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Monday, July 10, 2017

Cardiovascular Disease Death Before Age 65 in 168 Countries Correlated Statistically

Paradoxes concerning CVD abound. Food scientists hotly dispute whether a plant-based diet or an omnivorous diet is optimal for the prevention of CVD [1]. Cardiologists debate whether the vulnerable plaque hypothesis to explain coronary artery disease (CAD) events, a foundational basis of lipid-lowering treatment, should be abandoned [2]. A recent trial showed that evacetrapib, a drug that lowers low-density lipoprotein (LDL) cholesterol, had no effect on the CVD outcomes, bringing into question the mechanism of the benefit of statins in reducing CVD events [3]. Counterintuitively, while the incidences of obesity and diabetes (i.e. risk factors for CVD) have risen during recent decades in Western countries, deaths attributed to CVD have fallen markedly [4].

Globally, about 30% of all deaths are due to CVD. About 38% of people in high-income countries die of CVD compared to 28% in low and middle-income countries [5]. However, CVD death rates among young people (< age 65) are higher in low and middle-income countries because of the shorter average lifespan. Nearly 80% of deaths in high-income countries occur among those over the age of 60 compared to 42% in low and middle-income countries [6]. These and the other CVD paradoxes call for new hypotheses that better explain the diverse and puzzling data. This paper will present data that supports the hypothesis that vitamin K2 (menaquinones: MK-4–MK-13) plays a central role in CVD etiology, epidemiology, and pathogenesis.

Vitamin K comprises a family of fat-soluble, structurally-similar compounds that function as enzymatic co-factors in the cross-linking of γ-carboxyl with ε-amino side chains in vitamin K-dependent proteins. Vitamin K-dependent proteins include not only blood coagulation proteins manufactured in the liver but also components of many extrahepatic tissues including arterial vessels and bones. Vitamin K1 (phylloquinone) comes primarily from green leafy vegetables. Vitamin K2 molecules are designated as MK-4–MK-13 according to the lengths of their isoprenyl side chains attached to a 2-methyl-1,4-naphthoquinone ring. Some vitamin K2 comes from dietary animal products without bacterial action (MK-4). Other vitamin K2 originates from bacterial action in animal and human guts and from bacterial action in fermenting plants and dairy products (MK-5–MK-13) [7]. In conjunction with vitamin D, vitamin K2 regulates the deposition of calcium, so bones and teeth receive calcium while blood vessels such as coronary arteries do not [8].

Animal trials and human observational studies have demonstrated that vitamin K2 deficiency (dietary deficiency or vitamin K inhibition by warfarin) contributes to CVD by stiffening and calcifying coronary arteries and other vessels [9]. An eight-year-long observational study involving 4,807 men and women aged 55 years and older in Rotterdam, Netherlands found that people in the lowest tertile of intake (vitamin K2 < 21.6 µg/day) had 27% more CVD mortality than people in the mid tertile (vitamin K2 = 21.6–32.7 µg/day) and 57% more than those in the upper tertile (vitamin K2 > 32.7 µg/day) [10]. As per the Multi-Ethnic Study of Atherosclerosis (MESA) in the United States, CVD incidence over 11 years of observation increased progressively as vitamin K2-dependent protein activity decreased, with event rates of 5.9 and 11.7 per 1000 person-years in the highest and lowest quartiles, respectively [11].

Biometric markers such as BMI, FBS, hemoglobin A1c, SBP, and serum cholesterol/HDL-cholesterol ratio (TC/HDL) have been correlated with CVD events in developed countries [12]. Socioeconomic risk factors such as dropping out of school, poverty, and certain occupations have also been correlated with CVD [13]. It has been found that nutritional and other stresses on infants and young children are associated with higher CVD death rates later in life. Study of infants in utero during the influenza pandemic of 1918 [14] and during the Dutch famine of 1944 [15] showed that these individuals suffered increased rates of CVD deaths in later life. Early childhood mortality (age 0–5 years) provides a reasonable index of fetal, infant, and early childhood distress (FICD) that might correlate with mortality from CVD in early adult life and middle age.

This study will use multiple regression analysis of female and male cohort data worldwide to relate early death from CVD (dependent variable) with major CVD risk factors (independent variables) to determine the attributable risks for each of these factors. For conditions associated with CVD (i.e. obesity, diabetes, hypertension, and increased TC/HDL), similar multiple regression analysis-derived formulae will be used to determine the attributable risks.


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