Vitamin D and cardiovascular disease prevention

Vitamin D is a precursor of the steroid hormone calcitriol that is crucial for bone and mineral metabolism. Both the high prevalence of vitamin D deficiency in the general population and the identification of the vitamin D receptor in the heart and blood vessels raised interest in the potential cardiovascular effects of vitamin D. Experimental studies have demonstrated various cardiovascular protective actions of vitamin D, but vitamin D intoxication in animals is known to induce vascular calcification. In meta-analyses of epidemiological studies, vitamin D deficiency is associated with an increased cardiovascular risk. Findings from Mendelian randomization studies and randomized, controlled trials (RCTs) do not indicate significant effects of a general vitamin D supplementation on cardiovascular outcomes. Previous RCTs, however, were not adequately designed to address extra skeletal events, and did not focus on vitamin D-deficient individuals. Therefore, currently available evidence does not support cardiovascular benefits or harms of vitamin D supplementation with the commonly used doses, and whether vitamin D has cardiovascular effects in individuals with overt vitamin D deficiency remains to be evaluated. Here, we provide an update on clinical studies on vitamin D and cardiovascular risk, discuss ongoing vitamin D research, and consider the management of vitamin D deficiency from a cardiovascular health perspective.

Key points

• The vitamin D receptor (VDR) and enzymes for vitamin D metabolism are expressed throughout the cardiovascular system
• VDR and 1α-hydroxylase knockout mice have hypertension with myocardial hypertrophy and increased activity of the renin–angiotensin–aldosterone system
• The molecular effects of VDR activation indicate various anti-atherosclerotic and protective effects on the heart and on common cardiovascular risk factors
• Observational studies have shown that low 25-hydroxyvitamin D levels are associated with an adverse cardiovascular risk profile and significantly increased risk of cardiovascular events
• Mendelian randomization studies and randomized clinical trials have not shown significant effects of vitamin D on cardiovascular events, but these trials were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals
• Vitamin D supplementation is currently not indicated for the purpose of cardiovascular disease prevention, but treatment of vitamin D deficiency is critical for skeletal health

Introduction

The critical involvement of vitamin D in bone and mineral metabolism is historically known. The identification of the vitamin D receptor (VDR) in almost all human organs including the heart and the blood vessels, and observations that individuals deficient in vitamin D are at increased risk of various extraskeletal diseases, stimulated research on the role of vitamin D for overall and cardiovascular health. In this Review, we summarize the existing knowledge on the effects of vitamin D on cardiovascular diseases and associated risk factors, with a particular focus on meta-analyses of large, epidemiological studies and randomized, controlled trials (RCTs). First, we provide a short summary of vitamin D metabolism and current vitamin D guidelines, a historical perspective on vitamin D and cardiovascular diseases, and a brief overview on the mechanistic effects of VDR activation on cardiovascular risk factors, the blood vessels, and the heart. The principal aspect of this Review is an update on observational studies, Mendelian randomization studies, and RCTs on vitamin D and cardiovascular risk. Finally, we outline and discuss ongoing vitamin D research, including large RCTs, and present our conclusions on how to deal with the management of vitamin D deficiency from a public health and cardiovascular health perspective.

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Figure 1: Human metabolism of vitamin D.

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Source: NatureReviewsCardiology

Vitamin D and cardiovascular disease prevention

The mechanisms and functions of spontaneous neurotransmitter release

Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.

Key points

• Synaptic terminals can release neurotransmitter by spontaneous vesicle fusion that is independent of presynaptic action potentials.
• The traditional view of spontaneous neurotransmitter release suggests that spontaneous events occur randomly in the absence of stimuli owing to low-probability conformational changes in the vesicle fusion machinery.
• Recent studies have identified key distinctions between the synaptic vesicle fusion machineries that perform spontaneous versus evoked neurotransmitter release.
• In mammalian hippocampal synapses and at the Drosophila melanogaster neuromuscular junction, spontaneous and evoked neurotransmitter release events show some spatial segregation and activate distinct populations of postsynaptic receptors.
• Segregation of spontaneous neurotransmission enables selective neuromodulation that is independent of evoked release.
• In mammalian hippocampal synapses and at the D. melanogaster neuromuscular junction, spontaneous release events activate specific postsynaptic signal transduction cascades that maintain synaptic efficacy or regulate structural plasticity and synaptic development.
• Novel strategies that selectively target spontaneous release events are needed to address whether spontaneous release can signal independently during ongoing activity in intact neuronal circuits.
• Introduction

Introduction

Our current insights into the mechanisms underlying synaptic transmission originate from experiments that were conducted in the 1950s by Bernard Katz and colleagues. A key aspect of these studies was the discovery of spontaneous neurotransmitter release events, which seemed to occur in discrete 'quantal' packets. This fundamental observation enabled the complex and seemingly intractable nature of action potential-evoked neurotransmission to be analyzed and understood on the basis of its unitary components. Although the original work solely relied on electrophysiological analysis, later studies that used electron microscopy provided visual validation of the hypothesis that neurotransmission occurs through fusion of discrete synaptic vesicles that contain neurotransmitters with the presynaptic plasma membrane.

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Figure 3: Segregation of spontaneous and evoked neurotransmission.

Source: Nature Reviews Neuroscience