Small Dense LDL: Scientific Background, Clinical Relevance, and Recent Evidence Still a Risk Even with 'Normal' LDL-C Levels.

Residual cardiovascular disease event risk, following statin use and low-density lipoprotein cholesterol (LDL-C) reduction, remains an important and common medical conundrum. Identifying patients with significant residual risk, despite statin drug use, is an unmet clinical need. One pathophysiologic disorder that contributes to residual risk is abnormal distribution in lipoprotein size and density, which is referred to as lipoprotein heterogeneity. Differences in low density lipoprotein (LDL) composition and size have been linked to coronary heart disease (CHD) risk and arteriographic disease progression. The clinical relevance has been investigated in numerous trials since the 1950s. Despite this long history, controversy remains regarding the clinical utility of LDL heterogeneity measurement. Recent clinical trial evidence reinforces the relevance of LDL heterogeneity measurement and the impact on CHD risk prediction and outcomes. The determination of LDL subclass distribution improves CHD risk prediction and guides appropriate treatment.

Coronavirus disease 2019: a comprehensive review and meta-analysis on cardiovascular biomarkers.

PURPOSE OF REVIEW: Preventive cardiology has an important role to play in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The SARS-CoV-2 pandemic has been observed to have a greater mortality impact on subgroups of people in the population who are deemed to be at higher medical disease risk. Individuals with cardiovascular disorders are one such COVID-19-associated high-mortality risk group. RECENT FINDINGS: Evidence is accumulating that COVID-19 infection may worsen an individual's future cardiovascular health, and, preinfection/postinfection cardiovascular evaluation may be warranted to determine if progressive cardiovascular damage has occurred because of COVID-19 infection. In this study, we conducted a systematic review and meta-analysis, focusing on the association between COVID-19 severity and cardiac-specific biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin T (TnT)/troponin I (TnI), lactate dehydrogenase (LDH), creatine kinase, and creatine kinase isoenzyme (CK-MB). TnT had the highest odds ratio or OR (11.83) indicating the greatest association with COVID-19 severity, followed by NT-proBNP (7.57), TnI (6.32), LDH (4.79), D-dimer (4.10), creatine kinase (3.43), and CK-MB (3.35). All of the biomarkers studied were significantly correlated with COVID-19 severity including severe symptoms, ICU care, and mortality (P < 0.0001, except P < 0.01 for CK-MB). SUMMARY: COVID-19 infection results in short-term and long-term disease risk that may involve adverse cardiovascular health issues including heart failure. Cardiac-specific biomarkers appear to identify a subset of COVID-19 patients who have the highest risk of an adverse medical outcome. Preventive cardiology has an important role to play in the COVID-19 pandemic.The risk/benefit analysis of maintaining or eliminating the use of the angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitor (ACE-I) medications deserves further investigation.

Omega-3 Fatty Acid Blood Levels Clinical Significance Update.

The potential benefit of fish oil (omega-3 fatty acids) consumption to reduce cardiovascular disease (CVD) risk remains controversial. Some investigations report reduced CVD risk associated with fish or fish oil consumption while others report no benefit. This controversy is in part resolved when consideration is given to omega-3 blood levels in relation to CVD risk as well as blood levels achieved in clinical trials of omega-3 supplementation and CVD benefit. There is a wide variation in omega-3 blood levels achieved between individuals in response to a given dose of an omega-3 supplement. Many studies tested a daily dose of 1 gram omega-3 supplementation. The individual variation in blood omega-3 levels achieved in response to a fixed daily dose helps to explain why some individuals may obtain CVD protection benefit while others do not due to failure to achieve a therapeutic threshold. Recent development of a population range in a United States population helps to provide clinical guidance since population omega-3 blood level ranges may vary due to environmental and genetic reasons. Omega-3 supplementation may also be of benefit in reducing the adverse impact of air pollution on CVD risk.

High-density lipoprotein subclasses and their relationship to cardiovascular disease.

OBJECTIVE: To assess the clinical utility of measuring high-density lipoprotein (HDL) subfractions to assess coronary heart disease (CHD) risk. METHODS: Literature review of 80 published investigations. RESULTS: Measurements of HDL2b by gradient gel electrophoresis provided more consistent evidence of CHD risk than measurement of HDL2 cholesterol. Five of the seven studies that compared the extent or progression of atherosclerosis with gradient gel electrophoresis estimates of HDL subclasses (71%) assigned statistical significance to HDL2b. Ten of the 11 case-control comparisons (91%) reported lower HDL2b in cases. In contrast, of the 16 association studies relating HDL2 cholesterol and HDL3 cholesterol to extent of disease, five reported no significant relationships with either subfraction, two reported significant relationships with both HDL2 and HDL3 cholesterol, four reported significant relationships with HDL2 but not HDL3 cholesterol, and five reported relationships with HDL3 but not HDL2 cholesterol. Forty-five percent of the case-control comparisons reported that both HDL2 cholesterol and HDL3 cholesterol were significantly lower in cases than controls, 17% failed to find significance for either subfraction, and the remainder reported significantly lower values in cases for HDL2 cholesterol only (26%) or HDL3 cholesterol only (11%). On average, the case-control differences were similar for HDL2 (-0.12 ± 0.01 mmol/L) and HDL3 cholesterol (-0.10 ± 0.02 mmol/L), although relative to controls, the percent reduction was twice as great for HDL2 (-25.7 ± 2.9%) than HDL3 cholesterol (-12.1 ± 1.5%). Eight prospective studies were identified and four reported that both HDL2 and HDL3 predicted lower risk for CHD, one reported reductions in risk for HDL2 but not HDL3 cholesterol, and three reported reductions in risk for HDL3 but not HDL2 cholesterol. None of the prospective studies show that measurements of HDL cholesterol subfractions improve the identification of persons at risk. CONCLUSIONS: HDL2 and HDL3 cholesterol do not distinguish cardioprotective differences between HDL subclasses. More extensive characterization of HDL particles by one or two dimensional gel electrophoresis, ion mobility, or ultracentrifugation may provide more specific information about CHD risk than the measurement of HDL cholesterol, HDL3 cholesterol, or HDL2 cholesterol.

Genetic testing for early detection of individuals at risk of coronary heart disease and monitoring response to therapy: challenges and promises.

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient's lifetime, can help guide therapy selection, and may be of utility in family counseling.

Firefighters, heart disease, and aspects of insulin resistance: the FEMA Firefighter Heart Disease Prevention study.

OBJECTIVE: To determine the association of cardiovascular risk markers with noninvasive imaging of atherosclerosis in firefighters. METHODS: Cross-sectional investigation of subclinical atherosclerosis with metabolic, work related, and life-style variables in 296 professional firefighters. RESULTS: Calcified coronary atherosclerosis (CAC), carotid arterial intimal thickness (CIMT), and electrocardiogram provided independent CVD assessments. Homeostatic Model Assessment (HOMA) concentrations were related to heart-rate-corrected QT (QTc) (slope ± SE: 2.16 ± 65, P = 0.001), average common CIMT (0.019 ± 0.005 mm, P = 0.0005), and total CAC lesions (0.269 ± 0.116, P = 0.02). Stepwise linear regression selected fasting insulin as the strongest predictor for QTc, HOMA as the strongest predictor of average CIMT, and fasting glucose as the strongest predictor of total coronary lesion number and score. CONCLUSION: Firemen's HOMA and fasting insulin and glucose concentrations were significantly associated with three measures of CVD. Aspects of insulin resistance are related to CVD risk among firefighters.

Family coronary heart disease: a call to action.

A family history of coronary heart disease (CHD) is an accepted risk factor for cardiovascular events and is independent of common CHD risk factors. Advances in the understanding of genetic influences on CHD risk provide the opportunity to apply this knowledge and improve patient care. Utility of inherited cardiovascular risk testing exists by utilizing both phenotypes and genotypes and includes improved CHD risk prediction, selection of the most appropriate treatment, prediction of outcome, and family counseling. The major impediment to widespread clinical adoption of this concept involves un-reimbursed staff time, educational needs, access to a standardized and efficient assessment mechanism, and privacy issues. The link between CHD and inheritance is indisputable and the evidence strong and consistent. For clinicians, the question is how to utilize this information, in an efficient manner, in order to improve patient care and detection of high-risk family members.

Effect of combination nicotinic acid and gemfibrozil treatment on intermediate density lipoprotein, and subclasses of low density lipoprotein and high density lipoprotein in patients with combined hyperlipidemia.

The goal of this study was to determine, using analytic ultracentrifugation, the effect of nicotinic acid alone or nicotinic acid added to gemfibrozil on lipoprotein subclass distribution, including intermediate-density lipoprotein (IDL; low-density to very low density flotation rate [S(f)] 12 to 20); low-density lipoprotein (LDL) subfractions LDL-I (S(f) 7 to 12), LDL-II (S(f) 5 to 7), LDL-III (S(f) 3 to 5), and LDL-IV (S(f) 0 to 3); and high-density lipoprotein (HDL) subfractions HDL(2) (high-density flotation rate 3.5 to 9.0) and HDL(3) (high-density flotation rate 0 to 3.5). Patients with combined hyperlipidemia were randomized to nicotinic acid (1,500 mg/day) plus placebo or nicotinic acid plus gemfibrozil (1,200 mg/d) for 12 weeks. Baseline characteristics were similar between the 2 groups, and mean LDL cholesterol (180 +/- 33 mg/dl) and triglycerides (310 +/- 126 mg/dl) were typical for patients with combined hyperlipidemia. Treatment with nicotinic acid resulted in a reduction in dense LDL (S(f) 5 to 7; p = 0.02), which was counterbalanced by an increase in buoyant LDL (S(f) 7 to 12; p = 0.03) that resulted in no significant LDL mass or LDL cholesterol change. IDL was reduced (p = 0.005) and HDL(2) increased by 143% (p = 0.004). The combination of nicotinic acid and gemfibrozil resulted in a further 17.8% reduction in apolipoprotein B (p = 0.06), a further 33.8% reduction in IDL (p = 0.06), and a greater reduction in the apolipoprotein B/apolipoprotein A-I ratio (p = 0.02). The combination of nicotinic acid and gemfibrozil reduced atherogenic by IDL 71%, dense LDL-III by 52%, and apolipoprotein B by 37% and increased protective HDL(2) by 90%. In conclusion, this investigation revealed that a combination of a fibric acid derivative and nicotinic acid offers greater improvement in detailed lipoprotein subclass distribution and apolipoprotein ratios than monotherapy.

High-density lipoprotein subclass distribution in individuals of Asian Indian descent: the National Asian Indian Heart Disease Project.

Individuals of Asian Indian descent have significantly higher cardiovascular event rates as compared with other ethnic groups. The authors investigated the prevalence of metabolic disorders linked to coronary artery disease in an Asian Indian male population compared with non-Asian Indian males. Standard lipid measurements did not discriminate between groups, and the Asian Indian group exhibited less of the high coronary artery disease risk small low-density lipoprotein trait. Despite less of the small low-density lipoprotein trait in the Asian Indian group and no difference in high-density lipoprotein cholesterol, the Asian Indian group had a significantly higher prevalence (p < 0.0002) of low high-density lipoprotein 2b, implying impaired reverse cholesterol transport. This observation remained significant in the subgroup of patients with high-density lipoprotein cholesterol over 40 mg/dL, a region felt not to reflect impaired reverse cholesterol transport. Low high-density lipoprotein 2b combined with the higher lipoprotein(a) in the Asian Indian group may help explain the high prevalence of coronary artery disease in this ethnic population.

Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I.

We tested the hypothesis that treatment with nicotinic acid results in a differential blood lipid response in subjects classified as having a low-density lipoprotein (LDL) pattern A or B. One hundred eighty hypercholesterolemic subjects were randomized to placebo (n = 61), immediate-release niacin (3,000 mg/day, n = 59), or extended-release niacin (1,500 mg/day, n = 60) for 14 weeks. Lipids and lipoprotein cholesterol were determined with enzymatic methods. LDL subclass distribution was determined with 2% to 16% polyacrylamide gradient gel electrophoresis. Extended- and immediate-release niacin had significant effects on the decrease of triglycerides, total cholesterol, LDL cholesterol, apoprotein B, lipoprotein(a), and apoprotein A-I and significantly increased high-density lipoprotein cholesterol. The 2 nicotinic acid compounds and doses significantly increased mean LDL peak particle diameter and percent distribution in large LDL I and IIa, with a significant decrease in small LDL IIIa, IIIb, and IVb. In patients with LDL pattern B compared with those with pattern A, extended-release niacin (1,500 mg/day) increased LDL peak particle diameter significantly more and decreased the percent distributions of small LDL IIIa, LDL IIIb, and LDL IVa significantly more. With 3,000 mg/day, immediate-release nicotinic acid in patients with LDL pattern B exhibited a significantly greater increase in LDL peak particle diameter and large LDL IIa and IIb and significantly greater decreases in small LDL IIIa, IIIb, and IVa compared with patients with pattern A. These differences in response between patients with LDL pattern A and those with pattern B were not reflected by changes in the standard lipid profile, including apoproteins A-I and B. Nicotinic acid has a significantly different effect on lipids and lipoprotein subclass distribution in subjects classified as having LDL subclass pattern A or B. Nicotinic acid has a significantly greater effect on the decrease of small LDL subclass distribution and increase in LDL peak particle diameter in pattern B versus pattern A.

Small LDL and its clinical importance as a new CAD risk factor: a female case study.

The underlying metabolic cause of coronary heart disease in many patients is not high blood cholesterol. In fact, the Framingham study has reported that 80% of individuals who go on to have coronary artery disease have the same total blood cholesterol values as those who do not go on to have a cardiovascular event. The most common metabolic contributor to coronary artery disease is the atherogenic lipoprotein profile, characterized by an abundance of highly atherogenic small, dense low-density lipoprotein particles and a deficiency of the high-density lipoprotein (HDL) subtype most associated with coronary artery disease protection (HDL(2b)). This trait is present in 50% of men with coronary artery disease and is not reflected by total or low-density lipoprotein cholesterol values. While fasting triglycerides tend to he higher, and HDL cholesterol lower in patients with the atherogenic lipoprotein profile, the majority have triglyceride and HDL cholesterol values generally accepted to be in the "normal" range. An abundance of basic science and clinical trial evidence convincingly indicates that the presence of an atherogenic lipoprotein profile signifies a three-fold increased risk for a cardiovascular event and rapid arteriographic progression, but it also identifies a group of patients who respond particularly well to specific therapeutic interventions. Often the most effective interventions are the least expensive.