👤 Lena Rutkowska

Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5). We studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27-57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8-13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. In Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101. Show less

Left ventricular noncompaction cardiomyopathy (LVNC) is a rare cardiac disorder characterised by the presence of a two-layer myocardium with prominent ventricular trabeculation, intertrabecular deep depressions and an increased risk of heart failure, atrial and ventricular arrhythmias and systemic thromboembolic events in affected patients. The heterogeneous molecular aetiology solved in 10%-50% of patients more frequently involves sarcomeric, cytoskeletal or ion channel protein dysfunction-mainly related to causative Thirty-one paediatric patients prospectively diagnosed with LVNC by echocardiography and cardiovascular magnetic resonance examination were recruited into the study group. The molecular analysis included next-generation sequencing (gene panel or whole exome) and classic Sanger sequencing. All selected variants with high priority were co-segregated in the available parents. We identified 16 distinct variants in 11 genes in 16 patients (52%), including 10 novel alterations. The most frequent defects in our cohort were found in the genes This study expands the genetic and clinical spectrum of childhood LVNC. Although the molecular aetiology of LVNC varies widely, the comprehensive testing of a wide panel of cardiomyopathy-related genes helped to identify underlying molecular defects in more than half of the children in the study group. The molecular spectrum in our cohort correlated with the occurrence of arrhythmia, death and a family history of cardiomyopathy. We confirmed that genetic testing is an integral part of the work-up and management LVNC in children. Show less

The prolonged use of many currently available drugs results in the severe side effect of the disruption of glucose metabolism leading to type 2 diabetes mellitus (T2DM. Gut hormone receptors including glucagon receptor (GCGR) and the incretin hormone receptors: glucagon-like peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR) are important drug targets for the treatment of T2DM, as they play roles in the regulation of glucose and insulin levels and of food intake. In this study, we hypothesized that we could compensate for the negative influences of specific drugs on glucose metabolism by the positive incretin effect enhanced by the off-target interactions with incretin GPCR receptors. As a test case, we chose to examine beta-blockers because beta-adrenergic receptors and incretin receptors are expressed in a similar location, making off-target interactions possible. The binding affinity of drugs for incretin receptors was approximated by using two docking scoring functions of Autodock VINA (GUT-DOCK) and Glide (Schrodinger) and juxtaposing these values with the medical information on drug-induced T2DM. We observed that beta-blockers with the highest theoretical binding affinities for gut hormone receptors were reported as the least harmful to glucose homeostasis in clinical trials. Notably, a recently discovered beta-blocker compound 15 ([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide was among the top-scoring drugs, potentially supporting its use in the treatment of hypertension in diabetic patients. Our recently developed web service GUT-DOCK (gut-dock.miningmembrane.com) allows for the execution of similar studies for any drug-like molecule. Specifically, users can compute the binding affinities for various class B GPCRs, gut hormone receptors, VIPR1 and PAC1R. Show less

A disturbance of glucose homeostasis leading to type 2 diabetes mellitus (T2DM) is one of the severe side effects that may occur during a prolonged use of many drugs currently available on the market. In this manuscript we describe the most common cases of drug-induced T2DM, discuss available pharmacotherapies and propose new ones. Among various pharmacotherapies of T2DM, incretin therapies have recently focused attention due to the newly determined crystal structure of incretin hormone receptor GLP1R. Incretin hormone receptors: GLP1R and GIPR together with the glucagon receptor GCGR regulate food intake and insulin and glucose secretion. Our study showed that incretin hormone receptors, named also gut hormone receptors as they are expressed in the gastrointestinal tract, could potentially act as unintended targets (off-targets) for orally administrated drugs. Such off-target interactions, depending on their effect on the receptor (stimulation or inhibition), could be beneficial, like in the case of incretin mimetics, or unwanted if they cause, e.g., decreased insulin secretion. In this in silico study we examined which well-known pharmaceuticals could potentially interact with gut hormone receptors in the off-target way. We observed that drugs with the strongest binding affinity for gut hormone receptors were also reported in the medical information resources as the least disturbing the glucose homeostasis among all drugs in their class. We suggested that those strongly binding molecules could potentially stimulate GIPR and GLP1R and/or inhibit GCGR which could lead to increased insulin secretion and decreased hepatic glucose production. Such positive effect on the glucose homeostasis could compensate for other, adverse effects of pharmacotherapy which lead to drug-induced T2DM. In addition, we also described several top hits as potential substitutes of peptidic incretin mimetics which were discovered in the drug repositioning screen using gut hormone receptors structures against the ZINC15 compounds subset. Show less