Recognizing and addressing the challenges of concomitant cerebrocardiac infarction

Abstract

In this article, we comment on the article by Zheng et al. This case report shed light on concomitant cerebrocardiac ischemic (CCI) in a 27-year-old male patient, which is defined as a concurrent acute ischemic stroke (AIS) and acute myocardial infarction event. The patient received urgent systemic thrombolysis at the standard dose for AIS and then planned percutaneous coronary intervention was successfully conducted for ST-segment elevation myocardial infarction treatment. Considering the rarity of the comorbidity, the narrow time window for treatment of both AIS and acute myocardial infarction, as well as the complexity and severity of the condition, there are still no guidelines or consensus that have systematically recommended optimal treatment strategies. The successful treatment of this 27-year-old man suggests that urgent thrombolysis followed by planned percutaneous coronary intervention might be an alternative treatment options in the management of concomitant CCI. However, emergency treatment plans need to be developed according to the specific situation of the patients. A number of factors should be considered when making decision, including the location of occlusion of heart and brain, the hemodynamic instability, the ongoing ischemic symptoms, the presence of contraindications to thrombolysis, and the speed of response of cardiologists or neurointerventionists. Future, further research involving multidisciplinary experts, including neurologist, cardiologist, and specialists in critical care medicine is needed to improve the understanding and management of concomitant CCI.

Key Words: Acute ischemic stroke; Acute myocardial infarction; Cardio-cerebral infarction; Treatment strategies; Prognosis

Core Tip: Concomitant cerebrocardiac ischemic is a rare but urgent condition with extremely high mortality. The management of concomitant concomitant cerebrocardiac ischemic has some dilemmas. In the acute phase, the physicians must decide which disease to treat first, which is related to the severity of the heart and brain lesions. In chronic phases, the use of antiplatelet agents and drugs that improve myocardial remodeling remains controversial. The neurologists and cardiologists should make treatment decisions together.

INTRODUCTION

Concomitant cerebrocardiac ischemic (CCI) is characterized by the concomitant occlusions in the cerebral and coronary vasculature. This condition manifests as two distinct temporal patterns: Concomitant CCI, where acute ischemic stroke (AIS) and acute myocardial infarction (AMI) occur concurrently, and metachronous CCI, defined by the sequential occurrence of one event after the other. Generally, the concomitant CCI is considered to occur within 24 hours of the previous event[1]. Among patients initially diagnosed with AMI, 0.52% developed CCI within 24 hours, while in those initially diagnosed with AIS, CCI within 24 hours occurred in 0.29% patients[2,3]. The incidence of concomitant CCI is relatively high among elderly patients, up to 3.7%[4]. Overall, concomitant CCI remains a extremely rare disease.

The pathophysiology of concomitant CCI can be attributed to multiple mechanisms. First, certain pathological conditions may concurrently influence the cardiovascular and cerebrovascular systems, resulting in concomitant CCI. Atrial fibrillation promotes the generation of thrombosis and then increases the risk of cerebral coronary embolism[5]. In some of the patients with I-type aortic dissections, the dissection flap extends to the origins of the coronary and common carotid arteries, disrupting the hemodynamic stability and causing damage to cerebral artery and coronary artery[6]. Electrical injuries also contribute by causing concomitant coronary and cerebral vasospasms through vascular hyperreactivity[7]. Secondly, multiple cardiac pathologies may lead to concomitant CCI. In heart failure with reduced ejection fraction patients, pre-existing intracardiac thrombosis increases the risk of cardiovascular and cerebrovascular embolism[8]. Post-infarction hypotension exacerbates cerebral hypoperfusion, which potentially progresses to ischemic stroke[1]. This pathophysiological cascade shows the critical role of cardiac dysfunction and cerebrovascular vulnerability in concomitant CCI pathogenesis. Thirdly, dysregulation of the brain-heart axis plays an important role in the incidence of concomitant CCI. Structural abnormalities in the insular cortex are closely linked to cardiovascular system dysfunction. The abnormal electrical activity such as atrial fibrillation and structural damage like myocardial injury occurs more frequently in patients with insular lobule infarction, highlighting the bidirectional interaction between cortical dysfunction and cardiac pathology in concomitant CCI development[9].

Concomitant CCI is a serious life-threatening disease. A cross-sectional study from a tertiary center showed that the mortality rate of concomitant CCI patients within 30 days of onset was 45%[10]. A meta-analysis of 44 case reports from around the world reported that 9 patients died in the acute phase of concomitant CCI, indicating the mortality of about 20%. The data from the meta-analysis only contained what is reported by the published separate case reports. Given that death data for some cases cannot be obtained, the mortality rate reported in the meta-analysis may be lower than the actual mortality rate[11]. However, whether cross-sectional analysis based on real-world or literature review meta-analysis, cardiovascular death is the leading cause of death for concomitant CCI patients[10,11]. This high mortality rate is particularly concerning when compared to patients with stroke alone, as those with concomitant CCI show significantly worse prognosis. The patients with concomitant CCI face a three-fold higher mortality in 2 years than those with stroke alone, with only 20%-50% achieving favorable functional outcomes[2,12].

Given the rarity and urgency of concomitant CCI, its management is both controversial and challenging, with several dilemmas hindering optimization. This editorial critically comments on the case report about concomitant CCI and proposes individualized management frameworks for patients with varying clinical profiles[13].

RAPID IDENTIFICATION OF CONCOMITANT CCI AND EMERGENCY REPERFUSION TREATMENT DECISION-MAKING

Rapid and accurate diagnosis of concomitant CCI is critical to timely therapeutic intervention. Clinical data from a 29-case series revealed that 83% concomitant CCI patients presented to the emergency department with neurological symptoms, while only a small number of concomitant CCI patients reported AMI symptoms such as dyspnea or chest pain[10]. Obvious neurological symptoms, particularly global aphasia and reduced pain perception, often delay AMI diagnosis in concomitant CCI patients, suggesting the necessity for routine electrocardiogram (ECG) screening in all AIS patients[14]. However, ECG interpretation requires caution. Some common ECG changes in AIS patients may interfere with the diagnosis of AMI through ECG, but ST-segment elevation occurs in only 6% of AIS patients, indicating potential myocardial injury[15]. Concurrently, sedative and myorelaxant use in AMI patients may mask neurological symptoms. Advanced imaging examinations, such as magnetic resonance imaging and computed tomography, are in need for AMI patients with cerebrovascular risk factors or subacute neurological signs[16].

Antiplatelet therapy serves as the cornerstone of concomitant CCI management. Once concomitant CCI is diagnosed, whether to start antiplatelet therapy immediately depends on the subsequent reperfusion strategy. Oral aspirin should be promptly initiated in patients who do not undergo thrombolytic therapy, whereas the antiplatelet administration should be delayed in thrombolysis recipients until 24 hours after intervention[17].

The regional disparities in medical resources increase the difficulty in the management of concomitant CCI. The physicians should make decisions based on current diagnostic and treatment capacity of medical institutions and the Severity of the patient’s condition, weighting advanced care benefits against transfer-related deterioration risks.

The therapeutic priority of restoring cardiac vs cerebral perfusion remains controversial due to the time-sensitive nature of both AIS and AMI. Although current American Heart Association/American Stroke Association guidelines recommend intravenous alteplase thrombolysis within 4.5 hours for eligible concomitant CCI patients, the individualized decision-making is essential[18]. Hemodynamic stability determines the sequence of reperfusion therapy. Unstable hemodynamics, such as cardiac arrest, pulseless ventricular tachycardia, or cardiogenic shock warrant immediate percutaneous coronary intervention (PCI), particularly combined with severe cardiac pathology like reduced ejection fraction of left ventricular and left main lesions[19]. In contrast, thrombolysis with intravenous recombinant tissue plasminogen activator should be administered first in patients with stable hemodynamics, as long as they arrived within the thrombolytic time window (< 4.5 hours). For the patients presenting severe neurological symptoms due to basilar or posterior occlusion but relatively less severe coronary lesions, such as non-ST-segment elevation myocardial infarction, thrombolysis has greater benefits than PCI. To avoid hemorrhagic transformation, the dosage of alteplase is consistent with cerebral ischemia protocol[20].

Delayed PCI remains advisable for AMI patients undergoing thrombolysis treatment due to uncertain low-dose alteplase efficacy[21]. Despite the risk of hemorrhagic transformation in AIS patients, previous studies have not found a direct correlation between PCI surgery and intracranial hemorrhage in concomitant CCI patients. A 126-patient cohort demonstrated no significant increase in intracranial hemorrhage after early cardiac catheterization and antithrombotic therapy in AIS patients. However, potential selection biases must be acknowledged, as patients with indications for cardiac catheterization but high intracerebral hemorrhage risk were excluded after risk-benefit assessments by physicians. This exclusion might cause underestimation of the incidence of intracranial hemorrhage in the real word. Moreover, about 30% of the AIS patients undergoing cardiac catheterization were diagnosed with stable angina pectoris rather than AMI. The inclusion of stable angina patients, whose pathophysiology differed markedly from AMI, may increase the heterogeneity and limit the generalizability of conclusions to concomitant CCI populations[22]. Subsequent nationwide studies excluding stable angina patients came to the same conclusion in AIS patients with concomitant ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction. However, selection bias persisted as physicians demonstrated the tendency to perform PCI in patients with milder clinical presentations. Retrospective designs limited causal inference[23,24]. At present, further research is still needed to determine the safety and efficacy of PCI in patients with concomitant CCI. While large-scale prospective studies can indeed enhance the quality of evidence, considering the rarity of concomitant CCI, conducting such studies may require substantial time and financial resources. Therefore, we encourage researchers to perform meta-analyses of existing retrospective data to rapidly and effectively generate higher-quality evidence-based medical evidence regarding the safety and efficacy of PCI in patients with concomitant CCI.

Endovascular thrombectomy (EVT) is suitable for large-vessel occlusions, significantly improving functional outcomes[25]. Beyond cerebrovascular benefits, enhanced cerebral perfusion may attenuated cardiovascular symptoms via the modulation of brain-heart axis. However, EVT is not applicable to those with lacunar infarction. Furthermore, EVT is unavailable in certain healthcare institutes, particularly in low-income countries with limited medical resource[26,27].

In this case, the 27-year-old patient was admitted to the emergency department because of sudden onset of unconsciousness, right hemiplegia, dense aphasia but no chest pain. Considering the more obvious neurological symptoms and the stable hemodynamic, thrombolysis with intravenous-recombinant tissue plasminogen activator was performed immediately to address the neurological damage. Then dual antiplatelet therapy was initiated on the 3^rd day after admission, and planned PCI was performed on the 8^th day after admission, rather than immediately after admission. The delay of treatment might reduce the risk of hemorrhagic transformation of AIS caused by antiplatelet therapy and the use of anticoagulants during PCI[13].

SUBSEQUENT MANAGEMENT AFTER REPERFUSION THERAPY FOR CONCOMITANT CCI

Even if concomitant CCI patients survive through the acute phase, post-reperfusion management remains important in long-term prognosis. After the acute phase, patients are confronted with the long-term rehabilitation challenge of superimposed damage to heart and brain functions. It is necessary to combine the prevention of complications, coordinated rehabilitation of heart and brain, and secondary prevention to improve functional prognosis and reduce the risk of recurrence.

Preventing complications is one of the key points in the rehabilitation of concomitant CCI patients. Malignant arrhythmias are the leading cause of mortality in concomitant CCI survivors, so continuous telemetry electrocardiographic monitoring is necessary in concomitant CCI patients[2]. Notably, insular cortex damage due to middle cerebral artery occlusion elevates the risk of fatal arrhythmia caused by autonomic dysfunction[28]. Right insular lesions drive parasympathetic overactivity, while left insular damage amplifies sympathetic activity[29]. The physicians should identify patients with high risk of malignant arrhythmias. The close observation and cardiac monitoring for arrhythmia helps physicians capture and handle fatal arrhythmias timely, thereby reducing the mortality rate of concomitant CCI patients[1].

Dysphagia, a prevalent post-stroke complication, significantly increases aspiration pneumonia risk and then leads to poorer outcomes and extended hospitalizations[30]. The nomogram model by Wang et al[31] integrated age, National Institutes of Health Stroke Scale score, dysphagia, atrial fibrillation, and biomarkers (C-reactive protein, neutrophils, albumin) to predict aspiration pneumonia risk in AIS patients. Due to the complexity and severity of the condition in patients with concomitant CCI, the risk of aspiration pneumonia in patients with concomitant CCI may be higher. However, considering the lack of relevant research, more large-scale prospective studies are needed to confirm the hypothesis. Current guidelines advocate dysphagia screening and early preventive measures, such as standardized oral hygiene with chlorhexidine rinses and nasogastric tube feeding in AIS patients[18]. A recent randomized controlled trial (RCT) demonstrated that adding physical therapy and neuromuscular electrical stimulation standard care reduced aspiration pneumonia in AIS patients[32]. Additionally, domperidone, a dopamine-2 receptor antagonist, showed promise in reducing aspiration risk via its antiemetic and prokinetic effects[33]. Due to the rarity of concomitant CCI, almost no concomitant CCI patients were included in these studies, leading to the lack of the evidence in the real world on the prevention of aspiration pneumonia in concomitant CCI patients. More studies are needed in the future to confirm the effectiveness and safety of the above measures in concomitant CCI patients.

Heart failure is a common complication in AMI patients. β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used to reverse ventricular remodeling and improve survival[34,35]. However, the hypotensive effects of β-blockers and angiotensinconverting enzyme inhibitors or angiotensin receptor blockers may exacerbate cerebral hypoperfusion and enlarge infarcts in concomitant CCI patients[36]. In this case report, given the young age, favorable life expectancy, and absence of hemodynamic instability, angiotensin receptor blocker and β-blocker therapy was initiated to optimize cardiac function and reduce the risk of unfavorable prognosis[13]. Long-term data on the efficacy and safety of betablockers and angiotensinconverting enzyme inhibitors or angiotensin receptor blockers in concomitant CCI is deficient, emphasizing the need to evaluate the ventricular remodeling benefits and cerebral perfusion risks in the future.

Rehabilitation strategy for patients with concomitant CCI requires the integration of cardiac rehabilitation and neurological rehabilitation, emphasizing the principle of treating heart and brain simultaneously. Developing a reasonable long-term functional recovery strategy is crucial for the rehabilitation of concomitant CCI patients. Long-term functional rehabilitation aims to improve motor function, cognitive function, and activities of daily living[37,38]. Rehabilitation exercises include aerobic exercises that aid in cardiac rehabilitation, as well as resistance training and balance training that facilitate neurological rehabilitation[39,40]. It’s worth noting that warming up before rehabilitation exercises, monitoring blood pressure and heart rate during exercise, and gradual cooling down after exercise are essential to ensure safety[41]. Memory games, logical reasoning exercises combined with transcranial magnetic stimulation to improve cerebral blood flow can enhance patients’ cognitive function[42,43]. Active training in activities of daily living is crucial for improving the quality of life in concomitant CCI patients. It is recommended to start with basic actions such as eating and dressing, then gradually progress to more complex activities like household chores and community engagement activities[44]. For patients with severe impairment in self-care abilities, assistive devices can be used to enhance their daily living capabilities.

Effective secondary prevention can slow down the progression of AMI and AIS and reduce the risk of recurrence. Optimized antithrombotic therapy is a key link in secondary prevention. However, the antithrombotic strategies after reperfusion in concomitant CCI patients is also unclear. Dual antiplatelet therapy is standard for AMI, whereas AIS patients typically receive single antiplatelet therapy unless intracranial stents are placed[18,45]. A retrospective 85-patient concomitant CCI study noted higher dual antiplatelet use among survivors. However, confounding factors limited the strength of this conclusion. Larger infarction scale, higher risk of bleeding and more comorbidities in death group might force physicians to be more careful with antithrombotic drugs[46]. In this case, in order to avoid hemorrhage transformation, the patient did not receive antiplatelet therapy at admission. But given the severe occlusion of the coronary and the absence of comorbidities, the 27-year-old patients was considered to be in relatively higher thrombosis risk and lower bleeding risk. Therefore, dual antiplatelet therapy, aspirin and clopidogrel were prescribed for the long-term antithrombotic treatment[13]. In the clinical practice, the severity of cardiovascular and cerebrovascular disease, reperfusion strategy and comorbidities should be considered comprehensively to develop individualized anti-thrombotic strategies for different patients in order to obtain the maximum benefit/risk ratio. High-intensity statin therapy remains foundational for secondary prevention in both AMI and AIS. Atorvastatin was promptly initiated in this case, indicating the necessity of lipid-lowering therapy to stabilize plaques and reduce recurrence[18,45].

CONCLUSION

The case report presented by Zheng et al[13] highlighted the complexities of concomitant CCI management. Rapid identification and optimal reperfusion strategies are critical for saving the lives of concomitant CCI patients and mitigating the functional impairment during the acute phase. Effective management of complications after reperfusion therapy such as malignant arrhythmias, aspiration pneumonia, heart failure, and recurrent thrombosis are essential to improving long-term outcomes in concomitant CCI patients. However, the complexity and lethality of concomitant CCI, the disparities in medical resources across regions, as well as the lack of standardized diagnostic and treatment guidelines, have caused difficulties for timely and specialized care in these patients. In the future, neurologists, cardiologists, and critical care specialists should collaborate closely to develop comprehensive management guidelines for concomitant CCI. These guidelines should include the standardized diagnostic criteria, the decision trees for referral across different healthcare settings, the selection of reperfusion strategies according to specific factors of individuals, and the protocols for long-term management in the chronic phase. Given the rarity of concomitant CCI, conducting large-scale RCTs to identify optimal treatment strategies remains challenging. Advanced clinical research methodologies, such as sequential trials and basket trials, may enhance the feasibility of RCTs and reduce the costs. Additionally, large-scale, multicenter prospective cohort studies are needed to optimize risk factor management, medication strategies, and rehabilitation protocols and improve the prognosis. In summary, concomitant CCI is a complex clinical syndrome that requires close collaboration among multidisciplinary teams in neurology, cardiology, and critical care. Based on high-quality clinical evidence, standardized and individualized management protocols should be developed for concomitant CCI patients to reduce in-hospital mortality and improve long-term quality of life.