👤 Niels Møller

Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] measurements to the RF-CL model improves predictions of obstructive CAD. In a derivation cohort (N = 4262; 54% male; mean age 58 years), the prevalence of obstructive CAD at invasive angiography with fractional flow reserve was assessed by Lp(a)-strata. On the basis of initial results, an Lp(a)-adjusted model (RF-CLLp(a)) was developed: RF-CL was multiplied by 1.5 in patients with elevated Lp(a) (≥125 nmol/L) and otherwise unchanged. Discrimination, calibration, and reclassification were compared. Findings were validated in an external validation cohort (N = 1595; 49% male; mean age 60 years) using a comparative endpoint; significant stenosis at invasive angiography or coronary computed tomography.In the derivation cohort, 473 patients (11.1%) had obstructive CAD; in the validation cohort, 206 patients (12.9%) had significant stenosis. The relative risk in patients with elevated Lp(a) was 1.51 [95% confidence interval (CI) 1.23-1.86] and 1.19 (95% CI 0.88-1.60) in the derivation and validation cohort, respectively. In the derivation cohort, the RF-CLLp(a) model showed a higher area under the receiver operating curve than the RF-CL model [0.743 (standard error 0.011) vs. 0.740 (0.013)] and better calibration in patients with elevated Lp(a). Reclassification from RF-CL to RF-CLLp(a) improved likelihood stratification in the derivation cohort but not in the validation cohort. Adding elevated Lp(a) as a risk factor to the RF-CL model improves accuracy of obstructive CAD in patients with high Lp(a). Show less

Drugs that lower plasma apolipoprotein B (ApoB)-containing lipoproteins are central to treating advanced atherosclerosis and provide partial protection against clinical events. Previous research showed that lowering ApoB-containing lipoproteins stops plaque inflammation, but how these drugs affect the heterogeneous population of plaque cells derived from smooth muscle cells (SMCs) is unknown. SMC-derived cells are the main cellular component of atherosclerotic lesions and the source of structural components that determine the size of plaques and their propensity to rupture and trigger thrombosis, the proximate cause of heart attack and stroke. Using lineage tracing and single-cell techniques to investigate the full SMC-derived cellular compartment in progressing and regressing plaques in mice, here we show that lowering ApoB-containing lipoproteins reduces nuclear factor kappa-light-chain-enhancer of activated B cells signaling in SMC-derived fibromyocytes and chondromyocytes and leads to depletion of these abundant cell types from plaques. These results uncover an important mechanism through which cholesterol-lowering drugs can achieve plaque regression. Show less

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB. Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects. In a randomized, placebo-controlled, cross-over study, nine obese men were examined after injection of 1) a GH bolus, and 2) a GH-receptor antagonist followed by four adipose tissue biopsies obtained over a 5-h period. In a second study, nine hypopituitary men were examined in a 2 × 2 factorial design including GH and acipimox (an anti-lipolytic agent), with biopsies from adipose tissue and skeletal muscle obtained during a basal period and a subsequent hyperinsulinemic-euglycemic clamp. The mRNA expression of ANGPTL4 and LPL as well as LPL activity were analyzed in the biopsies. In both studies, GH increased serum FFA levels, upregulated ANGPTL4 mRNA expression and suppressed LPL activity. In study 2, acipimox completely suppressed FFA levels and antagonized the effects of GH on ANGPTL4 and LPL. These human in vivo studies demonstrate that GH upregulates ANGPTL4 mRNA and suppresses LPL activity via an FFA-dependent mechanism. Show less

Glucocorticoid (GC) excess increases lipolysis, circulating free fatty acid concentrations and lipid oxidation rates in humans. In vitro and animal studies have shown that GCs increase adipocyte ATGL and HSL mRNA contents and HSL phosphorylations, but the effects of GC on in vivo lipase signaling in humans are uncertain. Our study was designed to test how GC administration affects ATGL and HSL related signals in human adipose tissue. Nine healthy young men underwent 5 days administration of 37.5 mg prednisolone/d in a randomized, double-blinded, placebo-controlled crossover design. At the end of each 5 d period the subjects were studied after an overnight fast for 6.5 h including a basal period and a 2½ h hyperinsulinemic euglycemic clamp. Adipose tissue biopsies were sampled from the abdominal subcutaneous adipose tissue at the end of the basal period and the clamp. GC treatment increased serum FFA concentrations and comparative gene identification-58 (CGI-58) mRNA - an ATGL activator - and decreased G0/G1 switch 2 gene (G0S2) mRNA - an ATGL inhibitor - in adipose tissue biopsies. In addition, pro-lipolytic ser High dose GC administration to humans leads to pro-lipolytic alterations of CGI-58, G0S2 and ANGPTL4 mRNA transcripts, increases PKA signaling to lipolysis and inhibits the insulin signal in adipose tissue. The increased CIDE-A and CIDE-C mRNA levels suggest concomitant stimulation of lipolysis and lipid storage. Show less

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the Western world. Autophagy is a highly conserved process in eukaryotic cells. In CLL autophagy is involved in mediating the effect of chemotherapy but the role of autophagy in CLL pathogenesis remains unknown. In the present study, we used real-time RT-PCR to analyze expression of the PIK3C3, PIK3R4, and BECN1 genes. These genes encode the components of the PI3K core complex, which is central to initiation of autophagy. A consecutive series of 149 well-characterized CLL cases from Region of Southern Denmark were included in the study. All three genes were observed to be independent markers of prognosis in CLL with high expression being associated with more aggressive disease. With this clear association with outcome in CLL, these genes thereby represent promising candidates for future functional studies on the role of autophagy in CLL, and they may further represent targets of treatment. Show less

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease. Show less