Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion

Danish Heart Foundation (Grant No. 15-R99-A5837-22920)Health Research Fund of Central Denmark RegionNational Institute for Health Research Biomedical Research Centre at Barts

Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion

Danish Heart Foundation (Grant No. 15-R99-A5837-22920)Health Research Fund of Central Denmark RegionNational Institute for Health Research Biomedical Research Centre at Barts

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.

Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects

Diagnostic performance of clinical likelihood models of obstructive coronary artery disease to predict myocardial perfusion defects.

AIMS: Clinical likelihood (CL) models are designed based on a reference of coronary stenosis in patients with suspected obstructive coronary artery disease (CAD). However, a reference standard of a myocardial perfusion defects (MPD) could be more appropriate.We aimed to investigate the ability of the 2019 European Society of Cardiology pre-test probability (ESC-PTP), the risk factor-weighted (RF-CL) and coronary artery calcium score-weighted (CACS-CL) models to diagnose MPDs. METHODS AND RESULTS: Symptomatic stable de novo chest pain patients (n = 3374) underwent coronary computed tomography angiography (CTA) and subsequent myocardial perfusion imaging by single photon emission tomography (SPECT), positron emission tomography (PET) or cardiac magnetic resonance (CMR). For all modalities, MPD was defined as coronary CTA with suspected stenosis and stress-perfusion abnormality in ≥2 segments. The ESC-PTP was calculated based on age, sex and symptom typicality, and the RF-CL and CACS-CL additionally included a number of risk factors and CACS.In total, 219/3374 (6.5%) patients had a MPD. Both the RF-CL and CACS-CL classified substantially more patients to low CL (<5%) of obstructive CAD compared to the ESC-PTP (32.5% and 54.1% vs. 12.0%, p < 0.001) with preserved low prevalences of MPD (<2% for all models). Compared to the ESC-PTP (AUC 0.74 (0.71-0.78), the discrimination of having a MPD was higher for the CACS-CL (AUC 0.88 (0.86-0.91), p < 0.001) while similar for the RF-CL model (AUC 0.73 (0.70-0.76), p = 0.32). CONCLUSIONS: Compared to basic CL models, the RF-CL and CACS-CL models improve down-classification of patients to a very low-risk group with low prevalence of MPD