Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: A follow-up study
Abstract and Figures
Matrix-Gla Protein (MGP) is a strong inhibitor of vascular calcification, the expression of which is vitamin D dependent. MGP contains five gamma-carboxyglutamic acid (Gla)-residues which are formed in a vitamin K-dependent carboxylation step and which are essential for its function. Hence vascular vitamin K-deficiency will result in undercarboxylated, inactive MGP which is a potential risk factor for calcification. In the present study we describe the effects of vitamin K1 and D supplementation on vascular properties in postmenopausal women. In a randomized placebo-controlled intervention study, 181 postmenopausal women were given either a placebo or a supplement containing minerals and vitamin D (MD-group), or the same supplement with vitamin K1 (MDK-group). 150 participants completed the study and analysis was performed on 108 participants. At baseline and after three years, vessel wall characteristics, including compliance coefficient (CC), distensibility coefficient (DC), intima-media thickness (IMT) and the Young's Modulus (E) were measured to assess the effect of the supplements on the change of these parameters. The results showed that the elastic properties of the common carotid artery in the MDK-group remained unchanged over the three-year period, but decreased in the MD- and placebo-group. Comparing the MDK- and placebo-group, there were significant differences in decrease of DC (8.8%; p<0.05), CC (8.6%; p<0.05), and in increase of PP (6.3%; p<0.05) and E (13.2%, p<0.01). There were no significant differences between the MD-group and placebo. No significant differences were observed in the change of IMT between the three groups. It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall.
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... Vitamin D deficiency may also contribute to high blood pressure through its effects on the renin-angiotensin-aldosterone system [37]. Vitamin D supplementation may improve media and intimal compliance, as well as elasticity and thickness of blood vessels [38]. Our study highlights potential roles of vitamin D, suggesting that oral supplementation could be an effective method for addressing vitamin deficiency. ...
Background
The association between vitamin D and pregnancy-induced hypertension (PIH) remains contentious. The aim of our study was to evaluate the existence of an association between serum vitamin D levels and the incidence of PIH.
Methods
We conducted a literature search in PubMed, the Cochrane Library, and Embase databases in June 2024 using the following search terms: 25-hydroxyvitamin D (25(OH)D), Vitamin D, 1,25(OH)2D, VD, 1,25-dihydroxyvitamin D or 25(OH)D, combined with PIH. Two reviewers independently screened the literature based on inclusion and exclusion criteria. Data were then extracted and assessed for quality. Comparisons were made between the highest and lowest categories of serum vitamin D levels. Relative risks (RRs) and 95% confidence intervals (CIs), adjusted for multivariable effects, were pooled using a random-effects model. A two-stage dose-response meta-analysis was used to evaluate the trends.
Results
17 studies met the inclusion criteria. Of these, 11 prospective studies investigated the relationship between vitamin D levels and gestational hypertension, involving 8834 events and 17,104 participants. The results showed that vitamin D was only marginally associated with hypertensive disorders in pregnancy (summary RR = 0.99; 95% CI: 0.97–1.02; I² = 67.5%; p = 0.001). However, 6 case-control studies investigated the relationship between vitamin D levels and gestational hypertension, involving 80,814 events and 330,254 participants. The results showed that vitamin D is not associated with pregnancy hypertensive disorders (summary RR = 1.09; 95% CI: 0.84–1.41; I² = 75.4%; p = 0.001). In the subgroup analysis, the pooled effect of 25-hydroxyvitamin D (25(OH)D) showed a slight association with gestational hypertension (pooled RR = 0.99; 95% CI: 0.96–1.02; I² = 72.6%; p = 0.000). The dose-response analysis showed that increasing vitamin D doses are marginally associated with a decrease in the incidence rate.
Conclusions
Our research suggests that the risk of PIH may not be related to the vitamin D levels. Our research supports the hypothesis that gestational hypertension may not be associated with low levels of vitamin D, indicating that the role of vitamin D may not be significant.
... Vitamin K administration also significantly delayed the progression of coronary artery calcifications and the deterioration of arterial elasticity [63]. A lower risk of coronary heart disease and severe aortic calcifications was observed with higher menaquinones intake, but not with phylloquinone intake. ...
... In fact, it was suggested that the Western diet does not contain sufficient vitamin K to fulfill the gammacarboxylation of extrahepatic tissues, such as the vascular system and bones [48]. Although several interventional clinical trials have established the beneficial effects of vitamin K supplementation in bone and vascular health, others have reported a lack of effects [49][50][51][52][53][54][55][56]. This can be explained by the lack of standardized protocols, the use of different vitamin K vitamers, different follow-up and endpoint measurements, and different approaches to determining vitamin K levels [6,7]. ...
The Mediterranean diet (MD) is associated with improved longevity and the prevention and management of chronic inflammatory diseases (CIDs). Vitamin K, which is present in MD core components such as leafy green vegetables, is also known as a protective factor for CIDs. Estimates of vitamin K intake in Mediterranean settings are still scarce, and the association between MD and vitamin K intake is yet to be established. This study analyzed vitamin K intake and MD adherence in the Algarve region, in Portugal. We conducted a cross-sectional study in a nonrandom sample of adults using an online questionnaire which included a validated food-frequency questionnaire and a screener for MD adherence. A total of 238 participants were recruited (68% women and 32% men). Adherence to the MD was low (11%). Only 10% of the participants had vitamin K intake below the adequate intake. Adherence to the MD was positively correlated with vitamin K intake (r = 0.463; p < 0.001) and age (r = 0.223; p < 0.001). Our findings underscore the importance of promoting adherence to the MD for optimal vitamin K intake, and future research should focus on developing effective interventions to promote this dietary pattern, particularly among younger individuals and men.
... Nevertheless, there is evidence that VD and VK act synergistically, especially in terms of bone and cardiovascular health. Moreover, VK prevents calcification [21][22][23][24]. This provides the rationale for supplementation with both vitamins together, rather than considering VK as an independent anti-MM agent. ...
Multiple myeloma (MM) is a plasma cell malignancy that, despite recent advances in therapy, continues to pose a major challenge to hematologists. Currently, different classes of drugs are applied to treat MM, among others, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most of them participate in an interplay with the immune system, hijacking its effector functions and redirecting them to anti-MM activity. Therefore, adjuvant therapies boosting the immune system may be potentially beneficial in MM therapy. Vitamin D (VD) and vitamin K (VK) have multiple so called "non-classical" actions. They exhibit various anti-inflammatory and anti-cancer properties. In this paper, we investigated the influence of VD and VK on epigenetic alterations associated with the proliferative potential of MM cells and the development of BTZ resistance. Our results showed that the development of BTZ resistance is associated with a global decrease in DNA methylation. On the contrary, both control MM cells and BTZ-resistant MM cells exposed to VD alone and to the combination of VD and VK exhibit a global increase in methylation. In conclusion, VD and VK in vitro have the potential to induce epigenetic changes that reduce the proliferative potential of plasma cells and may at least partially prevent the development of resistance to BTZ. However, further ex vivo and in vivo studies are needed to confirm the results and introduce new supplementation recommendations as part of adjuvant therapy.
Aging is a complex process and a significant risk factor for chronic diseases. Menopause, a component of aging in women, is associated with several important cardiometabolic conditions including metabolic syndrome, osteoporosis, and cardiovascular diseases. Menopausal women could benefit from preventative strategies that may decrease morbidity and mortality and improve their quality of life. Vitamins D and K are essential nutrients required for bone health, immune function, and reducing cardiovascular risks, yet their synergistic effect is less understood in aging women. This is the first comprehensive review to summarize the evidence found in randomized clinical trials of the beneficial effects of vitamin D and K co-treatment in postmenopausal women. In our literature search across key electronic databases such as Cochrane, PubMed, and Ovid, we identified 31 pertinent studies. Overall, significant findings indicate that the combined intake of vitamins D and K may positively affect cardiovascular and bone health in postmenopausal women, emphasizing the importance of maintaining a healthy diet rich in vegetables and fermented dairy products. Given the challenges in obtaining all necessary nutrients solely through the diet, vitamin D and K supplements are recommended for postmenopausal women to promote healthy aging and well-being.
Vitamin K (VK) is an essential micronutrient impacting many systems in the body. This lipid-soluble vitamin is found in various plant and animal products and is absorbed via the lymphatic system. This biomolecule’s importance to human health includes but is not limited to its promotion of brain, cardiovascular, bone, and immune functions. These biological properties are also necessary for maintaining domesticated animal health. The synergistic impact of both VK and vitamin D (VD) maximizes these health benefits, specifically for the circulatory and skeletal systems. This manuscript reviews VK’s properties, molecular structures, nutrikinetics, mechanisms of action, daily requirements, safety in supplemental form, biomarkers used for its detection, and impacts on various organs. The purpose of synthesizing this information is to evaluate the potential uses of VK for the treatment or prevention of diseases.
Cardiovascular disease (CVD) is a major global health concern for both men and women. However, disease manifestation in women differs from that in men, with women more likely to be diagnosed with microvascular coronary disease, heart failure with preserved ejection fraction (HFpEF), and endothelial dysfunction. Men, on the other end, are more prone to macrovascular disease or heart failure with reduced ejection fraction (HFrEF). Furthermore, although women are considered to be generally protected from CVD at the pre-menopausal stage, having pre-existing comorbidity, such as diabetes mellitus, obesity or smoking, increases the risk for cardiovascular disease in the younger years in women to similar extent as in men. However, although there is strong evidence suggesting differences in CVD between men and women, CVD in women remains under-studied and under-diagnosed and therefore, there is an increasing need to understand the key differences between men and women in regards to prevention, diagnosis, treatment and management of CVD. Lipophilic vitamins, including vitamins A, D, E, and K, have emerged as crucial factors in maintaining optimal cardiovascular health. These vitamins exhibit potential cardioprotective effects by mitigating key cardiovascular risk factors, including dyslipidemia, inflammation, oxidative stress, endothelial dysfunction, and hypertension. In this chapter, we provide an overview of the impact of lipophilic vitamins on women’s heart health. We discuss the clinical and epidemiological evidence of the effects of lipophilic vitamins, the potential risks and considerations associated with their intake, and future directions to utilize lipophilic vitamins in the prevention and management of CVD in women.
Background:
Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis.
Methods:
In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome).
Results:
In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors.
Conclusions:
In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.
Background:
Calcification of the media of peripheral arteries is referred to as Mönckeberg's sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media.
Methods and results:
In situ hybridization, immunohistochemistry, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the expression of mineralization-regulating proteins in human peripheral arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipid. These VSMCs expressed the smooth muscle-specific gene SM22alpha and high levels of matrix Gla protein but little osteopontin mRNA. Compared with normal vessels, vessels with MS globally expressed lower levels of matrix Gla protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibited osteoblastic properties and mineralized in vitro.
Conclusions:
These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.
The stiffness of the thoracic aorta can be assessed non-invasively. If aortic stiffness can be shown to be related to coronary heart disease, perhaps it can be used to identify which patients with hypercholesterolaemia are most likely to have atheromatous changes and thus to be selected for intensive cholesterol-lowering treatment. Hence the distensibility of the transverse aortic arch was measured by echocardiography of the aortic arch in four groups of patients--symptom-free patients with normal serum cholesterol; symptom-free patients with raised serum cholesterol; patients with coronary heart disease (all with raised serum cholesterol), and post-heart-transplant patients. In all groups distensibility fell with age. The regression slope was steeper (p less than 0.05) for patients with known coronary disease than for either of the disease-free groups, and among cardiac transplant recipients there was also a segregation of distensibility values between those with and without atheroma in their native hearts. The results indicate that aortic distensibility might be an indicator of coronary heart disease and that it might be useful in identifying which symptom-free subjects with modest hypercholesterolaemia should be treated aggressively.
As ultrasonographically assessed carotid arteriosclerosis is being used as a surrogate measure for coronary arteriosclerosis, we performed a prospective longitudinal study of the association of our high-resolution ultrasound assessment of extracranial carotid morphology with the risk of acute coronary events in 1,288 eastern Finnish men. The presence of any structural changes in the common carotid arteries or carotid bulbs was associated with a 3.29-fold (95% confidence interval, 1.31-8.29; p = 0.0074), intimal-medial thickening with a 2.17-fold (95% confidence interval, 0.70-6.74; p = NS), small carotid plaques with a 4.15-fold (95% confidence interval, 1.51-11.47; p less than 0.01), and large ("stenotic") plaques with a 6.71-fold (95% confidence interval, 1.33-33.91; p less than 0.01) risk of acute myocardial infarction compared with men free of any structural changes in the carotid artery wall at baseline. These data confirm the close relation between carotid artery wall morphology and coronary heart disease.
The synthesis of matrix Gla protein (MGP) and bone Gla protein (BGP) have been shown to be mutually exclusive in all osteosarcoma cell lines investigated. In the cell lines that produce the respective proteins, synthesis is stimulated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) within the first several hours of hormone treatment. In the present studies we have investigated the effects of longer-term treatment with 1,25(OH)2D3 in the ROS 17/2 cell line, a cell line that synthesizes BGP constitutively but does not synthesize MGP. In agreement with earlier studies, the rate of BGP synthesis increases within 8 hours of hormone treatment, is maximal by 24 hours, and remains at the maximal rate through 48 hours of 1,25(OH)2D3 treatment. The present study is the first to report that the rate of BGP secretion at times beyond 48 hours declines to that of control cultures despite the continued administration of 1,25(OH)2D3, and that MGP synthesis is induced in ROS 17/2 cells by 48 hours of 1,25(OH)2D3 treatment. At this time, MGP mRNA could be detected by northern blot analysis and MGP secretion could be demonstrated by radioimmunoassay of culture medium. Both the level of MGP message per unit total RNA and the rate of MGP secretion into culture medium increased steadily between 2 and 6 days of 1,25(OH)2D3 treatment. The MGP synthesized by the 1,25(OH)2D3-treated ROS 17/2 cells was identical to that found in bone by northern blot analysis of message and by western blot analysis of the media antigen. Half-maximal induction of MGP synthesis was obtained with 0.3 nM 1,25(OH)2D3, a 60-fold higher dosage than was required for the half maximal stimulation of BGP synthesis in these cells. Treatment of ROS 17/2 cells with 24,24-F21,25(OH)2D3 suggests that the observed difference in dose dependence is not due to an increased rate of hormone catabolism.
Vitamin K functions as a cofactor during the posttranslational modification of proteins. The reaction in question is the carboxylation of glutamate (Glu) residues into γ-carboxyglutamate (Gla). The discovery of vitamin K in 1935 and the identification of Gla in the early 1970s have been reviewed elsewhere and will not be detailed in this paper. Here we intend to summarize the recent advances in vitamin K research.
Doppler signal processing cannot only be employed to detect the local blood velocity as function of time, but also to assess transcutaneously the displacement of the arterial walls during the cardiac cycle (distension waveform) and, hence, the time-dependent changes in arterial diameter relative to its initial diameter at the start of a cardiac cycle. The distension waveform normalized with respect to the local pulse pressure provides useful information about the local elasticity of the arterial wall. The displacement of the arterial wall can be obtained by processing the RF-signals within a sample volume coinciding with the arterial wall. To evaluate this method a dedicated high-speed memory system has been developed storing the RF-signal, as obtained with a conventional echo-imager in M-mode, over a number of successive sweeps covering a selected depth range. The data are transferred line after line to a personal computer (PC) and processed on the fly, thereby relieving the memory requirements of the PC. It can be concluded that a RF-signal memory in combination with a PC provides a useful tool to extract detailed diameter waveforms from the RF-signals obtained. Although the system does not process the signals in real-time the process can be considered to be on-line since the results become available within one minute after the acquisition of the data is completed.
We investigated the progression of carotid atherosclerosis in a population-based sample of 100 Eastern Finnish men aged 42, 48, 54 or 60 years. A high-resolution B-mode ultrasonographic examination was repeated after a follow-up of 24 months for each subject. The intimal-medial thickness (IMT) in the common carotid artery increased by -0.06 mm to 0.90 mm (mean 0.12 mm, SD 0.20 mm). Age (standardised partial coefficient, beta = 0.325, P = 0.0003), serum LDL cholesterol concentration (beta = 0.229, P = 0.0011), pack-years of smoking (beta = 0.274, P = 0.0023), blood leukocyte count (beta = 0.201, P = 0.0239), and platelet aggregability (beta = 0.165, P = 0.0646), measured at baseline, were the strongest predictors of atherosclerosis progression. Neither hypertension, current blood pressure level, serum HDL cholesterol nor serum HDL2 cholesterol concentration at the baseline examination had any association with the change of IMT over 2 yrs.
To determine whether vitamin K administration affects urinary calcium excretion in postmenopausal women.
Before- and after-trials with a 2-week treatment period.
Healthy postmenopausal women (55 to 75 years old) were recruited from the convents in and around Maastricht. Controls (25 to 40 years old) were healthy premenopausal volunteers.
Daily administration of 1 mg of vitamin K for 2 weeks.
Serum immunoreactive osteocalcin: hydroxylapatite binding (HAB) capacity of serum immunoreactive osteocalcin; excretion of calcium, hydroxyproline, and creatinine in the urine during the last 2 h of a 16-h fasting period.
In premenopausal women, no effect of vitamin K administration was seen. In the postmenopausal group, vitamin K induced increased serum immunoreactive osteocalcin concentration; normalization of the HAB capacity of serum immunoreactive osteocalcin (this marker was less than 50% that of the controls in the pretreatment samples); a decrease in urinary calcium excretion, notably in the "fast losers" of calcium; and a parallel decrease in urinary hydroxyproline excretion in the fast losers of calcium.
The serum immunoreactive osteocalcin level may vary with vitamin K status. This variance should be taken into consideration if osteocalcin is used as a marker for osteoblast activity. Vitamin K is one factor that may play a role in the loss of bone mass in postmenopausal osteoporosis.
The static elastic properties of arterial tree (abdominal aorta and common carotid artery) were studied in 19 normal subjects and in 49 patients with myocardial infarction with an ultrasonic phase-locked echo-tracking system that allows continuous transcutaneous measurement of the arterial diameter. The stiffness index beta, which represented the mechanical properties in the arterial wall, was calculated from the relation between systemic blood pressure and the diameter of the artery. Patients with myocardial infarction underwent coronary angiography in their convalescent period to determine involved vessels. In 11 patients, coronary artery was patent; 15 patients had one-vessel disease, 12 had two-vessel disease, and the remaining 11 patients had three-vessel disease. In normal subjects, increasing age was associated with an increase in arterial stiffness. An average value of the stiffness index of the abdominal aorta was 8.58 +/- 3.02 (mean +/- SD) and that of common carotid artery was 9.17 +/- 2.22. In patients with three-vessel disease, these values were significantly higher (22.37 +/- 4.29 in abdominal aorta and 13.17 +/- 4.56 in common carotid artery) than those in normal subjects. Stiffness index of patients with two- or one-vessel disease was also increased but lower than those in patients with three-vessel disease (p less than 0.05). Forty-four of 49 patients with infarction had an arterial stiffness index of abdominal aorta higher than the 95% confidence limits of the normal data (p less than 0.05). Twenty-eight patients were outside the nomogram of common carotid artery (p less than 0.05). The mechanical properties of these elastic arteries provided sufficiently reliable information on changes caused by atherosclerosis.