Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule.

Lipoprotein(a) [Lp(a)], aka "Lp little a", was discovered in the 1960s in the lab of the Norwegian physician Kåre Berg. Since then, we have greatly improved our knowledge of lipids and cardiovascular disease (CVD). Lp(a) is an enigmatic class of lipoprotein that is exclusively formed in the liver and comprises two main components, a single copy of apolipoprotein (apo) B-100 (apo-B100) tethered to a single copy of a protein denoted as apolipoprotein(a) apo(a). Plasma levels of Lp(a) increase soon after birth to a steady concentration within a few months of life. In adults, Lp(a) levels range widely from <2 to 2500 mg/L. Evidence that elevated Lp(a) levels >300 mg/L contribute to CVD is significant. The improvement of isoform-independent assays, together with the insight from epidemiologic studies, meta-analyses, genome-wide association studies, and Mendelian randomization studies, has established Lp(a) as the single most common independent genetically inherited causal risk factor for CVD. This breakthrough elevated Lp(a) from a biomarker of atherosclerotic risk to a target of therapy. With the emergence of promising second-generation antisense therapy, we hope that we can answer the question of whether Lp(a) is ready for prime-time clinic use. In this review, we present an update on the metabolism, pathophysiology, and current/future medical interventions for high levels of Lp(a).

Statins but not fibrates improve the atherogenic to anti-atherogenic lipoprotein particle ratio: a randomized crossover study.

BACKGROUND: Prior studies suggested low density lipoprotein particle (LDLP) size is a predictor of atherosclerosis. Knowledge of effects of lipid lowering drugs on lipoprotein subclasses is useful. We treated subjects with hyperlipidemia sequentially with statins and fibrates, the 2 main classes of lipid lowering therapy and studied changes in NMR lipoprotein subclasses. METHODS: 35 subjects (21 males; 60 +/- 12 y) were enrolled in a crossover study. Subjects had baseline lipid profile & apoB. Lipoprotein subclasses, particle numbers and diameters were assessed with NMR spectroscopy. Subjects were randomized to simvastatin 20 mg or fenofibrate 200 mg. Repeat testing was done at 12 weeks. After 6 week washout, subjects were started on alternate drug for 12 weeks with pre/post tests. RESULTS: Both therapies resulted in expected changes in lipids and apoB. Decreases in total cholesterol, LDL and apoB were greater with simvastatin. Fenofibrate led to small increase in HDL. Both therapies decreased LDLP. Reduction in LDLP was greater with simvastatin (32%, p < .001) compared to fenofibrate (17%; p = .036 vs pre; p = .027 vs simvastatin end). Fenofibrate resulted in 17% rise in large LDLP (p = .06 vs pre) and 32% drop in small LDLP (p = .007 vs pre). Simvastatin led to decrease in both LDLP fractions (19% large LDLP; p = .001 vs fenofibrate end; 34% small LDLP, p = .019 vs pre). With fenofibrate, LDLP size increased from 20.4 nm to 20.8 nm (p = .037). There was no change in LDLP size with simvastatin. There was 18% increase in HDL particle number (HDLP) with fenofibrate (p = .05). There were no changes in HDLP with simvastatin. There were no changes in HDLP size with either drug. Pre- and post-therapy LDLP/HDLP ratio was similar with fenofibrate but was reduced by simvastatin (p = .045). CONCLUSION: Simvastatin reduced LDLP across all subclasses with no effect on size. Simvastatin had no effect on HDLP. Fenofibrate had weak effect on LDLP number but increased LDLP size by raising large LDLP and reducing small LDLP. Fenofibrate had weak effect on HDLP number with no change in size. Importantly, net atherogenic to antiatherogenic lipoprotein ratio (LDLP/HDLP) was reduced by simvastatin but not by fenofibrate.

Dietary measures and exercise training contribute to improvement of endothelial function and atherosclerosis even in patients given intensive pharmacologic therapy.

PURPOSE: Atherosclerosis contributes to cardiovascular mortality and morbidity even with aggressive lipid management. Our objective is to determine whether a combined pharmacological and lifestyle intervention can improve atherosclerosis. METHODS: We conducted a 2-year observational study at a specialized clinic in a tertiary care hospital. One hundred fifty-six subjects with coronary disease were enrolled in an intensive pharmacological management and lifestyle measures (including counseling and exercise training) program designed to reach specific targets. The main outcome measures were carotid intima media thickness and plaque area; brachial artery flow-mediated dilation; nitroglycerin-mediated dilation; flow-mediated dilation-nitroglycerin-mediated dilation ratio; laboratory parameters including lipids, glucose, creatinine, and homocysteine; and physical fitness. RESULTS: At completion, there were improvements in lipids and physical fitness. There were no overall changes in flow-mediated dilation, nitroglycerin-mediated dilation, or carotid intima media thickness in the entire cohort. However, multivariate logistic regression showed that dietary and exercise variables, such as increasing fiber intake and reducing body weight and body fat percentage, were independent predictors of improvements in endothelial function and carotid plaque burden. CONCLUSIONS: Even in the setting of intensive pharmacological therapy, lifestyle interventions, including exercise training and dietary changes, are important determinants of improved endothelial function and atherosclerosis.

Effectiveness of high-intensity interval training for the rehabilitation of patients with coronary artery disease.

We found that interval training provides an effective means to improve the cardiovascular fitness and health status of highly functional patients with coronary artery disease. We also revealed that interval training improves anaerobic tolerance to a greater extent than the traditional exercise training model without increasing the risk to the patient. This research supports the implementation of interval training for highly functional patients with coronary artery disease.

Are cardiovascular disease and osteoporosis directly linked?

For years, osteoporosis and cardiovascular disease were thought to be two independent consequences of aging; however, mounting evidence supports an association between these diseases. Recently, a widespread class of cholesterol-lowering drugs known as statins have demonstrated (in rodents and cell cultures) the ability to induce bone formation. This finding is significant since current therapies are limited to the prevention or slowing down of bone loss rather than (enhancing/improving) bone formation. In humans, the ability of statins to generate new bone has not been consistent; however, several investigations have demonstrated a dramatic decrease in fracture risk. Although it has been proposed that statins induce new bone via increased bone morphogenetic protein-2, other conditions affected by statins such as dyslipidaemia, vascular calcification, endothelial dysfunction and impaired nitric oxide expression, may also contribute to the cardiovascular and bone health paradigm. Furthermore, the role of physical activity and its influence on cardiovascular and bone health, especially in postmenopausal women, may contribute to the discrepancy of findings in human data. In summary, it remains to be determined if statins contribute to bone health via improvements in vascular health or by pleiotropic properties unique to their pharmacology. This review provides information on our current understanding of the bone and cardiovascular association, as well as on novel areas of research to further our current understanding of these conditions.

Churg-Strauss syndrome with myocarditis manifesting as acute myocardial infarction with cardiogenic shock: case report and review of the literature.

A patient with a two-year history of worsening asthma presented with chest pain and shortness of breath. She developed cardiogenic shock. Analysis of blood chemistry detected increased troponin I concentration. Her electrocardiographic changes were consistent with a diagnosis of anteroseptal myocardial infarction. However, angiography showed normal coronary arteries. Left ventriculography showed severe mitral regurgitation and global hypokinesis. Peripheral eosinophilia was detected. Subsequent endomyocardial biopsy showed myocarditis with prominent eosinophil and plasma cell components. Churg-Strauss syndrome was diagnosed based on her history of asthma, evidence of peripheral eosinophilia and results of endomycardial biopsy. Treatment with a high dose of corticosteroids was initiated. As symptoms of heart failure improved - without recurrence of cardiac and respiratory symptoms - the dose of corticosteroids was gradually reduced. Eight months after her original presentation, she developed urticarial lesions on her abdomen and legs, with muscle soreness but no other associated symptoms. She was treated with a combination of prednisone and dapsone. After the diagnosis of Churg-Strauss syndrome, the patient remained symptom free with a normal ejection fraction for 15 months while taking prednisone.

The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease.

OBJECTIVES: The goal of this study was to determine the relative prognostic importance of noninvasive measures of endothelial function and atheroma burden in patients with coronary artery disease (CAD). BACKGROUND: Direct measurement of atherosclerosis by carotid ultrasound and endothelial function assessment by brachial artery flow-mediated dilation (FMD) have both been shown to predict vascular events. The combined prognostic utility of carotid ultrasound and FMD relative to traditional risk markers and cardiovascular fitness has not been evaluated. METHODS: A total of 152 patients with CAD underwent metabolic testing, exercise stress tests, carotid ultrasound, and endothelial function measurements. RESULTS: Patients were followed for 34 +/- 10 months during which 22 vascular events occurred. Peak FMD (p = 0.012) and FMD/nitroglycerin-mediated dilation (NMD) ratio (p = 0.008) were lower in subjects with events. Univariate analysis with Cox proportional hazards modeling identified plaque area (p = 0.0047), total area (p = 0.0085), peak FMD (p = 0.01), FMD/NMD ratio (p = 0.008), stress test workload (p = 0.027), long-acting nitroglycerin (NTG) (p = 0.0071), and calcium blockers (p = 0.0057) as predictors of adverse events. Multivariate analysis showed that FMD/NMD ratio (p < 0.0001), carotid plaque area (p = 0.06), and NTG (p = 0.005) were independent predictors. Based on median values, subjects were divided into high and low "plaque burden" groups and into high and low FMD/NMD subgroups. Patients with high FMD/NMD had low event rates irrespective of the degree of carotid atheroma. Patients with low FMD/NMD and high "plaque burden" had the highest event rate (p < 0.05). CONCLUSIONS: The structural and functional status of the vasculature are independent predictors of coronary events as shown by noninvasive measurement of endothelial function and carotid atheroma burden in patients with CAD. Preserved endothelial function attenuates the risk of future events associated with a high plaque burden.