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Using data from over 150 000 ST‑segment elevation myocardial infarction (STEMI) patients listed in a Polish national registry, we confirmed that heart attacks follow a strong circadian rhythm, peaking at 8:00 AM. Critically, patients experiencing symptoms during night‑time hours (midnight to 5:00 AM) waited twice as long before seeking medical help than those with daytime symptom onset, which represented a major barrier to timely treatment. We found that the specific coronary artery causing the heart attack varies by the time of day, with left anterior descending artery blockages peaking at night and right coronary artery blockages peaking during daytime, suggesting that circadian biology influences not just when heart attacks occur but also their anatomical manifestation. These findings highlight the need for targeted public health campaigns addressing night‑time treatment delays and suggest that chronobiological factors may influence coronary plaque vulnerability in different vascular territories. Future research should explore whether time‑specific preventive strategies could reduce STEMI incidence and improve outcomes.

Introduction

Acute cardiovascular events follow predictable temporal patterns governed by the body’s circadian rhythm.^1-3 This 24‑hour biological clock orchestrates physiological processes that prepare the body for sleep‑wake transitions. Epidemiologic studies have consistently demonstrated that major cardiovascular events—including acute myocardial infarction (MI), stroke, and sudden cardiac death—peak between 6:00 AM and noon across diverse populations.^1-5 This morning vulnerability reflects convergent prothrombotic and hemodynamic stressors accompanying the transition from sleep to wakefulness.^1-3 Awakening triggers a surge in sympathetic activity and circulating catecholamines, increasing heart rate, blood pressure, and myocardial oxygen demand.⁶ Concurrently, the hematologic system shifts toward a prothrombotic state: platelet aggregability peaks and plasminogen activator inhibitor‑1 (PAI‑1) activity rises, creating conditions favoring thrombus formation upon plaque rupture.^1,2,7 These endogenous rhythms are amplified by exogenous factors including postural changes, physical activity, and psychological stress.^1,2,6

Although the morning acute MI peak is well‑established, critical questions remain in modern cardiology.⁵ First, foundational studies predate widespread adoption of primary percutaneous coronary intervention (PCI) for ST‑segment elevation myocardial infarction (STEMI).^8,9 Whether this biological rhythm persists in contemporary populations treated within regional systems of care remains unclear.^8-11 Second, the impact of circadian patterns on modern STEMI treatment pathways requires clarification. Current guidelines recommend door‑to‑balloon times below 90 minutes for PCI‑capable hospitals.^12,13 While off‑hours presentation may delay treatment, this relationship has not been quantified in large contemporary registries.^11,14,15 Understanding how biological timing influences system performance is essential for optimizing care delivery. Finally, whether the circadian rhythm influences not only STEMI triggering but also the specific coronary artery that becomes occluded remains unexplored. Preliminary evidence suggests culprit vessel location may exhibit circadian variation, but robust data from large cohorts are lacking.^8,9 Identifying such patterns could provide new mechanistic insights into time‑dependent STEMI pathophysiology.¹

Using a large nationwide STEMI registry, this study aimed to characterize the 24‑hour pattern of STEMI onset by sex and age and investigate how cardiovascular risk factors influence this pattern. We sought to quantify the impact of onset time on treatment delays in the primary PCI pathway. Additionally, we tested the novel hypothesis that culprit vessel location exhibits circadian variation, potentially revealing time‑dependent differences in STEMI pathophysiology.

Patients and methods

The Polish National PCI Registry (ORPKI), a comprehensive national registry managed by the Jagiellonian University Medical College, Kraków, Poland, documents all coronary angiographies and PCIs performed in Poland.^16-18 Between January 1, 2014, and December 31, 2022, we analyzed data from 153 543 consecutive STEMI patients who underwent coronary angiography and primary PCI across 154 centers. Data were collected prospectively using standardized case report forms. STEMI diagnosis and treatment followed contemporary guidelines.¹² The primary variable for this analysis was the hour of symptom onset, as reported by patients or witnesses and documented by physicians, categorized into 24 one‑hour intervals. Treatment delays were calculated from 3 key time points: symptom onset, first medical contact (FMC), and PCI initiation (defined as first balloon inflation or wire passage). Delay intervals included: 1) pain‑to‑FMC time (patient delay), 2) FMC‑to‑PCI time (system delay), and 3) total ischemic time (pain‑to‑PCI).¹⁸ Operators determined pharmacotherapy and procedural techniques according to contemporary standards. The infarct‑related artery (IRA), identified on angiography, was categorized as the left anterior descending (LAD) or right coronary artery (RCA) to examine circadian variation in culprit vessel location. The primary clinical outcome was periprocedural mortality (in catheterization laboratory). In addition, data on other periprocedural complications, including stroke, cardiac arrest, coronary artery perforation, dissection, no‑reflow, allergic reaction, and puncture site bleeding were collected.

Results

A total of 153 543 patients with STEMI were included in the final analysis. Table 1 presents the baseline demographic and clinical characteristics of the cohort. The study population included predominantly men (68%), at a mean age of 65.2 (12.1) years.

The onset of STEMI demonstrated a distinct and significant circadian variation across the 24‑hour cycle. As illustrated in Figure 1, STEMI incidence followed a bimodal pattern characterized by a prominent morning peak and a smaller evening peak. The frequency of STEMI onset rose steeply after 5:00 AM, culminating in a sharp peak at 8:00 AM that accounted for 7.3% of all daily events. Following this peak, incidence gradually declined throughout the day before reaching a secondary, less pronounced peak between 6:00 PM and 8:00 PM. The nadir occurred during the late night and early morning hours, with the lowest frequency observed between 1:00 AM and 3:00 AM.

Both sexes exhibited a broadly similar bimodal circadian pattern of STEMI onset. However, the distribution differed by sex (P <⁠0.001). Median onset occurred earlier in men (10:00 AM [6:00 AM–4:00 PM]) than in women (11:00 AM [7:00 AM–4:00 PM]; P = 0.007). The circadian pattern remained unaffected by age (>65 vs ≤65 y), diabetes status, or COPD.

The time of symptom onset significantly influenced treatment delays. Patient‑related delay, measured as pain‑to‑FMC time, was longest for nocturnal STEMIs. Median pain‑to‑FMC time for 3:00 AM events was 180 (60–360) minutes, that is, 2 times longer than for 1:00 PM events (90 [59–196] min; P <⁠0.001; Figure 2). System‑related delays showed similar patterns, with median FMC‑to‑PCI time longer for morning‑onset STEMIs (87 [60–14] min at 7:00 AM) than afternoon‑onset events (77 [52–120] min at 1:00 PM). Consequently, total ischemic time from chest pain onset to PCI varied significantly by time of day. When stratified by baseline characteristics, the circadian variation in pain‑to‑FMC delays persisted across all subgroups. Formal interaction testing showed that sex was not a significant effect modifier (P = 0.15). However, several comorbidities demonstrated significant interactions with circadian timing. Patients with diabetes (P = 0.004), CKD (P <⁠0.001), COPD (P = 0.008), and aged above 65 years (P <⁠0.001) exhibited more pronounced nocturnal delays than those without these characteristics. Prior cardiovascular history (previous MI, PCI) similarly influenced the circadian distribution of both STEMI onset times and treatment delays (P <⁠0.001 for all; Supplementary material, Figure S1).

A novel finding of this study is a confirmation of opposing circadian rhythms for IRA location (P <⁠0.001). LAD involvement peaked around midnight and reached its nadir at noon, showing greater frequency during nocturnal hours. Conversely, RCA involvement demonstrated the opposite pattern, peaking during daytime hours and reaching its nadir at night (Figure 3). Contrast volume and radiation exposure demonstrated modest circadian variation. Mean contrast volumes were slightly lower in the patients presenting during the early morning hours, as compared with daytime presentations (eg, midnight vs 6:00 AM: mean difference –4.9 [1.2] ml; P = 0.01). Similarly, radiation exposure was significantly lower for STEMIs occurring at midnight than late evening (mean difference –71.7 [18.4] mGy; P = 0.02; Supplementary material, Figure S2). However, these differences, while significant owing to the large sample size, were of limited clinical significance.

Periprocedural death occurred in 1.18% of patients. An analysis stratified by the hour of symptom onset demonstrated mortality rates ranging from 1.05% to 1.58% (Figure 4). Peak mortality was observed among the patients with symptom onset at 9:00 PM (1.58%; 95% CI, 1.21–2.04) and 6:00 PM (1.48%; 95% CI, 1.12–1.93). The χ² analysis demonstrated temporal heterogeneity in mortality risk across the 24‑hour period (P = 0.03). In comparison with the overall cohort mortality rate, the patients presenting with symptom onset at 9:00 PM (P = 0.03) and 6:00 PM (P = 0.04) showed a significantly elevated crude mortality risk. However, these associations did not remain significant following the Bonferroni correction for multiple comparisons. Similarly, STEMI onset hour predicted the occurrence of periprocedural complications (P = 0.02) and the composite end point of PCI‑related complications or death (P = 0.02). Pain‑to‑FMC time was a strong independent predictor of adverse outcomes, with longer delays associated with increased complication and mortality rates (P <⁠0.001). Importantly, no significant interaction was detected between the onset hour and delay time, indicating that prolonged ischemic time confers an increased risk regardless of the circadian timing of symptom onset.

Discussion

This large‑scale, nationwide registry study confirms that STEMI onset, rather than occurring randomly, follows a distinct circadian pattern, even in the modern era of primary PCI. Our primary finding—a morning peak in STEMI incidence around 8:00 AM—aligns with extensive historical and contemporary evidence.^4,5,8-11 This morning vulnerability results from converging physiological changes that occur upon awakening: sympathetic nervous system activation, elevated blood pressure and heart rate, and a prothrombotic state characterized by increased platelet aggregability and PAI‑1 activity.^1-3,6,7,19 Data from over 153 000 patients robustly confirm that these fundamental biological rhythms remain powerful STEMI triggers, regardless of advances in cardiovascular therapies.

While our study demonstrates clear circadian patterns in STEMI timing, it is crucial to recognize that these patterns are not uniform across all populations.^20-28 The timing of STEMI represents a highly personalized risk profile shaped by the complex interplay between the body’s molecular clock and individual demographic and clinical characteristics.^1,2 Sex influences remain complex and controversial.^20,21,27 Although our data show both men and women exhibit the primary morning peak, the literature harbors conflicting evidence. Some studies report attenuated morning peaks or bimodal patterns (morning and evening) in women, potentially reflecting either confounding factors—as women in cardiovascular studies tend to be older and have more comorbidities—or underlying genetic differences, including sex‑specific variations in the CLOCK gene.²⁷ Age effects are more consistently established.^25,26 While the morning peak persists across all age groups, elderly patients frequently develop a secondary evening peak, creating a bimodal pattern rarely seen in younger individuals. This shift likely reflects age‑related weakening of circadian system resilience, allowing later‑day stressors to trigger cardiovascular events.^6,21,25,26 In addition, clinical comorbidities act as powerful circadian modulators. Long‑standing diabetes can significantly blunt or abolish the morning STEMI peak, primarily through diabetic autonomic neuropathy that dampens the physiological morning sympathetic surge.^21,23,24,28 Similarly, the “nondipper” hypertensive phenotype, where nocturnal blood pressure fails to decline, creates continuous rather than periodic hemodynamic stress, potentially disrupting typical circadian patterns.^20-22 High triglyceride levels uniquely accentuate the morning peak on weekdays but not weekends, suggesting work‑stress interactions.²¹ These factors underscore that STEMI timing reflects not just molecular clock function but its complex interaction with individual pathophysiology. Our subgroup analyses further support the notion that patient characteristics modulate circadian patterns in treatment delays. Although sex was not a significant effect modifier of circadian delays (P = 0.15), the patients with diabetes, CKD, COPD, and those aged over 65 years exhibited more pronounced nocturnal delays than their respective counterparts without these characteristics. Prior cardiovascular disease (previous MI or PCI) similarly influenced the circadian distribution of both symptom onset and treatment delays. These findings suggest that comorbidities may amplify circadian vulnerability, predisposing high‑risk subgroups to disproportionately longer delays when symptoms occur during nocturnal hours.

Our analysis brought to light a novel and mechanistically intriguing finding, that is, opposing circadian rhythms for culprit vessel location. The predominance of LAD as IRA at night and RCA involvement during the day represent a significant discovery previously suggested only in smaller studies.⁸ The morning peak in RCA‑related events corresponds with established cardiovascular pathophysiology. Upon waking, abrupt increases in sympathetic tone, blood pressure, and heart rate create substantial hemodynamic stress.^1,2,7 This vulnerability is further explained by the RCA’s unique hemodynamic profile: while both coronary arteries exhibit predominantly diastolic flow,²⁹ Seligman et al³⁰ demonstrated that the RCA has a significantly lower diastolic‑to‑systolic velocity ratio, exposing it to higher systolic flow and pressure. As RCA perfusion occurs throughout both cardiac phases, this increased systolic exposure combined with morning sympathetic surges may particularly predispose the RCA to plaque rupture during early morning hours.^29,30 Conversely, the nocturnal LAD‑related STEMI peak suggests different triggering mechanisms. LAD perfusion occurs predominantly during diastole, when nocturnal conditions feature lower heart rate and blood pressure alongside distinct hormonal and autonomic states, including increased vagal tone and inflammatory mediators.^29,30 Factors beyond the morning sympathetic surge—such as nocturnal inflammation, endothelial dysfunction, or sleep‑related phenomena (eg, obstructive sleep apnea³¹)—may preferentially trigger LAD events. Our findings gain particular significance when compared with recent international studies. Chan et al⁸ in Australia similarly reported morning RCA occlusion peaks and reduced morning LAD occlusion frequency, supporting our results. However, Seneviratna et al⁹ in Singapore found anterior STEMIs (LAD occlusion surrogates) most prevalent during midnight to 6:00 AM. These discrepancies likely reflect multiple factors: study design differences, population genetics, and environmental influences. Singapore’s tropical climate with minimal day‑night temperature variation may affect circadian rhythms differently than Poland’s or Australia’s temperate climates.^8,9 Additionally, ethnic composition differences across study populations may influence genetic predisposition to specific coronary event types. This differential timing carries significant clinical implications. It raises the possibility of chronotherapy, timing medications such as aspirin or P2Y₁₂ inhibitors based on individual coronary anatomy and risk profiles to maximize protection during peak vulnerability periods. Moreover, emerging circadian medicine approaches targeting PER2 pathways through pharmacologic agents or intense light therapy could provide novel cardioprotective strategies, with the time‑of‑day administration being critical for therapeutic efficacy.^1,32 Thus, further research should explore the mechanisms underlying this vessel‑specific circadian pattern to develop more personalized prevention strategies.^1,2

Our study shows that onset time significantly affects treatment delays. Patient‑related delay (pain‑to‑FMC time) doubles for nocturnal‑onset STEMI, as compared with daytime events—a critical observation consistent with previous reports.^4,5,11 Multiple factors contribute to this delay, including symptom misattribution, reluctance to disturb family or emergency services during night‑time hours, or delayed recognition when symptoms begin during sleep. This finding carries immediate practical implications, underscoring the need for public health campaigns emphasizing that chest pain constitutes a medical emergency at any hour and requires immediate action to preserve myocardial tissue. Additionally, the observed increase in system‑related delay (FMC‑to‑PCI) during morning hours, despite higher case volumes, suggests that health care systems continue to face operational challenges during the transition to standard working hours.^14,15 These delays carry clinical significance, as each minute from symptom onset to reperfusion increases mortality risk.¹³ By examining the association between circadian onset timing and outcomes, we found that both onset hour and ischemic time independently predicted complications, but no significant interaction was detected. This indicates that prolonged delays are deleterious regardless of when the symptoms begin. Clinically, this highlights that while circadian timing influences patient behavior and cardiovascular pathophysiology, every additional minute of ischemia confers harm, reinforcing the universal urgency of timely reperfusion strategies. However, despite significant time‑of‑day variations in treatment delays, we observed no difference in periprocedural mortality—a finding consistent with some large‑scale analyses but contrasting with studies linking off‑hour presentation to worse outcomes.^18,33-35 The ORPKI registry’s highly efficient national primary PCI network may sufficiently mitigate immediate mortality risk associated with extended ischemic times. However, periprocedural mortality represents only a short‑term end point. Extended ischemic times correlate with larger infarct size, strongly predicting long‑term adverse outcomes, including heart failure and subsequent mortality.^13,33-38 Therefore, while immediate survival remains unaffected, increased nocturnal STEMI delays may still produce significant long‑term clinical consequences.