The challenge of an expanded therapeutic window in pulmonary hypertension

Our understanding of the causes and consequences of pulmonary hypertension is limited. Consequently, its most distinctive forms with the worst prognosis have been the focus for diagnosis and treatment. We highlight the emerging challenge of reframing the prevalence and prognostic implications of pulmonary hypertension, focusing on the optimal therapeutic window to address the high mortality linked to this condition

Mild pulmonary hypertension and premature mortality among 154 956 men and women undergoing routine echocardiography

Background Although mild pulmonary hypertension is known to be associated with increased mortality, its impact on premature mortality is largely unknown. Methods We studied the distribution of estimated right ventricular systolic pressure (eRVSP) among a total of 154 956 adults with no evidence of left heart disease investigated with echocardiography. We then examined individually linked mortality, premature mortality and associated life-years lost (LYL) according to eRVSP levels. Results The cohort comprised 70 826 men and 84 130 women (aged 61.3±17.7 and 61.4±18.4 years, respectively). Overall, 85 173 (55.0%), 49 276 (31.8%), 13 060 (8.4%) and 7447 (4.8%) cases had eRVSP levels indicative of no (<30.0 mmHg), mild (30.0–39.9 mmHg), moderate (40.0–49.9 mmHg) or severe (≥50.0 mmHg) pulmonary hypertension, respectively. During a median (interquartile range) 5.7 (3.2–8.9) years of follow-up, 38 456/154 986 (24.8%) individuals died. Compared with eRVSP <30.0 mmHg, age and sex-adjusted hazard ratios for all-cause and cardiovascular-related mortality were 1.90 (95% CI 1.84–1.96) and 1.85 (95% CI 1.74–1.97), respectively, for eRVSP 35.0–39.9 mmHg. Overall, 6256 (54%) men and 7524 (55%) women died prematurely. As a proportion of all deaths, premature mortality rose from 46.7% to 79.2% among those with eRVSP <30.0 versus ≥60.0 mmHg with a mean of 5.1–11.4 LYL each time. However, due to more individuals affected overall, eRVSP 30.0–39.9 mmHg accounted for 58% and 53% of total LYL among men (40 606/70 019 LYL) and women (47 333/88 568 LYL), respectively. Conclusions These data confirm that elevated eRVSP levels indicative of mild pulmonary hypertension are associated with increased risk of death. Moreover, this results in a substantive component of premature mortality/LYL that requires more proactive clinical surveillance and management

Relative incidence and predictors of pulmonary arterial hypertension complicating type 2 diabetes: The Fremantle Diabetes Study Phase I

Aims: To determine the relative incidence and predictors of pulmonary arterial hypertension (PAH) in type 2 diabetes. Methods: Hospitalizations for/with and death from/with PAH, and all-cause mortality, were ascertained from validated databases for participants from the longitudinal, community-based Fremantle Diabetes Study Phase I (FDS1; n = 1287) and age-, sex- and zip code-matched people without diabetes (n = 5153) between entry (1993–1996) and end-2017. Incidence rates (IRs) and IR ratios (IRRs) were calculated. Cox proportional hazards and competing risk models generated cause-specific (cs) and subdistribution (sd) hazard ratios (HRs) for incident PAH. Results: In the pooled cohort (mean age 64.0 years, 49% males), 49 (3.8%) of the type 2 diabetes participants and 133 (2.6%) of those without diabetes developed PAH during 106,556 person-years of follow-up (IRs (95% CI) 262 (194– 346) and 151 (127–179) /100,000 person-years, respectively; IRR 1.73 (1.22–2.42), P = 0.001). Type 2 diabetes was associated with an unadjusted csHR of 1.97 (1.42–2.74) and sdHR of 1.44 (1.04–2.00) (P ≤ 0.03); after adjustment for age, sex, and co-morbidities, these were 1.43 (0.83–2.47) and 1.36 (0.97–1.91), respectively (P ≥ 0.07). Conclusions: Type 2 diabetes is associated with an increased risk of PAH but this is no longer significant after adjustment for other explanatory variables and the competing risk of death. © 2020 Elsevier Inc. All rights reserved

Incident aortic stenosis in 49 449 men and 42 229 women investigated with routine echocardiography

Objective We addressed the paucity of data describing the characteristics and consequences of incident aortic stenosis (AS). Methods Adults undergoing echocardiography with a native aortic valve (AV) and no AS were studied. Subsequent age-specific and sex-specific incidence of AS were derived from echocardiograms conducted a median of 2.8 years apart. Progressive AV dysfunction and individually linked mortality were examined per AS category. Results 49 449 men (53.9%, 60.9±15.8 years) and 42 229 women (61.6±16.9 years) with no initial evidence of AS were identified. Subsequently, 6293 (6.9%) developed AS—comprising 5170 (5.6%), 636 (0.7%), 339 (0.4%) and 148 (0.2%) cases of mild, moderate, severe low-gradient and severe high-gradient AS, respectively. Age-adjusted incidence rates of all grades of AS were 17.5 cases per 1000 men/annum and 18.7 cases per 1000 women/annum: rising from ~5 to ~40 cases per 1000/annum in those aged 80 years. Median peak AV velocity increased by +0.57 (+0.36 to +0.80) m/s in mild AS compared with +2.75 (+2.40 to +3.19) m/s in severe high-gradient AS cases between first and last echocardiograms. During subsequent median 7.7 years follow-up, 24 577 of 91 678 cases (26.8%) died. Compared with no AS, the adjusted risk of all-cause mortality was 1.42-fold higher in mild AS, 1.92-fold higher in moderate AS, 1.95-fold higher in severe low-gradient AS and 2.27-fold higher in severe, high-gradient AS cases (all p<0.001). Conclusions New onset AS is a common finding among older patients followed up with echocardiography. Any grade of AS is associated with higher mortality, reinforcing the need for proactive vigilance

Incident pulmonary hypertension in 13488 cases investigated with repeat echocardiography : A clinical cohort study

Background We addressed the paucity of data describing the characteristics and natural history of incident pulmonary hypertension. Methods Adults (n=13 448) undergoing routine echocardiography without initial evidence of pulmonary hypertension (estimated right ventricular systolic pressure, eRVSP <30.0 mmHg) or left heart disease were studied. Incident pulmonary hypertension (eRVSP ≥30.0 mmHg) was detected on repeat echocardiogram a median of 4.1 years apart. Mortality was examined according to increasing eRVSP levels (30.0–39.9, 40.0–49.9 and ≥50.0 mmHg) indicative of mild-to-severe pulmonary hypertension. Results A total of 6169 men (45.9%, aged 61.4±16.7 years) and 7279 women (60.8±16.9 years) without evidence of pulmonary hypertension were identified (first echocardiogram). Subsequently, 5412 (40.2%) developed evidence of pulmonary hypertension, comprising 4125 (30.7%), 928 (6.9%) and 359 (2.7%) cases with an eRVSP of 30.0–39.9 mmHg, 40.0–49.9 mmHg and ≥50.0 mmHg, respectively (incidence 94.0 and 90.9 cases per 1000 men and women, respectively, per year). Median (interquartile range) eRVSP increased by +0.0 (−2.27 to +2.67) mmHg and +30.68 (+26.03 to +37.31) mmHg among those with eRVSP <30.0 mmHg versus ≥50.0 mmHg. During a median 8.1 years of follow-up, 2776 (20.6%) died from all causes. Compared to those with eRVSP <30.0 mmHg, the adjusted risk of all-cause mortality was 1.30-fold higher in 30.0–39.9 mmHg, 1.82-fold higher in 40.0–49.9 mmHg and 2.11-fold higher in ≥50.0 mmHg groups (all p<0.001). Conclusions New-onset pulmonary hypertension, as indicated by elevated eRVSP, is a common finding among older patients without left heart disease followed-up with echocardiography. This phenomenon is associated with an increased morality risk even among those with mildly elevated eRVSP

Orbital Dimer Model for Spin-Glass State in Y2_2Mo2_2O7_7

The formation of a spin glass usually requires both structural disorder and frustrated magnetic interactions. Consequently, the origin of spin-glass behaviour in Y$_2$Mo$_2$O$_7$ $-$ in which magnetic Mo$^{4+}$ ions occupy a frustrated pyrochlore lattice with minimal compositional disorder $-$ has been a longstanding question. Here, we use neutron and X-ray pair-distribution function (PDF) analysis to develop a disorder model that resolves apparent incompatibilities between previously-reported PDF, EXAFS and NMR studies and provides a new and physical mechanism for spin-glass formation. We show that Mo$^{4+}$ ions displace according to a local "2-in/2-out" rule on each Mo$_4$ tetrahedron, driven by orbital dimerisation of Jahn-Teller active Mo$^{4+}$ ions. Long-range orbital order is prevented by the macroscopic degeneracy of dimer coverings permitted by the pyrochlore lattice. Cooperative O$^{2-}$ displacements yield a distribution of Mo$-$O$-$Mo angles, which in turn introduces disorder into magnetic interactions. Our study demonstrates experimentally how frustration of atomic displacements can assume the role of compositional disorder in driving a spin-glass transition.Comment: 6 pages, 3 figure

Local structure and order-disorder transitions in "empty" ferroelectric tetragonal tungsten bronzes

JAM would like to acknowledge the School of Chemistry, University of St Andrews for the allocation of a PhD studentship through the EPSRC doctoral training grant (EP/K503162/1). AR would like to acknowledge support through the Strategic Grant POSDRU/159/1.5/S/133255, Project ID 133255 (2014), co-financed by the European Social Fund within the Sectorial Operational Program Human Resources Development 2007–2013 and also the University of Craiova and University of Cambridge for the mobility grant “Resonant ultrasound spectroscopy. (RUS) characterization of dielectric and ferroelectric tetragonal tungsten bronzes”. The work carried out at the University of St Andrews and University of Cambridge is part of an EPSRC- funded collaboration (EP/P02453X/1 and EP/P024904/1).The ‘empty’ tetragonal tungsten bronze Ba4La0.67 1.33Nb10O30 displays both relaxor-like and normal dielectric anomalies as a function of temperature; the former is associated with loss of ferroelectricity and was proposed to originate from anion disordering [Chem. Mater., 2016, 28 , 4616-4627]. Here we present total neutron scattering and pair distribution function (PDF) analysis which shows an increase in the distribution of oxygen-oxygen distances at the relaxor transition and which supports the proposed anion disordering mechanism. The disordering process can be destabilised by reducing the average A-cation size (i.e. Nd-doping: Ba4(La1-xNdx)0.67Nb10O30); this introduces a more strongly propagating tilt system in line with the previously reported crystal-chemical framework model [Chem. Mater., 2015, 27 , 3250-3261]. Mechanical loss data obtained using resonant ultrasound spectroscopy also indicate destabilisation of the disordering process with increasing Nd-substitution.PostprintPeer reviewe

Counting the cost of premature mortality with progressively worse aortic stenosis in Australia: a clinical cohort study

Background: Aortic stenosis is the most common cardiac valve disorder requiring clinical management. However, there is little evidence on the societal cost of progressive aortic stenosis. We sought to quantify the societal burden of premature mortality associated with progressively worse aortic stenosis. Methods: In this observational clinical cohort study, we examined echocardiograms on native aortic valves of 98 565 men and 99 357 women aged 65 years or older across 23 sites in Australia, from Jan 1, 2003, to Dec 31, 2017. Individuals were grouped according to their peak aortic valve velocity in 0·50 m/s increments up to 4·00 m/s or more (severe aortic stenosis), using 1·00–1·99 m/s (no aortic stenosis) as the reference group. Sex-specific premature mortality and years of life lost during a 5-year follow-up were calculated, along with willingness-to-pay to regain quality-adjusted life years (QALYs). Findings: Overall, 20 701 (21·0%) men and 18 576 (18·7%) women had evidence of mild-to-severe aortic stenosis. The actual 5-year mortality in men with normal aortic valves was 32·1% and in women was 26·1%, increasing to 40·9% (mild aortic stenosis) and 52·2% (severe aortic stenosis) in men and to 35·9% (mild aortic stenosis) and 55·3% (severe aortic stenosis) in women. Overall, the estimated societal cost of premature mortality associated with aortic stenosis was AU$629 million in men and$735 million in women. Per 1000 men and women investigated, aortic stenosis was associated with eight more premature deaths in men resulting in 32·5 more QALYs lost (societal cost of $1·40 million) and 12 more premature deaths in women resulting in 57·5 more QALYs lost (societal cost of$2·48 million) when compared with those without aortic stenosis. Interpretation: Any degree of aortic stenosis in older individuals is associated with premature mortality and QALYs. In this context, there is a crucial need for cost-effective strategies to promptly detect and optimally manage this common condition within our ageing populations

Spin-ice physics in cadmium cyanide

Spin-ices are frustrated magnets that support a particularly rich variety of emergent physics. Typically, it is the interplay of magnetic dipole interactions, spin anisotropy, and geometric frustration on the pyrochlore lattice that drives spin-ice formation. The relevant physics occurs at temperatures commensurate with the magnetic interaction strength, which for most systems is 1–5 K. Here, we show that non-magnetic cadmium cyanide, Cd(CN)2, exhibits analogous behaviour to magnetic spin-ices, but does so on a temperature scale that is nearly two orders of magnitude greater. The electric dipole moments of cyanide ions in Cd(CN)2 assume the role of magnetic pseudospins, with the difference in energy scale reflecting the increased strength of electric vs magnetic dipolar interactions. As a result, spin-ice physics influences the structural behaviour of Cd(CN)2 even at room temperature.ISSN:2041-172