Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

BACKGROUND: Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. RATIONALE: Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. AIM: The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. CONCLUSION: Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity.

OBJECTIVE: N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance. MATERIALS AND METHODS: We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels. RESULTS: Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels. CONCLUSIONS: Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

Oral bisphosphonate-induced osteonecrosis complications in patients undergoing tooth extraction: a systematic review and literature updates.

OBJECTIVE: Bisphosphonates, the most common anti-resorptive medications, are internalized by osteoclasts, where they inhibit the macrophage colony-stimulating factor (M-CSF) pathway, preventing their differentiation, inhibiting anchorage to the cell membrane, and inducing apoptosis. In patients undergoing oral bisphosphonate therapy, oral surgery involves a high risk of developing drug-related osteonecrosis of the jaws (BRONJ/MRONJ), among the possible complications. MATERIALS AND METHODS: A systematic search was carried out on the PubMed, Scopus and Cochrane Library search engines, using the keywords "oral bisphosphonates AND tooth extraction", "third molar extraction AND oral bisphosphonates". In addition, we manually evaluated the articles included in references from other sources and an analysis of the Gray Literature was performed. A secondary outcome was to evaluate the assessment of pharmacological (antibiotics) use in the BRONJ/MRONJ management. The revision protocol followed the indications of the Cochrane Handbook, and was registered in the INPLASY database, while the drafting of the manuscript was based on PRISMA. RESULTS: The results of the systematic review, after the study identification and selection process, included a total of 7 studies: 4 retrospective studies, 2 prospective studies and 1 case report. The main complication was represented by osteonecrosis of the jaws, which appears to be related to the duration of treatment with bisphosphonates; in addition, data regarding the anatomical location of post-extraction sites, the sex and age of patients, comorbidities and various systemic risk factors were extrapolated. The most frequent post-extraction complication in patients treated with oral bisphosphonates is osteonecrosis of the jaws, with a significant prevalence in the posterior region of the mandible. In some cases, delayed healing of the surgical wound was also found; moreover, the duration of exposure to oral bisphosphonates influences the onset of complications. CONCLUSIONS: Ongoing studies continue to unravel the role of the oral environment response in alveolar bone homeostasis and how it might contribute to the induction of BRONJ/MRONJ. Approaching the problem from this perspective could provide new directions for the prevention of BRONJ/MRONJ and expand our understanding of the unique oral microenvironment.

Age Dependency of Cardiovascular Outcomes With the Amyloidogenic pV142I Transthyretin Variant Among Black Individuals in the US.

Importance: Hereditary transthyretin cardiac amyloidosis is an increasingly recognized cause of heart failure (HF) with distinct treatment. The amyloidogenic pV142I (V122I) variant is present in 3% to 4% of Black individuals in the US and increases the risk for atrial fibrillation (AF), HF, and mortality. Since hereditary transthyretin cardiac amyloidosis demonstrates age-dependent anatomic penetrance, evaluation later in life may identify survivors at particularly high risk. Objective: To estimate age-dependent risks for cardiovascular events with the variant. Design, Settings, and Participants: This cohort study analyzed Black participants from the Atherosclerosis Risk in Communities (ARIC) study attending visit 1 (1987-1989) (followed up until 2019; median follow-up, 27.6 years). Data analyses were completed from June 2022 to April 2023. Exposure: pV142I carrier status. Main outcomes: The association between the variant and AF, HF hospitalization, mortality, and a composite of HF hospitalization or mortality was modeled by generating 10-year absolute risk differences for each year between ages 53 (the median age at visit 1) and 80 years, adjusting for the first 5 principal components of ancestry and sex. As an example, 5- and 10-year risk differences were specifically estimated for the composite outcome among participants surviving to age 80 years. Results: Among 3856 Black participants (including 124 carriers) at visit 1, 2403 (62%) were women, 2140 (56%) had hypertension, and 740 (20%) had diabetes, with no differences between groups. The 10-year absolute risk difference between ages 53 and 80 years increased over time for each outcome. Statistical significance for increased 10-year risk difference emerged near ages 65 years for AF, 70 years for HF hospitalization, and 75 years for mortality. Among participants surviving to age 80 years, carriers had a 20% (95% CI, 2%-37%) and 24% (95% CI, 1%-47%) absolute increased risk for HF hospitalization or death at 5 and 10 years, respectively. Thus, at age 80 years, only 4 carriers would need to be identified to attribute 1 HF hospitalization or death over the following decade to the variant. Conclusions and Relevance: In this study, age-specific risks were provided for relevant outcomes with the pV142I variant. Despite a relatively benign course during earlier years, Black individuals who carry the pV142I variant surviving into later life may be particularly vulnerable. These data may inform timing for screening, risk counseling to patients, and potential strategies for early targeted therapy.

AL Amyloidosis for Cardiologists: Awareness, Diagnosis, and Future Prospects: JACC: CardioOncology State-of-the-Art Review.

Amyloid light chain (AL) amyloidosis is a rare, debilitating, often fatal disease. Symptoms of cardiomyopathy are common presenting features, and patients often are referred to cardiologists. Cardiac amyloid infiltration is the leading predictor of death. However, the variable presentation and perceived rarity of the disease frequently lead to delay in suspecting amyloidosis as a cause of heart failure, leading to misdiagnoses and a marked delay in diagnosis, with devastating consequences for the patient. A median time from symptom onset to correct diagnosis of about 2 years is often too long when median survival from diagnosis for patients with AL amyloidosis and cardiomyopathy is 4 months to 2 years. The authors highlight the challenges to diagnosis, identify gaps in the current knowledge, and summarize novel treatments on the horizon to raise awareness about the critical need for early recognition of symptoms and diagnosis of AL amyloidosis aimed at accelerating treatment and improving outcomes for patients.

Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 2 of 2-Diagnostic criteria and appropriate utilization.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

The amyloidogenic V122I transthyretin variant in elderly black Americans.

BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).

Echocardiography in cardiac amyloidosis.

Echocardiography is the most widely used noninvasive test in patients with heart failure or abnormal cardiac findings on examination. Patients with amyloidosis may have significant cardiac abnormalities, several of which are highly suggestive of the disease. This article reviews echocardiographic features found in cardiac amyloidosis.