Fluoride and Cardiovascular Diseases: Epidemiologic Investigations and Mechanistic Insights.

Fluorine is a trace element that is beneficial to human health. However, long-term and excessive fluoride exposure can damage bone and teeth, as well as the cardiovascular, nervous, and reproductive systems, etc. Since 2001, a growing body of evidences suggests that excessive fluoride exposure is associated with cardiovascular diseases. Although some original studies have focused on this topic, general and narrative reviews are rare. This article summarizes the effects of fluoride on blood pressure/hypertension, vascular sclerosis (mainly atherosclerosis), and myocardial/ cardiac damages based on epidemiologic investigations, in vivo and in vitro mechanistic studies. Most studies suggest that excessive fluoride exposure can initiate and aggravate hypertension through endothelial dysfunction (ED) manifested as abnormal endothelium metabolism, endothelium apoptosis, hyper-permeability, and impaired vasomotor function (imbalance of endothelin-1/nitric oxide), oxidative stress (over generation of ROS), and abnormal activities of the renin-angiotensin-aldosterone system covered up-regulation of AT1R, AT2R, ACE3 and down-regulation of ACE2. Besides ED, excessive fluoride exposure induced and accelerated atherosclerosis via lipid metabolism disorders (elevated plasma triglyceride, total cholesterol, and low-density lipoprotein cholesterol, etc. levels), up-regulation of adhesion molecules (P-selectin, ICAM-1 and VCAM-1), over-proliferation and phenotypic changes of vascular smooth muscle cells. Except for oxidative stress, excessive fluoride exposure caused myocardial and cardiac functional damage via myocardium injuries, inflammation (IL-6 and IL-10 increased), and mitochondrial dysfunction (ATP and ATPase decreased), then presenting electrocardiographic abnormalities. The review will help to clarify harms of fluoride on the cardiovascular system and provide basis for adjustments of drinking water standards.