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Background: Echocardiographic indexes of aortic stenosis may not comprehensively reflect disease morbidity. Plasma proteomic profiling may add prognostic value in these patients., Methods and Results: Proximity extension assays (Olink) of 183 circulating cardiovascular and inflammatory proteins were performed in a prospective follow-up study of 122 asymptomatic/minimally symptomatic patients (mean±SD age, 69.1±10.9 years; 61% men) with moderate to severe aortic stenosis and preserved left ventricular ejection fraction. Protein signatures of higher-risk echocardiographic subgroups were determined. Associations of proteins with the primary composite outcome (heart failure hospitalization, progression to New York Heart Association class III-IV, or all-cause mortality) were evaluated using competing risk analyses, with aortic valve replacement being the competing risk. Network analysis unveiled mutually exclusive communities of proteins and echocardiographic parameters, connected only through NT-proBNP (N-terminal pro-B-type natriuretic peptide). Members of the tumor necrosis factor receptor superfamily (TNFRSF1A, TNFRSF1B, and TNFRSF14), and trefoil factor-3 were major hub proteins among the circulating biomarkers. Left ventricular global longitudinal strain >-15% was associated with higher levels of proteins, primarily of inflammation and immune regulation, whereas aortic valve area <1 cm 2 , E/e' >15, and left atrial reservoir strain <20% were associated with higher levels of NT-proBNP. Of 14 proteins associated with the primary end point, phospholipase-C, C-X-C motif chemokine-9, and interleukin-10 receptor subunit β demonstrated the highest hazard ratios after adjusting for clinical factors ( q <0.05)., Conclusions: Plasma proteins involved in inflammation and immune regulation were differentially expressed in patients with aortic stenosis with reduced left ventricular global longitudinal strain, and associated with adverse clinical outcomes. Their incorporation into aortic stenosis risk stratification warrants further assessment.

Background: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%., Methods: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk., Results: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value., Conclusions: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS)., Methods: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses., Results: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker., Conclusion: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS., Competing Interests: Competing interests: SHE reports personal fees from Medtronic, Edwards Lifesciences and Abbott Medical, outside the submitted work. ZPD reports personal/speaker fees from GE and Phillips, and non-financial support from Phillips, outside the submitted work. AMR reports grants from National Medical Research Council of Singapore during the conduct of the study, is a long-term collaborator with Roche Diagnostics, the provider of assays central to this submission, and received support in kind, grants, speaker’s honoraria and acted on advisory boards for Roche Diagnostics. LHHL reports grants from National Medical Research Council of Singapore during the conduct of the study., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ 2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF., Competing Interests: The department of Cardiology at Leiden University receives unrestricted research grants from Abbott Vascular, Bayer, Biotronik, BIoventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare, MSD, Medtronic and Novartis. JJB received speaker fees from Abbott Vascular. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Le, Huang, Singh, Toh, Ewe, Tang, Loo, Bryant, Ang, Tay, Soo, Yip, Oon, Gong, Lunaria, Yong, Lee, Yeo, Chai, Goh, Ling, Ong, Richards, Delgado, Bax, Ding, Ling and Chin.)

Frailty is associated with future cardiovascular events in older adults. This cross-sectional study examined the relationship between subclinical vasculopathy with measures of skeletal muscle mass and function. Asymptomatic community-dwelling Asians ≥55 years underwent assessments for subclinical vasculopathy (carotid intima-media thickness (cIMT), aortic and carotid stiffness, and endothelial function), muscle mass (calf circumference adjusted for body mass index) and function (knee extension strength, 6-meter fast gait speed). Multivariable regression analyses for associates of muscle mass/function controlled for demographics and cardiometabolic risk factors. Among 336 participants (median age 62 years, 55.1% male, 3.6% sarcopenia), cIMT, aortic and carotid stiffness inversely correlated with muscle mass, strength and gait speed; cIMT remained independently associated with gait speed (β=-0.26) in multivariable analyses. Age and sex significantly modified the relationship between subclinical vasculopathy and muscle mass/function. Associations, only found in those aged ≥70, included cIMT with gait speed (β=-0.48) and knee strength (β=-9.33), and aortic augmentation index and aortic stiffness composite z-score with gait speed (β=-0.11 and β=-0.19 respectively). Among males, cIMT correlated with gait speed (β=-0.31). The association of subclinical vasculopathy with skeletal muscle mass and function in asymptomatic adults ≥55 years is best reflected by cIMT. The roles of mediating pathways deserve further evaluation.

Background: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease., Objective: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases., Methods: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors., Results: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045)., Conclusion: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.