Factors associated with time to initiation of a PCSK9 inhibitor after hospital discharge for acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower atherosclerotic cardiovascular disease (ASCVD) event risk. OBJECTIVE: Analyze patient characteristics associated with time to PCSK9i initiation following an acute myocardial infarction (AMI). METHODS: We analyzed characteristics of patients ≥21 years of age in the Marketscan or Medicare databases who initiated a PCSK9i 0-89 days, 90-179 days, or 180-365 days after an AMI between July 2015 and December 2018 (n=1,705). We estimated the cumulative incidence of recurrent ASCVD events before PCSK9i initiation. RESULTS: Overall, 42%, 25%, and 33% of patients who initiated a PCSK9i did so 0-89 days, 90-179 days, and 180-365 days following AMI hospital discharge, respectively. Taking ezetimibe prior to AMI hospitalization and initiating ezetimibe within 30 days after AMI hospital discharge were each associated with a higher likelihood of PCSK9i initiation in the 0-89 days versus 180-365 days post-discharge (adjusted odds ratio [OR] 1.83, 95% confidence interval [95%CI] 1.35-2.49 and 1.76, 95%CI 1.11-2.80, respectively). Statin use before and statin initiation within 30 days after AMI hospitalization were associated with a lower likelihood of PCSK9i initiation 0-89 days versus 180-365 days post-discharge (adjusted OR 0.64, 95%CI 0.49-0.84 and 0.39, 95%CI 0.28-0.54, respectively). Overall, 8.0%, 10.5%, and 12.5% of patients had an ASCVD event at 90, 180, and 365 days following AMI hospital discharge and before initiating a PCSK9i, respectively. CONCLUSION: Among patients initiating a PCSK9i after AMI, a low proportion did so within 89 days of hospital discharge. Many patients had a recurrent ASCVD event before treatment initiation.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

HDL-C levels modify the association between C-reactive protein and coronary artery calcium score.

BACKGROUNDS AND AIMS: C-reactive protein (CRP) levels predict incident and recurrent cardiovascular disease (CVD) events; however, associations between CRP and pre-clinical atherosclerosis is less certain. Since high concentrations of high-density lipoprotein cholesterol (HDL-C) are inversely associated with CVD risk, we investigated whether HDL-C modified the association between CRP concentration and measures of preclinical atherosclerosis. METHODS AND RESULTS: Data were analyzed from a Korean occupational cohort of 12,030 male subjects who underwent a cardiac computed tomography (CT) estimation of coronary artery calcification (CAC) score and an assessment of CVD risk factors. Logistic regression was used to describe associations between CRP and measures of pre-clinical atherosclerosis, such as CAC scores >0. As many as 1351 (11.2%) participants had a CAC score>0. CRP was stratified into 3 groups based on clinical category: <1 mg/L, 1 to <2 mg/L, and ≥ 2 mg/dL. In the bottom CRP group, 907/8697 (10.4%) of subjects had a CAC score >0, compared with 242/1943 (12.5%) in the middle group and 202/1396 (14.5%) in the top CRP group (p < 0.0001). After adjustment for multiple CVD risk factors, there was a positive association between CRP and CAC score>0 (OR between top and bottom CRP groups, 1.41 [1.04, 1.90], p = 0.027) in the lowest HDL-C quartile but not in the highest HDL-C (OR between top and bottom CRP group, 0.80 [0.46, 1.39], p = 0.425). CONCLUSION: The association between CRP concentration and CAC score differed according to HDL-C levels.

Prevalence of low LDL-cholesterol levels and elevated high-sensitivity C-reactive protein levels in apparently healthy Korean adults.

BACKGROUND AND AIMS: The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality in patients with elevated C-reactive protein (CRP) and low LDL-cholesterol (LDL-C) levels treated with statins. The aims of this study were to determine the proportion of "JUPITER-eligible" Korean adults and to describe their characteristics. METHODS AND RESULTS: As many as 15,154 subjects with serum LDL-C levels <130 mg/dL were selected among 28,851 middle-aged participants (men ≥ 50 years, women ≥ 60 years) who participated in a routine health check-up program. Among the participants with LDL-C less than 130 mg/dL, only 15% had CRP levels ≥2.0 mg/L (7.9% of original participants). Subjects were divided into four groups according to CRP levels (<0.5, ≥0.5 - <1.0, ≥1.0 - <2.0, and ≥2.0 mg/L). Mean HDL-C and apolipoprotein A1 levels decreased significantly as the mean CRP values increased. The insulin and homeostasis model of insulin resistance was significantly different according to CRP quartile. The number of subjects with metabolic syndrome and its components increased significantly as the mean CRP values increased. CONCLUSION: In this Asian population, few individuals with low LDL-C levels had CRP levels ≥2.0 mg/L. Elevated CRP levels were associated with components of atherogenic dyslipidemia and insulin resistance. Additional clinical trials should be designed and performed in different ethnic groups, as different CRP cut-off levels may be required in different ethnic groups.

Does microvascular disease predict macrovascular events in type 2 diabetes?

AIM: Population studies suggest a link between albuminuria, reduced glomerular filtration rate (GFR) and retinopathy and macrovascular events in type 2 diabetes. The aim of this review was to investigate whether this association extended to the presence of any diabetic microvascular complication. METHOD AND RESULTS: PUBMED was searched from 1999 to 2010 using the terms 'albuminuria', 'nephropathy', 'chronic kidney disease', 'estimated GFR', 'retinopathy', 'autonomic neuropathy', 'peripheral neuropathy', or 'microvascular' and 'cardiovascular disease', 'stroke', 'coronary heart disease' or 'peripheral vascular disease' and 'type 2 diabetes' and MESH equivalents. Prospective studies with at least 200 type 2 diabetes subjects that evaluated hard cardiovascular endpoints were selected. In 25 studies (n=54,117) included in the review there was evidence of an association between microvascular complications (notably retinopathy or nephropathy) and cardiovascular events. Diabetic retinopathy was associated with ∼ 1.7-fold increased risk for cardiovascular events, and albuminuria or reduced GFR associated with ∼ two-fold increased risk for cardiovascular events. In the presence of more than one complication, this risk was accentuated. These associations remained even after adjustment for conventional cardiovascular risk factors, diabetes duration and glycaemic control. These data suggest that similar mechanisms may be relevant to the pathogenesis of both micro- and macrovascular disease in type 2 diabetes. It is likely that endothelial dysfunction, low-grade inflammation and rheological abnormalities are common mechanistic denominators. CONCLUSIONS: This review highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.

The accumulative effects of physical activity in hypertensive post-menopausal women.

BACKGROUND: Lifestyle modifications, such as physical activity, are recommended as first-line or adjunctive therapy for hypertension. However, controversy exists regarding the type, amount, and intensity of physical activity for optimal blood pressure lowering. DESIGN AND METHODS: This study evaluated the blood pressure changes in 18 post-menopausal, sedentary, untreated hypertensive women randomized to an individualized 8-week programme of intermittent moderate-intensity physical activity versus no change in physical activity. The physical activity group was asked to select activities (such as walking) to engage in physical activity for 10 min, three times a day, 5 days per week at an intensity of 50-60% heart rate reserve. RESULTS: Independent T-tests were used to compare the difference in resting blood pressure between groups. After 8 weeks, resting blood pressure was 8/5 mmHg lower in the physical activity group (systolic blood pressure, P= 0.006 and diastolic blood pressure, P = 0.059). The between group differences remained significant after adjustment for age, baseline blood pressure and previous use of antihypertensive drug therapy. CONCLUSION: These data show that hypertensive, post-menopausal women who engage in intermittent, moderate-intensity physical activity experience a reduction in blood pressure.

Variability in fibrinogen measurements: an obstacle to cardiovascular risk stratification.

The clinical utility of fibrinogen measurement has been limited by large intraindividual variability. Several approaches that have been shown to improve the repeatability of fibrinogen include acquisition of samples at the same time of day, standardized sample procurement techniques, and multiple replicate sampling. This study employed established pre-analytical and analytical techniques known to reduce fibrinogen variability, including the acquisition of three replicate samples, each analyzed in duplicate, to evaluate the impact of intraindividual variability in fibrinogen measurement at baseline and 3 months on cardiovascular risk in 60 healthy subjects. Classification accuracy was evaluated by the ability to categorize subjects into tertiles of fibrinogen. Only 55% (33/60) of the subjects were correctly assigned to the appropriate fibrinogen tertile. Fibrinogen measurements varied by more than 10% in 45% of subjects and by 5% in 80% of subjects. Intraindividual variability in fibrinogen measurement with a functional assay limits cardiovascular risk assessment even when three replicates are averaged.

Elevated blood viscosity in systemic lupus erythematosus.

OBJECTIVES: It has been proposed that elevated blood viscosity contributes to atherothrombotic and thromboembolic processes. We evaluated whether there is increased blood viscosity in systemic lupus erythematosus (SLE) that might contribute to cardiovascular complications and reduced tissue perfusion. METHODS: Blood viscosity profiles were evaluated in SLE patients to determine whether rheologic disturbances contribute to the cardiovascular risk profile. Blood viscosity profiles were evaluated in 27 patients with SLE and 46 age- and gender-matched controls. Blood viscosity was measured at 37 degrees C and shear rates of 1 s(-1) and 100 s(-1), then corrected to the average hematocrit of the SLE patients. RESULTS: Corrected blood viscosity values were higher in SLE patients than in controls at 100 s(-1) (P =.002). Positive correlations were found between the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for SLE, which quantifies damage to 12 organ systems and fibrinogen (rho =.39; P =.042) and plasma viscosity (rho =.38; P =.049). CONCLUSIONS: Our data indicate that blood viscosity values at a standard hematocrit are elevated in SLE patients. Further investigations are needed to evaluate whether the increased blood viscosity values in SLE patients contribute to cardiovascular complications and tissue ischemia. CLINICAL RELEVANCE: Because blood viscosity values correlate with the clinical severity of SLE, blood viscosity may contribute to the cardiovascular complications and reduced tissue perfusion in SLE patients. Semin Arthritis Rheum 31:52-57.

Oral 17beta-estradiol and medroxyprogesterone acetate therapy in postmenopausal women increases HDL particle size.

Menopause is accompanied by changes in lipoprotein particles that include an increase in density of low density lipoproteins (LDL) and high density lipoproteins (HDL) particles. The effect of 3 months of oral hormone replacement therapy (HRT) on lipoprotein particle size in postmenopausal women who were randomized to (1) estrogen replacement therapy (ERT) alone (either 17beta-estradiol (1 mg) or conjugated equine estrogens (CEE) (0.625 mg); (2) combination therapy (17beta-estradiol plus medroxyprogesterone acetate (MPA) or CEE plus MPA); and (3) placebo were examined. Lipoprotein subclass concentrations and particle size were quantified by nuclear magnetic resonance spectroscopy (NMR). Combination HRT resulted in significant (P=0.002) increases in HDL particle size as compared with those on placebo formulations or ERT alone. Women assigned to combined HRT had lower concentrations of smaller HDL particles after 3 months (P=0.005) and higher concentrations of larger HDL particles (P=0.02), whereas women assigned to ERT or placebo experienced non-significant changes. In summary, combined HRT increases HDL particle size by altering concentrations of the smallest and largest HDL subspecies.

Comparative study of HMG-CoA reductase inhibitors on fibrinogen.

Statins have a variable response on fibrinogen, and these changes may have implications on cardiovascular events. In this randomized placebo-controlled crossover study, we evaluated whether changes in fibrinogen levels were different between atorvastatin and other statin-treated patients. Adult coronary heart disease (CHD) patients aged 39-83 years with LDL cholesterol levels > or = 130 mg/dl were randomized to atorvastatin 80 mg (n = 84) and one of the following statins: fluvastatin 80 mg (n = 23), lovastatin 80 mg (n = 20), pravastatin 40 mg (n = 22) or simvastatin 40 mg (n = 20) each for 12 weeks in either order. Fibrinogen was analyzed by an automated method of Clauss. Three independently acquired samples were obtained within 1 min of tourniquet application, and each specimen was measured in duplicate. Statistical analyses were performed using a mixed model repeated measures analysis of variance procedure with SAS version 6.12. There were no significant changes in fibrinogen between treatment groups. This study evaluated changes in fibrinogen with established pre-analytical and analytical procedures known to minimize variability in fibrinogen measurement, and we did not observe any differences in fibrinogen levels in the treatment groups.

Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy.

Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA reductase inhibitors increased endothelial nitric oxide levels i.e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factoralpha, interleukin (IL)-6 and IL-1beta]. HMG-CoA reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia.

Asessing coronary heart disease risk and managing lipids.

Elevated low-density lipoprotein (LDL) and below normal high-density lipoprotein (HDL) cholesterol are risk factors for coronary heart disease (CHD). According to clinical guidelines, LDL cholesterol is the primary target for lipid-altering therapy. Many patients who develop CHD have LDL and HDL cholesterol levels that fall within the desirable or low-risk category; consequently, conventional measurements of plasma lipids may not accurately detect high-risk patients. This article discusses the clinical significance of lipoprotein subclasses and methods of measurement. Assessing lipoprotein subclasses provides a more comprehensive and efficacious therapeutic approach compared with the standard lipid profile.

Basic mechanisms of stroke prevention with lipid-lowering therapy.

Cholesterol-lowering therapy has not been considered an important risk factor for stroke; however, lipid-lowering therapies reduce cerebrovascular events in patients with coronary heart disease (CHD). The basic mechanisms of cerebrovascular protection have emphasized reduced atheroemboli from the left ventricle and aortic arch, delayed carotid artery disease progression, stabilization of vulnerable carotid atherosclerotic plaque, and improvement in cerebral blood flow.

Biological basis for statin therapy in stroke prevention.

Hypercholesterolemia has not been considered an important risk factor for stroke; however, statin therapy reduces stroke in coronary heart disease patients. Statins may provide cerebrovascular protection through various mechanisms that include a reduction in the incidence of embolic stroke from cardiac, aortic and carotid sites, stabilization of vulnerable carotid atherosclerotic plaque, and improvement in cerebral blood flow.

Low high density lipoprotein levels are associated with an elevated blood viscosity.

Low levels of high density lipoprotein (HDL) have been inversely correlated with blood viscosity and plasma viscosity; however, the contribution of concomitant hypertriglyceridemia may confound this association. This study evaluated the relationship between blood viscosity and HDL cholesterol in 70 subjects with fasting levels of total cholesterol <5.2 mmol/l (200 mg/dl) and triglycerides <2.3 mmol/l (200 mg/dl). Viscosity (mPa x s) was measured at 37 degrees C with a coaxial cylinder microviscometer. HDL cholesterol was inversely associated with corrected blood viscosity at 100 s(-1) (beta = -0.49, P<0.00005) and 20 s(-1) (beta = -0.38, P = 0.001) but not at 1 s(-1) (beta = -0.05, P = 0.69) using stepwise multivariate analyses. Low HDL levels are associated with an elevated blood viscosity, and this rheological abnormality may contribute to cardiovascular risk in subjects with isolated low HDL levels.