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Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Abstract Background Heart failure and preserved ejection fraction (HFpEF) is a heterogeneous entity including patients with different phenotypes of reduced, normal, and supernormal left ventricular (LV) function. Objectives To assess the value of resting LV elastance with transthoracic echocardiography (TTE) to identify HFpEF phenotypes. Methods In a prospective, observational, multicenter study, 2380 HFpEF patients were recruited from July 2016 to May 2024 by 35 certified laboratories of 15 countries. HFpEF was diagnosed according to the European Society of Cardiology (ESC) guidelines. Systolic blood pressure (SBP) was measured. We assessed wall motion score index (WMSI), LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (AE, SBP/SV), ventricular-arterial coupling (VAC, as SV/ESV), and left atrial volume index (LAVI). Global longitudinal strain (GLS) was available in 1164 (48.9%) patients. In 271 (11.4%) patients, N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed. Patients were divided into three groups based on rest force: low rest force group (< 25% percentile, Group 1), median rest force group (≥ 25% percentile & ≤ 75% percentile, Group 2), and high rest force group (> 75% percentile, Group 3). Results 330 (13.9%) patients presented with ischemic RWMA. The 3 groups showed a gradient with descending values (Group 3>2>1) for SBP, EF, GLS, AE, and VAC, with the opposite gradient (Group 1> 2> 3) for EDV, EDVi, ESV, ESVi, SV, SVi, and LAVI values (all P<0.01). Patients in Group 3 have higher NTproBNP level and higher percentage of B-line compared to groups 1 and 2 (P<0.05). The 3 groups were similar for values of coronary flow velocity, systolic pulmonary artery pressure, and E/e’ (see table). Univariable linear regression analysis showed that NTproBNP was correlated with force (r = 0.271, p < 0.001), VAC (r = 0.194, p = 0.001), LAVI (r = 0.327, p < 0.001), LVEDV (r = -0.245, p < 0.001), LVEDVi (r = -0.261, p < 0.001), LVESVi (r = -0.190, p = 0.002) and LVESV (r = -0.187, p = 0.002) (see figure). However, multivariable linear regression analysis showed that NTproBNP was independently associated with LAVI (β= 0.211, p < 0.001) and force (β= 1.804, p = 0.002). Conclusions HFpEF patients present with different LV contractile phenotypes, easily identified with resting LV force and volumetric TTE. LV force is linearly correlated with cardiac natriuretic peptide levels. The dominant hemodynamic feature of hypocontractile phenotype is a preload recruitment with dilation of LV EDV and normal SV, while the hypercontractile phenotype is characterized by a small LV with reduced SV. heat map

The pathogenesis of chronic aortic regurgitation (AR) is different in male and female. Female patients with AR showed less aortic valve inflammation and collagen accumulation as compared with male. Valvular cells from female patients secreted less inflammatory molecules and collagen and higher levels of proteoglycans. Valvular interstitial cells from females were more sensitive to transforming growth factor (TGF)-β-induced proteoglycans secretion. Our study opens a new perspective oriented toward sex-specific molecular pathways and therapeutic targets in chronic severe AR.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

AbstractBackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.