Stroke–heart syndrome: mechanisms, risk factors, and adverse cardiovascular events

Abstract

New-onset cardiovascular complications following an ischaemic stroke, hereafter termed stroke–heart syndrome, are a major medical challenge of the 21st century, yet are under-recognized and under-researched.1,2 Acutely, stroke–heart syndrome associates with poorer functional prognosis and increased mortality following stroke.3 In the long term, stroke–heart syndrome associates with significantly higher mortality compared with matched controls.4 Risk factors for stroke and cardiovascular diseases are well documented5 and we have a reasonable understanding of the likely underlying mechanisms of stroke–heart syndrome,6 however, specific risk factors for stroke–heart syndrome and subsequent adverse events have not been previously investigated. Also, whether stroke–heart syndrome impacts males and females differently and whether there are sex-specific risk factors for poor outcomes is unknown. The aim of this study was to investigate the sex-specific incidence of stroke–heart syndrome and 5-year mortality, recurrent stroke, and acute myocardial infarction (AMI) in males and females stratified by different pre-existing cardiovascular risk factors. This multi-centre cohort study utilized complete case, anonymized data within TriNetX, a global federated health research network with access to electronic medical records (EMRs) from participating academic medical centres, specialty physician practices, and community hospitals, predominantly in the USA. As a federated network, research studies using TriNetX do not require ethical approval or patient informed consent as no identifiable information is received. The TriNetX network was searched on 3 January 2023 and de-identified data sets were analysed that included data from 2002 to 2023 with at least 5 years of follow-up (i.e. index event (incident ischaemic stroke) occurred at least 5 years ago). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (see Supplementary material online, Table S1). More detailed information regarding the online database and methods used can be found within the supplementary file. To gain access to TriNetX data, a request can be made (https://live.trinetx.com), but costs may be incurred, a data-sharing agreement is necessary, and no patient identifiable information can be obtained. Patients with incident acute ischaemic stroke, aged ≥18 years with at least 5-years of follow-up (unless deceased during follow-up), were identified from the first instance of an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code I63 (cerebral infarction). A composite of newly diagnosed cardiovascular complications (within 4 weeks of ischaemic stroke) was identified via ICD-10-CM codes: I20-I25 (ischaemic heart diseases) (i.e. ACS), I48 (atrial fibrillation/flutter), I50 (heart failure), I49.0 (ventricular fibrillation/flutter) and I47.2 (ventricular tachycardia) (i.e. severe ventricular arrhythmias), and I51.81 (Takotsubo syndrome). The cohort was stratified by sex (female/male), age (≥75/<75 years), and modifiable risk factors [obesity (body mass index ≥30), hypertension (systolic blood pressure ≥140), type 2 diabetes (T2DM) (HbA1c > 6.5%), high low-density lipoprotein (LDL) cholesterol (≥116 mg/dL), and history of smoking]. Patients with stroke–heart syndrome were 1:1 propensity score matched with patients who experienced an ischaemic stroke only (i.e. without cardiac complications). The comparisons stratified by cardiovascular risk factors included patients with stroke-heart syndrome and a cardiovascular risk factor versus patients with ischaemic stroke only. At the time of the search, 56 (primarily US-based) participating healthcare organizations provided data. Following propensity score matching, Cox proportional hazards regression models produced hazard ratios (HR) with 95% confidence intervals (CIs) for 5-year incidence of all-cause mortality, recurrent stroke, and AMI, comparing patients with stroke and new-onset cardiovascular complications (stroke–heart syndrome) versus propensity-matched controls with ischaemic stroke only. Statistical significance was set at P < 0.05 (Figure 1). Forest plots presenting hazard ratios and 95% confidence intervals for mortality (A), recurrent stroke (B), and acute myocardial infarction (C) comparing patients with stroke–heart syndrome to propensity score matched patients without stroke–heart syndrome following incident ischaemic stroke. The analyses stratified by cardiovascular risk factors (age, obesity, hypertension, diabetes, low-density lipoprotein, smoking) include patients with stroke–heart syndrome and the risk factor of interest versus patients with ischaemic stroke only. Sample size represents the exposure and control cohort. AMI; acute myocardial infarction HTN; hypertension, LDL; low-density lipoprotein; T2DM; type 2 diabetes mellitus. Of 682 203 patients with ischaemic stroke, 20% (n = 135 834) presented with stroke–heart syndrome (49% (n = 67 008) female and 50% (n = 67 683) male). Following propensity score matching, there were 269 210 patients in the overall analyses, 135 366 matched males, and 132 856 matched females. Overall, the cohorts were well-matched for age, sex, ethnicity, included comorbidities, cardiovascular procedures, and cardiovascular medications (see Supplementary material online, Supplement S3 and Tables S2–S4). Following propensity score matching, composite stroke–heart syndrome associated with significantly higher risk of 5-year mortality (HR 1.47, 95% CI 1.44–1.49, P < 0.01), recurrent stroke (HR 1.12, 1.11–1.13, P < 0.01), and AMI (HR 2.50, 2.43–2.58, P < 0.01), compared with ischaemic stroke without cardiac complications. Overall, the HRs for these outcomes were similar for females and males. Hypertension was the most common risk factor for male and female patients with stroke-heart syndrome. Stroke-heart syndrome associated with a higher risk of all outcomes across all investigated risk factors, compared to patients with ischaemic stroke only. The increased risk of poor outcomes seemed to be particularly elevated for patients with stroke–heart syndrome and a history of smoking, those of which had the highest risk of mortality for females (HR 1.88, 1.78–1.99, P < 0.01) and males (HR 72, 1.65–1.80, P < 0.01) as well as the highest risk of AMI for males (HR 3.53, 3.26–3.81, P < 0.01). T2DM also associated with substantially elevated risks of mortality and AMI, including the highest risk of AMI in females (HR 2.91, 2.61–3.24, P < 0.01). The highest risks for recurrent stroke were seen for patients with stroke–heart syndrome and hypertension in both females (HR 1.82, 1.79–1.85, P < 0.01) and males (HR 1.88, 1.85–1.92, P < 0.01). Three other risk factors seemed important for recurrent stroke risk with T2DM for females (HR 1.67, 1.61–1.74, P < 0.01) and males (HR 1.74, 1.68–1.81, P < 0.01), high LDL cholesterol for females (HR 1.60, 1.54–1.65, P < 0.01) and males (HR 1.62, 1.56–1.68, P < 0.01), and history of smoking for females (HR 1.46, 1.41-1.52) and males (HR 1.57, 1.53-1.62) also associated with substantially elevated risk of recurrent stroke. In this multi-centre cohort study of 682 203 patients with first ischaemic stroke, stroke–heart syndrome had 20% incidence and associated with significantly higher risk of mortality, recurrent stroke, and AMI compared with patients with ischaemic stroke but without new-onset cardiac complications. Incidence was similar for males and females but highest among those aged ≥75 years and those with hypertension. Although overall, the risk for 5-year mortality, recurrent stroke, and AMI were similar for females and males, the risk tended to be higher for those with certain modifiable risk factors (i.e. hypertension, T2DM, high LDL, and smoking history) (Table 1). Incidence of each investigated risk factor with stroke–heart syndrome and associated 5-year event rates for mortality, recurrent stroke, and acute myocardial infarction, following propensity score matching AMI; acute myocardial infarction, CI; confidence interval, HR; hazard ratio, HTN; hypertension, LDL; low density lipoprotein, SHS; stroke–heart syndrome, T2DM; type 2 diabetes mellitus, 95% CI; 95% confidence interval. aComparison of stroke–heart syndrome vs. ischaemic stroke only. Prior work has shown that major adverse cardiovascular events following ischaemic stroke are comparable for males and females and occur in people without known pre-existing risk factors.7 Interestingly, a higher mortality and lower health-related quality of life, seen following ischaemic stroke for females compared with males, is attenuated after correction for age, stroke severity, and pre-morbid function.8,9 Therefore, no clear sex-based differences in outcomes following stroke–heart syndrome seem in agreement with prior work in ischaemic stroke cohorts. Our finding of higher adverse event risk following stroke–heart syndrome for all investigated (pre-existing) cardiovascular risk factors does, however, emphasize the importance of cardiovascular health in patients with cardiac involvement following stroke. This is particularly emphasised in the higher risk of worse outcomes in patients with hypertension, T2DM, high LDL cholesterol, and a history of smoking. It is important to note when interpreting these findings that distinguishing stroke–heart syndrome from (otherwise unknown) concomitant or preceding cardiovascular complications is challenging and reverse causation may have impacted the results. Nonetheless, these results highlight the importance of a broad and comprehensive cardiovascular health focus to promote secondary prevention following stroke.10 One example of a comprehensive cardiovascular health approach is the American Heart Associations’ ‘Life’s Essential 8’.9 For example, it has been shown that when maintaining ideal cardiovascular health (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure), there was a lower lifetime risk of coronary heart disease. Further, the American Heart Association’s recent primary care agenda11 emphasized modifiable risk factors for cognitive decline including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidaemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. This focus on both heart and brain health is topical and supported by the present study’s findings. Collectively, this highlights a need for a comprehensive cardiovascular health rehabilitation pathway for those with multi-morbid brain–heart conditions, such as stroke–heart syndrome.10 Further research is therefore warranted which (prospectively) investigates integrated and comprehensive cardiovascular health rehabilitation for patients with stroke–heart syndrome. Overall, the incidence of new-onset cardiac complications following ischaemic stroke (stroke–heart syndrome) was 20% and comparable for females and males. Stroke–heart syndrome associated with higher 5-year risk of mortality, recurrent stroke, and AMI compared with matched patients with ischaemic stroke but without cardiac complications. Risk was similar for males and females. However, of those with stroke–heart syndrome, the highest risk of poor prognosis was in those with additional modifiable risk factors, particularly hypertension, T2DM, high LDL cholesterol, and a history of smoking. It is noteworthy that these risk factors are all modifiable. Supplementary material is available at European Journal of Preventive Cardiology online. B.J.R.B. contributed to the conception and design of the work. B.J.R.B. and S.L.H. contributed to the acquisition, analysis, and interpretation of data for the work. B.J.R.B. drafted the manuscript. S.L.H., D.A.L., A.H., G.Y.H.L. critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy. There was no specific funding received for this study. TriNetX LLC funded the acquisition of the data used through use of the network database. To gain access to TriNetX data, a request can be made (https://live.trinetx.com), but costs may be incurred, a data-sharing agreement would be necessary, and no patient identifiable information can be obtained.

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