Clinical trials with reno-vascular end points in patients with diabetes: Changing the scenario over the past 20 years.

Major clinical advances over the last 20 years in the area of diabetic kidney disease (DKD) have been confirmed in large seminal clinical trials. These findings add to the previously identified benefits resulting from intensive glucose and blood pressure control therapies. Furthermore, newer glucose lowering treatments such as SGLT2 inhibitors and GLP-1 agonists appear very promising and are likely to transform the management and outlook of DKD over the next decade. In addition, novel mineralocorticoid receptor antagonists and a recently reported trial with an endothelin receptor blocker also have the potential to change clinical practice.

A Novel RUNX1 Genetic Variant Identified in a Young Male with Severe Osteoporosis.

This case describes a young man with an unusual cause of severe osteoporosis and markedly deranged bone microarchitecture resulting in multiple fractures. A potentially pathogenic germline variant in the runt-related transcription factor 1 (RUNX1) gene was discovered by a focused 51-gene myeloid malignancy panel during investigation for his unexplained normochromic normocytic anemia. Further bone-specific genetic testing and a pedigree analysis were declined by the patient. Recent experimental evidence demonstrates that RUNX1 plays a key role in the regulation of osteogenesis and bone homeostasis during skeletal development, mediated by the bone morphogenic protein and Wnt signaling pathways. Therefore, rarer causes of osteoporosis, including those affecting bone formation, should be considered in young patients with multiple unexpected minimal trauma fractures. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pyridoxamine prevents increased atherosclerosis by intermittent methylglyoxal spikes in the aortic arches of ApoE-/- mice.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes.

Recent advances in the pharmacotherapeutic management of diabetic kidney disease.

INTRODUCTION: Diabetic kidney disease (DKD) remains a major cause of morbidity and mortality in diabetes and is a key cause of end-stage kidney disease (ESKD) worldwide. Major clinical advances have been confirmed in large trials demonstrating renoprotection, adding to the benefits of existing intensive glucose and blood pressure control therapies. Furthermore, there are exciting new treatments predominantly at an experimental and early clinical phase which appear promising. AREAS COVERED: The authors review DKD in the context of existing and emerging therapies affording cardiorenal benefits including SGLT2 inhibitors and GLP-1 receptor agonists. They explore novel therapies demonstrating potential including a newly developed mineralocorticoid receptor antagonist and endothelin receptor blockade, while evaluating the utility of DPP4 inhibitors in current clinical practice. They also consider the recent evidence of emerging therapies targeting metabolic pathways with enzyme inhibitors, anti-fibrotic agents, and agents modulating transcription factors. EXPERT OPINION: Significant improvements have been made in the management of DKD with SGLT2i and GLP-1 agonists providing impressive renoprotection, with novel progress in renin-angiotensin-aldosterone system (RAAS) blockade with finerenone. There is also great potential for several new experimental therapies. These advances provide us with optimism that the outlook of this devastating condition will continue to improve.

Postmortem Interrogation of Cardiac Implantable Electronic Devices: A 15-Year Experience.

OBJECTIVES: This study sought to define the feasibility and utility of postmortem cardiac implantable electronic device (CIED) interrogation. BACKGROUND: The diagnostic yield of routine postmortem interrogation of CIEDs including pacemakers, defibrillators, and implantable loop recorders has not been established. METHODS: The study reviewed all CIED interrogations in deceased individuals undergoing medicolegal investigation of sudden or unexplained death by the Victorian Institute of Forensic Medicine between 2005 and 2020. RESULTS: A total of 260 patients (68.8% male, median age 72.8 years [interquartile range: 62.7-82.2 years]) underwent CIED interrogation (202 pacemakers, 56 defibrillators, and 2 loop recorders) for investigation of sudden (n = 162) or unexplained (n = 98) death. CIEDs were implanted for median of 2.0 years (interquartile range: 0.7-5.0 years), with 19 devices at elective replacement indicator and 5 at end of life. Interrogation was successful in 256 (98.5%) cases. Potential CIED malfunction was identified in 20 (7.7%) cases, including untreated ventricular arrhythmias (n = 13) and lead failures (n = 3, 2 resulting in untreated ventricular arrhythmia). Interrogation directly informed cause of death in 131 (50.4%) cases. A total of 72 (27.7%) patients had abnormalities recorded in 30 days preceding death: nonsustained ventricular tachycardia (n = 26), rapid atrial fibrillation (n = 17), elective replacement indicator or end-of-life status (n = 22), intrathoracic impedance alarms (n = 3), lead issues (n = 3), or therapy delivered (n = 1). In 6 cases in which the patient was found deceased after a prolonged period, interrogation determined time of death. In 1 case, CIED interrogation was the primary means of patient identification. CONCLUSIONS: Postmortem CIED interrogation frequently contributes important information regarding critical device malfunction, premortem abnormalities, mechanism, and time of death or patient identity. Device interrogation should be considered for select patients with CIEDs undergoing autopsy.

Epigenetic programming, early life nutrition and the risk of metabolic disease.

Time separates the past from the present, during this period memory are formed - written in code and decoded to be read while other memories are erased - but when it comes to the epigenome some memories are harder to forget than others. Recent studies show chemical information is written in the context of the epigenome and codified on histone and non-histone proteins to regulate nuclear processes such as gene transcription. The genome is also subject to modification in the form of 5-methylcytosine, which has been implicated in metabolic memory. In this review, we examine some of the chemical modifications that signal early life events and explore epigenetic changes that underlie the diabetic vasculature. The fine balance between past and present is discussed, as it pertains to gestational diabetes and obesity in context to the Barker hypothesis. We also examine emerging experimental evidence suggesting the hypothalamus as a central regulator of obesity risk and explore current genomic medicine. As for how cells recall specific chemical information, we examine the experimental evidence implicating chemical cues on the epigenome, providing examples of diet during pregnancy and the increased risk of disease in offspring.