2024 Volume 10 Pages 5-10
The brain-heart axis denotes the intricate bidirectional communication vital for maintaining overall physiological balance, or homeostasis. Numerous studies underscore the profound impact of cardiovascular conditions on brain health. Conditions such as atrial fibrillation and left ventricular hypertrophy have been identified as potential contributors to cerebrovascular diseases and cognitive impairment. Utilizing of tools such as the electrocardiogram (ECG) are instrumental in identifying atrial fibrillation and left ventricular hypertrophy. Notably, findings from such diagnostic tests correlate with cortical microinfarcts and diminished cerebral blood flow. An elevated P-wave terminal force in lead V1 on an ECG has emerged as a promising indicator of left atrial abnormalities, serving as a potential precursor to atrial fibrillation and cognitive impairment. Ultrasound modalities, such as echocardiography and carotid ultrasound, offer additional insights into the intricate relationship between cardiac function and cognitive dysfunction. In addition to imaging techniques, blood-based markers of cardiac disease, including N-terminal pro-B-type natriuretic peptide (proBNP), high-sensitivity cardiac troponin T, and Growth Differentiation Factor 15, have been associated with cognitive impairment, emphasizing an intricate heart-brain connection. Although exploring the roles of these biomarkers holds significant promise for future research, the interconnectivity between cardiac biomarkers and the brain remains poorly elucidated. The numerous underlying mechanisms linking the heart and the brain continue to elude our understanding and warrant further investigation.
The intricate relationship between the heart and brain is underlined by a robust bidirectional connection, primarily facilitated by circulatory interactions1). A growing body of research has consistently demonstrated the influence of the cardiovascular system on various aspects of brain function. While cardioembolic stroke resulting from conditions such as atrial fibrillation (AF) is well-recognized, acknowledging the broader spectrum of factors contributing to this intricate relationship is essential, including small vessel diseases (SVD) and cerebral hypoperfusion2). Understanding these relationships is crucial, as they significantly impact cognitive function. The Framingham study not only confirmed the association between elevated cardiovascular risk and impaired cognitive function but also shed light on the intricate links between cardiovascular conditions and neurodegenerative diseases3). Stroke has been associated not only with vascular cognitive impairment but also with conditions such as Alzheimer’s disease (AD). The higher Framingham General Cardiovascular Risk Score (Table 1) has been found to correlate with AD pathology (Odds ratio: OR, 1.06, 95%CI 1.01–1.12), emphasizing the importance of cardiovascular health in maintaining cognitive well-being4). Insights from studies, such as those recently conducted in Asia, have further revealed interesting information about the complex interplay between cardiovascular and neurodegenerative factors in cognitive health. For instance, preclinical stages of AD have been associated with white matter lesions, a form of SVD, independently contributing to cognitive impairment, irrespective of amyloid-β accumulation5). In the background of recent advancements, the effectiveness of interventions such as Lecanemab targeting amyloid-β6) highlights evolving therapeutic approaches. As scientific evidence accumulates, understanding the role of cardiac biomarkers is becoming paramount for both diagnosis and prognosis. This narrative review aimed to synthesize the current knowledge of cardiac biomarkers and their significance in the context of cognitive impairment.
| Variables |
|---|
| Age |
| Sex |
| Smoking |
| Diabetes mellites |
| Systolic blood pressure |
| Total cholesterol |
| HDL-cholesterol |
The electrocardiogram (ECG) serves as a noninvasive and cost-effective screening tool for cardiac disease and is widely employed in healthcare worldwide. Its role in detecting AF, which is a condition strongly linked to cognitive impairment, is of particular significance. Consistent findings from community-based observational studies indicate a higher incidence of cognitive decline and an elevated risk of dementia in individuals with AF7). This correlation is partially attributed to the heightened risk of clinical stroke in AF and other mechanisms, such as silent cortical microinfarcts and cerebral hypoperfusion. A cross-sectional study conducted on patients in a memory clinic using 3 Tesla MRI revealed a strong association of cortical microbleeds with AF, ischemic heart disease, and congestive heart failure8). Given the frequency of cortical microinfarcts and their negative correlation with cognitive function, a potential link exists between AF and cognitive impairment through cortical microinfarcts. Additionally, AF can influence cerebral blood flow, potentially impacting brain function. A study demonstrated that individuals with persistent AF exhibited a notable 12% reduction in total cerebral blood flow compared to those without AF9). This decreased cerebral blood flow may affect cerebral vasodilatory reserve, autoregulation, and neurovascular coupling, further contributing to cognitive impairment10). Despite these findings, a study using Atherosclerosis Risks in Communities data found an association between AF and longitudinal sulcal grade and ventricular grade, with no significant correlation to total brain volume or white matter hyperintensity11). Further research is warranted to explore the mechanisms and causality between AF and cognitive impairment.
Left ventricular hypertrophy is an additional risk factor for cognitive impairments. A systematic review indicated that the assessment of left ventricular hypertrophy commonly relies on criteria such as the Cornell voltage or Sokolow-Lyon voltage (Table 2), with QT and QRS-T angles also being utilized12). ECG-derived indicators have demonstrated effectiveness in predicting cognitive decline and dementia. Despite emerging evidence, definitive markers remain elusive, underscoring the need for further investigation.
| Name | Criteria |
|---|---|
| Cornell voltage | amplitude voltage RaVL + SV3 > 28 mm for men and 22 mm for women |
| Sokolow-Lyon voltage | amplitude voltage SV1 + (max RV5 or RV6) > 35 mm |
Recently, the P-wave terminal force in lead V1 (PTFV1; Fig. 1) has emerged as a valuable marker for identifying left atrial abnormalities, including dilatation, fibrosis, and elevated filling pressure. This association is rooted in the understanding that left atrial remodeling often precedes ventricular hypertrophy in individuals with hypertension13). Consequently, PTFV1 has been linked to white matter lesions14,15) and cerebral microbleeds in the basal ganglia16), indicating its potential as a reflection of hypertensive brain injury. Notably, its reported association with cortical infarction suggests a potential association with paroxysmal AF17). Elevated PTFV1 levels have been observed in patients with cryptogenic stroke, with implantable loop recorders revealing a high detection rate of AF18). Moreover, there are reports highlighting the correlation between its presence and the progression of cognitive decline, particularly in the context of vascular dementia16,19). Furthermore, a recent study investigating the influence of the autonomic nervous system on cognitive function has yielded promising results, suggesting that heart rate variability may serve as a potential biomarker for early cognitive impairment20).
PTFV1 is defined as the absolute value of the depth (μV) of the downward deflection (terminal portion) of the P-wave in ECG lead V1 multiplied by its duration (ms). Elevated PTFV1 is usually defined as PTFV1 greater than 4,000 μV × ms.
Numerous studies have established significant connections between echocardiogram findings and cognitive function. A cohort study demonstrated that impaired left atrial function independently heightened the risk of incident dementia, irrespective of AF occurrence21). Adjusting for confounding factors, the hazard ratios (HR) for the lowest versus highest quintile of left atrium function against dementia were noteworthy: reservoir strain (HR 1.98, 95%CI 1.42–2.75), conduit strain (HR 1.50, 95%CI 1.09–2.06), contractile strain (HR 1.57, 95%CI 1.16–2.14), emptying fraction (HR 1.87, 95%CI 1.31–2.65), and active emptying fraction (HR 1.43, 95%CI 1.04–1.96)21). In the Kerala–Einstein study, left ventricular hypertrophy showed an association with cognitive dysfunction, and echocardiographic markers such as left atrium function and aortic valve regurgitation were correlated with AD and vascular dementia22). These findings suggest a connection between left atrial and ventricular function, similar to ECG findings and cognitive function.
Carotid ultrasound, deemed a crucial indicator, has been linked to cognitive function. Adjusting for sociodemographic and vascular risk factors, higher carotid intima-media thickness (IMT) exhibited a negative association with processing speed and a borderline association with executive function23). A systematic review has supported the utility of IMT as a metric for identifying individuals at risk of cognitive decline24). Additionally, high plaque scores were associated with reduced performance in the digit-symbol coding and tapping tests25). Concerning SVDs, carotid IMT was linked to an increased white matter hyperintensity volume over a 5-year period26). Another study reported a correlation between low peak systolic velocity and white matter hyperintensity27). Ultrasound, due to its low invasiveness and high safety, is regarded as a suitable modality for assessing the risk of conditions such as dementia and cerebral SVD. Further research and development in the domain of cognitive impairment are warranted.
Natriuretic peptides, encompassing B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), are not only valuable indicators of hemodynamic stress but have also garnered increasing attention in recent years for their association with cognitive function and small vessel disease (SVD)28). Higher levels of BNP were associated with declines in the domain of memory and the incidence of cerebral microbleeds29). Similarly, regarding ANP, elevated plasma concentration of ANP was identified as an independent factor in vascular dementia30), and higher ANP levels were associated with increased white matter hyperintensities (Northern Manhattan Study31)). BNP, released by the heart ventricles in response to excessive cardiac wall stress, plays a pivotal role in regulating blood pressure and fluid balance. Triggered primarily by myocyte stretching, BNP synthesis responds to excessive cardiac wall stress. Moreover, N-terminal proBNP (NT-proBNP), a precursor of BNP, is considered to be more sensitive for detecting early heart failure. Unlike BNP, which remains stable for only 4 h at room temperature, NT-proBNP demonstrates a prolonged stability of 72 h and remains unaffected by hemolysis. Consequently, NT-proBNP has robust supporting data for its use in patient management and therapy monitoring compared with BNP. In contrast, ANP originates from the atrium, suggesting a potential difference in behaviors concerning brain damage and cognitive impairments28). Despite these distinctions, the specific differences remain unclear, with the only established association being between ANP and conditions such as dementia and SVD30,32).
Cardiac troponins, including cardiac troponin I (cTnI) and cardiac troponin T (cTnT), are sensitive biomarkers of myocardial injury. High-sensitivity cardiac troponin T (hs-cTnT) is commonly used to evaluate cardiac conditions, especially for diagnosing acute myocardial infarction and assessing the extent of damage. Elevated hs-cTnT levels indicate heart muscle damage and are associated with an increased risk of cardiovascular events and mortality. The hs-cTnT test also serves in the risk stratification of patients with cognitive impairment, reflecting cerebral hypoperfusion or cardiac embolism. In a study conducted at a memory clinic in Singapore, elevated hs-cTnT levels were associated with cognitive impairment, depending on the presence of cerebrovascular diseases33). Another study revealed that patients with higher levels of NT-proBNP and hs-cTnT had an increased risk of vascular events such as incident microbleeds and cortical infarcts29).
Growth Differentiation Factor 15 (GDF-15), encoded by the GDF-15 gene and a part of the transforming growth factor beta superfamily, plays a role in diverse biological processes, including angiogenesis, cell repair, and growth. Demonstrating robust prognostic potential, GDF-15 has emerged as a significant protein marker for various diseases, such as heart disease and neurodegenerative conditions. A systematic review and meta-analysis suggested that elevated GDF-15 levels could serve as a biomarker for mild cognitive impairment and AD, especially in individuals exhibiting white matter hyperintensities34). In individuals aged > 60 years, higher GDF-15 levels have been associated with an increased risk of incident dementia35). However, not all studies have consistently established a significant association between GDF-15 levels and AD.
The association between blood-based cardiac biomarkers and cognitive impairment or brain damage involves diverse mechanisms, including microinfarcts, cerebral hypoperfusion resulting from reduced cardiac output, metabolic disturbances at the capillary level, and blood-brain barrier dysfunction28). One notable avenue involves cardiac embolism, particularly microinfarcts triggered by conditions such as AF. These microembolic events can result in a cascade of neurological consequences that potentially influence cognitive function. Another significant mechanism centers around cerebral hypoperfusion. Reduced cardiac output leads to cerebral hypoperfusion, diminishing blood flow to the brain and potentially causing cognitive challenges. Concurrently, metabolic disturbances at the capillary level introduce the prospect of biochemical alterations affecting neural function, adding complexity to the overall understanding36). Despite numerous hypothesized mechanisms, several aspects remain unclear, underscoring the need for further investigation. Whether the relationship is direct or indirect, the well-established link between cardiac markers and cognitive function suggests their potential use in convenient screening tests. Nevertheless, the intricacies of these associations call for continued exploration to gain a comprehensive understanding.
In recent decades, novel biomarkers have been investigated for early detection and prognosis. Notably, myeloperoxidase, a cardiac biomarker derived from proteins found in the azurophilic granules of polymorphonuclear neutrophils and macrophages, has been effective in diagnosing and stratifying the risk of acute coronary artery syndrome37). Elevated levels of myeloperoxidase are believed to be associated with pre-existing coronary artery disease and inflammation. Ischemia Modified Albumin (IMA) serves as another protein-derived biomarker that demonstrates elevated levels upon interaction with ischemic heart tissues and circulating serum albumin38). It proves to be a reliable discriminator that effectively distinguishes between patients with ischemic and non-ischemic conditions. Creatinine kinase-MB (CK-MB), a myocardium-related isoenzyme of creatine kinase found in both the heart and skeletal muscles, exhibits peak levels 4–6 h after injury to these cells, with the highest concentration occurring at 24 h39). Subsequently, within 48–72 h, CK-MB levels typically return to normal. Although less specific than troponin, it is useful for diagnosing reinfarction. Notably, cTnT levels did not increase after stroke. The presence of normal cTnT alongside elevated CK-MB suggests that CK-MB is not a biological marker for myocytolysis, indicating a higher likelihood of a noncardiac origin40). Cystatin-C, a protein derivative present in all nucleated cells, serves as an indicator of acute kidney injury and cardiovascular disease41). Its levels increase within 8 h of cardiac surgery when acute kidney injury develops, making it a valuable tool for the early detection of renal impairment in patients undergoing cardiac surgery. Among lipid-derived biomarkers, oxylipins and lipoprotein-associated phospholipase A2 show considerable promise. Oxylipins, which are found in all nucleated cells, manifest at heightened levels in the context of cardiovascular diseases42). Developing early diagnostic tools for cardiovascular diseases based on altered levels of oxylipins is necessary. Lipoprotein-associated phospholipase A2, a lipid derivative primarily found in leukocytes, is elevated in response to cardiovascular inflammation and heart failure, typically peaking 24 h after the onset of inflammation43). This enzyme serves as a valuable marker for determining the risk of cardiovascular and coronary heart disease, as well as ischemic stroke. Meanwhile, certain protein-and amino acid-derived biomarkers have shown significant promise. Trimethylamine N-Oxide (TMAO), an amino acid derivative in the intestinal lumen, is linked to cardiovascular and renal diseases44). Its concentrations elevate within 24 h, and monitoring TMAO proves crucial in foreseeing the potential risks of heart attack, stroke, and kidney disease. Myoglobin, an oxygen-sorting protein derived from proteins located in the heart and skeletal muscles, functions as an indicator of injury to these cells45). Following an injury, myoglobin levels peak at 8–12 h, returning to normal within 24 h. In conjunction with troponin, myoglobin contributes to the early diagnosis of heart and skeletal muscle injuries. Finally, fibrinogen, a glycoprotein synthesized in the liver, is associated with tissue and vascular injury, potentially increasing in the presence of inflammation46). Elevated levels can be observed 5 days after injury, and monitoring fibrinogen can be used to assess bleeding disorders and evaluate the risk of cardiovascular diseases. While reports on the association between these cardiac biomarkers and cognitive function are limited, they can reflect various pathologies of cardiac function and hold potential for establishment as biomarkers for cognitive function and SVD in the future.
The heart and brain, which are both highly vascularized and oxygen-demanding organs, are closely interdependent. Cardiac function plays a pivotal role in maintaining brain homeostasis. Utilizing cardiac biomarkers, such as electrocardiograms, ultrasound, and blood biomarkers, provides essential insights into cerebrovascular disease and cognitive impairment (Fig. 2). In recent decades, the exploration of novel biomarkers has significantly advanced early detection and prognostic efforts for various medical conditions. Certain biomarkers show substantial promise for diagnosing and stratifying the risks associated with acute coronary artery syndrome, cardiovascular diseases, and renal impairment. These discoveries emphasize the potential for developing effective early diagnostic tools that offer valuable insights into diverse medical conditions, ranging from cardiac events to renal and vascular health. In future studies, consistently recognizing the intricate connections between the brain and the heart is crucial.
Cardiac biomarkers such as electrocardiograms, ultrasound, and blood tests are valuable for assessing cognitive function and cerebrovascular diseases. EEG, electrocardiogram; AF, atrial fibrillation; LVH, left ventricular hypertrophy; PTFV1, P-wave terminal force in lead V1; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; NT-proANP, N-terminal pro-atrial natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; cTnT, cardiac troponin T; cTnI, cardiac troponin I; hs-cTnT, high-sensitivity cardiac troponin T.
None.
The authors have no conflict of interest.
