Molecular signatures of cardiovascular disease risk: potential for test development and clinical application

Most cardiovascular diseases are multifactorial by etiology. As an example, the development of myocardial infarction is promoted by numerous risk factors, ranging from rather modifiable lifestyle habits (e.g. smoking, physical activity) to genetic predisposition. With respect to the latter, 15 years of candidate gene analyses have failed to explain the molecular basis for the genetic predisposition to myocardial infarction. By contrast, recent genome-wide association studies have identified chromosomal loci that reproducibly displayed some association with myocardial infarction risk. When molecular genetic studies of coronary artery disease were first begun, it was assumed that genetic factors would soon be routinely incorporated into risk prediction scores. A number of biomarkers have been identified and tested in combination with the classical risk factors for refined risk prediction. However, the strategy for individualized risk prediction by incorporation of new biomarkers in established scores has so far proven to be more difficult than at first hoped.     

Association of lecithin-cholesterol acyltransferase activity and low-density lipoprotein heterogeneity with atherosclerotic cardiovascular disease risk: a longitudinal pilot study

Background

Lecithin-cholesterol acyltransferase (LCAT) is believed to be involved in reverse cholesterol transport, which is known to play a key role in suppression of atherosclerosis. However, recent investigations have demonstrated that higher LCAT activity, measured in terms of the serum cholesterol esterification rate by an endogenous substrate method, is associated with increased formation of triglyceride (TG)-rich lipoproteins (TRLs), leading to a decrease in the low-density lipoprotein (LDL) particle size. The purpose of this hospital-based longitudinal study was to clarify the causal relationship between changes in the LCAT activity and changes in the LDL-particle size.

Methods

The subjects were a total of 335 patients, derived from our previous study cohort, with one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). For this study, we measured the LDL-particle size (relative LDL migration [LDL-Rm value]) by polyacrylamide gel electrophoresis in the subjects, along with the changes in the LCAT activity, at the end of a follow-up period of at least 1 year.

Results

The results revealed that the absolute change (Δ) in the LDL-particle size increased significantly as the quartile of Δ LCAT activity increased (p =?0.01). A multi-logistic regression adjusted-analysis revealed that Δ LCAT activity in the fourth quartile as compared to that in the first quartile was independently predictive of an increased LDL-particle size (odds ratio [95% confidence interval]: 2.03 [1.02/4.04], p =?0.04). Moreover, the ? LCAT activity was also positively correlated with ? TRL-related markers (i.e., TG, remnant particle-like cholesterol [RLP-C], apolipoprotein B, apolipoprotein C-2, and apolipoprotein C-3).

Conclusions

The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in the LDL-particle size in patients at a high risk for ASCVD. To reduce the risk of ASCVD, it may be important to focus not only on the quantitative changes in the serum LDL-cholesterol levels, but also on the LCAT activity.

Trial registration

UMIN (https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi) Study ID: UMIN000033228 retrospectively registered 2 July 2018.

     

Improvements in cardiovascular risk profile with large-volume liposuction: a pilot study

In this study, the authors investigated the physiologic effects of the altered body composition that results from surgical removal of large amounts of subcutaneous adipose tissue. Fourteen women with body mass indexes of greater than > 27 kg/m2 underwent measurements of fasting plasma insulin, triglycerides, cholesterol, body composition by dual-energy x-ray absorptiometry (DXA), resting energy expenditure, and blood pressure before and after undergoing large-volume ultrasound-assisted liposuction.There were no significant intraoperative complications. Body weight had decreased by 5.1 kg (p < 0.0001) by 6 weeks after liposuction, with an additional 1.3-kg weight loss (p < 0.05) observed between 6 weeks and 4 months after surgery, for a total weight loss of 6.5 kg (p < 0.00006). Body mass index decreased from (mean +/- SEM) 28.8 +/- 2.3 to 26.8 +/- 1.5 kg/m2 (p < 0.0001). This change in body weight was primarily the result of decreases in body fat mass: as assessed by DXA, lean body mass did not change (43.8 +/- 3.1 kg to 43.4 +/- 3.6 kg, p = 0.80), whereas DXA total body fat mass decreased from 35.7 +/- 6.3 to 30.1 +/- 6.5 kg (p < 0.0001). There were significant decreases in fasting plasma insulin levels (14.9 +/- 6.5 mIU/ml before liposuction versus 7.2 +/- 3.2 mIU/ml 4 months after liposuction, p < 0.007), and systolic blood pressure (132.1 +/- 7.2 versus 120.5 +/- 7.8 mmHg, p < 0.0002). Total cholesterol, high-density lipoprotein cholesterol, plasma triglycerides, and resting energy expenditure values were not significantly altered after liposuction.In conclusion, over a 4-month period, large-volume liposuction decreased weight, body fat mass, systolic blood pressure, and fasting insulin levels without detrimental effects on lean body mass, bone mass, resting energy expenditure, or lipid profiles. Should these improvements be maintained over time, liposuction may prove to be a valuable tool for reducing the comorbid conditions associated with obesity.     

Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors

A major consequence of diabetes mellitus type 2 is the accelerated development of atherosclerosis. Assessment of conventional risk factors such as plasma lipids, lipoproteins and hypertension only partly account for the excessive risk of developing cardiovascular disease in this population. Increasing evidence has emerged suggesting that conditions associated with diabetes mellitus type 2, such as insulin resistance, hyperinsulinemia and hyperglycemia, may also play a significant role in regulating 'novel' cardiovascular risk factors. These factors and their potential roles in the development of atherosclerosis and cardiovascular events are discussed in this review.     

Comparison of prognosis for men with type 2 diabetes mellitus and men with cardiovascular disease

Background

People with type 2 diabetes mellitus are at high risk for cardiovascular disease. In some studies, the mortality rate among people with this condition has been equivalent to that among people with cardiovascular disease. We compared cardiovascular mortality between incident cases of diabetes and cardiovascular disease.

Methods

The study population was part of a random sample of 4376 men from Quebec, Canada, aged 35 to 64 years, who did not have cardiovascular disease in 1974 and who were followed until 1998. Three groups of incident cases were identified: diabetes without cardiovascular disease, first cardiovascular event (myocardial infarction, unstable angina or stroke) without diabetes, and both cardiovascular disease and diabetes. These cases were age-matched to a control group without diabetes or cardiovascular disease.

Results

During the 24-year follow-up period, new diabetes without cardiovascular disease was documented in 137 men. A first cardiovascular event without diabetes was documented in 527 men. Relative to the 627 controls, men with 1 of the 2 diseases of interest had higher cardiovascular mortality (age-adjusted relative risk [RR] 3.11, 95% confidence interval [CI] 1.96–4.92) for those with diabetes and 4.46 (95% CI 3.15–6.30) for those with cardiovascular disease). However, within the first 5 years after diagnosis, men with cardiovascular disease had higher cardiovascular mortality than men with diabetes (age-adjusted RR 2.03, 95% CI 1.01–4.08).

Interpretation

Men with isolated type 2 diabetes and men with isolated cardiovascular disease had similar cardiovascular mortality rates several years after initial diagnosis of either condition. These findings reinforce the need to prevent and optimally manage diabetes and cardiovascular disease.In 1971, type 2 diabetes mellitus was already considered an epidemic, affecting more than 170 million people worldwide.¹ In 2001, it was estimated that diabetes prevalence would increase by nearly 50% by the year 2010.¹ Epidemiologic studies performed in randomly sampled populations and initiated in the 1970s and 1980s have shown that diabetes increases the risk of all-cause death, as well as death due to cardiovascular disease and coronary artery disease.^2–23 In some studies,^12–17 but not all studies,^18–23 coronary or cardiovascular mortality among people with type 2 diabetes without previous cardiovascular disease was equivalent to that of people without diabetes who had had a first myocardial infarction or first cardiovascular event. Thus, there is controversy as to whether diabetes alone confers a risk of cardiovascular mortality similar to that associated with having had a first coronary or cardiovascular event. The differences in findings among various studies may be attributable to several factors such as age, sex, duration of diabetes and cardiovascular disease, ethnicity, cardiovascular risk factors and therapies. Furthermore, most studies used prevalent cases without considering the duration of cardiovascular disease or diabetes and did not exclude high-risk patients who had angina or intermittent claudication before the diagnoses of diabetes and cardiovascular disease.The rationale for undertaking the present study was the need for more information about the cardiovascular prognosis of men with type 2 diabetes relative to men with cardiovascular disease. We used incident instead of prevalent cases, without prior angina and without intermittent claudication. We speculated that the adverse prognosis associated with a diagnosis of diabetes would be similar to the prognosis associated with a diagnosis of cardiovascular disease over the long term but would be less similar over the short term. We formulated 2 hypotheses: first, that within the first few years after diagnosis, the risk of a fatal cardiovascular event would be higher among men with a first cardiovascular event and no diabetes than among men with type 2 diabetes and no cardiovascular disease; and second, that over the longer term, the risk of death within these 2 clinical subsets would tend toward equivalence.     

A pilot Croatian survey of risk factor (CRO-SURF) management in patients with cardiovascular disease

A pilot survey was performed to determine the presence of known risk factors for cardiovascular disease in Croatian patients with diagnosed coronary heart disease (CHD) using a new questionnaire. The idea was to test this new and very simple questionnaire but also to compare the data collected in this pilot survey with the results of the last Croatian national survey (TASPIC-CRO V) and so to obtain the information whether secondary prevention has improved between 2003 and 2010. 122 patients with established CHD (88 men, 34 women, mean age 66.3 years) treated in Zagreb University Hospital Center were included. Data collection was based on filling the SURF questionnaire right after the clinical exam or later using review of medical records. Patients were hospitalized because of CABG (1%), PCI (8%), ACS (35%) or chronic stable angina (56%). The history of arterial hypertension had 95%patients (however, on admission mean systolic pressure was 130.1 mmHg, diastolic 76.8 mmHg), 90% had dyslipidaemia (total cholesterol <4.5 mmol/L had 43%; <4.0 mmol/L 33%; LDL-cholesterol <2.5 mmol/L 49%; <2.0 mmol/L 32%; HDL>1.2 mmol/L (women) or >1.0 mmol/L (men) had 67%), 25% had diabetes which was poorly regulated (mean HbA1c 8.2%), 18% were active smokers. After discharge only 24% performed cardiac rehabilitation. Mean body mass index of the patients was 28.3 kg/m2 (32% were obese, 72% overweight). Compared to TASPIC-CRO V there was lower usage of aspirin than recommended on discharge. This was also true for statin therapy. More patients were taking beta blockers, calcium antagonists and diuretics than 7 years ago. This pilot survey showed that CRO-SURF questionnaire is short, quick, effective and simple to use. It is a good and cost effective tool to collect data on CVD risk factors and their management. The results obtained by using it indicate that there is still a high prevalence of modifiable risk factors in Croatian patients with CHD.     

Newborn screening with targeted sequencing: a multicenter investigation and a pilot clinical study in China

Different newborn screening (NBS) programs have been practiced in many countries since the 1960s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing (NESTS) program to screen 11,484 babies in 8 Women and Children's hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85% (902/11,484). With 45.89% (414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07% (50/414), estimating an average of 0.95% (7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.     

Metabolite profiles and the risk of developing diabetes

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.     

Protein-based HDL subspecies: Rationale and association with cardiovascular disease,diabetes, stroke,and dementia

HDL-cholesterol is associated with reduced risk of cardiovascular disease, and is used in clinical practice for risk stratification. HDL is composed of many protein-defined subspecies that each comprises just a few percent of the total, some associated with lower and some with higher risk of CVD. HDL that contains apoC3 or apoE are subspecies that have opposing actions on HDL reverse cholesterol transport and opposing associations with risk of future CVD, apoC3 adverse and apoE beneficial. In addition to coronary heart disease, HDL that contains apoC3 is associated with risk of future type 2 diabetes and insulin resistance; ischemic stroke and cerebral infarction; dementia and the deposition of beta-amyloid in the brain. HDL that contains apoE and apoE itself are associated with lower risk of dementia. Other HDL subspecies that contain complement C3, alpha-2 macroglobulin, plasminogen, or haptoglobin are associated with higher future risk of coronary heart disease, whereas others such as HDL that contains apoC1 are associated with lower risk. At this time, these findings provide improved understanding of the multifaceted HDL system to better determine risk and targeting of therapy for the most prevalent chronic lifestyle diseases in our society.     

Type 2 diabetes and cardiovascular disease: getting to the fat of the matter

The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.     

Relationship of metabolic risk factors and development of cardiovascular disease and diabetes

The prevalence of obesity and diabetes has reached pandemic proportions. Obesity, particularly in association with high waist circumference and high BMI, is an independent risk factor for coronary heart disease (CHD) and diabetes. Several large studies have shown that marginal (5 lb) to moderate (11 to 22 lb) weight gain in adulthood (age 20 to 50 years) increases the risk of chronic disease and negatively affects CHD risk status. The metabolic syndrome, a clustering of cardiovascular and metabolic risk factors that includes abdominal obesity, is increasing among adults and children and is strongly associated with the development of diabetes and CHD. Recent evidence suggests that elevated liver enzymes, an indicator of non-alcoholic fatty liver disease, may comprise an additional component of the metabolic syndrome and may serve as a surrogate marker for type 2 diabetes, particularly if used in conjunction with C-reactive protein.     

Serum metabolic signatures of fulminant type 1 diabetes

Fulminant type 1 diabetes (FT1DM) is a relatively new clinical entity featured by acute destruction of pancreatic beta cells. Clinical consequences of FT1DM could be fatal when timely medications are not provided, suggesting the particular importance of rapid and accurate diagnosis. Here we report a serum metabonomics study of FT1DM patients, together with healthy control subjects (NC), type 2 diabetes (T2DM), classic type 1 diabetes (T1DM), and diabetic ketoacidosis (DKA) patients, with the aim of discovering metabolic markers associated with FT1DM. A total of 79 subjects were enrolled (22 NC, 22 T1DM, 22 T2DM, 8 DKA and 5 FT1DM) and the serum metabolic profiling of fasting blood samples was performed using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) coupled with multivariate and univariate statistical analyses. Serum metabolites differentially expressed in FT1DM relative to NC, or to T2DM, T1DM and DKA were identified. Three metabolite markers, 5-oxoproline, glutamate, and homocysteine, were significantly altered among FT1DM, T2DM, T1DM, and DKA. In addition, the three metabolite markers, 5-oxoproline, glutamate, and homocysteine, presented similar patterns of distribution across groups. The results showed that the metabolic signatures of FT1DM identified in this study could be of potential clinical significance for the accurate diagnosis of FT1DM.