Validation of contemporary electrocardiographic indices of area at risk and infarct size in acute ST elevation myocardial infarction (STEMI).

BACKGROUND: Electrocardiographic (ECG) methods to assess area at risk (AAR) and infarct size (IS) in patients with ST-elevation myocardial infarction (STEMI) have been previously established but not validated against contemporary benchmark Cardiac Magnetic Resonance (CMR) measures. We compared ECG-determined and CMR-determined measures for (a) AAR, (b) IS, and (c) myocardial salvage. METHODS: Sixty patients with ECG evidence of STEMI and CMR imaging performed within 13 days were included. The ECG-determined (a) AAR scores (Aldrich and Wilkins), (b) IS (Selvester score), and (c) myocardial salvage (i.e. [AAR-IS] / AAR × 100%), were compared with CMR-determined measures. RESULTS: Compared with CMR-determined AAR, both the Wilkins & Aldrich scores underestimated AAR, although the Wilkins (r = 0.72, p < 0.001) showed a better correlation than the Aldrich (r = 0.54, p < 0.001). Bland-Altman analysis revealed a bias of 2.6% (95% limits of agreement: 18.5%, -13.3%) for the Wilkins and 5.9% (95% limits of agreement: 25.6%, -13.8%) for the Aldrich. Estimation of IS was similar between the Selvester score and CMR, with good correlation (r = 0.77, p < 0.001) and agreement (fixed bias 0.4%, 95% limits of agreement 20.8%, -15.5%). However, ECG-determined myocardial salvage significantly underestimated CMR-determined myocardial salvage, with an inverse correlation (r = -0.33, p = 0.01). CONCLUSIONS: The Wilkins score is superior to Aldrich score as an ECG-AAR index, Selvester score is a reasonable ECG estimate of infarct size, though ECG derived myocardial salvage does not have enough accuracy to be used in the clinical setting; it may be an inexpensive surrogate for myocardial salvage in large research studies. Further validation and prognostic studies are required.

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities.

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband's paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology. Learning points: Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history. Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management. Identification of a genetic disorder may have important implications for family planning.

Achondroplasia with SRY-positive 46, XX disorder of sex development: an extremely rare association.

A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways. LEARNING POINTS: The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.

Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.

Seizure induced by sudden cessation of pregabalin in a patient with chronic kidney disease.

A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a diarrhoeal illness. She was found to have acute on chronic renal impairment with an estimated glomerular filtration rate (eGFR) of 10 mL/min, and her usual 150 mg/day of pregabalin was abruptly ceased. Although renal recovery to her baseline of eGFR 15 mL/min was achieved within 3 days, her pregabalin was not restarted. She suffered a tonic-clonic seizure 4 days later, thought to be due to pregabalin withdrawal as there were no other likely causes identified. She suffered no further seizures on recommencement of pregabalin at a renally adjusted dose of 75 mg/day.