Risk of Cardiovascular disease: Low Vitamin D, low HSPCs and high hsCRP - Jan 2024

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Vitamin D and Cardiovascular Risk: Stemming the Tide of Poor Outcomes in Coronary Heart Disease Editorial Comment

JACC: Advances Volume 3, Issue 2, February 2024, https://doi.org/10.1016/j.jacadv.2023.100803
Gian Paolo Fadini MD, PhD a b, Marella Marassi MD a
Refers to: Vitamin D Deficiency, Inflammation, and Diminished Endogenous Regenerative Capacity in Coronary Heart Disease
JACC: Advances, Volume 3, Issue 2, February 2024, Pages 100804 - see below

Figure 1. The Triangulation Between Vitamin D Deficiency, Chronic Inflammation, and Impaired Regenerative Capacity

Vitamin D deficiency (VDD) is highly prevalent in the general population, reaching up to 50% in areas with limited sunlight exposure. Being a vitamin D (VD) receptor widely expressed across human tissues, it is understandable that VDD is associated with a variety of disparate changes in multiple organs, not limited to the calcium-phosphate metabolism and bone health.

The epidemiological association between VDD and cardiometabolic diseases has fueled intense research in the quest to tackle the cardiovascular risk burden. Indeed, observational studies have consistently found a heightened incidence of various cardiometabolic conditions, including hypertension, stroke, diabetes, coronary heart disease, and cardiovascular mortality among individuals with VDD.1 The activation of the renin-angiotensin-aldosterone system, secondary hyperparathyroidism, and atherogenesis exacerbation are some of the potential mechanisms for the increased cardiovascular risk in VDD.1 However, causality linking VDD to cardiovascular diseases (CVDs) is not yet established; randomized trials testing VD supplementation have overall failed to ameliorate cardiometabolic outcomes. To date, VD supplement strategies have shown no benefits on blood pressure, incident diabetes, stroke, myocardial infarction, and cardiovascular mortality; hence, their use for cardiovascular protection remains questionable.2

Should we then discard VDD as an innocent bystander of cardiovascular risk or try to dissect its role further?

In this issue of JACC: Advances, Desai et al3 provide new exciting evidence to help redefine who could benefit from targeted VD supplementation. By analyzing a large cohort of patients with coronary heart disease from the Emory Cardiovascular Biobank, the authors confirmed the association between VDD and an excess risk of major adverse cardiovascular events and cardiovascular and all-cause mortality, with a cut-point at the traditional VD level of <20 ng/dL. The association was independent from confounders and consistent across some strata of the population. Of note, participants with VDD exhibited significant elevations in high-sensitive C-reactive protein (hsCRP), the prototypical inflammatory cardiovascular risk biomarker and a predictor of adverse outcomes.

Although enhanced inflammation has been consistently associated with both VDD and CVD,4 available data regarding the effects of VD supplementation on hsCRP levels are inconclusive, even in populations at high cardiovascular risk.5, 6, 7 At present, whether VD supplementation diminishes hsCRP and whether this in turn mediates cardiovascular protection remains controversial.

Despite VDD and high hsCRP were correlated, each predicted incident adverse events independently from the other, and individuals with both VDD and high hsCRP displayed the worst outcome. This finding implies an interaction between VDD and inflammation in determining cardiovascular risk, but Desai et al went further and built on the recent understanding that chronic low-grade inflammation impinges upon the endogenous organism’s self-repair capacity. The levels of circulating CD34+ cells, mostly representing hematopoietic stem/progenitor cells (HSPCs), represent such regenerative capacity because human CD34+ cells aid vascular repair.8 In addition, several cohort studies show that individuals with cardiovascular, metabolic, or kidney disease exhibit poorer outcomes when they have low circulating CD34+ cells, including excess all-cause mortality.9 This was confirmed by the authors in their cohorts. However, contrary to a prior study showing a direct correlation between VD and CD34+ cell subsets,10, 11, 12 the authors here reported no association between VDD and HSPC levels. This seems to suggest that VDD and low HSPCs are totally independent drivers of cardiovascular risk.

Probably the paper’s most outstanding finding is the exceptionally high cardiovascular risk conferred by the simultaneous presence of VDD, high hsCRP, and low HSPCs in the same individuals. Such a deadly triangulation (Figure 1) deserves special attention as the paper’s most notable output.

The risk for cardiovascular disease lies in the middle of this triangle and is contributed by each of the triangle corners. The figure illustrates excess visceral fat and kidney disease as possible additional drivers and leaves space for occult drivers that have yet to be elucidated. hsCRP = high-sensitive C-reactive protein; HSPC = hematopoietic stem/progenitor cell.

While the authors provide no hint on the association between hsCRP and HSPCs, there is now considerable evidence that inflammation underlies the shortage of circulating HSPCs. Myelopoiesis in the bone marrow elicits autocrine/paracrine signals within the stem cell niche that impede HSPCs from reaching the bloodstream.13 HSPC levels are susceptible to therapeutic manipulation14 and cardiovascular even rates can be reduced with anti-inflammatory therapies,15 but there is still no evidence that countering inflammation rescues HSPC levels and that this contributes to cardiovascular protection.

Along the other side of the triangle, a connection between VDD and circulating HSPC levels would be intriguing in view of the role of VD in bone homeostasis. As HSPCs are released into the circulation from their bone marrow niches, conditions affecting bone integrity, like VDD, could disrupt the HSPC niche and impair their mobilization. Also, circulating progenitor cells have been implicated in the so-called bone-vascular axis to explain the co-occurrence of osteoporosis and vascular calcification, driving cardiovascular events. Indeed, circulating progenitors can undergo a pro-calcific drift characterized by expression of typical bone-related markers.16 Desai et al3 did not examine CD34+ cell phenotype in more detail to assess whether VDD was characterized by osteogenic differentiation, but this is an area of possible future investigation because VDD may change CD34+ cell properties more than their levels.

Furthermore, this apparent triangle may hide occult drivers of CVD. First, while the authors controlled for the effect of body mass index, they did not consider visceral adiposity, which is a cause of VDD and a determinant of inflammation and HSPC traffic.17 Second, chronic kidney disease seems to be an obvious common denominator of VDD, inflammation, and HSPC defects. Recently, we found that patients with diabetic kidney disease present with low HSPCs, and HSPC pauperization, in turn, predicted worsening of kidney function.18 Whether VDD plays any role in this process is worth investigating.

In the end, we are still left with the possibility that each of the tree corners of the triangle are just epiphenomena of a hitherto unidentified factor and that we should target such core mechanism(s) instead of its visible manifestations.

Meanwhile, it is fascinating that, when combined with inflammation and hindered regenerative capacity, VDD projects its detrimental cardiovascular effect sky high. In line with the modern precision medicine paradigm, in place of a one-fits-all strategy of VDD correction, we have a new target population of patients for VD supplementation in future studies.
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Vitamin D Deficiency, Inflammation, and Diminished Endogenous Regenerative Capacity - Feb 2024

 Download the PDF from Vitamin D Life

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Vitamin D Life - 7 studies in both categories CVD and Inflammation

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Vitamin D Life - 34 studies in both categories CVD and Omega-3

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Vitamin D Life – Cardiovascular category:

507 items In Cardiovascular category

Cardiovascular category is associated with other categories: Diabetes 31, Omega-3 31 , Vitamin K 25 , Intervention 22 . Mortality 20 , Skin - Dark 18 , Magnesium 17 , Calcium 14 , Hypertension 14 , Trauma and surgery 13 , Stroke 13 , Kidney 12 , Metabolic Syndrome 11 , Seniors 10 , Pregnancy 8 as of Aug 2022

• Overview Cardiovascular and vitamin D
• Cardiovascular Disease is treated by Vitamin D - many studies 39+ meta-analyses
• Coronary Artery Disease and Vitamin D - many studies 18+
• Cardiovascular problems reduced by Omega-3 - many studies 34+
• Arteries and Atherosclerosis and Vitamin D - many studies 71+
• Atrial Fibrillation decreased by Vitamin D or Magnesium - many studies 26+
• Statins and Vitamin D - many studies 25+
• Arterial Stiffness and Vitamins – only Vitamin D was found to help – meta-analysis Feb 2022
• Those raising Vitamin D above 30 ng were 1.4 X less likely to die of Heart Attack (VA 19 years) – Oct 2021
• Giving free vitamin D to every Iranian would pay for itself by just reducing CVD – Oct 2021
• Sudden Cardiac Arrest – 2.8 X higher risk if low vitamin D – 2019
• Peripheral arterial disease risk is 1.5X higher if low vitamin D – meta-analysis March 2018
• Heart attack ICU costs cut in half by Vitamin D – Oct 2018
• Cardiovascular disease 2.3 X more-likely if poor Vitamin D Receptor – Aug 2022

Cholesterol, Statins

• Cholesterol is needed to produce both Vitamin D and Cortisol
• Overview Cholesterol and vitamin D
• Statins and Vitamin D - many studies statins often reduce levels of vitamin D
• Statin side-effects are reduced by Vitamin D – US patent Application – April 2019