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Abstract Aim The normal (i.e. expected) haemodynamics in adults post-Fontan remain poorly delineated. Moreover, the definitions of elevated exercise pulmonary artery (PA) and PA wedge pressure (PAWP) for this population have not been described. Methods and results Seventy-two adults post-Fontan undergoing exercise catheterization were categorized into abnormal (Group I, n = 59; defined as resting mean PA ≥14 mmHg and/or PAWP ≥12 mmHg, ΔPAWP/Δsystemic flow [Qs] >2 mmHg/L/min, and/or ΔPA/Δpulmonary flow >3 mmHg/L/min) and normal (Group II, n = 13) haemodynamics. Thirty-nine patients with non-cardiac dyspnoea (NCD) were included as controls. There was no difference in exercise arterial oxygen saturation (87% [81–92] vs. 89% [85–93], p = 0.29), while exercise PA pressure (27 [23–31] vs. 16 [14.5–19.5] mmHg, p < 0.001) and PAWP were higher (21 [18–28] vs. 12 [8–14] mmHg, p < 0.001) in Group I. At peak exercise, Group I had lower heart rate (97 [81–120] vs. 133 [112.5–147.5] bpm, p < 0.001) and Qs response (67.3 [43.8–93.1] vs. 105.9 (82–118.5) % predicted, p < 0.001) than Group II. Exercise superior vena cava pressures were higher (16 [14–22.5] vs. 5.5 [3–7.3] mmHg, p < 0.001) and arterial oxygen saturation lower (89% [85–93] vs. 97% [96–98], p < 0.001) in Group II compared to NCD, while no differences in PAWP, stroke volume index, heart rate, or Qs response were seen. If defined as two standard deviations above mean values for Group II, elevated PAWP and mean PA pressure post-Fontan would correspond to 20.6 mmHg and 25.8 mmHg, respectively. Conclusion PAWP >20 mmHg and mean PA pressure >25 mmHg could be used to define elevated values during exercise in adults post-Fontan. The major discrepancy in exercise haemodynamics among Group II compared to controls appears to be the degree of systemic venous hypertension and arterial desaturation.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Abstract Background Myocarditis is an inflammation of the heart muscle most often caused by an immune response to viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood. Methods Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis to understand sex differences in the transcriptional landscape of myocarditis and identify candidate transcription factors that might drive sex differences in myocarditis. Results The hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. When comparing females to males with myocarditis, males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial transcriptional support (e.g., mitochondrial electron transport genes). In contrast, females were enriched for pathways related to mitochondrial respiration and bioenergetics, which were confirmed by higher transcript levels of master regulators of mitochondrial function including peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), nuclear respiratory factor 1 (NRF1) and estrogen-related receptor alpha (ERRα). TRANSFAC analysis identified ERRa as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Conclusions Master regulators of mitochondrial function were elevated in females with myocarditis compared to males and may promote sex differences in mitochondrial respiratory transcript expression during viral myocarditis resulting in less severe myocarditis in females following viral infection.

Background: Impaired left ventricular (LV) global longitudinal strain (GLS) is associated with worse outcomes in patients with severe aortic stenosis (AS). However, its prognostic value in patients with moderate AS is still unknown. The aim of this study is to investigate the impact of LV GLS on outcomes of patients with moderate AS. Methods: PubMed/Medline, Scopus, and Google Scholar databases were systematically reviewed to find relevant studies through June 2023 reporting data on the relationship between the LV GLS and long-term mortality in patients with moderate AS. Binary random effects models were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). I2 statistics were used to interpret heterogeneity, with I2>75% indicating substantial inter-study variation. Leave-one-out meta-analysis was performed to evaluate the effect of each study on the overall estimate. A p<0.05 was considered statistically significant. Results: A total of 172 studies were reviewed, and 4 studies between 2000-2023 were included in our meta-analysis with a median follow-up of 48.5 months and GLS cut-off varying from 11% to 16%. The pooled univariate analysis revealed a significant association between LV GLS and long-term mortality in patients with moderate AS with a pooled OR of 2.02 (95CI 1.04-3.93) p=0.04, I2=94.25%. The multivariate analysis, after adjusting for overall modifiable risk factors, yielded significant results, with an adjusted odds ratio (aOR) of 1.56 (95CI 1.21-2.01) p<0.01, I2=89.48%. Sensitivity analysis, using leave-one-out method, demonstrated robustness and stability of the results with aOR 1.56 (95CI 1.21-2.01) p<0.01. Conclusions: In patients with moderate AS, impaired LV GLS is associated with an increased risk for all-cause mortality. If further randomized studies confirm the prognostic ability of impaired GLS, moderate AS can be redefined, and GLS can be considered in determining the optimal timing for aortic valve intervention.

Background: Catheter ablation (CA) is an effective and potentially curative treatment in patients with atrial fibrillation (AF). However, the recurrence of AF following CA treatment in cases of persistent atrial fibrillation (PeAF) remains a significant concern. This study aims to establish a correlation between the peak flow velocity of the left atrial appendage (LAAV) and the AF recurrence post-CA for PeAF. Methods: PubMed/Medline, EMBASE, and SCOPUS databases were systematically reviewed to find studies through June 2023 reporting data on the relationship between the LAAV and the recurrence of AF in individuals who have undergone CA for PeAF. Binary random effects models were used to estimate pooled outcomes. I2 statistics were used to interpret heterogeneity, with I 2 >75% indicating substantial inter-study variation. Leave-one-out meta-analysis was performed to evaluate the effect of each study on the overall estimate. A p<0.05 was considered statistically significant. Results: A total of 9 studies between 2000-2023 were included in our meta-analysis. The pooled univariate analysis revealed no association between LAAV and recurrence of AF in individuals who have undergone CA with a pooled OR of 1.09 (95CI 0.96-1.22) p=0.45, I2=86.59%. The multivariate analysis, after adjusting for overall modifiable risk factors, yielded significant results, with an adjusted odds ratio (aOR) of 1.41 (95CI 1.15-1.74) p<0.01, I2=85.24%. Sensitivity analysis, using the leave-one-out method&nbsp;demonstrated the robustness and stability of the results, indicating that no single study disproportionately influenced the overall&nbsp;findings with aOR 1.41 (95CI 1.15-1.74) p<0.01. Conclusions: This meta-analysis revealed that low LAAV is associated with high-risk of AF recurrence following CA. Identifying a specific subgroup of individuals at high risk of AF recurrence with the help of pre-CA LAA velocity will facilitate the early institution of alternative treatment strategies.

Introduction: Sepsis and its associated systemic inflammatory response syndrome in the heart can lead to septic cardiomyopathy. We aim to explore new onset cardiac dysfunction in septic shock patients and its association of right heart dysfunction with hospital outcomes. Hypothesis: Early development of correct ventricular abnormalities due to septic shock may lead to worse hospital outcomes. Methods: We conducted a retrospective study of 102 patients who were hospitalized at the Mayo Clinic between August 2018 and September 2022 with septic shock and had at least one pre-sepsis echo (within one year before admission) and one post-sepsis echo (within seven days of access). Information on patient demographics, comorbidities, echo parameters, and outcomes was collected from our sepsis database and retrospective chart review. Categorical variables were described as percentages and compared by Chi-square test, and continuous variables as medians and compared using an independent sample t-test. Statistical analysis was performed using BlueSky Statistics v10.3.1. Results: Our study included 102 patients with a median age of 68 (55, 78) years, the majority being men (68%) and Caucasians (80%). Between pre- and post-sepsis echos, there was a noticeable decrease in LVEF (60% vs 50.5 %; p=0.002). Moreover, there was an increase in reduced RV function (31.6% vs. 62.6%, p<0.001), reduced LV function (56.5% vs. 85.2%, p=0.048), and RV dilatation (35.8% vs. 51.5%, p=0.03). There was also a noticeable decrease in IVC collapsibility of more than 50% (65.9% vs 22.9%, p<0.001). There was no significance in terms of demographics, comorbidities, and baseline vitals and labs among patients with RV dysfunction and without RV dysfunction except for a lower LVEF (49% vs 62 %, p= 0.004) and decreased >50 % IVC collapsibility (14.5% vs 48%, p=0.005) in RV dysfunction group. We found no differences in hospital mortality, ICU and hospital LOS, or mechanical ventilation requirements amongst patients with RV abnormalities in function and size. Conclusions: Our retrospective study shows that abnormalities in RV function and RV size are commonly observed in the initial week of septic shock. However, such RV abnormalities did not translate into worse hospital outcomes.