Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections.

https://www.mdpi.com/1422-0067/23/21/12906/pdf?version=1667196615

The Role of Inflammation in Cardiovascular Disease

Cardiovascular health interacts with cognitive and mental health in complex ways, yet little is known about the phenotypic and genetic links of heart-brain systems. We quantified heart-brain connections using multiorgan magnetic resonance imaging (MRI) data from more than 40,000 subjects. Heart MRI traits displayed numerous association patterns with brain gray matter morphometry, white matter microstructure, and functional networks. We identified 80 associated genomic loci (P < 6.09 × 10−10) for heart MRI traits, which shared genetic influences with cardiovascular and brain diseases. Genetic correlations were observed between heart MRI traits and brain-related traits and disorders. Mendelian randomization suggests that heart conditions may causally contribute to brain disorders. Our results advance a multiorgan perspective on human health by revealing heart-brain connections and shared genetic influences. Description Editor’s summary It is known that cardiovascular disorders correlate with some neurological and psychiatric conditions, but it is not always clear what the connections are and whether they are caused by an innate predisposition or by the stress induced by having a medical condition. To detangle these questions, Zhao et al. examined imaging and genetic data from tens of thousands of participants in the UK Biobank and BioBank Japan (see the Perspective by Sacher and Witte). Through this large-scale analysis, the authors uncovered correlations between structure and function of both the heart and the brain, such as links between specific features of cardiac imaging and neuropsychiatric disorders. The authors also used Mendelian randomization to demonstrate shared genetic influences on both the brain and the heart. —Yevgeniya Nusinovich Biobank-scale imaging traits reveal phenotypic and genetic links between the human heart and brain. INTRODUCTION There is increasing evidence pointing to a close relationship between heart health and brain health, with cardiovascular diseases potentially leading to brain diseases such as stroke, dementia, and cognitive impairment. Magnetic resonance imaging (MRI) is a valuable tool that can be used to assess both the heart and brain, generating biomarkers and endophenotypes for various clinical outcomes. However, although recent large-scale analyses have been conducted on heart and brain MRI-derived traits separately, few studies have explored the potential for multiorgan MRI to examine heart-brain connections and identify shared genetic effects. The structural and functional links between the heart and the brain remain unclear. RATIONALE Using multiorgan MRI and genetic data from >40,000 subjects, we aimed to quantify interorgan connections between the heart and brain and identify the underlying genetic variants. Specifically, we analyzed 82 cardiac and aortic MRI-derived traits across six categories: left and right ventricles, left and right atria, and ascending and descending aortas, as well as 458 brain MRI traits that measured structure and function. RESULTS After controlling for various covariates, we found that heart MRI traits were clearly associated with the brain across all imaging modalities studied. We observed multiple patterns of association for brain gray matter morphometry, white matter microstructure, and functional networks. For example, we found that the left ventricle of the heart showed the strongest correlations with microstructure metrics of cerebral white matter tracts, suggesting that adverse heart features were associated with poorer white matter microstructure. Our genome-wide association analysis of heart MRI traits identified 80 associated genomic loci (P < 6.09 × 10−10). We performed sex-specific analysis and found that the genetic effects on heart structure and function were highly consistent between both sexes. Further, we conducted a systematic search of previously reported genetic results in these genomic loci and found that heart MRI traits had shared genetic influences and colocalized with heart and brain diseases and complex traits. We identified genetic correlations between heart MRI traits and various brain complex traits and diseases such as stroke, eating disorders, schizophrenia, cognitive function, and mental health traits. For example, adverse myocardial wall thickness condition was positively genetically correlated with stroke. We further used two-sample Mendelian randomization to explore causal genetic links between the heart and brain, and our findings suggest that adverse heart features have genetic causal effects on several brain diseases such as psychiatric disorders and depression. CONCLUSION This study deepened our understanding of heart-brain links and their genetic basis. We observed that MRI measurements of the two organs were associated with each other, and this was independent of a wide variety of body measures, shared risk factors, and imaging confounders. We also uncovered genetic colocalizations and correlations between heart structure and function and brain clinical end points, suggesting that adverse heart metrics may have implications for brain abnormalities and the risk of brain diseases. By understanding human health from a multiorgan perspective, we may be able to improve disease risk prediction and prevention and mitigate the negative effects of one organ disease on other organs that may be at risk. Heart-brain connections revealed by multiorgan imaging genetics. Top left: Quantifying the heart and brain structure and function in MRI. Top right: Examples of associations between heart MRI traits and brain white matter tracts. Bottom left: Genomic loci associated with heart MRI traits that overlapped with traits and disorders of the heart and/or brain. Bottom right: Selected genetic correlations between heart MRI traits and brain disorders.

Heart-brain connections: Phenotypic and genetic insights from magnetic resonance images

After ischemic stroke, there is a significant burden of cardiovascular complications, both in the acute and chronic phase. Severe adverse cardiac events occur in 10% to 20% of patients within the first few days after stroke and comprise a continuum of cardiac changes ranging from acute myocardial injury and coronary syndromes to heart failure or arrhythmia. Recently, the term stroke-heart syndrome was introduced to provide an integrated conceptual framework that summarizes neurocardiogenic mechanisms that lead to these cardiac events after stroke. New findings from experimental and clinical studies have further refined our understanding of the clinical manifestations, pathophysiology, and potential long-term consequences of the stroke-heart syndrome. Local cerebral and systemic mediators, which mainly involve autonomic dysfunction and increased inflammation, may lead to altered cardiomyocyte metabolism, dysregulation of (tissue-resident) leukocyte populations, and (micro-) vascular changes. However, at the individual patient level, it remains challenging to differentiate between comorbid cardiovascular conditions and stroke-induced heart injury. Therefore, further research activities led by joint teams of basic and clinical researchers with backgrounds in both cardiology and neurology are needed to identify the most relevant therapeutic targets that can be tested in clinical trials. 

https://www.ahajournals.org/doi/pdf/10.1161/JAHA.122.026528

Stroke–Heart Syndrome: Recent Advances and Challenges

Abstract Cardiovascular disease and brain disorders, such as depression and cognitive dysfunction, are highly prevalent conditions and are among the leading causes limiting patient’s quality of life. A growing body of evidence has shown an intimate crosstalk between the heart and the brain, resulting from a complex network of several physiological and neurohumoral circuits. From a pathophysiological perspective, both organs share common risk factors, such as hypertension, diabetes, smoking or dyslipidaemia, and are similarly affected by systemic inflammation, atherosclerosis, and dysfunction of the neuroendocrine system. In addition, there is an increasing awareness that physiological interactions between the two organs play important roles in potentiating disease and that sex- and gender-related differences modify those interactions between the heart and the brain over the entire lifespan. The present review summarizes contemporary evidence of the effect of sex on heart–brain interactions and how these influence pathogenesis, clinical manifestation, and treatment responses of specific heart and brain diseases. 

/pdf/oup-accepted-manuscript-1y6hm5i0.pdf

OUP accepted manuscript

Atherosclerosis is the leading cause of death worldwide and leukocyte recruitment is a key element of this phenomenon, thus allowing immune cells to enter the arterial wall. There, in concert with accumulating lipids, the invading leukocytes trigger a plethora of inflammatory responses which promote the influx of additional leukocytes and lead to the continued growth of atherosclerotic plaques. The recruitment process follows a precise scheme of tethering, rolling, firm arrest, crawling and transmigration and involves multiple cellular and subcellular players. This review aims to provide a comprehensive up-to-date insight into the process of leukocyte recruitment relevant to atherosclerosis, each from the perspective of endothelial cells, monocytes and macrophages, neutrophils, T lymphocytes and platelets. In addition, therapeutic options targeting leukocyte recruitment into atherosclerotic lesions—or potentially arising from the growing body of insights into its precise mechanisms—are highlighted.

https://www.frontiersin.org/articles/10.3389/fcvm.2021.813984/pdf

Where the Action Is—Leukocyte Recruitment in Atherosclerosis

Aims Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear. Methods and results Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques. Conclusion Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.

/pdf/acute-mental-stress-drives-vascular-inflammation-and-4ev3g7fkro.pdf

Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis

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Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis