Impact of Maternal Circadian Rhythm Disruption during Pregnancy on Cardiac Remodeling in Offspring: A Comprehensive Review

Emerging evidence from both human and animal studies indicates that circadian rhythm disruption during critical developmental periods can have profound long-term consequences for cardiovascular health. This review synthesizes current knowledge on the impact of maternal circadian disturbance during pregnancy on cardiac remodeling in offspring, with particular emphasis on sex-specific effects and underlying molecular mechanisms. Drawing from recent experimental models, we explore how in utero circadian disruption predisposes offspring, especially males, to pathological cardiac remodeling, characterized by ventricular chamber dilatation, enhanced myocardial fibrosis, decreased contractility, and increased susceptibility to arrhythmias. However, emerging evidence also indicates that female offspring are not entirely spared, with risks potentially mediated through other pathways such as pregnancy complications. The review highlights the emerging role of sex-specific molecular pathways, including the secret globin gene, Scgb1a1, alongside other key mechanisms such as epigenetic regulators and inflammatory pathways, and discusses how circadian gene expression alterations in the heart contribute to these phenotypes. Understanding these relationships provides crucial insights into the developmental origins of cardiovascular disease and may inform future prevention strategies targeting circadian health during pregnancy.

The circadian clock is an evolutionarily conserved time-keeping system that enables organisms to anticipate and adapt to daily environmental changes, optimizing physiological processes accordingly [1-3]. In mammals, this system consists of a central pacemaker located in the Superchiasmatic Nucleus (SCN) of the hypothalamus, which synchronizes peripheral clocks in virtually every cell and tissue throughout the body [4]. At the molecular level, circadian rhythms are generated through auto regulatory transcription-translation feedback loops composed of core clock genes such as CLOCK, BMAL1, PER, and CRY [5]. These molecular oscillators regulate the timing of numerous physiological processes, including sleep-wake cycles, metabolism, hormone secretion, and cardiovascular function [6,7].

The cardiovascular system exhibits particularly strong circadian influences, with heart rate, blood pressure, cardiac output, and endothelial function all demonstrating significant diurnal variations [8-10]. Consequently, circadian disruption has been implicated in the pathogenesis of various cardiovascular diseases, including hypertension, myocardial infarction, and heart failure [11-14]. Epidemiological studies consistently show that individuals engaged in shift work, who experience chronic misalignment between their internal circadian clocks and external environment, face increased risks of cardiovascular morbidity and mortality [15,16].

A particularly vulnerable period for circadian influences occurs during fetal development [17-19]. The fetal circadian system develops gradually and is heavily influenced by maternal timing cues [18,20]. During pregnancy, maternal circadian rhythms regulate numerous physiological processes that directly impact the intrauterine environment and fetal development. Experimental evidence suggests that the fetus receives timing information through various maternal signals, including hormonal rhythms [21,22], body temperature fluctuations [23], and nutrient availability [24,25]. When these maternal circadian signals are disrupted, fetal development may be adversely affected, potentially leading to long-term health consequences [24,26].

While the adverse effects of circadian rhythm disruption on the cardiovascular system in adults have been extensively documented, research exploring how maternal circadian rhythm disturbances during pregnancy impact fetal heart development and predispose offspring to cardiovascular diseases later in life has only begun to emerge in recent years. This growing body of evidence now includes contributions from our own research [27,28]. This review aims to synthesize current understanding of how circadian disturbances during fetal development influence cardiac remodeling in offspring, with particular attention to sex differences in susceptibility, potential molecular mechanisms, and implications for cardiovascular disease prevention.

Prenatal circadian disruption and direct effects on offspring cardiac structure

Chronic gestational exposure to Circadian rhythm Disruption (CCD) induces significant structural and functional remodeling of the developing heart, with emerging studies demonstrating that these effects are more pronounced in male offspring table 1 [27,29]. Experimental models using chronic phase shifts of the light-dark cycle during pregnancy-simulating conditions similar to shift work or jet lag in humans-have demonstrated that male offspring exposed to such circadian disruption develop remarkable pathological cardiac remodeling resembling characteristics of heart failure [27]. These structural changes include ventricular chamber dilatation, wall thinning, and increased collagen deposition within the myocardial interstitium. To our knowledge, our study provides the first direct evidence detailing how maternal CCD affects both the structure and function of the developing offspring heart.

The myocardial structural alterations observed in CCD-exposed male offspring are consistent with a profile of pathological remodeling [30]. Specifically, these animals exhibit enlarged heart diameter along the short axis, reduced heart weight-to-body weight ratio, and noticeable passivation of the cardiac apex compared to controls gestated under normal circadian conditions [31]. Histological analyses further confirm enhanced myocardial fibrosis in CCD-exposed males, with Sirius Red staining revealing larger fibrotic areas containing type I and III collagen fibers between myocardial fibers [26]. This fibrotic response represents a key feature of pathological remodeling that can disrupt electrical conduction and impair mechanical function [32-34].

The structural impact of prenatal circadian disruption exhibits striking sexual dimorphism. While male offspring demonstrate significant alterations in cardiac architecture, female offspring exposed to identical in utero conditions show minimal structural changes. This differential susceptibility suggests that sex-specific factors, potentially including gonadal hormones or sex-chromosome complement, modulate the cardiac response to developmental circadian disruption [35,36]. Epidemiological observations consistently show that premenopausal women have lower incidence rates of a variety of cardiovascular diseases relative to age-matched males [37-39].

Sex-specific cardiac functional outcomes induced by circadian disruption

Circadian disruption exerts sex-dimorphic effects on cardiac function. Males often exhibit more significant contractile dysfunction, as seen in heart failure models where circadian misalignment impairs calcium handling and reduces ejection fraction. In terms of arrhythmia susceptibility, circadian rhythm disturbances can increase the risk of ventricular arrhythmias, with studies noting a higher propensity in males under conditions like chronic heart failure, where clock gene (e.g., Bmal1) dysregulation alters T-type calcium channel expression. Conversely, females may be protected through mechanisms involving estrogen, which is suggested to stabilize cardiac repolarization and mitigate adverse electrical remodeling, potentially explaining their relative resilience in some contexts of circadian-induced cardiac stress [40-42].

Circadian disruption induces significant sex-dimorphic alterations in cardiac contractility. Clinical studies report that the confluence of endogenous circadian disruption, younger age, and male sex in chronic heart failure defines a patient phenotype characterized by lower ejection fraction and higher NYHA class [43]. In murine models, male mice exposed to chronic circadian misalignment (e.g., repeated light-cycle shifts) develop more pronounced contractile dysfunction, characterized by reduced ejection fraction and impaired calcium handling in cardio myocytes, compared to females [44]. This sexual dimorphism is echoed in clinical observations, where men subjected to long-term shift-work demonstrate a higher incidence of cardiomyopathy and heart failure with reduced ejection fraction than their female counterparts [45].

The underlying mechanisms are multifaceted, involving sex chromosome complement (e.g., XX vs. XY) and gonadal hormones [44,46]. Experimental models manipulating these factors show that the absence of ovarian hormones in females [47] or the presence of testes-derived factors in males significantly influences the expression of circadian clock genes within the heart, thereby modulating contractile protein function and energy metabolism.

Estrogen signaling and cardio protection: Estrogen signaling plays a central cardio protective role. Estrogen acts through its receptors (ERa, ERb, and GPER1) to mitigate adverse electrical remodeling, partly by modulating potassium currents like IKs. It activates pro-survival pathways such as PI3K/Akt and MAPK, reducing apoptosis and cellular stress. In models of circadian disruption, the cardio protective effects in females are diminished after ovariectomy but restored with estrogen supplementation [48].

Sex-specific clock gene regulation: Sex-specific clock gene regulation contributes to this protection. The core circadian machinery (e.g., Bmal1, Per, Cry) exhibits inherent sexual dimorphism [49]. Evidence suggests the female circadian system is more resilient to external perturbations, potentially maintaining more robust oscillations of clock-controlled genes involved in cardiac metabolism and function, even when challenged. Research in mice with targeted disruptions of core clock genes (e.g., Clock or Bmal1) reveals that male mice develop more severe electrophysiological instability, including action potential duration prolongation and increased susceptibility to pacing-induced ventricular arrhythmias [50,51].

Sex-specific transcriptional responses: Sex-specific transcriptional and epigenetic landscapes enhance female resilience. Under stress, female tissues exhibit distinct gene expression profiles, including coordinated activation of protective immune and metabolic pathways [52]. This is influenced by the XX sex chromosome complement and genes escaping X-inactivation (e.g., Kdm5c, Kdm6a), which promote a more adaptive transcriptional response to damage [53]. Furthermore, sex chromosome complement, independent of hormones, contributes to differences in the transcriptional regulation of ion channels in a sex-dimorphic manner, potentially exacerbating arrhythmia risk in males when circadian homeostasis is disturbed [54-56].

Sex-specific cardiac electrical remodeling: Susceptibility to arrhythmias following circadian rhythm disruption exhibits clear sexual dimorphism, influenced by sex-specific electrophysiological properties [57,58] and hormonal milieus [59]. Females are consistently observed to have a higher baseline risk for certain arrhythmias, such as drug-induced Torsades de Pointes, linked to their intrinsically longer QT interval [60]. However, in the context of circadian disruption, males may demonstrate heightened vulnerability to different forms of arrhythmogenesis, including atrial fibrillation and ventricular tachycardia, as evidenced by studies on shift-working populations and animal models [58,61]. This male-biased susceptibility is mechanistically linked to sex hormone modulation of ion channel expression (e.g., potassium channels Kv4.3, Kv1.5) and calcium handling proteins [62]. Estrogen in females appears to stabilize cardiac repolarization by modulating potassium currents (IKs) [63]. Testosterone exhibits a biphasic modulation of cardiac calcium cycling; while it potentially promotes calcium overload and triggered activity by enhancing calcium influx, acute blockade has also been reported. This dual nature is considered a fundamental mechanism for the heightened electrical heterogeneity and predisposition to ventricular arrhythmias observed in males [64].

In summary, the convergence of protective hormonal signaling, a more stable circadian clock, and a robust, sex-specific transcriptional program may collectively safeguard cardiac function in female offspring exposed to prenatal circadian disruption. Whether this protection persists after menopause, when cardiovascular risk increases, remains a critical question for longitudinal studies.

From circadian disruption to cardiac remodeling.

The path from prenatal circadian disruption to cardiac pathology in offspring involves complex molecular mechanisms that are only beginning to be elucidated. Current evidence points to a cascade of events involving direct circadian clock disruption, metabolic reprogramming, and activation of specific fibrotic pathways, with significant sex-specificity at each level. It is summarized in figure 1 and table 2 that the molecular mechanisms through which circadian rhythms regulate cardiac remodeling are categorized.

Figure 1: Proposed pathways linking maternal circadian disruption to offspring cardiac remodeling. Maternal circadian rhythm disruption (e.g., due to shift work) can impact the offspring's heart through multiple interconnected mechanisms: (1) Inducing placental dysfunction; (2) Triggering dysregulation of key molecular pathways in the offspring's heart, including the core circadian clock, Scgb1a1 upregulation, epigenetic modifications, inflammatory signaling, and metabolic sensors; and (3) Causing systemic metabolic changes that create an adverse milieu. These pathways collectively contribute to pathological cardiac remodeling phenotypes. Offspring biological sex is a critical modulating factor that influences each of these mechanisms and the final phenotypic outcome.

Circadian gene expression alterations

The core molecular clock, composed of Transcription-Translation Feedback Loops (TTFL) involving genes such as Bmal1, Clock, Per, and Cry, is a critical regulator of cardiac function [9,65]. Disruption of these genes can directly lead to pathological cardiac remodeling. For instance, Bmal1 plays a crucial role in cardio myocyte growth and histone turnover during cardiac development and stress responses [19]. Altered expression of clock genes can disrupt the rhythmic transcription of downstream output genes, affecting myocardial contraction, metabolism, and inflammatory responses, thereby promoting maladaptive remodeling characterized by fibrosis and hypertrophy [9,65]. For example, the circadian nuclear receptor Rev-erbα modulates the expression of key genes involved in cardiac hypertrophy and fibrosis, and its deletion exacerbates adverse remodeling in response to stress.

The mechanisms extend beyond the core TTFL. The circadian protein CACNA2D3 is implicated in female reproductive health [49], and its disruption can alter the expression of circadian genes (e.g., Clock, Per3, Cry1) [27]. Furthermore, the core clock transcription factor BMAL1 can form a functional heterodimer with HIF2A (A key responder to myocardial ischemia) to modulate circadian variations in myocardial injury [66]. This BMAL1-HIF2A heterodimer regulates the rhythmic transcription of target genes like amphiregulin (AREG), thereby mediating cardio-protection in a time-of-day-dependent manner.

Metabolic reprogramming

Circadian disruption initiates profound metabolic reprogramming in the heart, primarily through the dysregulation of core clock genes such as Bmal1 and Rev-erbα/β, which are pivotal transcriptional regulators of metabolic pathways. The myocardial-specific knockout of Rev-erbα/β in mice disrupts the diurnal metabolic rhythm, leading to impaired fatty acid oxidation during the rest phase (Light cycle) and a compensatory shift towards enhanced glucose utilization, ultimately progressing to dilated cardiomyopathy and heart failure [67]. This metabolic shift is driven by clock-controlled transcriptional networks; for instance, Rev-erbα directly represses E4bp4, and its loss leads to sustained E4bp4 expression, which suppresses fatty acid oxidation genes [67]. Concurrently, circadian disruption systemically alters metabolic homeostasis. The circadian protein CACNA2D3 is implicated in female reproductive health, and its ablation disrupts circadian gene expression (e.g., Clock, Per3, Cry1) [68]. Furthermore, metabolites such as NAD+ exhibit rhythmicity and influence clock gene expression; age-related decline in NAD+ disrupts this rhythm, while supplementation with its precursor nicotinamide riboside can restore metabolic oscillations [69]. Gut microbiota-derived metabolites, including butyrate and FAD, also participate in this regulation by influencing peripheral clock function in organs like the liver and kidneys [69].

Notably, prenatal circadian disruption can program long-term metabolic vulnerabilities in offspring. Offspring from circadian-disrupted pregnancies exhibit altered placental function and reprogrammed liver metabolism, predisposing them to diet-induced obesity. This is characterized by hyperphagia, leptin resistance, and disrupted rhythmic expression of hepatic metabolic genes, which are associated with a phase shift in the maternal-fetal circadian synchrony [70]. These findings underscore that circadian gene disruptions rewire both cardiac and systemic metabolism through direct transcriptional control and metabolite-mediated feedback, establishing a critical link between circadian misalignment and maladaptive metabolic remodeling in the heart and beyond.

The Scgb1a1 pathway

Secretoglobin, Family 1A, Member 1 (Scgb1a1), also known as Uteroglobin (UGB), Clara Cell Protein 10 (CC10), Clara Cell Protein 16 (CC16), Clara Cell Secretory Protein (CCSP), Urinary Protein 1 (UP1), or Polychlorinated Biphenyl Binding Protein (PCB-BP), is emerging as a potential regulator in the link between circadian rhythm disruption and cardiac remodeling. Traditionally regarded as a biomarker for lung injury [71,72], growing evidence indicates that its expression in the heart is modulated by the circadian clock and may contribute to pathological changes. Clinical studies have revealed a distinct circadian oscillation in serum levels of Scgb1a1[73]. Our research demonstrates that prenatal circadian disruption induces pathological cardiac remodeling in adult male offspring, characterized by ventricular dilation, exacerbated fibrosis, and upregulation of cardiac Scgb1a1 expression [27]. Forced overexpression of Scgb1a1 is sufficient to induce cardio myocyte hypertrophy, indicating a direct role for this protein in maladaptive cardiac responses [27]. Further clinical evidence supports the involvement of SCGB1A1 in cardiovascular disease, suggesting it may participate via influencing metabolic pathways [74]. Functionally, Scgb1a1 acts as an endogenous inhibitor of phospholipase A2, binds to phosphatidylcholine and phosphatidylinositol, and exhibits weak binding to progesterone, implying a potential role in cellular lipid metabolism [75]. Moreover, Scgb1a1 participates in immunomodulation through key signaling pathways, including p38 MAPK-ERK and the NF-κB pathway [76, 77].

The impact of prenatal circadian disruption on offspring cardiac health does not occur in isolation but interacts with various genetic, environmental, and temporal factors. Understanding these complex interactions is essential for developing targeted prevention and intervention strategies [78-83].

Placental dysfunction

The placenta serves as a crucial interface between maternal and fetal physiology, and its function is influenced by maternal circadian rhythms [69,84]. Studies demonstrate that circadian disruption during pregnancy alters placental structure and transcriptome, leading to increased placental efficiency (Higher fetal-to-placental weight ratio) but potentially at the cost of altered nutrient transfer [69]. Specifically, CCD placentas show upregulation of specific marker genes and suppression of genes related to embryonic development, such as Prl2c2 [69].

These placental alterations may contribute to the cardiac phenotype in several ways: (1) Through modified nutrient transfer affecting cardiac development [85]; (2) Via altered secretion of placental hormones that influence cardiovascular development [86]; or (3) Through changes in placental clock function that disrupt the synchronization of fetal tissues [87]. The placenta itself possesses a functional circadian clock that coordinates its functions, and disruption of this clock may have cascading effects on fetal development.

Metabolic disorders

Prenatal circadian disruption appears to program offspring for broader metabolic dysfunction that can exacerbate cardiac pathology. In animal models, offspring exposed to maternal circadian disruption develop more severe diet-induced obesity when challenged with high-fat diet in adulthood. This metabolic programming, characterized by hyperphagia, leptin resistance, and disrupted hepatic metabolic gene rhythms, creates a pro-inflammatory and profibrotic systemic milieu that can synergize with primary cardiac alterations to accelerate remodeling and worsen outcomes. These offspring exhibit increased white adipose tissue accumulation, liver steatosis, and hyperleptinemia, along with altered expression of hypothalamic neuropeptides regulating appetite [69,88]. It is also important to note that such metabolic disturbances and their cardiovascular consequences may not be exclusive to male offspring, as maternal circadian disruption can predispose both sexes to metabolic disorders through mechanisms like altered placental function and fetal programming [89].

This metabolic programming may create an unfavorable systemic environment that accelerates cardiac remodeling. The combination of obesity, insulin resistance, and leptin resistance creates a pro-inflammatory, profibrotic milieu that can synergize with primary cardiac alterations to worsen outcomes. This is particularly relevant given the well-established connections between metabolic syndrome and cardiovascular disease in human populations.

Epigenetic regulation

While direct evidence in the context of circadian disruption is still emerging, epigenetic mechanisms likely mediate the persistent effects of developmental circadian disruption on cardiac gene expression. DNA methylation [90,91], histone modifications [92], and non-coding RNAs [93] represent plausible mechanisms through which transient circadian disruption during critical developmental windows could establish long-lasting alterations in gene expression patterns.

The sex-specificity of the cardiac phenotype further suggests that these epigenetic modifications may interact with sex chromosomes or gonadal hormones. For instance, genes escaping X-chromosome inactivation or regulated by Y-chromosome genes might display sexually dimorphic epigenetic responses to circadian disruption [94,95]. Understanding these epigenetic mechanisms could reveal novel targets for interventions aimed at reversing the programmed cardiac vulnerability.

The translation of these preclinical findings to human health represents a critical challenge with significant potential implications for cardiovascular prevention and pregnancy management.

Public health and clinical implications

For women of reproductive age, particularly those engaged in shift work or experiencing frequent trans meridian travel, the potential consequences of circadian disruption during pregnancy warrant attention. While complete avoidance of circadian disruption may be impractical, several strategies might mitigate risks:

Circadian hygiene: Optimizing light-dark exposure, maintaining regular sleep-wake schedules, and timing meals appropriately may help stabilize circadian rhythms during pregnancy.

Targeted monitoring: Offspring born to mothers with significant circadian disruption during pregnancy might benefit from enhanced cardiovascular monitoring throughout life, potentially enabling earlier detection of subclinical dysfunction.

Biomarker identification: The discovery of Scgb1a1 as a potential mediator suggests that circulating levels of this or similar proteins might serve as biomarkers identifying individuals with increased susceptibility to cardiac remodeling.

For patients with tachycardia-induced cardiomyopathy, understanding the molecular links between circadian disruption, metabolic rewiring, and contractile dysfunction may reveal novel therapeutic approaches. The demonstration that NAD+ supplementation can accelerate functional recovery in model systems highlights the potential for targeting the metabolic consequences of circadian disruption [96].

Future research directions

Several key questions merit attention in future research:

Longitudinal studies: Most current data come from young adult animals. Longitudinal studies tracking cardiac structure and function throughout the lifespan are needed to determine whether females remain protected with aging and whether cardiac abnormalities in male’s progress to overt heart failure.

Mechanistic dissection: The relative contributions of circadian disruption versus associated stress responses need clarification through studies specifically dissecting these pathways, potentially using conditional genetic approaches.

Human studies: Prospective cohort studies examining the relationship between maternal circadian patterns during pregnancy and offspring cardiovascular development are essential to translate these findings to human health.

Interventional strategies: Research exploring specific interventions to prevent or reverse the adverse cardiac effects of developmental circadian disruption is needed, including pharmacological approaches targeting identified pathways (e.g., Scgb1a1) and lifestyle interventions.

Cross-generational effects: Preliminary evidence suggests that some effects of circadian disruption may persist across multiple generations [88,97]. The mechanisms and implications of such transgenerational inheritance warrant further investigation.

These findings highlight the importance of circadian health during pregnancy as a potentially modifiable factor influencing cardiovascular disease risk in subsequent generations. They also underscore the necessity of considering biological sex as a critical variable in understanding developmental programming of cardiovascular disease. while acknowledging that risk manifestations can be complex and are not always exclusive to one sex. Future research should aim to clarify these sex-specific and shared risk pathways, including how maternal circadian disruption may elevate risk for all offspring through pregnancy complications (e.g., preeclampsia, gestational diabetes), which themselves have lasting cardiovascular consequences. Future research translating these findings to human populations and developing targeted interventions could have significant impact on preventing cardiovascular disease through early-life interventions that account for this complexity.

Conceptualization, design-review, literature search and analysis, manuscript writing-initial draft and finalizing, Y.Z., Z.Y.G., X.W.D. and Z.P.; table-revision and manuscript writing, Z.P. All authors have read and agreed to the published version of the manuscript.

This work was supported by Sichuan Province Science and Technology Support Program: NO. 2024NSFSC0305.

The authors declare no conflict of interest.

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