Dyslipidemias and Cardiovascular Prevention: Tailoring Treatment According to Lipid Phenotype.

PURPOSE OF REVIEW: This study aimed to present the current information on the genetic background of dyslipidemias and provide insights into the complex pathophysiological role of several plasma lipids/lipoproteins in the pathogenesis of atherosclerotic cardiovascular disease. Furthermore, we aim to summarize established therapies and describe the scientific rationale for the development of novel therapeutic strategies. RECENT FINDINGS: Evidence from genetic studies suggests that besides lowering low-density lipoprotein cholesterol, pharmacological reduction of triglyceride-rich lipoproteins, or lipoprotein(a) will reduce risk for coronary heart disease. Dyslipidemia, in particular hypercholesterolemia, is a common clinical condition and represents an important determinant of atherosclerotic vascular disease. Treatment decisions are currently guided by the causative lipid phenotype and the presence of other risk factors suggesting a very high cardiovascular risk. Therefore, the identification of lipid disorders and the optimal combination of therapeutic strategies provide an outstanding opportunity for reducing the onset and burden of cardiovascular disease.

Increased Plasma Concentrations of Soluble ST2 Independently Predict Mortality but not Cardiovascular Events in Stable Coronary Heart Disease Patients: 13-Year Follow-up of the KAROLA Study.

PURPOSE: sST2 (soluble suppression of tumorigenicity 2), a member of the interleukin-1 family, has been suggested to play a role in cardiac remodeling and inflammatory signaling. We assessed the association between sST2 in patients with stable coronary heart disease (CHD) with multiple cardiovascular outcomes and total mortality, simultaneously controlling for a large number of potential confounders. METHODS: Plasma concentrations of sST2 (ELISA, Critical Diagnostics) were measured at baseline in a cohort of 1081 patients. The Cox-proportional hazards model was used to determine the prognostic value of sST2 on a combined cardiovascular disease (CVD) endpoint, on cardiovascular death, and on total mortality after adjustment for covariates. RESULTS: The median sST2 level was 28.9 ng/mL (IQR 23.8, 35.1) (mean age at baseline 58.9 years, 84.6% male). sST2 concentration was positively correlated with inflammatory markers and emerging risk factors, e.g., cystatin C, N-terminal probrainnatriuretic peptide (NT-proBNP), high-sensitivity (hs)-Troponin T and I, mid-regional pro-atrial natriuretic peptide (MR-proANP), and growth differentiation factor 15 (GDF-15). Results after short- and long-term (4.5 and 12.3 years, respectively) follow-up (FU) displayed no statistically significant association with the combined endpoint of non-fatal and fatal CVD events when the top quartile (Q4) of sST2 concentration was compared to the bottom quartile (Q1). A relationship during long-term FU was seen with CVD mortality even after multivariable adjustments including clinical risk variables (HR 1.65; 95% CI 1.02-2.86), but not in a fully adjusted model whereas, in contrast, it was still highly significant after short-term FU (HR (5.97 (95%CI 1.32-27.06)). In addition, the sST2 concentration was still strongly associated with total mortality in the fully adjusted model including clinical variables and cystatin C based estimated glomerular filtration rate, NT-proBNP, hsCRP and hs-TnI comparing Q4 vs Q1 during long-term FU (HR of 1.48 (95% CI 1.03-2.13)) and short-term FU (HR 3.06 (95% CI 1.29-7.24)). CONCLUSIONS: Elevated levels of sST2 concentration in stable CHD patients may independently predict short- and long-term risk for fatal CVD events and total mortality but not non-fatal CVD events.

[Lipid-lowering therapy in Europe and the United States - treat to target or fire and forget?]. / Lipidsenkende Therapie in Europa und den USA.

The 2013 AHA/ ACC guidelines on the assessment of cardiovascular risk recommend high-dose statin treatment to reduce LDL-cholesterol (LDL-C) by at least 30-50% without suggesting a specific target value 1. Favoring a strict Evidence Based Medicine approach the authors focus on randomized clinical trials only and neglect a target value since none of the randomized trials has titrated statin therapy to a specific LDL-C concentration. This is in contrast to current European guidelines. This paradigm shift has created a lot of controversy and confusion due to the lacking opportunity to assess medication adherence and the addition of further lipid lowering therapy. Moreover, these new guidelines might discourage clinicians to individualize patient care.

[ASA - from cardiovascular to cancer prevention]. / Acetylsalicylsäure - von der kardiovaskulären zur Karzinomprävention.

Cardiovascular disease and cancer are the leading causes of morbidity and mortality worldwide. Low-dose ASA has been shown to effectively prevent about one fifth of atherothrombotic vascular complications in patients with previous myocardial infarction, peripheral arterial occlusive disease (PAOD), or stroke 2. In secondary prevention, the benefits of antiplatelet therapy substantially exceed its risk 2. By contrast, recommendations for the use of ASA in primary prevention are still a matter of controversy. The aim of this article is to review the current evidence for the efficacy of low-dose ASA in primary and secondary prevention of cardiovascular diseases as well as to discuss its potential additional chemopreventive action.

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis.

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.