Intracerebral hemorrhage (ICH) is a devastating subtype of stroke accounting for 15–20% of all stroke cases, and is associated with significant mortality and long-term disability [1,2,3]. Recent evidence has increasingly underscored the critical role of the brain-heart interaction in the pathophysiology of acute brain injury [4,5,6]. Following the onset of ICH, neurohormonal and autonomic dysregulation frequently precipitate a hyperadrenergic state, which imposes substantial stress on the cardiovascular system [5,6].

This hyperadrenergic state triggers an acute increase in metabolic demand and hemodynamic burden, significantly elevating cardiac workload. When the cardiac workload surpasses the intrinsic cardiac reserve, the resulting mismatch between myocardial oxygen supply and consumption predisposes the myocardium to injury [7,8]. Furthermore, as optimal cardiac performance is crucial for maintaining cerebral perfusion pressure during acute brain injury, excessive cardiac workload may compromise the stability of cerebral blood flow [9,10], potentially exacerbating secondary brain injury and contributing to poor clinical outcomes. However, direct measurement of cardiac workload is technically complex [11,12] and challenging to implement during the acute phase of ICH. As a result, the clinical significance of early cardiac workload in patients with ICH remains inadequately elucidated.

The rate-pressure product (RPP), calculated as the product of heart rate (HR) and systolic blood pressure (SBP), serves as a well-validated and readily accessible surrogate for myocardial oxygen consumption [13,14]. It is widely utilized to quantify cardiac workload [15,16,17]. In the field of cardiology, RPP is a well-established prognostic marker for adverse outcomes in heart failure and coronary artery disease [18,19,20,21]. Additionally, among neurological disorders, RPP has been linked to mortality in acute aneurysmal subarachnoid hemorrhage and traumatic brain injury [15,22]. However, its prognostic significance in ICH has been rarely explored. Therefore, this study aimed to investigate the association between early cardiac workload, as measured by RPP, and long-term outcomes.

In this large, multicenter, prospective cohort study, we systematically demonstrated that (1) RPP was independently associated with long-term unfavorable functional outcome and all-cause mortality in patients with acute ICH; (2) RPP exhibited greater predictive performance compared with either HR or SBP alone; and (3) the adverse prognostic risk associated with high RPP was mitigated by in-hospital β-blocker treatment. Collectively, these findings identify elevated early cardiac workload as a potent prognostic factor for poor long-term outcomes following ICH.

Although the precise mechanisms linking cardiac workload to ICH prognosis remain incompletely understood, we postulate that the pathological activation of the brain-heart axis plays a pivotal role. First, the mass effect of the hematoma and surrounding edema, along with the toxic effects of blood breakdown products, may structurally and functionally compromise the central autonomic network (CAN) [24]. This injury can lead to the disinhibition of sympatho-excitatory centers, precipitating a hyperadrenergic state. Such sympathetic hyperactivity has been shown to aggravate secondary brain injury by inducing disruption of the blood-brain barrier, exacerbating perihematomal edema, and promoting a pro-inflammatory state [24,25,26], ultimately worsening patient prognosis [27,28]. Second, previous studies have demonstrated that stroke events can trigger neurovascular uncoupling and impair cerebral autoregulation, making cerebral blood flow more dependent on systemic hemodynamics [6,29]. In this vulnerable state, elevated cardiac workload may not only impair cerebral perfusion but also transmit excessive hydrostatic pressure to the injured neurovascular unit, potentially exacerbating perihematomal edema and increasing the risk of hematoma expansion, thereby worsening neurological injury. Third, the RPP, also known as the double product, is a well-validated, non-invasive index of myocardial oxygen consumption [13,14]. During exercise and stress conditions, myocardial oxygen demand rises largely in proportion to the tension-time work and afterload faced by the left ventricle; HR strongly determines the frequency and cumulative duration of systolic tension development, whereas SBP serves as a convenient clinical surrogate for left ventricular afterload [30,31]. Accordingly, RPP increases in parallel with oxygen requirements. Classic invasive studies in patients with angina demonstrated a close relationship between RPP and directly assessed indices of myocardial oxygen consumption and myocardial blood flow [13,32]. Consequently, a high admission RPP may indicate an abrupt surge in myocardial oxygen demand. This acute demand-supply mismatch may deplete cardiac reserve and trigger subclinical myocardial injury [7,8], thereby reducing physiological resilience to post-ICH complications.

Our findings align with a previous smaller retrospective study that identified RPP as a predictor of short-term (30-day) mortality [33]. However, our study further extends prior evidence by demonstrating associations with long-term unfavorable functional outcomes and mortality. Importantly, these associations remain significant even after adjusting for baseline severity markers such as GCS and hematoma volume. This finding implies that elevated RPP is not merely an epiphenomenon of the initial injury severity. Instead, it likely reflects a component of systemic physiological dysregulation that is independently associated with poor functional recovery.

Furthermore, we found that RPP demonstrated superior prognostic performance to either HR or SBP alone. This observation aligns with existing cardiology literature regarding coronary artery disease [21,34]. Mechanistically, while SBP primarily reflects left ventricular afterload and HR reflects the chronotropic state, RPP integrates both parameters, providing a more comprehensive perspective on cardiac work. Furthermore, the physiological relationship between BP and HR is precisely regulated by autonomic mechanisms, such as the baroreceptor reflex, which maintain a dynamic negative feedback balance in a healthy state [35]. However, in acute ICH, CAN injury can disrupt this autonomic feedback [36,37], resulting in a simultaneous elevation of SBP and HR. RPP effectively captures this “double hit” on the cardiovascular system, thus providing a more accurate reflection of the severity of systemic physiological dysregulation.

A critical consideration in utilizing admission physiological parameters is the timing of measurement. While physiological changes are most volatile in the first few hours, accumulating evidence suggests that autonomic dysregulation after ICH is a sustained pathological state that persists throughout the early acute phase [38]. Sykora et al. demonstrated that baroreflex sensitivity remains significantly impaired in ICH patients within 72 hours of symptom onset compared to healthy controls [36]. Therefore, the RPP obtained within this window may reasonably capture the pathophysiology of autonomic dysregulation after ICH. Importantly, our sensitivity and subgroup analyses revealed that the association between RPP and outcomes remained consistent across all time windows, suggesting that the prognostic signal of RPP is not driven by a specific arrival window. Collectively, these findings establish admission RPP as a temporally stable and reliable prognostic biomarker during the early phase of ICH.

Current evidence regarding the use of β-blockers in ICH remains inconsistent. While some studies suggested benefits, including reduced perihematomal edema, lower infection rates, and decreased mortality [39,40,41], a recent large meta-analysis found no significant association with functional outcome or survival [42]. These divergent findings are likely attributable to the profound clinical and physiological heterogeneity of the ICH population, highlighting the need for a more targeted therapeutic strategy. Our study proposes a potential direction for stratification. We observed that the association between high RPP and poor outcomes was attenuated in patients receiving β-blockers. Given that β-blockers exert sympatholytic effects, this finding supports the hypothesis that high RPP may identify a hyperadrenergic phenotype. Therefore, RPP holds the potential to serve as a biomarker for stratifying patients who might derive greater benefit from targeted sympatholytic therapy. This hypothesis warrants prospective validation in randomized controlled trials.

While the brain-heart interaction is well-documented in the context of ischemic stroke, data regarding ICH remain limited [4,43]. Existing studies on ICH have predominantly focused on overt cardiac pathologies, such as myocardial infarction, heart failure, and severe arrhythmias [44,45,46], neglecting the clinical significance of concealed cardiovascular stress. Our findings underscore the prognostic value of early cardiac workload assessment using the RPP, an easily obtainable indicator. Incorporating RPP into initial risk stratification may assist clinicians in identifying patients experiencing excessive cardiovascular stress who may require intensified hemodynamic monitoring beyond standard blood pressure management.

In this large, multicenter, prospective cohort (67.1% male), early cardiac workload, quantified by the RPP, serves as a potent independent predictor of long-term unfavorable functional outcome and all-cause mortality in patients with ICH. These findings underscore the prognostic relevance of the brain–heart interaction and highlight the potential clinical value of monitoring cardiovascular stress during the acute phase of ICH.

The datasets used during the current study are available from the corresponding author on reasonable request.

CW, YH, and ZJ: drafted the manuscript; YH and ZJ: analyzed the data; XZ (Xiaoli Zhang) and AW: designed the methodology; XZ (Xiaoli Zhang), AW, YZ, KK, XZ (Xingquan Zhao), and WW: revised the manuscript critically; KK and WW:acquired, curated, and managed the data; CW, YZ, and XZ (Xingquan Zhao): conceived the study; KK, WW, and XZ: acquired funding. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Beijing Tiantan Hospital (IRB no. KY2014-023-02). Written informed consent was obtained from all participants or their legally authorized representatives.

We gratefully acknowledge all the clinical staff who contributed to the study.

This study was supported by the National Science and Technology Major Project for the Prevention and Treatment of Cancer, Cardiovascular and Cerebrovascular, Respiratory and Metabolic Diseases (Grant number: 2024ZD0522100), National Natural Science Foundation of China (Grant numbers: 82471489 and 82371320), and Health China·BuChangZhiYuan Public Welfare Projects for Heart and Brain Health (Grant number: HIGHER2023074).

The authors declare no conflicts of interest. Yujie Zhou is serving as one of the Editorial Board members of this journal. We declare that Yujie Zhou had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Davide Bolignano.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM49651.