Brain and Heart Health: At a Crossroads

As the seat of our thoughts, emotions, perceptions, and drives, the brain is the cornerstone of our health. And no organ is more intimately connected to the brain than the heart, on which the brain depends for a constant supply of energy via circulating blood.

The American Association and American Stroke Association (AHA/ASA) have recently issued a new Scientific Statement on Cardiac Contributions to Brain Health¹. In addition to describing well known contributions, such as the risk to the brain from hypoperfusion and cardiac emboli, this statement provides surprising evidence of new, incompletely understood contributions, including potential roles for covert stroke and ischemic white matter damage, neuroendocrine signaling, inflammation, blood-brain barrier alterations, and even possible connections with neurodegeneration from Alzheimer' s disease.

The epidemiological evidence that poor heart health is linked to poor brain health is abundantly clear. The field is now at a crossroads, where research is transitioning from identifying risk factors to considering mechanisms, with implications for clinical trials and public health promotion.

The Statement focuses on three highly prevalent cardiac conditions and their relationships with brain health: heart failure, atrial fibrillation, and coronary heart disease¹. The importance of these conditions cannot be overstated, as an individual's lifetime risk of any of them is about 60%². However, the reader should keep in mind that there are other cardiac conditions that contribute to brain health, including pediatric conditions such as congenital heart disease³, that were out of scope of this Statement but can hopefully be addressed in future ones.

Heart failure can be categorized by the ejection fraction, as either heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), or heart failure with mid-range EF (41-60%). Epidemiological evidence supports an association between heart failure and impairment on neuropsychological testing and increased risk for dementia, particularly for HFrEF. In addition to the well-known associations of HFrEF with cognitive impairment via reduced blood flow and risk for cardioembolism, there is emerging evidence that increase sympathetic nervous system activity and circulating cytokines and other pro-inflammatory proteins may also have adverse effects¹.

Atrial fibrillation has long been recognized as cause of cardioembolic stroke, but there is now strong evidence that it is also a strong risk factor for cerebral white matter damage (visible on magnetic resonance imaging (MRI) as white matter hyperintensity), and risk for dementia. However, the mechanisms are not clear—they could include circulating emboli, reduced cardiac output, and a systemic inflammatory state—and there is a lack of clinical trial to show whether anticoagulation prevents cognitive decline and dementia¹.

Coronary heart disease has also been associated with cognitive impairment and increased risk for future dementia¹. There is evidence that having an MI can accelerate age-related cognitive decline⁴, even in the absence of clinical stroke, and more research is needed to discover how this can happen.

Intriguingly, the Statement has uncovered potential links between heart disease and pathophysiological processes related to Alzheimer's disease¹. Hypoxia and ischemia from hypoperfusion can increase levels of brain amyloid-β and tau. Cardiac dysfunction has been associated with higher serum levels of amyloid-β and phosphorylated tau, which could be related to reduced renal excretion of these neurotoxic substances. Remarkably, intramyocardial deposits of amyloid-β have been detected in patients with Alzheimer's disease, and genetic variations in presenilin-1 and presenilin-2 have been associated with heart failure. Although larger, confirmatory studies are needed, these observations raise the possibility that Alzheimer's disease may affect the heart as well.

In response to the summarized knowledge, the Scientific Statement offers suggestions for research, public health efforts, and clinical care¹. This should include a renewed focus on risk factors, such as hypertension, that cause both cardiac and brain disease. Preventing and treating vascular risk factors, along with promoting cognitive resilience through early life education and cognitive stimulating activities including social engagement, are widely acknowledged to be key components of public health strategies to prevent dementia⁵. The AHA's Life's Essential 8 have been strongly associated with better cognitive health and lower risk of covert cerebrovascular disease⁶, and can be an important resource for clinicians to teach their patients how to improve their vascular and brain health.

In the Statement, the authors acknowledge that the scientific rationale for treating cardiac conditions to prevent dementia is mostly based on epidemiological evidence, with few data from randomized controlled trials (RCTs). Barriers to conducting RCTs include the large sample sizes required, the long trial durations that would be needed, and, in some cases, the inability to include randomized controls for ethical reasons, if the cardiac intervention is already part of standard care. To provide stronger evidence for causation, study designs other than RCTs will need to be employed. This could include newer epidemiological methods that provide stronger evidence for causation, such as Mendelian randomization. Existing longstanding population-based cohort studies should be renewed and strengthened, to better investigate cardiac contributions to brain health over the life course. It would also be helpful for cardiologists and trialists to begin to consider cognitive decline, impairment, and dementia as another type of major adverse cardiovascular event, by collecting data on cognitive-related function in cardiovascular prevention trials.

Recent improvements in Alzheimer's disease diagnostics will provide new opportunities to understand cardiac contributions to brain health. Blood testing for amyloid-β and tau has advanced to the point where they can be used to detect Alzheimer's disease with similar accuracy as testing cerebrospinal fluid (CSF) or by using positron emission tomography (PET)⁷. A substudy of a population-based cohort showed that a composite score of vascular risk factors in midlife was associated with presence of amyloid-β on cerebral PET scan in later life⁸, but the number of participants was relatively small. CSF and PET are invasive and expensive, and therefore infeasible on a large scale. Bood testing is more scalable, offering the opportunity to ask important questions such as: Which vascular risk factors are associated with higher risk for Alzheimer's disease? What is the relationship between the severity of the risk factor and the risk for Alzheimer's disease, and does it differ according to level of risk factor control? Do cardiac conditions such as heart failure increase the risk for dementia by contributing to risk for Alzheimer's disease, or is their contribution solely due to increasing the risk for vascular dementia?

The AHA's mission, most recently defined in 2020, is to "be a relentless force for a world of longer, healthier lives"⁹. Notably, this mission has evolved from an exclusive focus on preventing and treating cardiovascular disease and stroke to a broader focus on overall health, including brain health⁵. The Scientific Statement on Cardiac Contributions to Brain Health effectively summarizes the scientific evidence that better cardiac care will improve brain health outcomes as well as cardiac function.