HF Severity, Outcomes Tied to Markers of Neurodegeneration

Biomarkers of Alzheimer’s disease and other neurodegenerative diseases are increased among patients with signs of more severe heart failure with reduced ejection fraction (HFrEF), findings from a prospective registry study show.

Moreover, higher levels of these biomarkers—neurofilament lift chain (NfL), total tau (t-tau), amyloid beta 40 (Aβ40), and amyloid beta 42 (Aβ42)—were significantly associated with greater risks of all-cause death and HF hospitalizations, researchers led by Raphael Wurm, MD, and Suriya Prausmüller, MD (both from the Medical University of Vienna, Austria), report in the June 2024 issue of JACC: Heart Failure.

HF is a syndrome that affects many organ systems, including the brain, senior author Noemi Pavo, MD, PhD (Medical University of Vienna), told TCTMD, and “this is now the first study in a big cohort of well-characterized heart failure patients where we used very sensitive biomarkers . . . specific for neuronal damage, and we have shown this really obvious link between heart failure, heart failure severity, and levels of these biomarkers in serum.”

Though this provides evidence for an elevated risk for neurodegeneration in patients with HF, it’s just a starting point, Pavo indicated. “Of course, we have to show if this is associated with clinical neurocognitive function or accelerated decline in clinical characteristics,” she said, noting that it’s too early to start routinely measuring these biomarkers in patients with HF. But, she added, these results are “a hint that we have to dig deeper here.”

Comparison With NT-proBNP

Recent advancements in HF treatment mean that patients are living longer, underscoring the importance of maintaining cognitive function into the later years. Cognitive impairment has been shown to have a detrimental impact on the ability of patients with heart failure to care for themselves and on clinical outcomes, which was highlighted in a recent scientific statement from the Heart Failure Society of America.

For the current study, the investigators examined the link between blood-based biomarkers of neurodegenerative diseases and HF severity and outcomes to further explore the connection between the heart and brain. They measured biomarker levels in 470 stable patients with moderate-to-severe HFrEF (median age 62; 77% men)—but without known dementia—who were included in a prospective registry at the Vienna General Hospital. Most patients were in NYHA functional II (47%) or III (39%).

All four biomarkers correlated with the severity of HF as defined by NT-proBNP levels and NYHA functional class (P < 0.0001 for all), with some relationships also seen with various comorbidities. All biomarkers, for instance, were elevated in patients with chronic kidney disease and all but Aβ40 were increased in patients with known carotid artery stenosis. Only NfL levels were increased in patients with type 2 diabetes and CAD, whereas atrial fibrillation was associated with higher levels of NfL and t-tau.

Maybe we have really found something which mirrors neurological changes or pathophysiological alteration. Noemi Pavo

In terms of outcomes, 31% of patients died during a median follow-up of 3.7 years and 29% had an unplanned HF hospitalization during a median follow-up of 1.8 years. Higher levels of all four biomarkers were associated with greater risks of all-cause death (crude HRs per 1-log unit increase ranging from 3.90 to 5.14) and unplanned HF hospitalizations (crude HRs ranging from 2.48 to 3.48; P < 0.001 for all). The results were consistent after adjusting for potential confounders, including NT-proBNP level, in nearly all cases, except that the relationship between NfL levels and risk of HF hospitalizations was no longer significant.

Only NfL, however, had a discriminatory accuracy in predicting all-cause mortality that was similar to what was seen with NT-proBNP (C-index 0.70 vs 0.72; P = 0.225); accuracy was lower versus NT-proBNP with the other markers. For HF hospitalization, discriminatory accuracy was not significantly different between the four biomarkers and NT-proBNP.

Pavo noted that NfL should be a specific marker for neuroaxonal damage rather than a more general marker of a systemic issue. “So maybe we have really found something which mirrors neurological changes or pathophysiological alteration.”

Next Steps

These results “clearly demonstrate the presence of an ongoing neurodegenerative process, the researchers say, explaining that this may be accelerated because of shared risk factors between the two conditions. Direct mechanisms, such as impaired cerebral blood flow, proinflammatory disposition, or neurohumoral dysregulation, might also help explain the relationship.

Unclear, though, is what these findings might mean for the clinical care of patients with HFrEF. “The biomarkers studied could be used to identify patients prone to accelerated neurodegeneration in cardiocerebral syndrome,” the authors propose.

Beyond that, it remains to be seen whether “we can make it better with some intervention, be it early extended neurologic testing or other interventions,” Pavo said. “Also, we have to see if we treat heart failure better if this coincides with lowering the risk—so if we can really influence it with therapies.”

Additional research, she added, is needed to link these findings with results of neurocognitive function assessments and neuroimaging and to track how levels of these biomarkers change over time, particularly in response to intensification of guideline-directed medical therapy for HF.

In an accompanying editorial, Jan Traub, MD (University Hospital Würzburg, Germany), and colleagues note that the association between the biomarkers and clinical outcomes in patients with HFrEF suggests “a potential acceleration or exacerbation of neurodegenerative processes in patients with HFrEF, possibly due to factors including impaired cerebral blood flow and systemic inflammation. In turn, neurodegeneration may contribute to HFrEF progression itself in various ways, including suboptimal adherence to medication, diet, physical activity, and other lifestyle measures.”

Yet there remain many questions about the intersection of the heart and the brain that need to be explored, they say. “With improvements in survival and an increasingly elderly population and growing burden of heart failure and comorbidities, this is an area that must be a focus of research in order to improve the lives of our patients with heart failure.”