Introduction
The heart and brain are intricately linked in terms of their structure and function. The role of heart-brain communication in health and disease is attracting growing attention. Cardiovascular diseases are increasingly recognized as underlying contributors to various brain disorders, including stroke, dementia, and microvascular disease. For example, heart failure (HF) has been associated with Alzheimer’s disease (AD) and cognitive dysfunction [1]. Advances in medical imaging have deepened our understanding of the structural and morphological relationships between the heart and brain. MRI provides comprehensive structural and functional insights into brain changes. This commentary discusses the effects of the heart structure on brain MRI features, highlighting shared genetic factors that might simultaneously shape the morphology and structure of both organs. By addressing these interconnections, we aim to provide new insights into the prevention and treatment of heart-brain-related diseases.
Influence of Heart Failure on Brain MRI Features
HF can affect brain structure, function, and metabolism, and potentially lead to neurological complications. In patients with HF, the temporal-parietal region of the brain is significantly atrophied, and the myelin integrity is diminished in several brain regions, including the amygdala, hippocampus, cingulate gyrus, insula, cerebellum, prefrontal cortex, and several white matter regions [2]. HF also causes structural changes in the cortex. The correlation between cortical structural abnormalities and cognitive function indicates that cortical morphology might serve as a potential imaging biomarker and also provide a neuroanatomical basis for understanding cognitive impairment in chronic HF [3]. Patients with HF often experience changes in cerebral blood flow due to impaired output, thereby resulting in damage to gray matter and white matter. HF is associated with diminished cerebral blood flow in several brain regions responsible for autonomic regulation, emotional processing, and cognitive function [4].
HF with preserved ejection fraction (HFpEF), often associated with diastolic dysfunction, is particularly prevalent in older individuals. Whereas the systolic function and ejection fraction remain within normal ranges, significant structural and functional brain abnormalities may occur in HFpEF. MRI functional network analyses have shown that patients with HFpEF exhibit diminished static and dynamic functional connectivity, particularly within the default mode network and the bilateral frontoparietal networks. The progression and duration of HFpEF correlate with the development and severity of white matter lesions, thereby emphasizing their prognostic value [5].
Left ventricular hypertrophy (LVH) and increased LV mass result from chronic pressure overload, and contribute to impaired diastolic filling and elevated left atrial pressures. The LA responds to sustained elevated LV filling pressures by undergoing remodeling and enlargement, as reflected by increased LA size and volume. The left atrial volume index (LAVI) is a well-established marker of diastolic dysfunction and chronicity of elevated filling pressures. Left ventricular mass index and LVH are associated with increased white matter hyperintensity [6]. A LAVI >34 mL/m2 is a specific threshold indicating diastolic dysfunction. Significant correlations have been observed among LVH, LV mass, and LA size. LAVI, a marker of LA remodeling, has additional prognostic value in assessing diastolic dysfunction, which is associated with brain abnormalities [7]. HF biomarkers, such as NT-proBNP, are also associated with brain structure. Elevated NT-proBNP levels and LAVI are independently associated with multi-territorial and large cortical infarcts [8] (Figure 1).
Influence of Heart Failure on Brain MRI Features.
Brain MRI suggests that heart failure, with alterations in ventricular wall thickness and impaired ejection function, results in brain structural changes (brain volume and myelin integrity [2], cortical morphology abnormalities [3], white matter lesions [5], and cerebrovascular changes [4]).
Influence of Arrhythmia on Brain MRI Features
Atrial fibrillation (AF) is associated with a range of cerebrovascular pathologies. In patients with AF, diminished cardiac output can result in brain hypoperfusion and ischemia, and lead to brain tissue damage. Additionally, AF increases the risk of formation of blood clots, which can travel to the brain and cause cerebral embolism. During anticoagulant therapy, patients with AF are also at risk of developing cerebral microbleeds [6]. Furthermore, AF is associated with elevated risk of cognitive impairment and dementia. Patients with AF exhibit significant deficits in executive function, processing speed, and reasoning. Moreover, AF patients’ imaging studies have revealed diminished cortical thickness, enhanced extracellular free water content, and extensive white matter lesions indicative of small vessel disease [9].
Complete heart block is a cardiac conduction disorder characterized by complete interruption of electrical signal transmission between the atria and ventricles. A prospective cohort study has suggested that individuals with complete heart block might be predisposed to long-term anterior pituitary hormonal dysfunction [10].
Relationship with Cognitive Function
AD and multi-infarct dementia are characterized by cognitive decline and influenced by the heart. HF, AF, and reduced cardiac output might contribute to cerebral hypoperfusion, thereby facilitating AD. Atrophy of the medial temporal lobes has been observed in AD. Multi-infarct dementia typically manifests as white matter hyperintensity [6].
MRI characteristics represent neurocognitive outcomes to some extent. For example, certain MRI features – such as cortical morphology, cortical thickness, white matter abnormalities, and functional network connectivity – indicate alterations in cognitive or memory function [3, 5, 6]. The application of AI-assisted analysis enables the identification of early imaging biomarkers, thereby potentially improving the management of heart-related brain complications. Although research in this area remains in early stages, the ongoing development of advanced technologies and analytical models holds promise for clinical translation and improved outcomes.
Influence of Cardiovascular Confounding Risk Factors on Brain MRI Features
Cardiovascular confounding risk factors influence brain structure and function. Hypertension is associated with cerebral infarction, ventricle enlargement, and increased white matter hypersignal volume, and decreased hippocampal volume. Diabetes is associated with cerebral atrophy and ventricle enlargement [11]. MRI images of people with high cardiovascular risk scores show an enhanced white matter hypersignal, brain microbleeds, and diminished brain volume [12] (Figure 2).
Effects of Congenital Heart Disease on Brain MRI
Congenital heart disease (CHD) is the most prevalent birth defect worldwide. Although survival rates of children with CHD have decreased with surgical interventions, CHD, despite correction, can still result in neurological and developmental disorders [13].
Children with CHD often experience cortical injuries that manifest as diminished gray matter volume in regions such as the frontal, temporal, and parietal lobes, as detected by MRI. Specific decreases in cortical thickness and regional volumes, including the superior frontal cortex, anterior cingulate cortex, insula, fusiform gyrus, left parahippocampal gyrus, right middle temporal gyrus, and left superior frontal gyrus, reflect brain developmental damage [13].
CHD is also associated with global and regional decreases in brain volume. Severe CHD often coexists with placental pathology, thereby contributing to impaired cortical, cerebellar, and hippocampal development. Such structural impairments correlate with cognitive deficits and memory impairments [14].
Structural abnormalities in the cerebral vasculature may lead to impaired cerebral blood flow, altered hemodynamics, and increased risk of ischemia and hemorrhage, all of which may contribute to cognitive and neurodevelopmental challenges. In patients with CHD, disrupted neurovascular function, as measured through non-invasive MRI proxies, manifests as diminished vascular capacity in key networks such as the default mode, salience, and central executive networks [15].
Premature infants with patent ductus arteriosus have heightened risk of intraventricular hemorrhage and white matter damage. Children with cyanotic CHD, particularly those who have undergone Fontan palliation, show diminished white matter connectivity [16]. Hypoxia-ischemia, a hallmark of cyanotic CHD, contributes to early white matter injury and delayed structural brain development. The correlation between the duration of cyanotic CHD and MRI changes is well-established, and prolonged exposure to hypoxia and polycythemia have been found to be key drivers of progressive injury [17] (Figure 3).
Genetic Pleiotropy in Heart-Brain Interactions
Genetic pleiotropy, wherein a single gene influences multiple traits or conditions, is a key concept for understanding the heart-brain axis. Studies on twins and families have indicated that brain MRI features are heritable, and shared genetic factors influence cardiac morphology, brain structure, and neurodegenerative diseases [1].
For example, CHD7 mutations cause congenital heart defects and neurodevelopmental disorders, as seen in CHARGE syndrome, by disrupting chromatin remodeling crucial for heart and brain development [18].
The DMD gene encodes dystrophin. The loss of dystrophin in cardiomyocytes leads to myocardial damage and eventually HF. Children with DMD exhibit specific cognitive deficits, such as impairments in memory and learning ability, because of the lack of intrinsic dystrophin gene products within central nervous system [19].
MRI and Genetic Insights
Combining MRI with genetic analyses has provided unprecedented insights into the heart-brain axis: genetic overlap between cardiac MRI features and brain-related conditions such as intracranial aneurysms and neurodegenerative disorders have been identified, particularly in regions including 7p21.1 and 12q24.12 [1].
Genetic screening for APOE-ε4 and other variants may enable prioritization of early MRI for patients at risk of AD. In contrast, MRI abnormalities (e.g., unexplained brain atrophy or vascular changes) might prompt genetic analysis to uncover potential hereditary causes. Genetic testing excels in risk prediction and prioritizing high-risk individuals for imaging, whereas MRI enables definitive structural and functional assessments [6] (Figure 4).
Shared Genetic Effects on Cardiovascular and Cerebral Structures.
Brain MRI features are heritable, and shared genetic factors influence cardiac morphology and brain structure [1] (e.g., CHD7 and DMD).
Clinical Implications and Prospects
Some case-control studies comparing and analyzing brain MRI images between patients with HF and healthy controls have indicated diminished cortical thickness, white matter myelin integrity, and diminished blood flow to specific brain areas in patients with HF. These findings further strengthen the connection between HF and the brain [2, 3, 4]. In patients with CHD, MRI has indicated diminished brain volume or white matter connectivity [13, 16].
The brain changes may precede or follow a cardiac diagnosis [6]. Structural brain changes in fetuses with CHD typically begin around 30 weeks of gestation and persist through birth, childhood, and even adolescence [20]. After CHD surgery, increases in cerebral blood flow, particularly in hypoplastic left heart syndrome, have been associated with significant growth in brain volume, thereby indicating some recovery of neurodevelopmental potential [21]. These findings suggest that actively managing the progression of heart disease and risk factors might contribute to mitigating brain complications.
The emerging concept of the heart-brain axis supports a “heart-brain co-treatment” paradigm emphasizing simultaneous management of cardiovascular and neurological conditions. Future directions include (1) integrative imaging and genetics: leveraging multimodal imaging techniques (MRI and PET-CT) combined with genetic profiling to uncover intricate connections between the heart and brain; (2) personalized medicine: using genetic screening to predict risks and personalize interventions for heart-brain-related diseases; and (3) multidisciplinary collaboration: uniting cardiology, neurology, genetics, and developmental sciences to create comprehensive care models for conditions such as CHD, stroke, and neurodegenerative diseases.
Conclusion
Exploring the heart-brain axis through genetics and imaging deepens understanding of the interconnected pathophysiology of these vital organs. Continued research in this field holds promise in enhancing diagnostic accuracy, enabling early intervention, and fostering innovative treatment strategies aimed at decreasing the global burden of heart-brain-related diseases.
