Acidosis and Deafness in Patients with Recessive Mutations in FOXI1.

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

Where are we getting it wrong? Prevalence and causes of unplanned SAVR in a UK regional cardiac centre.

Surgical aortic valve replacement (SAVR) prolongs life and improves its quality in patients with severe aortic stenosis (AS). Unplanned SAVR is a failure of AS screening and follow-up programmes. We identified all elective, first, isolated SAVRs performed between 1 January and 31 December 2019 in a Welsh tertiary cardiac centre, and documented the clinical and echocardiographic variables, and reasons for unplanned SAVR. Of 140 isolated SAVR, 37 (26%) were unplanned (16 female, mean age 72.3 ± 8.4 years). Twenty had been on the SAVR waiting list and had expedited operations because of concerns about the severity of the AS (12 patients), or because of acute (four patients) or chronic (four patients) left ventricular failure (LVF). Of the 17 not on the waiting list, AS was known in seven: three had acute pulmonary oedema while under follow-up with 'moderate AS', one had been referred but developed pulmonary oedema while waiting for a surgical outpatient appointment, one refused SAVR but was subsequently admitted with acute pulmonary oedema and accepted SAVR, one was admitted directly from home because concerns about worsening AS, and one had infective endocarditis with severe aortic regurgitation. Of 10 patients with a new diagnosis of AS, five presented with LVF, four with angina and in three there was a history of syncope (p=0.003 vs. known AS; multiple symptoms). Survival, age, Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA) class, number of risk factors, peak and mean aortic valve (AV) gradients, AV area, and stroke volume index were not different between patients who had planned versus unplanned SAVR, or with known or new AS. Patients with a new diagnosis of AS had longer pre-operative wait (22.3 ± 9.3 vs. 6.0 ± 10.3 days, p<0.001). In conclusion, a quarter of SAVRs are unplanned and half are in patients without a prior diagnosis of AS. Unplanned SAVR is associated with prolonged length of hospital stay and with a history of syncope, but other conventional clinical and echocardiographic parameters do not differ between patients undergoing planned versus unplanned SAVR.

Myocardial revascularisation in complex patients: does it happen as prescribed by the heart team?

Guidelines recommend decision- making using the heart team (HT) in complex patients considered for myocardial revascularisation, but there are little data on how this approach works in practice. We data-mined our electronic HT database and selected patients in whom the clinical question referred to revascularisation, and documented HT recommendations and their implementation. We identified 154 patients (117 male), mean age 68.9 ± 11.4 years, discussed between February 2019 and December 2020. The clinical questions were coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI) (141 cases, 91%), and medical treatment versus revascularisation by PCI (eight cases, 6%) or by CABG (five cases, 3%). HT recommended CABG in 55 cases (35%), PCI in 43 (28%), medical treatment in 15 (10%), and equipoise in seven (5%) and further investigations in 34 (22%): non-invasive imaging for ischaemia in 11 (32%), invasive coronary physiology studies in eight (24%), further clinical assessment in seven (20%), structural imaging for five (15%), invasive coronary angiography in two (6%), and an electrophysiology opinion in one case (3%). Decisions were implemented in 135 cases (89%). The average time between the HT and the implementation of its decision was 80.5 ± 129.3 days. There were 17 deaths: 10 cardiac, six non- cardiac and one of unknown cause. Patients who survived were younger (68.6 ± 11.3 years) than those who died (73.8 ± 10.0 years, p = 0.03). In conclusion, almost 90% of the decisions of the HT on myocardial revascularisation are implemented, while ischaemia testing is the main investigation required for decision- making. Recent data on the futility of such an approach have not yet permeated clinical practice.