Vascular Disease In Later Life Research Articles

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations-higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Māori or Pacifica ethnicity) participating in the original CHALICE study-free of history of heart or renal disease at age 50 years and who consented to further study-will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. The study will commence in 2022 and be completed in 2024. Proving our hypothesis-that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively-opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. PRR1-10.2196/37011.

Hypoxia-induced inhibition of mTORC1 activity in the developing lung: a possible mechanism for the developmental programming of pulmonary hypertension.

Perinatal hypoxia induces permanent structural and functional changes in the lung and its pulmonary circulation that are associated with the development of pulmonary hypertension (PH) in later life. The mechanistic target of the rapamycin (mTOR) pathway is vital for fetal lung development and is implicated in hypoxia-associated PH, yet its involvement in the developmental programming of PH remains unclear. Pregnant C57/BL6 dams were placed in hyperbaric (760 mmHg) or hypobaric chambers during gestation (505 mmHg, day 15 through postnatal day 4) or from weaning through adulthood (420 mmHg, postnatal day 21 through 8 wk). Pulmonary hemodynamics and right ventricular systolic pressure (RVSP) were measured at 8 wk. mTOR pathway proteins were assessed in fetal (day 18.5) and adult lung (8 wk). Perinatal hypoxia induced PH during adulthood, even in the absence of a sustained secondary hypoxic exposure, as indicated by reduced pulmonary artery acceleration time (PAAT) and peak flow velocity through the pulmonary valve, as well as greater RVSP, right ventricular (RV) wall thickness, and RV/left ventricular (LV) weight. Such effects were independent of increased blood viscosity. In fetal lung homogenates, hypoxia reduced the expression of critical downstream mTOR targets, most prominently total and phosphorylated translation repressor protein (4EBP1), as well as vascular endothelial growth factor, a central regulator of angiogenesis in the fetal lung. In contrast, adult offspring of hypoxic dams tended to have elevated p4EBP1 compared with controls. Our data suggest that inhibition of mTORC1 activity in the fetal lung as a result of gestational hypoxia may interrupt pulmonary vascular development and thereby contribute to the developmental programming of PH.NEW & NOTEWORTHY We describe the first study to evaluate a role for the mTOR pathway in the developmental programming of pulmonary hypertension. Our findings suggest that gestational hypoxia impairs mTORC1 activation in the fetal lung and may impede pulmonary vascular development, setting the stage for pulmonary vascular disease in later life.

Heritability of Retinal Vascular Fractals: A Twin Study.

To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50°, disc-centered fundus photographs, the retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficients. Falconer's formula and quantitative genetic models were used to determine the genetic component of variation. The mean fractal dimension did not differ statistically significantly between monozygotic and dizygotic twin pairs (1.505 vs. 1.495, P = 0.06), supporting that the study population was suitable for quantitative analysis of heritability. The intrapair correlation was markedly higher (0.505, P = 0.0002) in monozygotic twins than in dizygotic twins (0.108, P = 0.46), corresponding to a heritability h2 for the fractal dimension of 0.79. In quantitative genetic models, dominant genetic effects explained 54% of the variation and 46% was individually environmentally determined. In young adult twins, the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the retinal vasculature may affect the retinal response to potential vascular disease in later life.

Long-Term Effects of Pregnancy Complications on Maternal Health: A Review.

Background: Most pregnancy-related medical complications appear to resolve at delivery or shortly thereafter. Common examples are preterm labor, placental abruption, preeclampsia, and gestational diabetes. Women who developed such complications are known to be at increased risk of developing similar complications in future pregnancies. It has recently become evident that these women are at an increased risk of long term medical complications. Methods: A search through scientific publications in English regarding the association of obstetric complications and long-term maternal illness. Results: There is a clear association between various obstetric complications and long-term effects on maternal health. Conclusions: Women with a history of adverse pregnancy outcomes are at increased risk of cardiovascular and metabolic diseases later in life. Data increasingly links maternal vascular, metabolic, and inflammatory complications of pregnancy with an increased risk of vascular disease in later life.

Maternal High Fat Diet Affects Offspring's Vitamin K-Dependent Proteins Expression Levels.

Studies suggest bone growth & development and susceptibility to vascular disease in later life are influenced by maternal nutrition, during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including Osteocalcin, Matrix-gla protein, Periostin, and Gas6, in bone and vascular development. This study extends the analysis of VKDPs previously conducted in 6 week old offspring, into offspring of 30 weeks of age, to assess the longer term effects of a maternal and postnatal high fat (HF) diet on VKDP expression. Overall a HF maternal diet and offspring diet exacerbated the bone changes observed. Sex specific and tissue specific differences were observed in VKDP expression for both aorta and femoral tissues. In addition, significant correlations were observed between femoral OCN, Periostin Gas6, and Vkor expression levels and measures of femoral bone structure. Furthermore, MGP, OCN, Ggcx and Vkor expression levels correlated to mass and fat volume, in both sexes. In summary the current study has highlighted the importance of the long-term effects of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure.

Maternal high-fat diet and offspring expression levels of vitamin K-dependent proteins.

Studies suggest that bone growth and development and susceptibility to vascular disease in later life are influenced by maternal nutrition during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including osteocalcin, matrix Gla protein, periostin, and growth-arrest specific- protein 6, in both bone and vascular development. We have examined whether there are alterations in these VKDPs in bone and vascular tissue from offspring of mothers subjected to a nutritional challenge: a high-fat diet during pregnancy and postnatally, using 6-week-old mouse offspring. Bone site-specific and sex-specific differences across femoral and vertebral bone in male and female offspring were observed. Overall a high-fat maternal diet and offspring diet exacerbated the bone changes observed. Sex-specific differences and tissue-specific differences were observed in VKDP levels in aorta tissue from high-fat diet-fed female offspring from high-fat diet-fed mothers displaying increased levels of Gas6 and Ggcx compared with those of female controls. In contrast, differences were seen in VKDP levels in femoral bone of female offspring with lower expression levels of Mgp in offspring of mothers fed a high-fat diet compared with those of controls. We observed a significant correlation in Mgp expression levels within the femur to measures of bone structure of the femur and vertebra, particularly in the male offspring cohort. In summary, the current study has highlighted the importance of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure.

Offspring birthweight is not associated with paternal insulin resistance

Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight. The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee. Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=-0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight. Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.

Homocysteine and Folic Acid: Implications for Pregnancy

The role of folic acid and homocysteine in pregnancy is becoming clearer. The efforts of many countries to prevent neural tube defects through public awareness of folic acid have been disappointing, but evidence is now emerging that the food fortification programs in the United States and Canada are effective in reducing the numbers of neural tube defects, and there may be additional benefits in terms of other congenital defects such as oral-facial clefts and congenital heart disease. Homocysteine has a significant association with vascular disease in later life, is elevated in preeclampsia, and has been associated with other pregnancy complications such as early pregnancy loss. The data from cohorts of women with a history of preeclampsia during pregnancy indicate that they are at increased risk for cardiovascular and cerebrovascular disease in later life. Elevated homocysteine concentrations may be a common link that accounts for these associations.

Do pregnancy complications and CVD share common antecedents?

Considerable data link low birth weight, due to intrauterine growth restriction, to increased offspring risk of vascular disease in later adult life. This is considered to be the result, in part, of programming through fetal nutrition [Ref 1: Am. J. Clin. Nutr. 71 (2000) 1344S]. These data support the hypothesis that pregnancy outcome in terms of birth weight is linked to the infant’s subsequent health. In contrast, much less attention has been focused on the relationship between adverse pregnancy outcomes, such as pre-eclampsia, gestational diabetes, pre-term delivery and intrauterine growth restriction, and the mother’s subsequent health. Interesting data have accumulated linking the maternal vascular, metabolic and inflammatory complications of pregnancy to an increased risk of vascular disease in later life (Table 1). This paper reviews the emerging evidence to support this fascinating concept, addresses potential mechanisms and discusses potential clinical implications.

Microvascular dysfunction: a link between pre‐eclampsia and maternal coronary heart disease

Epidemiological studies have recently demonstrated a relationship between pre-eclampsia and coronary heart disease. Insulin resistance has been implicated as a common factor. We have demonstrated, for the first time, using laser Doppler imaging in vivo, impaired microvascular function in women 15-25 years following a pregnancy complicated by pre-eclampsia. Thus, microvascular dysfunction, which is associated with insulin resistance, may be a predisposing vascular mechanism for both coronary heart disease and pre-eclampsia. Pregnancies complicated by pre-eclampsia may identify women at risk of vascular disease in later life and may provide the opportunity for lifestyle and risk factor modification to alter maternal vascular disease risk.

Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy.

Maternal fuel metabolism is known to exert long range effects on the later development of children of diabetic mothers. Recently cardiovascular disease in adult life has been linked retrospectively with foetal malnutrition. The aim of this study was to identify whether markers for fuel-related cardiovascular programming exist for the offspring of diabetic pregnancy. Sixty-one children aged 5 to 11 years, of mothers with Type I (insulin-dependent) diabetes mellitus were compared with 57 randomly selected control children of non-diabetic mothers similar in age, sex and social class. Fasting blood was taken for plasma glucose, insulin, lipids, IGF-1, plasminogen activating inhibitor 1 (PAI-1) and the adhesion molecules ICAM-1, VCAM-1 and E-Selectin. Fasting glucose and insulin were similar in the two groups. Differences existed between the offspring of diabetic and non-diabetic pregnancies (mean +/- SD) for total cholesterol (4.45+/-0.56 vs 4.18+/-0.66, p=0.03 ), LDL cholesterol (2.73+/-0.49 vs 2.39+/-0.54, p=0.001), Cholesterol-to-HDL ratio (3.41+/-0.76 vs 3.09+/-0.73, p=0.03), IGF-1 (22.5+/-7.3 vs 19.3+/-8, p=0.04), PAI-1 (20.1+/-6.2 vs 14.9+/-7.3, p=0.000), VCAM-1 (1852+/-444 vs 1509+/-385, p=0.000) and E-Selectin (geometric mean; 83.1 vs 63.9, p=0.001). These results indicate that important differences in cardiovascular risk factors exist between glucose-tolerant children of Type I diabetic and non-diabetic mothers, even in childhood. These data suggest that offspring of diabetic mothers might be at an increased risk for the development of vascular disease in later life.

Nutrition During Childhood: Implications for Coronary Vascular Disease in Later Life

Nutrition During Childhood: Implications for Coronary Vascular Disease in Later Life

An institutional approach to the dietary regulation of blood cholesterol in adolescent males

This study presents in detail an acceptable effective approach to initiate dietary modification to lower serum cholesterol in institutionalized, nonmotivated adolescent males. In order to simulate the traditional school menu pattern, considerable use was made of specially prepared food items to replace the ordinary market counterparts. During the Modified Diet periods, dietary fat intake was estimated to decrease from 39 (baseline) to 33% (modified diet) of total calories; saturated fatty acids decreased from 15 to 10% of total calories; and polyunsaturated fatty acids increased from 3 to 10% of total calories. The ratio of polyunsaturated to saturated fatty acids rose from 0.2 in the baseline diets to 1.0 on the modified diets, and mean daily intake of dietary cholesterol was reduced from 540 to 300 mg, a decrease of about 44%. Initial mean serum cholesterol level was 178 mg/100 ml. This was decreased promptly by about 15% upon introduction of the Modified Diet and returned to baseline levels after a short midterm vacation period and again after the summer vacation. Thus, an interrelationship between diet and level of blood cholesterol does exist in males as early as the second decade of life. Recognition and alteration of this environmentally determined risk factor during the adolescent years may result in lessened atherosclerotic vascular disease in later life.