Parathyroid hormone–PTH1R signaling in cardiovascular disease and homeostasis

• Published in: Trends in endocrinology and metabolism Vol. 35; no. 7; pp. 648 - 660
• Main Author: Towler, Dwight A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.07.2024
• Subjects: arteriosclerosis; coronary flow reserve; hyperparathyroidism; tachyphylaxis; vascular smooth muscle phenotypic modulation; arteriosclerosis; coronary flow reserve; hyperparathyroidism; vascular smooth muscle phenotypic modulation; tachyphylaxis
• ISSN: 1043-2760; 1879-3061; 1879-3061
• DOI: 10.1016/j.tem.2024.02.005

Dysregulated overproduction of parathyroid hormone (PTH), the prototypic calciotropic hormone, is a common endocrine disorder with the greatest prevalence in adult women.Hyperparathyroidism conveys increased risk for long-term cardiovascular (CV) morbidity and mortality independent of serum calcium levels.Primary hyperparathyroidism (pHPT) impairs normal arterial vasorelaxation and blood flow in response to physiological demands of the heart and kidneys.The PTH 1 receptor (PTH1R), shared by PTH and PTH-related protein, is highly expressed and biologically active in the CV system in addition to bone and kidney.Marked differences exist in the CV response to acute vs chronic PTH exposure, mediated in part via rapid tachyphylaxis to vascular PTH1R activation that normally improves arterial blood flow.A better understanding of vascular PTH/PTH1R signaling provides novel targets for therapeutic intervention CV disease including arteriosclerosis, CV fibrosis, and heart failure.Validated biomarkers are needed to establish the healthy ‘set point’ for CV PTH1R signaling tone to better guide the management of patients with pHPT or secondary hyperparathyroidism. Primary hyperparathyroidism (pHPT) afflicts our aging population with an incidence approaching 50 per 100 000 patient-years at a female:male ratio of ~3:1. Decisions surrounding surgical management are currently driven by age, hypercalcemia severity, presence of osteoporosis, renal insufficiency, or hypercalciuria with or without nephrolithiasis. Cardiovascular (CV) disease (CVD) is not systematically considered. This is notable since the parathyroid hormone (PTH) 1 receptor (PTH1R) is biologically active in the vasculature, and adjusted CV mortality risk is increased almost threefold in individuals with pHPT who do not meet contemporary recommendations for surgical cure. We provide an overview of epidemiology, pharmacology, and physiology that highlights the need to: (i) identify biomarkers that establish a healthy ‘set point’ for CV PTH1R signaling tone; (ii) better understand the pharmacokinetic–pharmacodynamic (PK-PD) relationships of PTH1R ligands in CV homeostasis; and (iii) incorporate CVD risk assessment into the management of hyperparathyroidism. Primary hyperparathyroidism (pHPT) afflicts our aging population with an incidence approaching 50 per 100 000 patient-years at a female:male ratio of ~3:1. Decisions surrounding surgical management are currently driven by age, hypercalcemia severity, presence of osteoporosis, renal insufficiency, or hypercalciuria with or without nephrolithiasis. Cardiovascular (CV) disease (CVD) is not systematically considered. This is notable since the parathyroid hormone (PTH) 1 receptor (PTH1R) is biologically active in the vasculature, and adjusted CV mortality risk is increased almost threefold in individuals with pHPT who do not meet contemporary recommendations for surgical cure. We provide an overview of epidemiology, pharmacology, and physiology that highlights the need to: (i) identify biomarkers that establish a healthy ‘set point’ for CV PTH1R signaling tone; (ii) better understand the pharmacokinetic–pharmacodynamic (PK-PD) relationships of PTH1R ligands in CV homeostasis; and (iii) incorporate CVD risk assessment into the management of hyperparathyroidism.