Insomnia and Cardiovascular Disease: Untangling a Complex Relationship

ABSTRACT

Insomnia is the most prevalent sleep disorder, affecting up to one third of the adult population and is increasingly recognised as a potential contributor to cardiovascular disease (CVD), a leading cause of global morbidity and mortality. This narrative review examines the complex relationship between insomnia and CVD, integrating epidemiological, genetic and mechanistic evidence to assess whether insomnia represents a causal cardiovascular risk factor. Large prospective cohort studies and meta‐analyses consistently show that insomnia symptoms and clinically diagnosed insomnia are associated with increased risks of hypertension, myocardial infarction, stroke, heart failure and cardiovascular mortality, with stronger associations observed in individuals with short sleep duration or persistent insomnia. Mendelian randomization studies involving millions of participants further support a likely causal link, suggesting that genetic liability to insomnia increases the risk of multiple cardiometabolic outcomes. Biological plausibility is supported by evidence of autonomic imbalance, hypothalamic–pituitary–adrenal axis activation, inflammation and adverse blood pressure profiles in individuals with insomnia. However, insomnia is a heterogeneous condition, frequently coexisting with other sleep disorders and influenced by psychosocial and circadian factors, which complicates causal inference. Importantly, evidence that treatment of insomnia reduces cardiovascular risk remains limited. While cognitive behavioural therapy for insomnia improves sleep outcomes and some cardiometabolic biomarkers, randomised trials have not demonstrated clear benefits on blood pressure or other cardiovascular endpoints and some pharmacological treatments may even be associated with harm. Overall, current evidence suggests that insomnia is a plausible and potentially causal risk factor for CVD, but definitive proof of reversibility through treatment is lacking. Well‐powered, rigorously designed trials targeting patients with clinically defined insomnia are needed to determine whether effective insomnia treatment can meaningfully reduce cardiovascular risk and inform future prevention strategies.

1. Introduction

According to global estimates, approximately 10% to 30% of the general population experience some form of insomnia during their lives (Roth 2007). This prevalence varies across age groups, with higher rates observed in the elderly. Insomnia is not merely a transient issue as it can last for years, often untreated, thus becoming chronic insomnia that affects up to 10% of adults. Furthermore, women tend to be more prone to develop insomnia than men and the prevalence often increases with the presence of comorbid medical or psychiatric conditions (Pengo et al. 2018).

The impact of insomnia extends beyond its immediate effects on sleep quality. Individuals with insomnia symptoms often report impaired daytime functioning, including difficulties in concentration, memory and mood disturbances (Roth 2007). Daytime impairment associated with insomnia can have important socioeconomic implications due to decreased work performance and an increased risk of work‐related accidents (Kessler et al. 2011).

CVD remains a global health challenge, contributing significantly to morbidity and mortality. The World Health Organization (WHO) estimates that CVDs account for approximately 17.9 million deaths annually, representing 31% of all global deaths (World Health Organization 2026). This category includes conditions such as coronary artery disease, heart failure, stroke and peripheral vascular disease.

The prevalence of CVD exhibits considerable variability across regions and populations. Lifestyle factors, including diet, physical activity and tobacco use, play a pivotal role in shaping the cardiovascular risk of individuals. Sleep quality and duration might also play a role, in fact most recently, the American Heart Association (AHA) has included sleep as an additional pillar of cardiovascular health suggesting that the improvement of sleep duration and quality could further improve cardiovascular prevention (Makarem et al. 2022). While sleep duration was one of the main sleep metrics included in the AHA's ‘Essential Eight’ due to its overall simplicity and the available literature, sleep duration co‐varies with sleep disorders such as insomnia. An improved understanding of the causal role of insomnia in the development or progression of CVD would inform future public health recommendations regarding sleep health targets.

2. Intersection of Insomnia and Cardiovascular Disease

The intersection of insomnia and CVD is an area of growing interest in both clinical and research settings. While each condition has been studied independently, mounting evidence suggests a potential bidirectional relationship (Javaheri and Redline 2017). Individuals with insomnia may face an elevated risk of developing CVD and conversely, those with existing cardiovascular conditions may often experience insomnia symptoms (Covassin and Singh 2016; Frøjd et al. 2021). Understanding the prevalence of both conditions and their co‐occurrence sets the stage for further exploration into the complex relationship between sleep and cardiovascular health.

It is important to note, however, that insomnia is a complex sleep disorder that can be further classified according to subtypes (e.g., considering duration of sleep), some of which exhibit stronger association with CVD. (Jarrin et al. 2018)

Sleep duration has already been proposed as an independent risk factor for CVD (Cappuccio et al. 2011) and therefore the combination of insomnia and reduced sleep duration may identify subjects at greater risk of developing cardiovascular events (Bertisch et al. 2018). This was demonstrated in a subset of patients from the Penn State cohort, followed up for 14 years: mortality risk was significantly increased in male insomniacs who slept less than 6 h compared to subjects with no insomnia and normal sleep duration (OR = 4.00, CI 1.14–13.99) after adjusting for diabetes, hypertension and other confounders (Vgontzas et al. 2010).

These data are supported by recent evidence showing that after adjusting for potential confounders, patients with chronic insomnia who slept < 7 h had 2.8‐fold increased odds of hypertension compared with normal sleepers (Dai et al. 2023). Thus, hypertension could represent the main cardiovascular risk factor mediating the relationship between insomnia and the development of CVD. A recent systematic review and meta‐analysis of prospective cohort studies showed that indeed the association between insomnia and hypertension might be bidirectional suggesting that patients with hypertension should be identified early to prevent insomnia and vice versa (Liu et al. 2022).

However, data suggesting that treatment of insomnia can improve blood pressure control are lacking.

Data from the Sleep Heart Health Study further supports the relationship between insomnia and CVD as higher risk of incident CVD was found in patients with insomnia coupled with short sleep duration compared to those with normal sleep duration (Bertisch et al. 2018).

An additional insomnia subtype that deserves to be mentioned is comorbid insomnia and obstructive sleep apnea (COMISA). COMISA is a common condition that leads to greater health issues than either insomnia or obstructive sleep apnea alone. Around 30%–50% of people with obstructive sleep apnea (OSA) experience insomnia and 30%–40% of those with insomnia also have OSA. Individuals with COMISA suffer from impaired sleep, daytime functioning, mental health, quality of life and cardiovascular health compared to those with just insomnia or OSA. These negative health outcomes are consistently observed across various diagnostic methods and severity levels, even in cases with mild OSA and less frequent insomnia (Vozoris 2012; Lechat, Loffler, et al. 2022).

A recent analysis of the Wisconsin Sleep Cohort confirmed that individuals with both insomnia and OSA exhibit a higher risk of all‐cause mortality compared to those without either condition. Interestingly, according to these data, having only insomnia or only OSA was not linked to an increased risk of death suggesting a synergic effect of these conditions in the development of CVD (Lechat, Loffler, et al. 2022).

3. Is There a Causal Relationship Between Insomnia and CVD?

As we delve into the intricate web of connections between insomnia and CVD, a pivotal question emerges: is there a causal relationship between these two prevalent health concerns? Establishing causality is a complex undertaking that requires a comprehensive exploration of the available evidence and goes beyond the scope of the present narrative review. However, in the present work we wanted to describe some of the most important aspects of this association such as temporality, strength, consistency and plausibility as a better understanding of the role of insomnia in CVD holds profound implications for both clinical practice and public health interventions. These criteria, known as the Bradford Hill criteria (Hill 1965), provide a framework for assessing the strength of evidence for causation in observational studies and can allow us to evaluate the causal link between the presence of insomnia and the development of CVD.

The following sections will discuss some of the Bradford Hill criteria in the context of insomnia and CVD, aiming to shed light on whether the available evidence suggests a causal link or a more complex interplay between these two health issues.

To accomplish this task, we reviewed the current literature exploiting the Medline database from inception to August the 1st 2025, including in the search strategy the following terms:

1. Insomnia, AND

2. (cardiovascular disease) OR (heart failure) OR (myocardial infarction) OR (atherosclerosis) OR (atrial fibrillation) OR (arrhythmias) OR (cardiovascular death) OR (stroke)

Studies were included in the review if they included adult subjects (≥ 18 years), were peer‐reviewed and in English language.

To facilitate the critical assessment of the literature by the reader we will refer throughout the text to insomnia when a clinical diagnosis of the disease according to internationally recognised criteria was reported, while we will refer to generic insomnia symptoms, when this was not specified in the study methods (Table 1).

TABLE 1.

Main characteristics of the studies included in the review and mapping each one to the Bradford Hill criterion it supports. ABPM, ambulatoy blood pressure measurement; ACS, acute coronary syndrome, BP, blood pressure; CAD, coronary artery disease; CBT‐I, cognitive behavioral therapy for insomnia; CRP, C‐reactive protein; CV, cardiovascular, CVD, cardiovascular disease, HF, heart failure; MI, myocardial infarction; TnT, troponin T;

Author	Cohort included	Study design	Number of patients	Insomnia diagnosis	Main findings associated with insomnia	Bradford‐Hill criteria
Ali et al. (2023)	Prospective, retrospective	Meta‐analysis	2,583,117	No	Increased CV mortality, MI, all‐cause mortality, CVD	Strength of association
Sofi et al. (2014)	Subjects free of CVD at baseline	Meta‐analysis	122,501	No	Increased risk of developing or dying CVD	Strength of association, consistency
Ge et al. (2019)	Adults > 18 years	Meta‐analysis	1598.628	No	Increased CV mortality, all‐cause mortality	Strength of association
Li et al. (2014)	Men 40–75 years	Prospective study	23,447	No	Increased CV mortality	Strength of association
Choi et al. (2017)	Subjects with sleep disturbance	Retrospective study	4225	Yes	Increased CV mortality	Strength of association
Zheng et al. (2019)	Subjects 30–79 years free of CHD, stroke at baseline	Prospective study	487,200	Yes	Increased risk of CVD	Strength of association, consistency, temporality, biological gradient
Chung et al. (2013)	Subjects with sleep disorders	Prospective study	147,297	Yes	Increased risk of ACS	Consistency
Kalmbach et al. (2016)	Adults	Cross‐sectional study	3911	Yes	Increased risk of stroke	Consistency
Dean et al. (2023)	Adults	Meta‐analysis	1184.256	No	Increased risk of MI	Consistency
Jia et al. (2022)	Adults	Mendelian randomization study	2500.086	No	Increased risk of ischemic stroke, CAD, HF	Specificity
Yuan et al. (2021)	Adults	Meta‐analysis	1331.010	No	Increased risk of ischemic stroke, CAD, HF, AFib	Specificity
Mahmood et al. (2021)	Adults ≥ 50 years	Prospective study	12,761	No	Increased risk of HF	Temporality, biological gradient
Thurston et al. (2024)	Women 42–52 years	Prospective study	2964	No	Increased risk of CVD	Temporality
Parthasarathy et al. (2015)	Subjects 21–75 years	Prospective study	1409	Yes	Increased risk of all‐cause and cardiopulmonary mortality	Temporality, biological gradient
Laugsand et al. (2014)	Adults	Prospective study	54,279	No	Increased risk of HF	Biological gradient
Horsley et al. (2016)	Adults enrolled in cardiac rehabilitation	Prospective study	121	No	Difficulty falling asleep associated with reduced parasympathetic tone	Plausibility
Pengo et al. (2017)	Adults with CKD	Prospective study	104	No	Increased nocturnal BP variability	Plausibility
Maiolino et al. (2021)	Adults	Meta‐analysis	924	Yes	Blunted nocturnal BP dipping	Plausibility
Li et al. (2021)	Adults	Meta‐analysis	395,641	Yes	Increased risk of hypertension	Plausibility
Liukkonen et al. (2007)	Adults	Prospective study	4011	No	Increased CRP levels	Plausibility
Sigurdardottir et al. (2023)	Adults	Prospective study	2188	No	Increased TnT levels	Plausibility
McGrath et al. (2017)	Adults with insomnia symptoms	RCT	134	No	CBT‐I did not decrease BP at ABPM vs. usual care	Reversibility
Javaheri et al. (2020)	Adults with insomnia symptoms and CHD	RCT	29	No	CBT‐I did not decrease BP vs. usual care	Reversibility
Johann et al. (2020)	Adults with insomnia	RCT	46	Yes	CBT‐I did not decrease BP at ABPM vs. no treatment	Reversibility
Haines et al. (2021)	Post‐menopausal women	Prospective study/RCT	40,728	No	Z‐drugs associated with increased risk for death and CVD	Reversibility
Sun et al. (2023)	Adults ≥ 20 years	Prospective study	484,916	No	Sleeping pills associated with increased risk all‐cause mortality	Reversibility
El‐Solh et al. (2023)	Adults with insomnia	Prospective study	7824	Yes	Sleeping pills associated with increased risk all‐cause mortality	Reversibility
Sato et al. (2020)	Adults with CHF	Prospective study	2213	No	Benzodiazepines associated with increased risk of rehospitalization for HF	Reversibility
Solanki et al. (2023)	Adults with hypertension	Meta‐analysis	422	No	Benzodiazepines did not decrease systolic BP	Reversibility
Mendelson et al. (2018)	Adults undergoing ABPM	Retrospective study	4938	No	Benzodiazepine associated with lower BP at ABPM among ≥ 60 years old.	Reversibility
Kario et al. (2019)	Adults with insomnia symptoms and hypertension	RCT	82	No	Suvorexant had no effect on BP	Reversibility
Weich et al. (2014)	Subjects ≥ 16 years prescribed sleeping pills vs. matched controls	Retrospective study	104,145	No	Sleeping pills associated with increased risk all‐cause mortality	Reversibility

3.1. Strength of Association

The strength of the association between insomnia and CVD varies according to different studies and outcomes considered. However, across all studies together and considering different study designs and target populations, there are consistent patterns of association.

A recent meta‐analysis of real‐world data found that individuals with insomnia symptoms, compared to those without sleep disorders, exhibit a higher risk of cardiovascular mortality (RR 1.53, p < 0.01), myocardial infarction (RR 1.48, p < 0.03), all‐cause mortality (RR 1.14, p < 0.03) and incidence of CVD (RR 1.31, p < 0.01) (Ali et al. 2023). However, the inclusion criteria were rather broad as patients with insomnia disorder or one of the associated four major symptoms including difficulty in initiating sleep, difficulty in maintaining sleep, non‐restorative sleep and early morning awakening were included. The authors did not report any sensitivity analysis considering the different insomnia definitions which makes it difficult to establish whether the sleep disorder itself or clinical features of the disease are more strongly associated with outcomes.

A meta‐analysis limited to prospective studies comprising 13 cohorts involving a total of 122,501 subjects followed for a time ranging from 3 to 20 years showed that insomnia symptoms were associated with an increased risk (45%) of developing or dying from CVD during the follow‐up (Sofi et al. 2014). Similarly to the previous analysis, in the studies included in this meta‐analysis the definition of insomnia involves clinical features of the disease such as difficulty initiating sleep, restless or disturbed nights and number of insomnia symptoms. Again, no sensitivity analysis was performed to understand the role of insomnia diagnostic classification in the association with CVD.

When only considering individual insomnia questions, similar associations were observed. In a recent systematic review and meta‐analysis, difficulty falling asleep was associated with a 13% higher risk of all‐cause mortality and a 20% higher risk of CVD mortality (Ge et al. 2019). Similarly, non‐restorative sleep was associated with a 23% higher risk of all‐cause mortality and a 48% higher risk of CVD mortality. Interestingly, in the latter study the association between difficulty falling asleep and all‐cause mortality was more evident in the mid to older‐aged population (age ≥ 65 years).

Furthermore, in a prospective cohort study of 23,447 men participating in the Health Professionals Follow‐up Study, those with difficulty initiating sleep and non‐restorative sleep most of the time had a 55% (HR:1.55; 95% CI:1.19–2.04; P‐trend = 0.01) and 32% (HR:1.32; 95% CI:1.02–1.72; P‐trend = 0.002) increased risk of CVD mortality, respectively (Li et al. 2014).

In a large retrospective study involving 4225 individuals who underwent polysomnography for sleep complaints, those diagnosed with insomnia (n = 661) exhibited a markedly increased risk of cardiovascular mortality (HR 8.11; 95% CI 1.03–63.58) compared to individuals without sleep disorders (Choi et al. 2017). Additionally, a large population‐based prospective cohort study found that insomnia (n = 10,801) was associated with a higher incidence of cardiovascular events (HR 1.18 95% CI 1.10–1.26 and 1.12 95% CI 1.08–1.17 in male and females, respectively) compared to subjects with no insomnia (n = 476,399) (Zheng et al. 2019).*

In summary, there is consistent evidence suggesting that insomnia could indeed represent an independent risk factor for CVD, albeit some sources of heterogeneity in the studies described should be acknowledged and discussed. Firstly, as mentioned earlier, inclusion criteria almost never did include patients with insomnia diagnosed according to international guidelines but rather patients with features or symptoms of the disease. This makes it difficult to consider all the findings of the studies together and should be considered for a more precise understanding of heterogeneity in research findings. Secondly, insomnia is often associated with other sleep disorders that can represent additional risk modifiers. For instance, insomnia patients with comorbid OSA, the so‐ called COMISA, exhibit a greater risk of all‐cause mortality compared to those with no insomnia/OSA (Lechat, Appleton, et al. 2022). Lastly, although studies hazard ratios for CVD outcomes showed moderate‐to‐high effect sizes (12% to 800% increased adjusted risk estimates) it is likely that not all confounders were considered, possibly mitigating the strength of the relationship. In a recent study that harmonised individual‐level data from > 1 million participants of 112 cohort studies conducted in 34 countries the five modifiable risk factors accounted for an aggregate population‐ attributable fraction of the 10‐year incidence of CVD of 57.2% among women and 52.6% among men (Global Cardiovascular Risk Consortium et al. 2023). Therefore, more studies are needed to confirm the role of insomnia on CVD development accounting for all main cardiovascular risk factors.

3.2. Consistency

Inconsistency of findings across studies and populations reduce the likelihood that associations are causal. With regards to the association between insomnia and CVD, consistency has been observed in numerous studies, supporting an increased risk of CVD incidence among individuals with insomnia.

Despite overall consistency in associations, insomnia symptom severity varies by demographic factors (such as gender, age and ethnicity) which in turn can also affect cardiovascular risk.

When considering the recent meta‐analyses, the association between insomnia and CVD does not seem to be influenced by the country of cohorts, although the data are not fully representative of the global population or addressed population‐specific effects (Sofi et al. 2014).

Cohort studies consistently demonstrate that individuals with insomnia are at increased risk of a range of cardiovascular outcomes, including cardiovascular mortality, myocardial infarction and stroke. These associations have been observed across both genders and diverse ethnic populations (Zheng et al. 2019; Chung et al. 2013; Kalmbach et al. 2016).

Finally, a recent systematic review and meta‐analysis including nine studies for a total of 1184.256 patients found that insomnia symptoms were significantly associated with an increased incidence of myocardial infarction. When evaluating potential confounders or effect modifiers, this association remained significant across all subgroups of patients, including younger and older age (< 65 and > 65), follow‐up duration (more or less than 5 years), male and female gender and common comorbidities (diabetes, high blood pressure or cholesterol) (Dean et al. 2023).

In summary, the adverse effects of insomnia were consistently confirmed in both genders, multiple ethnicities, age and comorbidities.

3.3. Specificity

Causation is likely if a relationship is observed in a sample and setting where there is little likelihood of confounding or reverse causality. Restricting analyses to samples with few confounders is challenging in studies of insomnia and CVD given that there are multiple genetic, social and environmental factors affecting both insomnia and CVD (Sato et al. 2020).

Evidence from Mendelian randomization studies, in which genetic data are used as instruments to reduce the effects of confounders, have provided evidence in support of a causal association between insomnia and CVD. In more than 2 million participants, Mendelian randomization analyses support the causal relationship between clinical features of insomnia and cardiometabolic diseases including ischemic stroke, coronary artery disease, heart failure and type 2 diabetes mellitus (Jia et al. 2022).

These findings were further confirmed in a study using genetic data for 367,586 women and men where genetic liability to insomnia was associated with higher risk of a broad range of CVDs (Yuan et al. 2021). However, genetic predisposition to insomnia appeared to influence body mass index, type 2 diabetes and smoking in an unfavourable manner and these factors might partly mediate the link between insomnia and these CVDs.

Nevertheless, some important confounders that could play a role in the relationship between insomnia and CVD are represented by the presence of circadian disorders that could be a CVD risk factor themselves as recently highlighted in a position paper by the American Heart Association (Knutson et al. 2025).

Related to this, working non‐traditional hours (e.g., during nighttime), can also determine additional misalignment leading to insomnia thus possibly mediating the relationship with CVD.

Indeed, a rather large body of evidence suggests that night shift workers exhibit greater risk of developing ischemic heart disease and that such association can depend also on the duration of rotating night shift work (Vetter et al. 2016).

In summary, Mendelian randomization studies involving over two million participants strongly support the specificity of the association between insomnia and CVD such as stroke, coronary artery disease, heart failure.

3.4. Temporality

As described already, most longitudinal studies investigating the association between insomnia and cardiovascular complications support the temporal sequence of events that insomnia precedes CVD. A recent study that analysed a database from the Health and Retirement Study in the US for a population‐representative sample of 12,761 middle‐aged and older adults (free of heart failure at baseline) followed‐up for 16 years found that insomnia symptoms both cumulatively and individually were associated with incident heart failure (Mahmood et al. 2021).

In one of the largest prospective studies, including approximately 0.5 million Chinese adults aged ≥ 50 years and followed for nearly a decade, insomnia reported in the month prior to enrollment emerged as an independent risk factor for incident CVD. The association was particularly pronounced among participants who were younger at baseline and had not yet developed hypertension (Zheng et al. 2019).

While the previous studies focused on temporality in the context of insomnia and CVD—the sequence of events where insomnia precedes the onset of CVD suggesting a cause‐and‐effect relationship—other studies focused more on how the duration of insomnia influences the risk of developing CVD over time.

Recently, a prospective study investigating 2964 women, who were followed‐up for more than 19 years, from the Study of Women's Health Across the Nation (SWAN) cohort showed that when participants were divided according to different trajectories of insomnia symptoms, those with insomnia symptoms persistent over midlife or occurring with short sleep exhibited a greater risk of CVD (Thurston et al. 2024).

Similarly, among 1409 adult participants of the community‐based, prospective cohort study Tucson Epidemiological Study of Airway Obstructive Disease, those with persistent insomnia (HR 1.58, 95% CI: 1.02–2.45) but not intermittent insomnia (HR 1.22, 0.86–1.74), exhibited increased all‐ cause and cardiopulmonary mortality than participants without insomnia (Parthasarathy et al. 2015).*

This supports the concept that the prolonged exposure to the stress, inflammation and hormonal imbalances caused by chronic insomnia increases the strain on the cardiovascular system over time. This extended period of poor sleep quality and its associated physiological disruptions can lead to the development and progression of cardiovascular conditions.

3.5. Biological Gradient

In the largest epidemiological study to date, Laugsand et al. collected baseline data on insomnia symptoms in 54,279 participants from the HUNT study conducted in Norway (Laugsand et al. 2014). After accounting for all major cardiovascular risk variables, their findings showed an association between the frequency of insomnia symptoms and the likelihood of newly diagnosed heart failure during an 11‐year follow‐up period. The possible impacts of time‐dependent variations in the severity of insomnia symptoms were not taken into consideration, though, because insomnia symptoms were only evaluated once at baseline. Furthermore, while the current study considered time‐varying symptoms of insomnia, it is not possible to determine if people with a waxing and waning pattern of insomnia were at a similar risk of getting heart failure as people with chronic persistent insomnia.

In a longitudinal population‐based study of 12,761 middle‐aged and older adults, Mahmood et al. reported that insomnia symptoms were associated with an elevated risk of incident heart failure, with risk increasing in a dose–response manner—from 22% with one symptom (HR 1.22; 95% CI 1.08–1.38) to 80% with four symptoms (HR 1.80; 95% CI 1.25–2.59) (Mahmood et al. 2021).

Similarly, Zheng et al. confirmed this dose–response relationship in a large cohort, showing that the risk of CVD increased from 7% with one symptom (HR 1.07; 95% CI 1.05–1.08) to 18% with three symptoms (HR 1.18; 95% CI 1.13–1.24) of insomnia (Zheng et al. 2019).

Furthermore, evidence from a community‐based prospective cohort study demonstrated that while persistent insomnia was associated with a 50% increase in cardiovascular mortality, intermittent insomnia did not confer an elevated risk (Parthasarathy et al. 2015).

Collectively, these findings indicate a biological gradient in the association between insomnia and CVD, with risk increasing both with the number of insomnia symptoms (Zheng et al. 2019) and with persistence of the disorder (Parthasarathy et al. 2015).

3.6. Plausibility

Several interconnected mechanisms underlie the relationship between insomnia and CVD including disruptions in the hypothalamic–pituitary–adrenal (HPA) axis, abnormal modulation of the autonomic nervous system such as heightened sympathetic nervous system (SNS) activity and increased systemic inflammation (Javaheri and Redline 2017) (Figure 1).

FIGURE 1.

Directed acyclic graph illustrating the multidirectional relationships among insomnia, cardiovascular disease and shared risk or mediating factors. The central nodes (Insomnia, Cardiovascular disease) appear in yellow and blue, respectively. Medical and biological factors (blue nodes), psychosocial and lifestyle factors (pink nodes) and intermediate pathophysiological pathways (green arrows) are displayed to highlight the complex interplay across domains. Arrow colours indicate directionality of influence: Green for pathways leading towards cardiovascular outcomes and magenta for pathways linking insomnia with its determinants and consequences.

Chronic insomnia is known as a state of conditioned hyperarousal, linked to increased SNS activity and raised levels of arousal‐ related hormones like cortisol. Patients with insomnia, particularly those with objectively short sleep duration, often exhibit increased adrenocorticotropic hormone and cortisol secretion, indicating heightened HPA axis activity thus representing a potential risk factor for the development of insulin resistance, impaired glucose metabolism and diabetes, acting as potential mediators in the path to CVD (Vgontzas et al. 2013).

Studies reveal increased SNS activity in both short sleepers and individuals with insomnia, as evidenced by elevated levels of plasma and urine norepinephrine, increased heart rate and altered heart rate variability (Vgontzas et al. 2010). SNS activity is of paramount importance for cardiovascular homeostasis, playing a crucial role in hypertension, arrhythmias, coronary heart disease and heart failure (Mehra et al. 2022).

A study linked difficulty falling asleep with reduced parasympathetic tone in patients with moderate to severe insomnia undergoing cardiac rehabilitation (Horsley et al. 2016).

In a study on 180 adults with chronic insomnia, those sleeping less than 6 h per night showed significantly dampened parasympathetic activation and increased sympathovagal imbalance compared to those sleeping > 6 h per night (Horsley et al. 2016).* [clinical trial with clinical diagnosis of insomnia] This reinforces the importance of sleep duration in patients with insomnia as a potential cardiovascular risk mediator and possibly modifier.

Overall, this evidence suggests an association between insomnia and the presence of an enhanced sympathetic activation that causes rises in heart rate and blood pressure, the latter through a stimulation of renin angiotensin aldosterone system (Maiolino et al. 2020). Increased sympathetic activation can also be responsible for sleep‐related increases in blood pressure in a study on chronic kidney disease patients where insomnia severity was associated with increased nocturnal blood pressure variability (Pengo et al. 2017).

Insomnia can contribute to raise nocturnal blood pressure and reverse BP dipping at night (Maiolino et al. 2021) therefore representing one of the mediators of the relationship between altered diurnal BP profile and CVD. The influence of nighttime blood pressure levels and the day‐night blood pressure dip on cardiovascular outcomes is consistent across different contexts, including both the general population (Sega et al. 2005) and patients with hypertension (Dolan et al. 2005). Recent studies, such as one published in The Lancet, highlight the greater prognostic value of nighttime blood pressure compared to office blood pressure measurements (Staplin et al. 2023).

As such insomnia can represent a risk factor for hypertension and indeed a recent meta‐analysis of prospective cohort studies found a significant association (risk ratio 1.21, 95% CI: 1.10–1.33) between insomnia and hypertension (Li et al. 2021). Interestingly this association was seen for sleep maintenance insomnia but not for sleep initiation insomnia and was observed in Europeans only.

Although not directly addressing insomnia, experiments with sleep curtailment and disruption show subsequent increases in blood pressure and inflammatory cytokines associated with atherogenesis, such as C‐reactive protein (CRP), tumour necrosis factor‐α and interleukin 6 (Shearer et al. 2001).

Epidemiologic data also suggest an association between insomnia and elevated CRP levels, with chronic persistent insomnia linked to cardiopulmonary mortality associated with increased CRP levels (Liukkonen et al. 2007). The presence of increased inflammatory markers can eventually promote myocardial inflammation and damage thus supporting the biological plausibility in the relationship between insomnia, myocardial infarction and cardiovascular mortality (Sigurdardottir et al. 2023).

3.7. Reversibility

If the association between insomnia and CVD is causal, treating insomnia should have an impact on cardiovascular prognosis (Figure 2). However, randomised controlled trials evaluating the impact of insomnia treatment on cardiovascular events are lacking. Consequently, evidence regarding reversibility derives primarily from studies focusing on surrogate endpoints, such as biomarkers and blood pressure.

FIGURE 2.

Evidence on how to manage insomnia in patients with elevated cardiovascular risk. CBT‐I, cognitive behavioural therapy for insomnia; CV, cardiovascular; CVD, cardiovascular disease.

The most effective non‐pharmacologic treatment for insomnia is cognitive behavioural therapy (CBT‐I), which has shown consistent evidence of improvements in both insomnia severity and quality of life (Riemann et al. 2017).

More recently, a meta‐analysis of randomised controlled trials indicated that CBT‐I can also reduce levels of CRP and glycated haemoglobin, two established risk factors for CVD (Savin et al. 2023).

To date, three randomised controlled trials have investigated the effects of CBT‐I on blood pressure in patients with insomnia; however, none demonstrated a significant impact on this outcome (McGrath et al. 2017; Javaheri et al. 2020; Johann et al. 2020). The Sleep to Lower Elevated Blood Pressure Trial (SLEPT) randomised 134 participants with self‐reported insomnia symptoms in the preceding three months to receive either CBT‐I or usual care (McGrath et al. 2017). Ambulatory blood pressure monitoring revealed no between‐group differences in systolic or diastolic blood pressure. It is notable, however, that this trial had several limitations: participants did not require a formal clinical diagnosis of insomnia, the intervention arm experienced a high dropout rate (19%) and the study was likely underpowered. Furthermore, inclusion criteria were modified during recruitment, lowering the systolic blood pressure threshold from 140–160 mmHg to 130–160 mmHg, thereby enrolling individuals who were not consistently hypertensive (McGrath et al. 2017).

A more recent randomised controlled trial aimed to enrol 60 patients with coronary artery disease and insomnia, as assessed by the Insomnia Severity Index (Javaheri et al. 2020). Due to resource constraints, only 29 participants completed the study, with randomization to either CBT‐I or control. In the intervention group, a non‐significant reduction in systolic (−3 mmHg) and diastolic (−1 mmHg) blood pressure was observed compared with controls. However, the trial was not specifically designed to evaluate blood pressure outcomes, was underpowered due to recruitment challenges and included more than 10% of participants without hypertension.

Finally, a preliminary randomised controlled trial investigated the role of CBT‐I on blood pressure (Johann et al. 2020).

Forty‐six patients with insomnia were randomised to CBT‐I or a waitlist control condition: intention‐to‐treat analyses did not show any significant treatment effects on 24 h blood pressure, CRP or heart rate variability despite successful insomnia treatment. However, the trial was likely underpowered to detect blood pressure changes, as the sample size was calculated to investigate early cardiovascular markers rather than blood pressure specifically. Moreover, at least half of the cohort was not hypertensive, as reflected by the mean baseline ambulatory blood pressure in the CBT‐I arm (systolic 124 ± 11 mmHg; diastolic 83 ± 7 mmHg).

Nonbenzodiazepine GABA agonists (Z‐drugs) are the most commonly prescribed sleep aids but their impact on cardiovascular risk profile is unclear. A recent study analysed the data of the Women's Health Initiative database, a multicentre national study of postmenopausal women conducted in the United States (Haines et al. 2021). After a follow up of 14 years, Z‐drugs use was associated with an increased risk of death and CVD in post‐menopausal women being treated for sleep disturbances. However, residual confounding and possible indication bias make interpretation of the finding difficult.

The combination of hypnotics and inadequate sleep duration may together contribute to increase mortality risk: in a cohort of 484,916 adults in Taiwan, the use of sleeping pills was associated with an increased risk of mortality and shortened life expectancy, with associations strongest among extreme short and long sleepers (sleep duration < 4 h or > 8 h) (Sun et al. 2023).

Similarly, in a study analysing the Veterans Affairs Corporate database of 16,064 newly diagnosed insomnia patients, treatment with hypnotics resulted in higher rates of major adverse cardiovascular events but not nonfatal major adverse cardiovascular events in benzodiazepine and Z‐drug users compared with nonusers (El‐Solh et al. 2023). Interestingly, the use of serotonin antagonist and reuptake inhibitors agents was suggested as having a protective effect against major adverse cardiovascular events.

Furthermore, a study on 826 Japanese patients who had been hospitalised for heart failure and were being treated for insomnia found that the use of benzodiazepines was an independent predictor of rehospitalization for heart failure (hazard ratio, 1.530; 95% CI, 1.025–2.284; p = 0.038) (Sato et al. 2020).

Given that hypertension is one of the main risk factors for heart failure, a systematic review and meta‐analysis of randomised clinical trials attempted to investigate the effect of benzodiazepines on BP (Solanki et al. 2023). The authors did not find significant difference in reduction of systolic blood pressure by benzodiazepines as compared to placebo; however, the mean difference of −6.35 mmHg; 95% CI [−14.82, 2.13], while not statistically significant, suggested a clinically meaningful effect. This finding is consistent with a retrospective analysis of blood pressure data from 4938 ambulatory blood pressure monitoring where long‐term use of benzodiazepines by ≥ 60 years old was independently associated with lower diastolic and systolic blood pressure (Mendelson et al. 2018). These findings suggest that while benzodiazepines may not produce statistically significant reductions in blood pressure in the short term, they could still have a clinically relevant impact, particularly in older adults.

Among the new medications licensed for insomnia, suvorexant is a selective, reversible dual orexin receptor antagonist that has been studied in relation with its potential effect on blood pressure. In the SUPER‐1 study, a multicentre, randomised, double‐blind study testing orexin antagonists in patients with insomnia and hypertension no differences on office or out‐of‐office blood pressure profile were seen comparing treatment and placebo arm (Kario et al. 2019).

Taken together these studies do not support a reduction of cardiovascular risk in patients treated for insomnia, although improvements in blood pressure were suggested in several studies. On the contrary, the available evidence to date highlights a potential association between hypnotics and risk of cardiovascular events and mortality, which likely reflects medication‐specific adverse effects rather than effects related to changes in insomnia (Weich et al. 2014).

In summary, evidence demonstrating the reversibility of the adverse cardiovascular effects of insomnia through treatment is currently lacking. Notably, randomised controlled trials of the most effective insomnia therapy, CBT‐I, have focused primarily on surrogate outcomes such as blood pressure and were underpowered to detect clinically meaningful effects. In contrast, trials of hypnotic medications—agents not recommended by current guidelines for long‐term management of insomnia—have even suggested potential harm.

4. Conclusion and Future Directions

Insomnia is the most prevalent sleep disorder and mounting evidence has identified it as a potential cardiovascular risk factor. The analysis of the Bradford Hill criteria as presented in this review seems to suggest a potential causal association between insomnia and CVD (Figure 1). However, this narrative review does not provide a systematic assessment of all available studies thus cannot prove causality and cannot confirm the reversibility criterion. Thus, there is a need for adequately powered and rigorously designed clinical trials in patients with a formal diagnosis of insomnia. Such studies should evaluate both hard cardiovascular outcomes (e.g., major cardiovascular events) and intermediate endpoints (e.g., blood pressure) to establish reversibility, strengthen causal inference, as well for motivating treatment of insomnia for CVD prevention and reduction (Maiolino et al. 2020) (Table 2) The development of new drugs for insomnia constitutes one of the new avenues to further confirm that effective treatment of insomnia can serve as an additional target to reduce the burden of CVD.

TABLE 2.

Future research directions to test the hypothesis that insomnia contributes to the development of cardiovascular disease.

Category	Design requirements	Key research needs
Interventional studies	–RCTs with formal diagnosis of insomnia (not just symptoms) –Adequate sample size and statistical power to detect effects on soft and hard cardiovascular outcomes –Long‐term follow‐up to assess durability of treatment effects –Comparison of different insomnia treatment on CV outcomes –Rigorous control groups –Inclusion of patients with comorbidities	–Test whether treating insomnia reduces incidence of CVD or improves prognosis in patients with established CVD. –Examine intermediate endpoints as mechanistic mediators. –Compare efficacy and safety of insomnia treatments in subgroups –Evaluate potential adverse cardiovascular effects of hypnotics vs. newer agents. –Assess combined treatment strategies for COMISA
Longitudinal observational studies	–Large‐scale, prospective cohort studies with standardised and validated diagnostic criteria for insomnia (ICSD‐3, DSM‐5) –Long‐term follow‐up across multiple populations and ethnic groups –Objective sleep measures (polysomnography, actigraphy) alongside self‐reports –Careful adjustment for major CVD risk factors –Stratification by insomnia subtypes –Repeated measures of insomnia status to track persistence vs. remission	–Clarify temporal sequence –Establish dose–response relationship –Identify vulnerable subgroups –Explore genetic predisposition and interaction with lifestyle factors using Mendelian randomization. –Evaluate regional and ethnic differences in insomnia‐CVD associations. –Confirm long‐term impact of insomnia trajectories on CVD progression and mortality.

Author Contributions

Martino F. Pengo: conceptualization, methodology, supervision, validation, writing – review and editing, writing – original draft.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.