Review Article

Impacts of Cardiac Dyssynchrony and Resynchronisation on Cellular Metabolism and Mitochondria: Current Understanding for Future Applications

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Abstract

Ventricular dyssynchrony serves as a cause of heart failure, resulting from impaired electrical conduction within the heart, commonly from bundle branch block or right ventricular pacing. It exceeds structural remodelling to cause significant cellular dysfunction, particularly in aberrant myocardial metabolism, alterations to myocardial oxygen consumption and cardiac efficiency, along with compromised mitochondrial activity. CRT is a therapeutic strategy that is used for the dyssynchronous ventricle by correcting electrical aberrance, while also improving cellular metabolic homeostasis, cardiac efficiency and mitochondrial function. This article provides a comprehensive review of the mechanisms responsible for ventricular dyssynchrony-induced cardiac remodelling and its reversal through cardiac resynchronisation therapy, focusing on the influence that these mechanisms exert on cellular metabolism and mitochondrial function. Additionally, it underscores the potential for risk assessment and individualised treatment targeting in dyssynchronous heart failure, using metabolic profiles, mitochondrial function indicators and metabolomic evaluation to enhance the efficacy of CRT and improve patient outcomes.

Keywords

Dyssynchrony, bundle branch block, right ventricular pacing, cardiac resynchronisation therapy, cellular metabolism, mitochondria,

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Accepted:

Published online:

DOI: https://doi.org/10.15420/aer.2025.69

Disclosure: All authors have no conflicts of interest to declare.

Funding: This work was supported by the Research Chair Grant from the National Research Council of Thailand (N42A670594) to NC, the Distinguished Research Professor Grant from the National Research Council of Thailand (N42A660301) to SCC, and the Chiang Mai University Center of Excellence Award to NC.

Correspondence: Nipon Chattipakorn, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. E: nchattip@gmail.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Ventricular synchronisation, including interventricular and intraventricular synchrony, is an essential component in maintaining the normal function of the heart.1 It necessitates the rapid conduction system, which facilitates coordinated electrical activation and efficient pumping function.2 Aberrant electrical activation, often resulting from bundle branch block, non-specific intraventricular conduction delay or right ventricular pacing (RVP), leads to considerable uncoordinated mechanical contraction. Prolonged ventricular dyssynchrony can result in progressive electrical/structural remodelling and heart failure with reduced ejection fraction, namely dyssynchronous heart failure (DHF).2,3 The incidence could potentially be 2% over 10 years in individuals with left bundle branch block (LBBB) and 6–22% over 3–16 years in those with RVP.4,5

A registry study suggested a shorter latency (6 months) to increased heart failure risk following RVP, probably related to rapid metabolic changes.6 The curative treatment for dyssynchronous heart failure is CRT, which is frequently achieved using the biventricular pacing (BiVP) technique.7 CRT can mechanistically correct electrical disturbance and reverse remodelling in DHF, ultimately leading to reduced all-cause mortality and decreased hospitalisations for heart failure.8,9 The response rate to CRT may vary between 32% and 91%.10

Alterations beyond structural remodelling regarding dyssynchrony and resynchronisation are not generally acknowledged. The heart – one of the organs with the highest metabolic activity crucial for its function – may experience alterations due to cardiac metabolic abnormalities and mitochondrial dysfunction, and their amelioration may yield advantageous outcomes in resynchronisation therapy. Although information on the development of DHF is limited, current proposed mechanisms encompass metabolic alterations and mitochondrial dysfunction in various heart failure models, such as coronary artery disease and chemotherapy-induced cardiomyopathy.11,12 Heart failure medications are widely prescribed and have clinical benefits. Renin–angiotensin–aldosterone system inhibitors and β-blockers have been shown to alleviate mitochondrial dysfunction, primarily through reducing cardiac preload, afterload and remodelling.13,14 Several treatments that directly target mitochondrial function have been demonstrated to improve heart failure.12

This comprehensive review explores the intricate relationship between cardiac dyssynchrony and its subsequent effects on cardiac metabolism and mitochondrial function. We also aim to illuminate the effects of CRT in restoring not only optimal heart function, but also metabolic homeostasis and the improvement of mitochondrial function. Moreover, the review sheds light on novel metabolic or mitochondrial function parameters that could be further integrated into clinical research or practice, particularly concerning the identification of individuals at risk for developing DHF and those who would benefit from CRT. Understanding the complexities of cardiac synchronisation and its effects on the cardiac energy-producing processes is crucial for developing better therapeutic strategies and improving patient outcomes.

Literature Search

Publications in PubMed dating from January 1981 to May 2025 were used for this review. The search was undertaken using specific search terms including “ventricular dyssynchron*,”, “Bundle branch block”, “LBBB”, “RBBB”, “intraventricular conduction delay”, “IVCD”, “ventricular pacing”, “RVP”, “dyssynchronous heart failure”, “cardiac resynchron*”, “CRT”, “physiologic pacing”, “biventricular pacing”, “conduction system pacing”, “His bundle pacing”, “left bundle branch area pacing”, “left bundle branch pacing”, “metaboli*”, “mitochondria*”, “oxidative phosphorylation”, “cellular respiration”, and “energy production”. The search retrieved 33 relevant original articles, all of which were incorporated in this review.

Physiological Cardiac Metabolism and Modifications in Heart Failure: Overview

The human heart is a metabolic engine, perpetually demanding energy to sustain its essential functions. In normal circumstances, cardiomyocyte predominantly relies on fatty acids (60–90%) and glucose (10–40%) as the main substrates, with minor contributions from ketone bodies and amino acids.15 All principal substrates, including fatty acid and glucose, converge on acetyl-CoA synthesis in the mitochondria through fatty acid β-oxidation and conversion from pyruvate generated through glycolysis via the pyruvate dehydrogenase enzyme. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle in the mitochondrial matrix, which leads to the production of redox molecules including NADH and FADH2 that donate electrons to Complexes I and II of the electron transport chain (ETC), respectively.16 Oxidative phosphorylation links ETC electron transport to adenosine triphosphate (ATP) production. The flow of electrons through the protein complexes (I–IV) in the ETC drives the translocation of protons from the mitochondrial matrix to the intermembrane space, establishing an electrochemical gradient (proton-motive force) that powers ATP synthase to generate ATP.17 Mitochondrial dynamics, calcium handling and redox signalling are crucial for metabolic regulation.18

Heart failure is characterised by profound metabolic remodelling. The pattern of metabolic remodelling differs between heart failure phenotypes, underlying aetiologies and comorbidity profiles.19 However, common themes include altered substrate usage, mitochondrial dysfunction, reduced oxidative capacity and decreased energetic efficiency.19,20 The metabolic changes and mitochondrial dysfunction in heart failure result from a complex interplay between cardiac remodelling and systemic factors.11,21 Changes in the heart, such as regional variations in energy demand during ischaemic episodes or modifications in mechanical load, result in adaptations that affect substrate preference, metabolism, and adversely influence mitochondrial function by reducing ATP production.11,22 Systemic factors such as insulin resistance, changes in circulating lipid profiles and inflammation or neurohormonal activation caused by heart failure, result in a maladaptive shift towards enhanced glucose usage, reduce cardiac efficiency, enhance lipid accumulation leading to lipotoxicity, further exacerbating mitochondrial dysfunction.21,23

Effects of Ventricular Dyssynchrony on Cardiac Metabolism: Evidence from Preclinical Studies

Preclinical studies were conducted exclusively in vivo using several animal models with ventricular pacing to create ventricular dyssynchrony. Studies consistently indicated that RVP-induced dyssynchrony hearts significantly altered cellular glucose and fatty acid uptake and metabolism, potentially linked to different workloads in various areas. In sheep and adult mongrel dog models, RVP induced heterogeneous glucose uptake across ventricular regions, as demonstrated by 18F-fluorodeoxyglucose (18F-FDG) uptake in cardiac PET scans.24,25 These reports demonstrate reduced uptake in the septal region and increased uptake in the lateral wall, along with diminished septal contraction and elevated lateral workload, indicating regional disparities in metabolic demand attributable to substantial mechanical dyssynchrony between the septal and lateral wall.24,25 Furthermore, in mice with ventricular dysfunction due to ischaemia–reperfusion injury, RVP augmented the expression of genes linked to glycolysis, gluconeogenesis, fatty acid catabolism and the TCA cycle, primarily in the lateral wall, signifying an elevated metabolic requirement in the more heavily loaded region.26

In a miniature pig with induced complete heart block, ventricular dyssynchrony induced by RVP increased fatty acid uptake via CD36, but exhibited diminished β-oxidation, along with a decline in hormone-sensitive lipase activity, leading to a decrease in the conversion of triglycerides (TG) and diacylglycerols (DAG) to monoacylglycerol.27 This metabolic alteration led to the accumulation of TG and DAG, culminating in lipotoxicity and ultimately leading to increased inflammation and replacement fibrosis, which may result in ventricular remodelling and dysfunction.27 Glucose absorption via GLUT4 and glycolysis were elevated to compensate for diminished energy production from fatty acid metabolism.27 These findings demonstrate that RVP-induced dyssynchrony initiates a change in substrate usage, with enhanced fatty acid uptake but compromised fatty acid β-oxidation, resulting in fat accumulation, which leads to lipotoxicity and ultimately ventricular remodelling, despite compensatory increases in glucose uptake and glycolysis.

The effect of RVP-induced dyssynchrony also affected cardiac efficiency. Multiple studies using canine models demonstrated that RVP diminished cardiac efficiency, especially at high pacing rates, while initially raising or thereafter sustaining myocardial oxygen demand (MVO2).28–31 Changes in cardiac efficiency result directly from alterations in mechanical parameters such as left ventricular (LV) power output, and do not directly reflect changes in metabolism. However, there is a potential relationship between changes in cardiac efficiency and metabolic alteration caused by dyssynchrony. As previously mentioned, dyssynchrony triggers a shift in substrate usage. The heart may exhibit increased dependence on glucose, which is a less efficient fuel, while demonstrating reduced capacity to effectively use fatty acids, which are more efficient. Dyssynchronous contraction produced workload heterogeneity in each ventricular segment also results in inefficient energy expenditure. Certain portions are contracting while others are relaxing, leading to inefficient force generation and energy consumption that does not facilitate effective ejection. To mitigate inefficiency, the heart may elevate its MVO2, despite the fact that actual cardiac output does not increase proportionately. These metabolic and mechanical alterations in dyssynchrony ultimately lead to reduced cardiac efficiency. In certain instances, anaerobic respiration is elevated with the higher pacing rate, indicating that the heart cannot fulfil its energy requirements only through aerobic metabolism.29

RVP-induced dyssynchrony initiates a cascade of metabolic, energetic and structural alterations in the heart. Regional variability in task allocation, resulting from dyssynchrony, leads to heterogeneous usage of glucose and fatty acids. The maladaptive transition of substrate from fatty acids to glucose occurs in a state of dyssynchrony. Despite enhanced fatty acid intake, fatty acid metabolism is compromised, resulting in fatty acid accumulation, lipotoxicity, and inflammation. Consequently, cardiomyocytes enhance glucose uptake and glycolysis as a compensatory mechanism. The metabolic aberrations resulting from dyssynchrony could potentially serve as a substantial factor contributing to detrimental heart remodelling and dysfunction, resulting in heart failure. Preclinical reports of the effect of ventricular dyssynchrony on cardiac metabolism are comprehensively summarised in Table 1.

Table 1: Effects of Ventricular Dyssynchrony on Cardiac Metabolism: Evidence from Preclinical Studies

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Effects of Ventricular Dyssynchrony on Cardiac Metabolism: Evidence from Clinical Studies

Consistent with preclinical reports, clinical studies also indicate the impact of cardiac dyssynchrony on glucose and fatty acid uptake, MVO2, oxidative phosphorylation and overall cardiac efficiency. Studies investigating LBBB in patients with dilated cardiomyopathy (DCM) consistently demonstrate heterogeneous glucose uptake patterns, evidenced by 18F-FDG uptake in cardiac PET scans, correlated with discrepancies in loading conditions between the septal and lateral wall.32,33 A study of human speckle-tracking echocardiography demonstrated that the lateral wall endured a greater burden than the septal wall in dyssynchronous ventricles with LBBB.34 In comparison to the septum, the lateral wall experiences delayed activation.

During mid to late systole, the lateral wall contracts later when LV pressure is higher, leading to a greater burden during its contraction phase. This delayed contraction may result in an exaggerated movement to mitigate the inefficient septal contribution.34 Ventricular dyssynchrony caused by LBBB decreases septal wall glucose uptake compared with the lateral wall, independent of myocardial blood flow (MBF).32 Moreover, another study showed that the heterogeneity in glucose uptake, characterised by diminished septal and augmented lateral uptake, exhibited a positive correlation with the extent of QRS duration, which serves as an indicator of electrical dyssynchrony.33 These findings indicate that dyssynchrony altered regional metabolic demand, perhaps resulting in energy imbalances across the ventricles.

Studies on RVP also reveal metabolic alterations similar to those observed in LBBB. Ventricular stimulation with RVP reduced glucose uptake in the septal wall and the surrounding pacing area, independent of MBF, demonstrating localised metabolic suppression likely due to decreased septal workload from dyssynchrony and the direct effects of electrical stimulation from pacing.35 RVP has also been shown to reduce fatty acid uptake, evidenced by decreased β-methyl-p-iodophenylpentadecanoic acid uptake from PET scans, in the septal, inferior and apical walls, indicating a reduction in fat usage in unloaded regions from mechanical dyssynchrony.36

Several studies have focused on the impact of ventricular dyssynchrony on myocardial efficiency and oxidative phosphorylation, which highlights the complex interplay between electrical dyssynchrony, mechanical stress and metabolic adaptation. During ventricular dyssynchrony, there is heterogeneity in oxygen consumption and oxidative phosphorylation between the septal and lateral walls. Individuals exhibiting ventricular dyssynchrony due to LBBB demonstrate elevated lateral wall MBF and MVO2, likely attributable to heightened mechanical stress relative to the septal region.37 Moreover, RVP has been shown to decrease cardiac efficiency and enhanced oxidative phosphorylation and MBF in the lateral wall compared with the septal wall, especially in individuals with substantial mechanical dyssynchrony.38 These findings suggest that the heart attempts to compensate for dyssynchrony by increasing energy production in the more heavily loaded regions. RVP has also been shown to decrease overall cardiac efficiency with increased MVO2, particularly at greater pacing rates, which is consistent with the results from animal studies.39 These findings demonstrate that dyssynchrony elevates energetic expenditure and MVO2 during cardiac contraction, particularly in regions of increased workload, which enhances substrate usage and oxidative phosphorylation; however, ineffective pumping and reduced output due to workload heterogeneity in dyssynchrony ultimately compromise cardiac efficiency.

In conclusion, clinical studies demonstrate that dyssynchrony, whether caused by LBBB or RVP, significantly alters cardiac metabolism. The heterogeneous patterns of glucose and fatty acid uptake, coupled with changes in MVO2, oxidative phosphorylation and cardiac efficiency, highlight the complex metabolic adaptations that occur in response to dyssynchrony. These could further contribute to reverse cardiac remodelling and impaired ventricular function. Clinical reports of the effect of ventricular dyssynchrony on cardiac metabolism are comprehensively summarised in Supplementary Table 1.

Effects of Cardiac Synchronisation on Cardiac Metabolism: Evidence from Preclinical Studies

In preclinical studies, several animal models have been examined to clarify the impact of atrioventricular (AV) and ventricular synchronisation on cardiac metabolism, myocardial efficiency and cardiac function. Studies investigating AV synchronisation demonstrated improvements in cardiac efficiency. Adult mongrel dogs with AV block, with dual-chamber pacemakers functioning in atrial synchronous RVP (VDD mode) to maintain AV synchronisation, exhibited enhanced cardiac efficiency by elevating LV power output while preserving identical MVO2 compared with atrial asynchronous RVP (VVI mode) at a comparable pacing rate.28 This suggests that coordinated atrial and ventricular contraction enhances the cardiac ability to generate effective work.

Ventricular resynchronisation shows an attenuation in metabolic abnormalities in dyssynchronised hearts in preclinical studies, whether being induced by RVP or LBBB. In sheep with preserved AV conduction, the cessation of RVP increased septal glucose uptake and alleviated the workload of the lateral wall after a period of rapid RVP.24 This indicates that restoring synchronous ventricular activation can redistribute metabolic demand and reduce regional stress. Lanyu miniature pigs undergoing ventricular resynchronisation via conduction system pacing, specifically his bundle pacing (HBP), demonstrated decreased inflammation and reversed remodelling. The results were presumably attributable to reduced fatty acid absorption, accumulation of fatty acyl glycerol and lipotoxicity, in contrast to the continued use of RVP.27 Additionally, HBP has been reported to decrease glucose uptake, glycolysis and pyruvate oxidation, signifying a rebalancing of substrate usage for energy production upon resynchronisation.27 These findings suggest that ventricular resynchronisation can reverse the adverse metabolic changes associated with dyssynchrony. In addition, in adult mongrel dogs with LBBB and DHF, resynchronisation therapy with BiVP enhanced cardiac function by promoting the pathways associated with cellular oxidative respiration, notably pyruvate oxidation, mitochondrial fatty acid translocation and enzymes facilitating the TCA cycle, including those involved in anaplerotic pathways.40 This indicates that BiVP can enhance energy production and improve cardiac function in the setting of LBBB and DHF.

Both AV and ventricular synchronisation provide a beneficial impact on cardiac metabolism and function. AV synchronisation improves cardiac efficiency by enhancing LV power output, which is particularly important in patients with dual-chamber permanent pacemakers. Furthermore, ventricular synchronisation induces metabolic remodelling by redistributing metabolic demand, reducing inflammation and lipotoxicity and enhancing energy production. These findings emphasise the significance of adequate AV synchronisation in pacemaker implantation and the ventricular synchronisation achieved through CRT in the restoration of coordinated cardiac contraction and the enhancement of cardiac outcomes. Preclinical reports on the effect of ventricular synchronisation on cardiac metabolism are comprehensively summarised in Table 2.

Table 2: Effects of Cardiac Synchronisation on Cardiac Metabolism: Evidence from Preclinical Studies

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Effects of Cardiac Synchronisation on Cardiac Metabolism: Evidence from Clinical Studies

CRT, achieved through BiVP, has been shown to render favourable metabolic remodelling in various clinical studies. CRT restored homogenous myocardial glucose uptake with balanced perfusion between the septal and lateral wall.41 These findings indicate that CRT alleviates heterogeneity in regional metabolic demand in the dyssynchronised heart and might prevent the negative remodelling. CRT also augmented energy production from mitochondrial metabolism, particularly β-oxidation of fatty acids, while concurrently reducing ketone body oxidation and anaerobic respiration in the context of DHF with LBBB.42 This illustrates the efficient energy production from oxidative phosphorylation in cardiomyocytes. A study on metabolomic analysis demonstrated that CRT equilibrated glucose and fatty acid metabolism while augmenting TCA cycle flux in patients with DCM and LBBB. This led to improved clinical outcomes, including enhanced ventricular function and the mitigation of heart failure symptoms.43 These findings suggest that efficient energy production may improve the clinical outcomes after the correction of ventricular dyssynchrony with CRT.

AV delay optimisation is a critical component of CRT because it maximises ventricular filling, enhances ventricular contractility and improves haemodynamic function.44 Proper AV timing can improve the response rate to CRT and promote reverse remodelling in patients with DHF.45 It has been shown to lead to sufficient ventricular filling and enhanced cardiac efficiency, surpassing the elevated MVO2.46 Optimal AV delay of 120 ms enhanced cardiac efficiency, while the “AV Opt” strategy, which adjusts the AV delay to achieve maximum systolic blood pressure, resulted in the most significant improvement in cardiac efficiency, surpassing the increased MVO2.46

CRT responders have shown improvement of LV function and exhibited superior clinical outcomes, including decreased mortality rates, mitigated exacerbation of heart failure and improved quality of life, compared with non-responders.47,48 Studies have also shown optimal metabolic adaptation among CRT responders, which may be responsible for the better outcomes. A study using plasma metabolome analysis demonstrated that CRT responders exhibited increased concentrations of leucine, isoleucine, phenylalanine and valine relative to non-responders.43 This indicates the existence of residual substrates from energy metabolism for protein synthesis, thereby facilitating myocardial protein synthesis and enhancing cardiac reverse remodelling. CRT responders also exhibited a lower fatty acid usage and required a lower ATP production relative to O2 intake to maintain function at the baseline prior to CRT intervention.49

A recent study in patients with non-ischaemic DCM indicated for CRT focused on metabolic flexibility during substrate infusion and demonstrated that CRT facilitated increased uptake of non-esterified free fatty acids during insulin + glucose infusion, with the extent of uptake related to reverse remodelling after 6 months.50 CRT also acutely enhanced stroke work without elevating O2 uptake, irrespective of substrate infusion.50 It can be inferred that, in patients with non-ischaemic DCM indicated for CRT, the metabolic phenotype of CRT responders is characterised by a less reliance on fatty acid metabolism and energy production at baseline to sustain function. Furthermore, if the heart can maintain metabolic flexibility and use fatty acids more effectively as the primary energy source, as the heart is reverted to its physiological state, this would correlate with a favourable response to CRT. CRT also enhances coordinated contraction, balancing energy generation and improving fat usage in each region, while simultaneously reducing lost energy and MVO2; hence, enhancing cardiac efficiency. This enhances cardiac efficiency and ultimately results in clinical improvement, particularly in the responder group.

In summary, CRT promotes beneficial metabolic changes, such as increased cardiac efficiency, normalised glucose absorption distribution and augmented energy output. Optimisation of AV delay in CRT might lead to improved AV synchronisation and increased efficacy of CRT. The improvement of metabolism may be the crucial contributor to improved outcomes in CRT responders; thus, data from metabolomic, flux balance analysis, metabolic flexibility and fat usage might be used as predictors of CRT response. Clinical reports of the effect of ventricular synchronisation on cardiac metabolism are comprehensively summarised in Supplementary Table 2.

Effects of Cardiac Dyssynchrony on Cardiac Mitochondria: Evidence from Preclinical Studies

Preclinical studies in various animal models have provided valuable insights into the mechanisms by which cardiac dyssynchrony affects mitochondria. A histopathological examination and genetic analysis of male beagle dogs with DHF, caused by LBBB induced by heart rate (LBB) ablation and rapid RVP to induce heart failure, revealed that DHF was associated with a reduction in mitochondrial quantity, an increase in mitochondrial damage (characterised by disorganisation and loss of internal cristae) and a decrease in autophagy and mitophagy due to the upregulation of the mitochondrial calcium uniporter (MCU).51 These findings indicate that dyssynchrony impeded mitochondrial turnover, leading to an accumulation of damaged mitochondria and potentially causing cellular dysfunction.

A histopathological and mitochondrial proteomics analysis was conducted on beagle dogs, where DHF was induced by LBBB via LBB ablation, followed by rapid RVP at a rate of 260 BPM for 2 weeks, subsequently decreased to 190 BPM for an additional week then RVP ceased for 4 weeks.52 Throughout this interval, subjects displayed solely LBBB and heart failure, unaffected by tachycardia, followed by specimen collection. The study revealed that DHF significantly decreased mitochondrial abundance and caused mitochondrial injury, increased apoptosis and caused calcium handling abnormalities through the upregulation of calpain-1, ultimately leading to negative cardiac remodelling and impaired systolic function.52 However, it is essential to recognise a methodological consideration in preclinical dyssynchrony models using rapid pacing to induce heart failure.

Although these studies offer significant insights, isolating the contribution of dyssynchrony from the effects of rapid pacing can be difficult. It is essential to consider this nuance when interpreting the isolated effects of dyssynchrony in these contexts. In beagle puppies with complete AV block that underwent RVP at an age-appropriate rate, dyssynchrony induced by RVP resulted in mitochondrial injury, characterised by increased size variability and disorganisation and reduced internal cristae.53 Apart from increased cardiac filling pressure, dyssynchrony has also been associated with sinus node dysfunction, particularly the extending sinus node recovery time and sinoatrial conduction time.53 Therefore, in addition to the structural remodelling resulting in impaired haemodynamics, ventricular dyssynchrony and impaired mitochondrial function could contribute to electrical remodelling. Moreover, dyssynchrony induced by RVP in a mouse model was shown to lead to elevated energy demand beyond supply capacity and increased anaerobic respiration, particularly at higher rates.54 These findings highlight the energetic consequences of dyssynchrony and the mitochondrial dysfunction that contributes to energy depletion.

This evidence strongly indicates that ventricular dyssynchrony causes substantial mitochondrial alterations, including structural damage, impaired dynamics and diminished generation of energy, leading to an imbalance between energy demand and supply. Preclinical reports of the effect of cardiac dyssynchrony on cardiac mitochondria are comprehensively summarised in Table 3.

Table 3: Effects of Cardiac Dyssynchrony on Cardiac Mitochondria: Evidence from Preclinical and Clinical Studies

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Effects of Cardiac Dyssynchrony on Cardiac Mitochondria: Evidence from Clinical Studies

Clinical studies in human hearts have provided further evidence of mitochondrial dysfunction in the setting of cardiac dyssynchrony. Dyssynchrony from RVP in patients with congenital complete AV block induced mitochondrial injury, characterised by enlargement and increased size variability.55 Mitochondrial injury could result in mitochondrial dysfunction, leading to adverse remodelling, as indicated by increased myofibril variation, fibrosis and fat deposition.55 However, a contradictory outcome emerged regarding the influence of dyssynchrony on mitochondrial function. Whole blood messenger RNA analysis in patients with sick sinus syndrome or AV block a week after pacemaker implantation revealed that RVP upregulated genes that augmented mitochondrial function and energy production including the mitochondrial fusion protein OPA1 gene and the NDUFA1 gene.56 It also downregulated genes associated with antioxidant activity and upregulating apoptotic genes, specifically PRDX1 and STK10, respectively.56 These findings indicate that dyssynchrony could initially enhance mitochondrial function and energy production. However, it can also induce cellular injury by elevating oxidative stress and cell death, potentially leading to mitochondrial dysfunction and adverse outcomes. Our recent cross-sectional study involving patients who underwent permanent pacemaker implantation demonstrated an increase in cellular oxidative stress and mitochondrial oxidative stress in peripheral blood mononuclear cells (PBMCs) of patients with substantial RVP (>40%) and prolonged RVP exposure, respectively.57 The dyssynchrony from RVP may induce an aberrant mitochondrial homeostasis in PBMCs, leading to an increase in p62 protein or sequestosome 1 and oxidative stress. This might be related to abnormal mitochondrial function in cardiomyocytes based on proximity theory, which suggests transit through damaged cardiac tissue with malfunctioning mitochondria.58 Additionally, increased inflammation and oxidative stress in cardiac tissue may facilitate immune cell recruitment and induce oxidative stress in immune cells.58

In conclusion, ventricular dyssynchrony induces significant mitochondrial alterations, including structural damage, impaired dynamics, reduced energy production and increased oxidative stress. These mitochondrial changes contribute to adverse cardiac remodelling and dysfunction. Clinical reports regarding the effect of cardiac dyssynchrony on cardiac mitochondria are comprehensively summarised in Table 3.

Effects of Cardiac Synchronisation on Cardiac Mitochondria: Evidence from Preclinical Studies

Preclinical studies have provided valuable insights into the mechanisms by which CRT modulates mitochondrial dynamics and function. Several studies have clarified the favourable effects of ventricular synchronisation on mitochondria, perhaps explaining the clinical benefits of CRT. Research has been conducted on the impact of CRT using BiVP on mitochondria in a canine model of DHF induced by LBBB from LBB ablation and rapid atrial pacing.51 In the CRT group of this study, following 4 weeks of rapid atrial pacing, CRT with BiVP was performed at the same rate as the rapid atrial pacing. This intervention demonstrated a reduction in mitochondrial injury, an increase in mitochondrial quantity and decreased mitochondrial damage, including reduced disorganisation and enhanced internal cristae. It can be inferred that the mitochondrial damage observed in the heart failure group was probably attributable to DHF and was alleviated by CRT. The mechanical effect of CRT facilitated autophagy and mitophagy via MCU downregulation and DNM1L/Drp1 upregulation. These modifications facilitated the elimination of dysfunctional mitochondria. The augmentation of properly functioning mitochondria and the lowering of dysfunctional mitochondria resulted in an enhancement of LV function.

In a canine model of LBBB-induced heart failure, cardiac resynchronisation with BiVP increased the respiratory control index, a measure of mitochondrial coupling efficiency and enhanced mitochondrial energy production via increased protein complexes in electron transport chain, and ATP synthase activity.59 Detailed ATP synthase analysis in this study showed that BiVP reduced β-subunit degradation, increased F0/F1 assembly and increased its specific activity for ATP production.59 Moreover, CRT upregulated the expression of peroxiredoxin 3, an antioxidant enzyme, and resulted in enhancing reactive oxygen species scavenging.40 The authors’ imaging study showed that CRT enhanced LV systolic function.40 All these findings suggested that cardiac resynchronisation improved mitochondrial function, particularly energy production, with reduced oxidative stress, resulting in improved cardiac function. In a canine model of LBBB-induced heart failure, CRT enhanced ATP synthase activity by modifying post-translational modifications at the cysteine 294 residue of α-subunit, thereby supporting the notion that cardiac resynchronisation improves energy production through increased ATP synthase activity.60

In summary, preclinical research supports the hypothesis that CRT enhanced mitochondrial dynamics and function. In the models of LBBB-induced heart failure, BiVP enhanced mitochondrial abundance, minimised damage, and promoted fission and autophagy for the elimination of injured mitochondria from cells, accompanied by raising mitochondrial energy generation and ATP synthase activity and lowering oxidative stress with higher levels of antioxidant enzymes. This enhancement in mitochondrial dynamics and function resulted in an improvement in LV function. Preclinical reports of the effect of cardiac synchronisation on cardiac mitochondria are comprehensively summarised in Table 4.

Table 4: Effects of Cardiac Synchronisation on Cardiac Mitochondria: Evidence from Preclinical Studies

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Effects of Cardiac Synchronisation on Cardiac Mitochondria: Evidence from Clinical Studies

Clinical studies have revealed the potential benefits of CRT on mitochondrial function. In patients with DHF resulting from LBBB, CRT using BiVP reduced mitochondrial depolarisation, as evidenced by a decreased technetium (99mTc) sestamibi (99mTc-MIBI) washout rate in a myocardial perfusion imaging scan conducted 6 months post-implantation. This may result in an augmented proton-motive force across inner mitochondrial membrane, which could promote ATP synthesis and contribute to improvement of LV function after CRT.42 Furthermore, among CRT responders – who exhibited superior electrical synchronisation and LV function relative to non-responders – there was a concomitant reduction in mitochondrial depolarisation, as indicated by a reduced 99mTc-MIBI washout rate.61 These findings suggest that the enhancement of ATP generation resulting from reduced mitochondrial depolarisation, particularly in the responder group, could be responsible for the improvement of LV function following CRT implantation. Furthermore, studying mitochondrial depolarisation with the 99mTc-MIBI washout rate might be used to assist the prediction of the response to CRT.

AnxA5 is a circulating protein associated with mitochondrial dysfunction.62 It has been demonstrated that AnxA5 levels were diminished in CRT responders, compared with non-responders, after 1 year of CRT implantation, presumably contributing to improved LV remodelling.62 This finding suggests that CRT might enhance cardiac mitochondrial function by decreasing AnxA5, and that its concentration might serve as a predictor of CRT responsiveness.

In summary, CRT leads to significant improvements in mitochondrial function, including enhanced energy production via the electron transport chain by reducing mitochondrial depolarisation. These mitochondrial adaptations contribute to improved cardiac function and reverse remodelling in individuals with CRT implantation. In the future, personalised CRT strategies based on mitochondrial function may further optimise cardiac function and improve patient outcomes. Clinical reports of the effect of cardiac synchronisation on cardiac mitochondria are summarised in Supplementary Table 3.

Future Research Perspectives

This review emphasises the substantial influence of cardiac dyssynchrony and resynchronisation on cellular metabolism and mitochondrial function; however, some critical areas require additional exploration. Future research on risk stratification and prevention strategies should concentrate on clarifying the effects of various types of dyssynchrony, including those induced by right bundle branch block versus LBBB, and LBBB versus intraventricular conduction delay, on cardiac metabolism and mitochondrial function. Further investigation should also focus on the domain of cardiac pacing to determine potential variations in RVP sites and their association with RVP proportions. Additionally, the correlation between these findings and the presence of several underlying cardiac conditions, including coronary artery disease and non-ischaemic DCM should be further determined. While this review predominantly addresses intrinsic cardiac processes, it is essential to comprehend the systemic consequences of dyssynchrony and resynchronisation, along with their association with alterations in cardiac metabolism, to achieve a comprehension of the overall effects of both conditions. Several parameters, including indicators of heightened lipotoxicity, heightened heterogeneity in oxidative phosphorylation, diminished ventricular efficiency, alterations in genetic expression associated with mitochondrial dysfunction, increased biomarkers related to mitochondrial impairment such as AnxA5 and the detection of mitochondrial depolarisation, are probable indicators of DHF in patients demonstrating ventricular dyssynchrony. Further research into these indicators in individuals with ventricular dyssynchrony would be advantageous.

Furthermore, future research on DHF therapies focusing on metabolic profiles and mitochondrial activity across alternative physiologic pacing techniques, including conduction system pacing (HBP, LBB area pacing), should be investigated. In individuals with RVP, the integration of advanced electrophysiological assessment tools, particularly ultra-high-frequency ECG, provides convenient methods for the early detection of pacing-induced cardiomyopathy, as well as improved optimisation and prediction of CRT response.63 Further research into this approach could improve metabolic and mitochondrial parameters, facilitating better patient stratification and optimisation of CRT outcomes, particularly for individuals requiring an upgrade from RVP to CRT. Earlier identification of CRT responders will be further examined using metabolomic characteristics and a reduction in mitochondrial depolarisation. In clinical practice, identifying patients unlikely to benefit from CRT with BiVP facilitates the exploration of alternative strategies, including conduction system pacing, expedited heart transplantation listing or destination therapy with long-term mechanical support, such as a ventricular assist device. Exploration of alternative targets in cardiac metabolism and mitochondria for DHF in individuals ineligible for device implantation, due to factors such as limited access or complex structural heart disease, should be conducted.

Figure 1: Impacts of Cardiac Dyssynchrony and Resynchronisation on Cellular Metabolism and Mitochondria

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Conclusion

This comprehensive review underscores the critical role of alterations in cellular metabolism and mitochondrial function in the pathophysiology of cardiac dyssynchrony and the therapeutic benefits of CRT (Figure 1 ). Cardiac dyssynchrony and resynchronisation exert substantial direct effects on cardiac metabolism and mitochondrial function. Electrical dyssynchrony, arising from conditions either LBBB or RVP, initiates a cascade of events ultimately leading to adverse outcomes in the heart, notably the development of DHF. Initially, electrical dyssynchrony directly causes heterogeneous mechanical work distribution across the LV. This disproportionate workload then triggers regional variations in heterogeneity of substrate uptake and energy demand, resulting in localised metabolic stress. Maladaptive metabolic alterations occur as compensatory mechanisms, characterised by regional variations in substrate usage and oxidative phosphorylation resulting from workload heterogeneity. Impaired fatty acid β-oxidation and lipolysis in cardiomyocytes result in lipid accumulation and lipotoxicity. Cardiomyocytes primarily depend on glucose metabolism for energy production. Additionally, mitochondrial injury and dysfunction induced by stress compromise the electron transport chain and ATP synthesis, leading to decreased cardiac efficiency despite increased oxygen consumption and the accumulation of oxidative stress. These maladaptive metabolic changes, sustained over time, contribute to adverse LV remodelling and the progression of heart failure. CRT, by correcting electrical disturbances and workload heterogeneity, promotes significant improvements in metabolic heterogeneity and mitochondrial function, including enhanced energy production, reduced oxidative stress and restored mitochondrial homeostasis.

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Clinical Perspective

  • Cardiac dyssynchrony impairs cellular metabolism and mitochondrial function, contributing to heart failure.
  • CRT improves metabolic and mitochondrial function, promoting better cardiac performance.
  • Future studies should explore the potential for risk stratification and optimisation of CRT strategies based on mitochondrial function, while acknowledging that further research is needed to determine whether mitochondrial function provides independent and clinically significant prognostic information.

References

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