Citations

Abstract Aims Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE. Methods and results We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A–B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36–0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30–0.63) was similar to controls (0.43, 0.35–0.57) but significantly lower than Stages A–B (0.61, 0.47–0.75) and HFpEF (0.63, 0.42–0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81–5.18), while rest and peak SBP were not. Kaplan–Meier analysis confirmed a worse survival probability in Stages A–B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF. Conclusion A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A–B and HFpEF.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Abstract Background Glial fibrillary acidic protein (GFAP) is a promising candidate blood‐based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease‐associated changes, its clinical correlates, and biofluid‐type dependency will influence its clinical utility. Methods We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ‐positive from Aβ‐negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion Our findings support a role for plasma GFAP as a clinical biomarker of Aβ‐related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Autosomal‐dominant, Dutch‐type cerebral amyloid angiopathy (D‐CAA) offers a unique opportunity to develop biomarkers for pre‐symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D‐CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D‐CAA carriers and non‐carriers, we observed divergence of white matter injury measures between D‐CAA carriers and non‐carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross‐sectional and longitudinal biomarkers of D‐CAA progression. ANN NEUROL 2022;92:358–363

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows epicardial adipose tissue (EAT) acts as a paracrine organ and may directly alter myocardial function by exerting mechanical compression. Purpose. We evaluated EAT thickness through transthoracic echocardiography and investigated its relationship with cardiopulmonary fitness and cardiovascular haemodynamics at rest and during exercise in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance, together with 44 healthy controls. We performed a resting state-of-the-art echocardiographic evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. Results. EAT thickness was higher in HFpEF (median 8 mm, interquartile range [IQR] 4–12 mm) and progressively reduced in controls (median 5 mm, IQR 3–7 mm; p < 0.0001) and HFrEF (median 3 mm, IQR 2–6 mm). In HFpEF, EAT thickness was inversely correlated with peak oxygen consumption (VO2) and peripheral oxygen extraction (AVO2diff), while a direct association was observed for the same parameters in HFrEF (Figure 1). Furthermore, EAT independently predicted peak VO2 and AVO2diff in HFrEF and HFpEF regardless of body mass index and waist circumference. These relationships were direct in HFrEF (standard regression coefficient [SRC] for peak VO2: 0.18, p = 0.02; SRC for peak AVO2diff: 0.17, p = 0.03) and indirect in HFpEF (SRC for peak VO2: -0.33, p < 0.0001; SRC for peak AVO2diff: -0.25, p < 0.0001). As there are no definite cut-off values to define increased EAT, patients were divided based on the median EAT value (5 mm) of the overall population. Thinner EAT (≤5 mm) was associated with worse LV systolic dysfunction (peak average S’) and remodeling (3D LV mass index) in HFrEF. In HFpEF, on the other hand, increased EAT (>5 mm) was related to worse right ventricular systolic dysfunction (3D right ventricular ejection fraction) and more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion. In HFpEF, increased EAT thickness is associated with a worse hemodynamic profile and functional capacity. Conversely, in HFrEF, EAT thinning portends more advanced LV dysfunction and impaired cardiopulmonary fitness. Abstract Figure 1 Abstract Figure 2

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows that increased epicardial adipose tissue (EAT) thickness is associated with metabolic syndrome, microvascular dysfunction and enhanced pericardial restraint. Purpose. We measured echocardiography-derived EAT thickness in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction to examine the relationship between EAT and prognosis at clinical follow-up. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. We considered a composite endpoint of cardiovascular death and HF-related hospitalization during follow-up. Results. Patients with HFpEF displayed greater EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p < 0.0001). During a median follow-up of 20.9 months (IQR 15-25 months), 34 cardiovascular deaths and 146 HF hospitalizations were reported, with no significant differences between the two HF phenotypes. EAT was shown to predict adverse events independently from body mass index, waist circumference and other well-established prognostic markers in HF (such as NT-proBNP and peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with increased EAT thickness had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion. EAT accumulation is increased in HFpEF compared to HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcomes, which may be due to the secretion of pro-inflammatory and pro-atherogenic adipokines and increased mechanical restraint. In HFrEF, EAT thinning is associated with a worse prognosis, probably reflecting a more advanced catabolic state (e.g., cardiac cachexia). Larger studies are needed to determine whether or not EAT has a causal role in influencing progression and survival in the different HF phenotypes. Abstract Figure 1