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Highlighted articles January 2019

Volume 280 Issue January 2019

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

In the January issue of Atherosclerosis, several articles addressed the role of time, age, and secular trends in the history and development of atherosclerotic diseases as well as risk factors.

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Highlighted articles

Severe atherosclerosis in the natural mummy of Girolamo Macchi (1648–1734), “major writer” of Santa Maria della Scala Hospital in Siena (Italy)

Atherosclerosis is one of the most common pathologies of the developed countries. Due to its connection with dietary habits, the disease had been considered peculiar of the modern, sedentary society with diet characterized by a rich intake of meat, sugar and fat. However, a high incidence of atherosclerosis in mummies belonging to different temporal horizons and different geographic contexts has been demonstrated. Leonardo da Vinci (1452–1519) was one of the first scientists to describe atherosclerosis as “vessels in the elderly that restrict the transit of blood through thickening of the tunics”. The presence of atherosclerosis in pre-contemporary individuals could suggest that the disease may be an inherent component of human ageing and not a characteristic of a specific diet or lifestyle. Paleopathology can contribute, with new cases, to give insights into this hypothesis.

In this study, Gaeta et al. report the analysis of a 17th century natural mummy, found in the crypt of S. Maria della Scala Hospital (Siena, Italy), and subsequently identified as Girolamo Macchi, accountant for the Hospital, who lived between 1648 and 1734.

Macroscopic, radiological, isotopic and histological analyses were performed on the mummy that showed a good preservation of the internal organs. The circulatory system revealed severe atherosclerosis, with multiple calcifications stenosing the lumen of the vessels, in particular of the lumbar aorta and the iliac arteries. The diagnosis was confirmed by imaging techniques (3D Cone Beam Scan) and histology.

These results confirm atherosclerosis as a disease of ancient times. The presence of atherosclerosis in pre-contemporary individuals could suggest that the disease may not only be uniquely characteristic of a specific diet or lifestyle, but it could also be an inherent component of human ageing.

Performance of gender- and age-specific cut-points versus NCEP pediatric cutpoints in dyslipidemia screening among Chinese children

Considerable attention is given nowadays to the presence of cardiovascular diseases risk factors in children. Abnormal blood lipid levels in childhood track into adulthood and are associated with preclinical atherosclerosis in later life. Therefore, early identification and treatment of children with lipid disorders may improve long-term cardiovascular health. The current blood lipid classification system for Chinese children was based on the United States National Cholesterol Education Program (NCEP) cutpoints, which did not take age, gender and race differences into account. Xiao et al. aimed at developing gender- and age-specific lipid cutpoints for dyslipidemia screening in Chinese children and compare the ability of new cutpoints and NCEP pediatric cutpoints to predict obesity and unfavorable blood pressure (BP) levels.

Data were obtained from a nationwide multicenter cross-sectional study: The China Child and Adolescent Cardiovascular Health Study, comprising 12,875 Chinese children aged 6–18 years. The authors calculated cutpoints for abnormal levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) that were linked to Chinese adult abnormal lipid thresholds using the General Additive Model for Location Scale and Shape method.

Borderline-high and high cutpoints (TC, LDL-C and TG) as well as low cutpoints (HDL-C) were developed to classify the abnormal blood lipid levels in Chinese children. Better performance for prediction of obesity, elevated BP, and hypertension were found with the proposed cutpoints in comparison with the NCEP pediatric cutpoints.

The study suggests that gender- and age-specific cutpoints should improve the accuracy of dyslipidemia screening in China.

Life course trajectories of cardiovascular risk: Impact on atherosclerotic and metabolic indicators

It is generally accepted that adult cardiovascular disease (CVD) risk factors are applicable as indicators of cardiometabolic health among children, with tracking and clustering of these risk factors over time, such that adverse CVD profiles in childhood are associated with similarly worse CVD profiles during young adulthood. In early adulthood, however, the risk of future cardiovascular disease (CVD) can be modified up to 95% through enactment of preventive measures such as a healthy diet, adequate exercise, and no use of tobacco products. In this analysis, Pollock et al. estimated population-level trajectory groups of life course cardiovascular risk to explore their impact on mid-life atherosclerotic and metabolic outcomes.

The Bogalusa Heart Study (BHS) is a series of long-term studies in a semirural biracial (65% white and 35% black) community in Bogalusa, Louisiana (USA), that begun in 1973, focusing on the early natural history of cardiovascular disease since childhood. In their analysis, the authors followed 1269 BHS participants, each with at least 4 study visits from childhood (1973) through adulthood (2016). They used discrete mixture modelling to determine trajectories of cardiovascular risk percentiles from childhood to adulthood. Outcomes included mid-life subclinical atherosclerotic measures [(carotid intima-media thickness (cIMT), pulse wave velocity (PWV)], metabolic indicators [(diabetes and body mass index (BMI)], and short physical performance battery (SPPB).

Between the mean ages of 9.6–48.3 years, they estimated five distinct trajectory groups of life course cardiovascular risk (High-Low, High-High, Mid-Low, Low-Low, and Low-High). Adult metabolic and vascular outcomes were significantly determined by life course cardiovascular risk trajectory groups. Those in the High-Low group had lower risks of diabetes and lower BMIs than those who remained at high risk (High-High) throughout life. However, the High-Low group had better cIMT and PWV than the High-High group. For all outcomes, those in the Low-Low group fared best.

In conclusion, considerable movement between low- and high-relative cardiovascular risk strata over the life course was found. Many children with high CVD relative risk factor burdens became low CVD risk adults. Atherosclerotic health is more modifiable than obesity and diabetes over the life course.

Coronary heart disease risk factor levels in eastern and western Finland from 1980 to 2011 in the cardiovascular risk in Young Finns study

 In the 1960s and 1970s, mortality due to coronary heart disease (CHD) was over 30% higher among Finns residing in eastern Finland compared with those residing in the west. Today, CHD mortality remains 20% higher among eastern Finns. The higher incidence of CHD mortality among eastern Finns has largely been explained by higher risk factor levels. Using a unique longitudinal cohort, Vähämurto et al. aimed at determining whether subjects who resided in eastern Finland during childhood had higher CHD risk factors in adulthood and from childhood to adulthood.

The Cardiovascular Risk in Young Finns Study is a population-based follow-up study aimed to examine atherosclerosis precursors, started in 1980 in Finland, and including children and adolescents aged 3–18 years, randomly chosen from the population register to form a representative sample of Finnish children. Vähämurto and colleagues analysed 2063 participants of the Cardiovascular Risk in Young Finns Study, born during the period 1962–1977, with risk factor data available from baseline (1980) when participants were aged 3–18 years, and had risk factor data collected again in adulthood (2011) when aged 34–49 years.

The results show that adult Finns aged 34–49 years had a similar CHD risk factor profile irrespective of whether they resided in eastern or western Finland during their childhood. However, when considering participants risk factor profiles over a 31-year period, those who resided in eastern Finland in childhood were associated with a less favorable CHD risk factor profile (higher systolic and diastolic blood pressures, total and LDL-cholesterol, triglycerides, apoB, and serum glucose) than those who resided in western Finland in childhood.

These findings suggest that in the future, a higher prevalence of clinical end-points could be observed in eastern Finns than in western Finns, owing to a legacy effect of higher CHD risk profile in childhood. However, the similar risk factor profile observed today suggests that the excess CHD mortality observed amongst eastern Finns might diminish in the future.

Trends in statin prescription prevalence, initiation, and dosing: Hong Kong, 2004–2015

Clinical practice guidelines recommend specific statin doses for the primary and secondary prevention of cardiovascular disease. The potential pharmacokinetic differences in Asian populations frequently necessitate a lower statin dose to achieve a comparable cholesterol reduction, as compared with Western populations. Currently, little is known about how statin utilization and dosing have evolved over time in Hong Kong. Blais et al. aimed to study trends in statin prevalence, initiation, and dosing in Hong Kong, from 2004 to 2015.

Patients receiving public health services, who were prescribed a statin, were included if they received a lipid test at a single center (n = 58,672). Using the territory-wide electronic health record, prescribed daily statin dose, nondaily dose frequency, and statin dose intensity were determined for statin prescriptions from 2004 to 2015. Statin prescription prevalence and initiation rates were estimated using the appropriate at-risk population in the hospital catchment area as the denominator. Prescribed daily doses were stratified by primary or secondary cardiovascular prevention status to assess changes in statin dosing over time.

The prescription prevalence of statins was higher in 2015 as compared with 2004. Initiation rates for new statin users increased from 2004 to 2013. High-intensity statins were infrequently prescribed. New users generally had higher statin initiation rates for primary prevention. There were small increases in the prescribed daily doses of statins. Nondaily statin dosing was infrequent.
These data show that the prevalence and initiation of statin prescriptions increased in Hong Kong, and was in part driven by low-intensity statins for the primary prevention of cardiovascular disease.

Atherosclerosis-associated differentially methylated regions can reflect the disease phenotype and are often at enhancers

Atherosclerosis is a widespread and complicated disease involving phenotypic modulation and transdifferentiation of vascular smooth muscle cells (SMCs), the predominant cells in aorta, as well as changes in endothelial cells and infiltrating monocytes. Alterations in DNA methylation are likely to play central roles in these phenotypic changes, just as they do in normal differentiation and cancer. Despite the importance of epigenetics for cell differentiation, there have been only a small number of reports about atherosclerosis-related epigenetic changes, and some of these studies focused on endothelial cells or non-aorta atherosclerosis.

Lacey et al. examined genome-wide DNA methylation changes in atherosclerotic aorta using more stringent criteria for differentially methylated regions (DMRs) than in previous studies and compared these DMRs to tissue-specific epigenetic features.

They found that disease-linked hypermethylated DMRs account for 85% of the total atherosclerosis-associated DMRs and often overlap aorta-associated enhancer chromatin. These hypermethylated DMRs were associated with functionally different sets of genes compared to atherosclerosis-linked hypomethylated DMRs. The extent and nature of the DMRs could not be explained as direct effects of monocyte/macrophage infiltration. Among the known atherosclerosis- and contractile SMC-related genes that exhibited hypermethylated DMRs at aorta enhancer chromatin were ACTA2, ELN, MYOCD, C9orf3, and MYH11. The analysis also suggests a role in atherosclerosis for developmental transcription factor genes having little or no previous association with atherosclerosis, such as NR2F2 (COUP-TFII) and TBX18.

The authors provide evidence for atherosclerosis-linked DNA methylation changes in aorta SMCs that might help minimize or reverse the standard contractile character of many of these cells by down-modulating aorta SMC-related enhancers, thereby facilitating pro-atherosclerotic phenotypic changes in many SMCs.

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