and apoptosis to interstitial fibrosis and chamber dilation—primarily triggered by hemodynamic overload, neurohormonal activation, or myocardial injury [5-8]. Although remodeling initially serves a compensatory role, its chronic progression contributes to maladaptive outcomes, including heart failure and sudden cardiac death [9, 10]. Importantly, emerging evidence supports the fact that electrical remodeling (including cardiac memory) and structural remodeling are not isolated events but represent parallel, mutually reinforcing pathways in the evolution of cardiac pathology. The interplay between cardiac memory and remodeling is orchestrated by complex signaling networks involving ion channel expression, calcium handling, oxidative stress, extracellular matrix remodeling, and inflammatory mediators [11]. Ion channel remodeling, particularly involving L-type Ca²⁺ channels, K⁺ channels (I_to, I_Kr), and connexins, underlies many of the electrophysiological changes seen in both cardiac memory and arrhythmogenic remodeling [12, 13]. Concurrently, cytokines (e.g., TNF-α, IL-6), matrix metalloproteinases (MMPs), and fibrotic pathways driven by transforming growth factor-beta (TGF-β) contribute to adverse structural remodeling [14]. Given the dual nature of these processes—protective in the short term but harmful when sustained—there is growing interest in therapeutic strategies that can harness adaptive features while mitigating maladaptive outcomes. In this regard, natural compounds and phytotherapeutic agents have gained attention for their potential to modulate molecular pathways involved in both cardiac memory and remodeling, offering a holistic and multi-targeted approach [15-17]. These compounds may support the enhancement of beneficial cardiac memory while concurrently suppressing the transition to pathological remodeling, representing a promising frontier in Neurocardiologic health. Figure 1. shows the interconnected physiological processes Methodology 1. Search Strategy A comprehensive literature search will be conducted across major scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. The search will include peer-reviewed articles, clinical trials, and systematic reviews. Keywords will include combinations of the following terms: herbal remedies, cardiac memory, cardiac remodeling, flavonoids, saponins, alkaloids, polyphenols, Green tea, Nigella sativa, Hypericum perforatum, Ginkgo biloba, Cinnamon, Hawthorn, Bacopa monnieri, and Curcuma longa. Boolean operators (AND, OR) will be used to optimize search sensitivity and specificity. 2. Inclusion and Exclusion Criteria Inclusion Criteria: Studies evaluating the effects of herbal compounds on cardiac memory and remodeling. Experimental studies on in vitro and in vivo studies Articles published in English. Studies that detail the mechanisms involving calcium and potassium ion channels, oxidative stress reduction, mitochondrial function enhancement, or anti-fibrotic effects. Exclusion Criteria: Review articles, opinion papers, and editorials. Studies not focused on cardiac-related outcomes. Non-English publications. Studies without detailed experimental data or mechanistic insights. Interplay Between Cardiac Memory and Remodeling Cardiac memory and remodeling are interconnected physiological processes that reflect the heart’s response to abnormal stimuli. While cardiac memory is traditionally considered an electrophysiological phenomenon marked by persistent changes in repolarization following altered activation, cardiac remodeling encompasses broader molecular, cellular, and structural adaptations in response to stress or injury. Increasing evidence suggests that these processes do not occur in isolation but influence each other through shared signaling pathways and functional consequences. One key aspect of cardiac memory is the remodeling of ion channel expression, which modifies cardiac excitability and conduction. A hallmark change is the reduction in the transient outward potassium current (I_to), primarily due to downregulation of the Kv4.3 channel and its auxiliary subunit KChIP. This leads to prolonged action potential duration and persistent T-wave abnormalities on electrocardiograms, even after the cessation of abnormal electrical activation [18]. Such electrical alterations are reinforced by modifications in L-type calcium channels (I_Ca,L), which demonstrate altered activation/inactivation kinetics in cardiac memory, affecting intracellular calcium dynamics and promoting arrhythmogenic potential [19]. Further, the decrease in the delayed rectifier potassium current (I_Kr), associated with reduced expression of the hERG channel prolongs the repolarization phase and raises susceptibility to arrhythmias [19]. Additionally, cardiac memory is characterized by remodeling of gap junctions, notably the altered expression and lateralization of Connexin43 (Cx43), which impairs electrical coupling between cardiomyocytes and creates a substrate for conduction abnormalities [20]. Simultaneously, the process of cardiac remodeling is initiated, involving a broader spectrum of molecular changes that mirror and compound the alterations seen in cardiac memory. For example, the PI3K/Akt/mTOR pathway, which regulates hypertrophic signaling, plays a role in both adaptive and maladaptive remodeling. While initially protective, its dysregulation contributes to pathological hypertrophy and cardiac dysfunction [21]. Moreover, oxidative stress and mitochondrial dysfunction—both outcomes of chronic myocardial stress—damage cellular components, diminish ATP production, and trigger apoptotic pathways, further impairing electrical and mechanical function [22]. Critically, abnormal calcium handling, which is central to both contractile function and electrophysiological stability, is altered in cardiac remodeling. Downregulation of SERCA2a and altered phospholamban activity reduce calcium reuptake into the sarcoplasmic reticulum, promoting diastolic dysfunction and afterdepolarizations that link remodeling back to arrhythmogenesis [23]. Taken together, cardiac memory and remodeling share overlapping signaling cascades, ion transport abnormalities, and inflammatory responses. This interplay creates a vicious cycle in which persistent electrical changes promote structural alterations, and vice versa. 1.Green tea Green tea, derived from the leaves of Camellia sinensis, has long been recognized for its numerous health benefits, including its cardioprotective and neuroprotective properties. Research has increasingly focused on the bioactive compounds found in green tea, such as catechins, flavonoids, and polyphenols, which exhibit potent antioxidant, anti-inflammatory, and cardioprotective effects. In one in vivo study, Epigallocatechin-3-gallate enhanced cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model [24]. Green tea extract (200 mg/kg orally via gavage daily for 21 days) reversed the sleep deprivation-induced reduction in PON1 and ARE levels in both the aorta (p = 0.046, p = 0.035) and the heart (p = 0.020, p = 0.019), indicating a recovery of antioxidant defenses. Additionally, it mitigated oxidative stress, as evidenced by reduced malondialdehyde (MDA) levels and improved nitric oxide metabolite (NOx) concentrations. Furthermore, the extract suppressed systemic inflammation by decreasing IL-6 and TNF-α levels [25]. Zhang et al. demonstrated that EGCG significantly improved cardiac function and myocardial morphology in heart failure (HF) rats by restoring left ventricular parameters and reducing myocardial damage. These effects were associated with downregulation of GRK2 membrane expression and upregulation of β1-AR expression, without changes in their total mRNA levels, suggesting a post-transcriptional mechanism [26]. Green tea (GT) reduced cardiac hypertrophy and improved heart function post-myocardial infarction (MI) in rats. It decreased oxidative stress markers (protein carbonyl), boosted Nrf-2, and restored antioxidant enzymes. GT also normalized energy metabolism and modulated extracellular matrix remodeling and apoptosis [27]. Following administration of green tea, rats exposed to a high-carbohydrate diet exhibited reversal of structural and functional cardiac abnormalities, such as elevated left ventricular mass, collagen deposition in the myocardium, stiffened diastolic function, and normalized plasma malondialdehyde levels [28]. Oral catechins treatment attenuated myocardial fibrosis and inflammation post-ischemia by suppressing NF-κB and MMPs, without adverse effects [29]. The cardioprotective agents EGCG, captopril, and losartan consistently reduced myocardial hypertrophy and cardiomyocyte apoptosis, although their regulatory actions on apoptosis-related proteins differed. Importantly, EGCG improved oxidative status, as indicated by diminished MDA content and enhanced SOD activity, and they also safeguarded telomere integrity by maintaining TRF2 expression. Conversely, captopril and losartan did not influence oxidative stress parameters or telomere-associated proteins [30]. Prevention of immune-mediated graft damage caused by suppressing NF-κB, fibrosis, and inflammatory infiltration through cytokine modulation was observed in murine cardiac transplants treated with Catechins [31]. EGCG and valsartan reduced cardiac collagen and ECM remodeling in TAC rats. EGCG also restored Th cell balance and modulated cytokines like IL-10 and IL-15 via STAT pathways [32]. Protection from doxorubicin (DOX)-induced cardiac remodeling due to green tea extract could achieved by enhancing heart function and reducing oxidative stress, and improving antioxidant enzyme activity and Top2-β expression, with no significant impacts in mitochondrial complex activities or inflammatory markers induced by DOX [33]. Anji white tea water soaking solution (AJWT, at 0.4–12.8 mg/ml of dry tea leaves) induced dose- and time-dependent vasorelaxation in multiple precontracted arteries, inhibited intracellular Ca²⁺ elevation, and downregulated the expressions of voltage-gated Ca2+ channels (VGCCs) and Kv currents, while EGCG, at equivalent concentrations, largely potentiated vascular contraction and enhanced Ca²⁺ influx [34]. Long-term administration of 100 or 200 mg EGCG mitigated aging-related cardiac dysfunction while protecting myocardial cells from apoptosis and mitochondrial damage. This effect may be linked to increased cTnI transcription and protein expression arising from the inhibition of histone deacetylase 1 (HDAC1) expression and activity, leading to reduced HDAC1 binding near the cTnI promoter, accompanied by increased levels of acetylated histone 3 (AcH3) and acetylated lysine 9 on histone H3 (AcH3K9) in aged mice [35]. In a randomized controlled trial, EGCG supplementation for 8 weeks led to significant reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) and an increase in the low-frequency (LF) to high-frequency power (HF) ratio (LF/HF ratio) among obese participants, indicating elevated sympathetic nervous system activity [36]. Calo et al. conducted a 6-month trial to evaluate the effect of GT treatment (1 g/day as a commercially available capsule) on cellular and plasma OxSt and proliferation related markers in 20 ESRD patients under chronic dialysis. Green tea therapy induced a downregulation of p22phox and pERK1/2, alongside an increase in HO-1, pointing to a shift toward antioxidant balance. LV mass was associated with elevated p22phox and oxLDL, both indicators of oxidative stress. GT treatment led to a significant reduction in LV mass, which was positively linked to oxLDL reduction. Of the nine patients with LV hypertrophy, five fully recovered and three showed partial regression, a change that was accompanied by favorable modulation of redox-sensitive markers [37]. Under high-glucose conditions (30 mM for 72 h), Cx43 protein levels were reduced, impairing cell-cell communication. EGCG reversed this effect in a dose- and time-dependent manner, although Cx40, Cx45, and Cx43 mRNA remained unaffected. EGCG (40 µM) also stimulated Erk, JNK, and p38 MAPK, with p38 inhibition (via SB203580) partially blocking its protective action. Therefore, EGCG preserves gap junction integrity during hyperglycemic stress, involving p38 MAPK signaling [38] (Table 1). Table 1. summarizes the cardioprotective effects of green tea 2. Nigella sativa Nigella sativa, commonly known as black seed or black cumin, has been utilized in traditional medicine for centuries. Its bioactive compound, thymoquinone (TQ), has garnered attention for its potential therapeutic properties, particularly in cardiovascular health. Nigella Sative oil (NSO), which contained linoleic acid (C18:2n-6) and oleic acid (C18:1n-9) as the predominant fatty acids, was shown to prevent QT and QTc interval prolongation and lower heart rate following MI over 28 days. The histological examination revealed significant enhancements in myofibrillary degeneration, necrosis, and inflammation. NSO treatment also led to a marked reduction in pro-inflammatory cytokines, particularly IL-1β and IL-6 in the NSO group. Additionally, NSO reduced pro-oxidant markers after 14 days, demonstrating its time-dependent antioxidant action [39]. The cardioprotective effects of TQ against myocardial ischemia-reperfusion (I/R) injury were investigated in Langendorff-perfused rat hearts. Animals pretreated with TQ prior to I/R exhibited enhanced cardiac function, reduced infarct size, lower levels of LDH and CK-MB, diminished oxidative stress and apoptosis, and increased autophagy, which was partially inhibited by chloroquine (CQ) [40]. Administered intraperitoneally at 10 mg/100 μl/kg, TQ given 20 minutes prior to coronary artery ligation significantly decreased infarct size and suppressed reperfusion-induced arrhythmias, including ventricular tachycardia and fibrillation, thereby demonstrating strong cardioprotective potential compared to vehicle-treated controls [41]. Al-Asoom et al. investigated how N. sativa supplementation influences structural and electrophysiological changes during exercise-induced cardiac hypertrophy in rats. The combination of N. sativa and endurance training led to enhanced heart weight and cardiomyocyte size without inducing fibrosis, while also improving ECG parameters such as lower heart rate and increased QRS amplitude, indicating a matched cardiac structural and electrical adaptation [42]. In a study on isolated rat hearts, Ghoreyshi et al. demonstrated that Nigella sativa postconditioning (Ns-PoC) mitigated ischemia-reperfusion injury by decreasing reactive oxygen species generation. The treatment improved hemodynamic indices such as left ventricular pressure (LVP) and rate pressure product (RPP), increased antioxidant enzyme activities, and lowered oxidative damage as shown by reduced MDA and 4-HNE levels [43]. Chronic oral treatment with TQ significantly enhanced peak myocardial tension, suggesting a positive inotropic effect, while other parameters such as relaxation time, flow rate, and heart size remained unchanged [44]. Rathod et al. reported that short-term thymoquinone treatment (5 mg/kg, i.p., every 4 hours for 2 days) effectively mitigated ISO-induced myocardial damage by improving left ventricular function, evident from reductions in elevated LV end-diastolic pressure and restoration of LVdP/dtmax and LVdP/dtmin. TQ also normalized cardiac enzyme levels, oxidative stress markers, and pro-inflammatory cytokines [45]. In rats exposed to prilocaine, there was a marked increase in neural and cardiac complications, such as cardiac arrhythmias and asystole at lower doses, accompanied by oxidative stress and inflammation in heart and brain tissues. TQ treatment counteracted these changes by restoring antioxidant capacity and inhibiting the overexpression of inflammatory markers such as NFκB-p65, and NFκB-p50 as well as AQP4 [46]. Moreover, TQ administration prior to ISP exposure resulted in restored myocardial architecture, decreased levels of cardiac biomarkers such as cTnI and LDH, oxidative and inflammatory mediators, inhibition of apoptosis, and preservation of cardiac mtDNA content [47]. TQ (5 and 10 mg/kg, ip) administration lowered MDA levels and enhanced SOD, CAT, and thiol activities in the heart and aorta of hypothyroid rats [48]. TQ significantly modified the electrical activity of cardiomyocytes by prolonging the action potential duration and reducing peak amplitude, primarily through inhibition of sodium current (INa) and transient outward potassium current (Ito). It also counteracted isoproterenol-induced and L-type calcium current (ICaL) enhancement, indicating a regulatory effect on β-adrenergic signaling relevant to cardiac hypertrophy and diabetic cardiomyopathy [49]. N. sativa extract (2–14 mg/mL) significantly reduced contractile responses in aortic rings via mechanisms involving intracellular calcium inhibition (evidenced by sensitivity to diltiazem and heparin) and potassium channel involvement (TEA sensitivity), while NO and prostaglandin pathways were not implicated [50]. By promoting the expression of cardioprotective proteins such as Cx43, HSP90, and HIF-1α, thymoquinone (10 mg/kg, i.p.) confers significant protection against MTX-induced myocardial damage, as demonstrated through histological evaluation [51] (Table 2). 3. Ginkgo Biloba Ginkgo biloba extract (GBE) has been shown to improve blood flow in various vascular beds, including cerebral and coronary arteries. This vasorelaxant activity is attributed to the potentiation of endothelial release of nitric oxide and prostanoids, as well as the blockage of calcium channels on vascular smooth muscle. These actions collectively enhance oxygen delivery to both brain and cardiac tissues. The flavonoids present in Ginkgo biloba possess antioxidant properties that help scavenge free radicals, thereby reducing oxidative stress. This reduction in oxidative stress protects myocardial cells from damage, contributing to improved cardiac function. In one in vivo study, ginkgo leaf extract, administered at 100 mg/kg daily, exerts anti-remodeling effects in both diabetic ApoE⁻/⁻ and viral myocarditis mouse models by repressing ER‑stress apoptosis and inflammatory cytokines (TNF‑α, IL‑6), and by downregulating profibrotic biomarkers such as TGF-β1, MMP-2, and MMP-9 mRNA levels [52-54]. Oral administration of 160 mg Ginkgo biloba extract (GBE) in healthy volunteers achieves plasma ginkgolide A (41.8 ng/mL), ginkgolide B (5.6 ng/mL), and bilobalide (37.6 ng/mL) concentrations and elicits concentration‑dependent vasorelaxation which is partially nitric oxide-dependent and calcium-sensitive, while bilobalide modulates cardiac ionic currents by enhancing Ca²⁺ and K⁺ conductances, in contrast to GBE, which inhibits them and prolongs action potential duration, notably ICa and IK [55]. Pretreatment of H9c2 cells with 10 µM GB significantly reduced Ang II‑induced increases in atrial natriuretic peptide (ANP) and β‑myosin heavy chain (β‑MHC) mRNA, while boosting autophagy, as evidenced by upregulated Beclin1 and downregulated P62, and restoring SIRT1 and FoxO1 protein levels [56]. Ginkgo biloba extract (GBS) at 50 mg/kg mitigates cyclosporine A (Cs-A)-induced cardiac injury by reducing oxidative stress, inflammation, and cardiac biomarkers (AST, ALT, LDH, troponin-I, IL-6, TNF-α) and by improving antioxidant levels (GSH, SOD, CAT), lipid profiles, and apoptosis-related proteins (Bcl-2), while modulating ERK1/2 and mTOR signaling pathways [57]. In rats with monocrotaline-induced right ventricular hypertrophy, treatment with 60 mg/kg of ginkgo biloba extract (EGB) significantly reduced right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVMI), TRPC6 expression, while improving myocardial structure and function compared to the MCT group, with notable decreases in oxidative stress and inflammatory markers [58]. The treatment of neonatal rat ventricular myocytes with Ginkgo biloba leaf extract (GBE50, 50 µg/mL) blocked LPS-induced TLR4/NF-κB signaling and reduced the expression of biomarkers such as angiotensinogen (ATG), AT1a receptor, and β-myosin heavy chain (β-MHC), contributing to the prevention of left ventricular remodeling [59]. Isoginkgetin (IGK, 10 mg/kg) treatment activated the Nrf2 signaling pathway in heart tissues, leading to increased Nrf2 nuclear translocation and the activation of antioxidant genes such as HO-1 and NQO1, ultimately protecting against obesity-induced cardiac diastolic dysfunction and mitochondrial defects in the heart tissues of the obese mice. Molecular docking and dynamics simulation assessments further demonstrated a strong binding interaction between IGK and the Nrf2/Keap1 complex [60] (Table 2). Table 2. summarizes the cardioprotective effects of Nigella sative and Ginkgo biloba. 4. Cinnamon Cinnamon, a widely used spice, has gained attention for its potential cardioprotective properties. Cinnamon contains several bioactive compounds such as phenolics and volatile compounds. Cinnamaldehyde and cinnamic acid are among the main cinnamon compounds that had protective effects on cardiovascular diseases through various molecular actions. A preclinical study demonstrated that oral administration of cinnamon extract prior to ischemia significantly decreased myocardial infarct size, stabilized ECG parameters including the ST segment, QTc interval, and R-wave amplitude, and optimized heart rate. Furthermore, it reduced ventricular arrhythmias and oxidative stress indicators while boosting antioxidant enzyme function [61]. The study by Zhang et al. examined how cinnamon polyphenols (CP) could treat diabetic cardiomyopathy (DCM) through changes in molecular signaling. Results showed CP regulated key biomarkers and gene expression, upregulating p-mTOR, p62, and PGC1α, and downregulating LC3II/LC3I, while improving myocardial energy balance [62]. Using a rat model of myocardial ischemia/reperfusion injury, HCA preconditioning at 50 mg/kg (administered intraperitoneally three times weekly for 2 weeks) enhanced cytosolic Bcl-2-associated athanogene 3 (BAG3) and Nrf2/HO-1 signaling, which in turn alleviated oxidative stress, decreased apoptotic and ferroptotic markers, and inhibited DRP1-driven mitochondrial fission [63]. The administration of cinnamon led to improvements in electrical conduction in elderly rats by regulating the QRS duration and Tpeak-Tend interval and alleviating oxidative stress in cardiac tissue [64]. Cinnamic acid treatment in Ang II-infused mice showed reduced hypertension and improved structural remodeling by lowering hypertrophy and fibrosis. Mechanistically, it inhibited mitochondrial oxidative stress and downregulated STAT3 and ERK1/2 signaling pathways activated by Ang II and IL-6 in cardiomyocytes [65]. In rats with cyclophosphamide-induced cardio-renal toxicity, treatment with cinnamaldehyde (90 mg/kg) and AdipoRon (25 mg/kg) led to reduced levels of creatine kinase–MB Isoenzyme (CK-MB), Lactate Dehydrogenase (Lactate Dehydrogenase), cardiac troponin I (cTnI), serum creatinine, and 8-OHdG, while simultaneously increasing GSH levels, Nrf2 expression, IL-10 production, and BCL2 expression [66]. In diabetic rats, treatment with cinnamon extract effectively mitigated cardiac injury by lowering CK-MB, AST, LDH, and the oxidative stress marker MDA; enhancing antioxidant enzyme activities; and downregulating the expression of angiotensin II type 1 receptor (AT1), atrial natriuretic peptide (ANP), beta-myosin heavy chain (β-MHC), and brain natriuretic peptide (BNP) [67]. Through whole‑cell patch‑clamp analysis, cinnamaldehyde was found to suppress L‑type Ca²⁺ channel activity in both ventricular and vascular smooth muscle cells, with a stronger inhibitory effect and greater differential inactivation observed in ventricular cardiomyocytes. This effect is partly attributable to the use of Ca²⁺ versus Ba²⁺ as the charge carrier [68]. In models of PE-induced cardiac hypertrophy, trans-cinnamaldehyde reduced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) signaling pathways and suppressed their nuclear entry. It also restored cardiomyocyte calcium dynamics by inhibiting ryanodine receptor type 2 (RyR2) and phospholamban (PLN) hyperphosphorylation [69] (Table 3). 5. Hawthorn (Crataegus spp.) Hawthorn ( Crataegus spp. ) is a medicinal plant widely recognized for its cardiovascular benefits. The bioactive components of hawthorn, such as flavonoids, oligomeric proanthocyanidins, and triterpenic acids, contribute to its cardioprotective effects. In a rat model of pressure overload-induced cardiac hypertrophy, Hawthorn extract (WS1442) at 1.3, 13, and 130 mg/kg/day reduced systolic and diastolic LV chamber volumes and improved Vcfc, suggesting attenuation of cardiac remodeling and enhanced contractile function [70]. Treatment with hawthorn leaf flavonoids (HLF) at a dose of 100 mg/kg/day via intragastric route over 8 weeks in rats was able to counteract the detrimental effects of simulated microgravity-induced cardiac remodelling on cardiac parameters, leading to notable restoration in LV-EF, LV-FS, and LV mass. Specifically, HLF raised LV-EF from 55.13% ± 0.98% to 71.16% ± 5.08%, LV-FS from 29.44% ± 0.67% to 41.62% ± 4.34%, and LV mass from 667.99 ± 65.69 mg to 840.02 ± 73.00 mg. Moreover, it significantly upregulated NPRA and PKG expression and downregulated PDE5A, NFATc1, and Rcan1.4 [71]. Supplementation with hawthorn berry extract (100 mg/kg for 10 weeks) in rats with obesity-induced cardiac injury mitigated the increase in body weight, oxidative stress markers (such as GPx1, SOD3, and CAT), inflammatory cytokines (IL-1β, IL-6, TNF-α), and cardiac injury biomarkers (cTnI, cTnT, CK-MB), while improving lipid profiles and reducing cardiac fibrosis and apoptosis [72]. Hawthorn flavonoid extract, provided at 0.1 and 0.2 ml/L for 42 days, lowered RV:TV, RV:BW, and TV:BW ratios, and decreased S and T wave amplitudes in pulmonary hypertensive chickens compared to control [73]. Rats treated with hawthorn extract (130 mg/kg) for five months after aortic constriction exhibited <10% increases in systolic and diastolic left ventricular (LV) volumes (compared to over 20% in controls), and showed approximately an 80% reduction in ANF mRNA induction and about 50% lower fibronectin expression compared to vehicle-treated animals [74]. In a study using JCR:LA-cp rats, administration of fireberry and hawthorn extracts for six weeks in a rat model resulted in significant decreased heart weight, LDL cholesterol, and improved heart function [75]. Pahlavan et al. found that a 1000 μg/mL dose of Crataegus pentagyna (hawthorn) leaf extract, applied acutely, exerted a dose-dependent negative chronotropic action and prolonged field potential durations in cardiomyocytes derived from healthy human embryonic stem cells, long QT syndrome type 2 (LQTS2), and catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) patient-specific induced pluripotent stem cells (iPSCs). At 300 and 1000 μg/mL, the extract significantly reduced β1-adrenergic-induced arrhythmogenic activity in CPVT1 CMs, while flavonoids isoquercetin and vitexin flavonoids significantly reduced the beating frequency induced by isoproterenol (5 μM) at concentrations of 3 and 10 μg/ml [76] (Table 3). 6. Turmeric (Curcuma longa ) Turmeric, and its active compound curcumin, have profound anti-inflammatory and cardioprotective effects. The potential effects of curcumin in the treatment of hypertensive vascular remodeling, through several pathways, have been reported in a review by Li et al., whose findings showed that curcumin (100 mg/kg/day) prevents Ang II–induced hypertension and myocardial fibrosis by downregulating AT1R and TGF‑β1, upregulating AT2R and ACE2, and reducing oxidative stress markers such as MDA and nitrotyrosine as well as fibrotic mediators like MMP‑9 [77]. In streptozotocin-induced diabetic rats, pioglitazone (20 mg/kg/day) and curcumin (100 mg/kg/day) significantly attenuated diabetic cardiomyopathy by lowering lipid profiles and cardiac injury biomarkers (serum creatine kinase-MB [CK-MB] and cardiac troponin I), suppressing TGF-β1 levels, and regulating the CaMKII/NF-κB and PPAR-γ signaling pathways [78]. Following myocardial infarction (MI), mice treated with Tetrahydrocurcumin (at a dose of 120 mg/kg/d) had preserved systolic function and reduced myocardial remodeling, which correlated with decreased reactive oxygen species (ROS) levels, restoration of Nrf2/SIRT3-mediated antioxidant responses, and improved mitochondrial health. These protective effects were reversed upon inhibition of either Nrf2 or SIRT3 [79]. In C57BL/6 mice subjected to left anterior descending (LAD) coronary artery ligation, oral curcumin at 50 or 100 mg/kg for four weeks significantly reduced post‑MI inflammation—marked by decreases in CD68⁺ macrophages and CD3⁺ T‑cell infiltration—improved cardiac function, and attenuated myocardial fibrosis. Mechanistically, curcumin‑treated macrophages released fewer pro‑inflammatory cytokines and IL‑18, which in co‑cultured cardiac fibroblasts led to suppression of the TGF‑β1–p‑SMAD2/3 signaling cascade and downregulation of fibrotic protein expression [80]. Yue et al. observed that daily oral curcumin at 200 mg/kg (4 mL/kg/d) for 28 days significantly shortened AF duration, reduced left atrial fibrosis, and lowered serum IL‑17A, IL‑1β, IL‑6, and TGF‑β1 levels in Sprague Dawley Male rats. Curcumin’s anti-fibrotic and anti-inflammatory effects against atrial fibrillation (AF) are primarily linked to its modulation of the IL-17 signaling pathway, influencing key genes including collagen type I alpha 1 chain (COL1A1), fatty acid synthase (FASN), phosphoenolpyruvate carboxykinase 1 (PCK1), bone morphogenetic protein 10 (BMP10), interleukin 33 (IL33), and c-fos-induced growth factor (FIGF) [81]. Four-week administration of C66 at 5 mg/kg post‑MI preserved systolic function, limited infarct expansion, and reduced myocardial hypertrophy and fibrotic scarring; mechanistic assays revealed that C66’s cardioprotection in hypoxic H9c2 cells depended on blocking JNK phosphorylation and consequent inhibition of inflammatory signaling and apoptosis [82]. Following 16 weeks of pressure overload, rats treated with curcumin (100 mg/kg/day, weeks 17–20) showed reduced thoracic aorta thickening, enhanced endothelium‑dependent relaxation, and decreased cardiac hypertrophy, fibrosis, and cell death. However, co‑administration of piperine (20 mg/kg/day) failed to augment. and in fact partly reversed these cardioprotective actions by attenuating curcumin’s upregulation of glucagon-like peptide-1 receptor (GLP-1R) in the heart and by lowering fasting glucagon-like peptide 1 (GLP-1) levels [83]. Oral curcumin at 50 mg/kg/day for six weeks prevents high‑salt diet–induced left ventricular hypertrophy in Dahl salt‑sensitive rats, as evidenced by reductions in posterior wall thickness, LV mass index, cardiomyocyte diameter, perivascular fibrosis, and hypertrophy‑response gene transcription, without altering blood pressure or systolic function. These effects were accompanied by decreased acetylation of the transcription factor GATA4, reflecting curcumin’s inhibition of p300 histone acetyltransferase activity [84]. In a Sprague-Dawley rat model of cardiac ischaemia/reperfusion injury, oral curcumin at 150 mg·kg⁻¹·day⁻¹ during the reperfusion phase (up to 42 days) significantly reduced maladaptive cardiac remodeling and preserved cardiac function. The mechanisms underlying these effects were associated with downregulated TGFβ1 and phospho-Smad2/3, upregulated Smad7, decreased malondialdehyde levels, inhibited MMP activity, and enhanced myocardial viability while improving echocardiographic parameters like stroke volume and ejection fraction [85]. Using patch-clamp and ECG-monophasic action potential recordings, 30 μmol/L curcumin (Cur) was shown to shorten action potential repolarization (APR50 and APR90 by 17% and 7%) and demonstrated a dose-dependent suppression of the late sodium current (INa.L), transient sodium current (INa.T), L-type calcium current (ICa.L), and rapidly activating delayed rectifier potassium current (IKr), with IC₅₀ values measured at 7.53, 398.88, 16.66, and 9.96 μmol/L, respectively. It also prevented ATX II– and Ca²⁺–driven depolarizations and limited the occurrence and average duation of I/R-triggered ventricular arrhythmias [86]. 7. Bacopa monnieri Bacopa, commonly known as Brahmi, is traditionally used as a cognitive enhancer, but its benefits extend to cardiac health. Bacopa monnieri has been shown to enhance coronary perfusion and left ventricular recovery after ischemia/reperfusion, notably reducing infarct size by over 50% at 100 μg/mL. However, it markedly suppressed ICa,L and exhibited cytotoxic effects at high concentrations in cardiomyocytes [87]. B. monniera (75 mg/kg orally for 3 weeks) also boosted cardiac antioxidant enzymes and HSP72 levels in an experimental model of ischaemia–reperfusion injury. This was accompanied by suppression of pro-apoptotic markers like caspase-3 and Bax [88]. Mohanet al. found that oral administration of Bacopa monniera extract (BME) at 75 or 150 mg/kg for 21 days significantly restored cardiac rhythm, reduced apoptosis, and preserved myocardial integrity in rats with isoproterenol (ISO)-induced cardiac injury. These effects were linked to activation of the Nrf2/HO-1/NQO1 antioxidant signaling pathway, normalization of apoptotic markers (Bax, Bcl-2), and increased glutathione levels [89]. Following H₂O₂-induced oxidative stress in Drosophila melanogaster, disruptions in circadian-regulated behaviors, antioxidant markers (SOD, CAT, GST and GSH), and per gene expression were observed, especially in cryb mutants. Administration of Bacopa monnieri extract restored these rhythms in wild-type flies, highlighting its circadian-linked antioxidant protective role [90]. In a 3-month open-label study, Bacopa monnieri was administered to cognitively healthy adults. This resulted in increased CREB phosphorylation and reduced NF-κB p65 phosphorylation, while serum mBDNF and proBDNF levels remained unchanged [91]. Bacopa monnieri demonstrated potent vascular relaxation and blood pressure-lowering effects in anaesthetized rats, largely mediated by endothelial nitric oxide signaling and inhibition of calcium influx and release in vascular tissue. These actions were supported by the saponins bacoside A3 and bacopaside II, which exhibited micromolar vasodilatory potency [92] (Table 3). 8. Hypericum perforatum Hypericum perforatum (commonly known as St. John’s Wort) is a perennial herb traditionally used for its antidepressant and neuroprotective properties. Recent preclinical studies have begun to reveal its potential in cardiovascular protection, particularly in mitigating cardiac remodeling and arrhythmias. Experimental models have demonstrated that H. perforatum extract exerts a significant inhibitory effect on cardiac remodeling. This action is attributed to its antioxidant and anti-inflammatory components, notably hypericin and hyperforin, which reduce oxidative stress and cytokine activity in myocardial tissue [93]. Hypericum perforatum, administered orally at 125 or 250 mg/kg/day, mitigated the cardiotoxic effects of doxorubicin by reversing bradycardia, reducing cardiac injury biomarkers such as creatine kinase–myocardial band (K-MB), lactate dehydrogenase (LDH) cardiac troponin T (cTnT ), oxidative stress markers such as MDA, and apoptosis-related genes such as Bax and caspase 3, while restoring AMPK signaling and antioxidant levels such as GSH, SOD, CAT, and GPx [94]. Treatment with hyperoside suppressed ER stress markers BiP and CHOP, reduced cardiomyocyte apoptosis, and enhanced anti-oxidative Nrf2 signaling, collectively resulting in improved myocardial energy metabolism. In addition, hyperoside improved cardiac functional recovery following ischemia/reperfusion (I/R), as evidenced by significantly enhanced left ventricular systolic pressure (LVSP), left ventricular Developed Pressure (LVDP), and maximum positive first derivative of left ventricular pressure (+LV dP/dtmax), while heart rate remained unaffected [95]. Hyperoside (Hyp) mitigated left ventricular remodeling and abnormal ECG alterations in myocardial infarction (MI) by reducing collagen volume fraction and myocardial hypertrophy, and lowering cardiomyocyte inflammation via autophagy-mediated suppression of the NLRP1 pathway; however, pharmacological blockade of autophagy using 3-MA nullified these protective actions [96]. Feng et al. established a spectrum–effect relationship model using High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography–Time-of-Flight Mass Spectrometry (LC-TOF-MS) to identify anti-arrhythmic components in Hypericum attenuatum from seven sources, revealing fingerprint peaks 5, 7, 13, and 14 as potential bioactive markers through pharmacodynamic and regression analysis [97]. In a study by Ma et al., rats were administered a daily dose of 100 mg/kg of total flavonoids from this plant for a week before inducing arrhythmias via an ischemia/reperfusion (I/R) model. They explored how the extract exerted its protective effects and found that it increased the expression of the Kir6.1 subunit in ATP-sensitive potassium channels, boosting their activity like class IIIb antiarrhythmics, and it lowered the levels of CaL-α1C, the critical subunit of L-type calcium channels, thereby reducing calcium entry similarly to class IV drugs [98]. Extract fractions of Hypericum perforatum (HpPet, HpCHCl₃, HpEtAc, HpAq) and its constituents (hyperforin, hypericin, and hyperoside) revealed tissue-specific spasmolytic, vasodilatory, and cardiomodulatory effects in isolated rabbit and guinea pig models, exerting Ca²⁺ channel-blocking and β-adrenergic potentiation effects similar to those observed in papaverine- and verapamil-treated groups. These findings highlight that H. perforatum fractions showed a dual pharmacological profile, acting as calcium antagonists and inhibitors of phosphodiesterase enzymes [99]. Gross et al. demonstrated that Hyperforin selectively induced TRPC6-mediated, LTCC-independent Ca²⁺ entry in adult feline ventricular myocytes (AFVMs), while also inhibiting L-type Ca²⁺ current (ICa,L) across all cell groups and altering voltage-dependent activation in dnTRPC6-expressing cells [100]. Formulating Hypericum perforatum into a dual nanoemulsion/nanosuspension system (HP.SNESNS) enhanced its cardioprotective and antidepressant actions and was effective in reducing myocardial injury markers, NO, and TNF-α, and promoting tissue repair. It also mitigated neurobehavioral disturbances through anti-inflammatory and neurotrophic effects, including decreased brain TNF-α and increased norepinephrine, serotonin, and BDNF. Additionally, it upregulated the expression of glial fibrillary acidic protein (GFAP) levels in the cortex and hippocampus and downregulated Bax levels in the cortex [101] (Table 3). Table 3. summarizes the cardioprotective effects of Hawthorn, Curcumin, Bacopa monnieri, and Hypericum perforatum. Conclusion The exploration of herbal remedies in modulating cardiac memory and remodeling presents a promising avenue for therapeutic intervention. Compounds such as Epigallocatechin gallate, Thymoquinone, Hypericin, Hyperforin, Ginkgolides, Bilobalide, Cinnamaldehyde, and cinnamon demonstrate significant potential in stabilizing ion channels, reducing oxidative stress, enhancing mitochondrial function, and mitigating pro-fibrotic pathways. These mechanisms collectively contribute to preserving electrical stability and preventing pathological structural changes within the heart. These mechanistic insights underscore the therapeutic potential of herbal-based interventions in both preserving cardiac function and preventing structural deterioration. Longitudinal studies are required to evaluate the long-term cardiovascular benefits and potential risks linked to the use of these natural remedies. Conflicts of interest: the author has no conflict of interest to declare. Funding statement: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 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Authors Affiliations Mohamed Ahmed [email protected] Cairo University Faculty of Veterinary Medicine View all articles by this author Metrics & Citations Metrics Article Usage 303 views 107 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Mohamed Ahmed. Cardiac Memory and Remodeling as dual Pathways of Cardiac Adaptation and Disease; A Natural Approach to Enhancing Cardiac Memory and Preventing Remodeling. Authorea . 26 May 2025. DOI: https://doi.org/10.22541/au.174823396.62816093/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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