Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

A new integrated approach to cardiac mechanics: reference values for normal left ventricle.

The association between left ventricular (LV) myocardial deformation and hemodynamic forces is still mostly unexplored. The normative values and the effects of demographic and technical factors on hemodynamic forces are not known. The authors studied the association between LV myocardial deformation and hemodynamic forces in a large cohort of healthy volunteers. One-hundred seventy-six consecutive subjects (age range, 16-82; 51% women), with no cardiovascular risk factors or any relevant diseases, were enrolled. All subjects underwent an echo-Doppler examination. Both 2D global myocardial and endocardial longitudinal strain (GLS), circumferential strain (GCS), and the hemodynamic forces were measured with new software that enabled to calculate all these values and parameters from the three apical views. Higher LV mass index and larger LV volumes were found in males compared to females (85 ± 17 vs 74 ± 15 g/m2 and 127 ± 28 vs 85 ± 18 ml, p < 0.0001 respectively) while no differences of the mean values of endocardial and myocardial GLS and of myocardial GCS were found (p = ns) and higher endocardial GCS in women (- 30.6 ± 4.2 vs - 31.8 ± 3.7; p = 0.05). LV longitudinal force, LV systolic longitudinal force and LV impulse were higher in men (16.2 ± 5.3 vs 13.2 ± 3.6; 25.1 ± 7.9 vs 19.4 ± 5.6 and 20.4 ± 7 vs 16.6 ± 5.2, p < 0.0001, respectively). A weak but statistically significant decline with age (p < 0.0001) was also found for these force parameters. This new integrated approach could differentiate normality from pathology by providing average deformation values and hemodynamic forces parameters, differentiated by age and gender.

CHA2DS2-VASc Score Predicts Adverse Outcome in Patients with Simple Congenital Heart Disease Regardless of Cardiac Rhythm.

Adult patients with simple congenital heart disease (sACHD) represent an expanding population vulnerable to atrial arrhythmias (AA). CHA2DS2-VASc score estimates thromboembolic risk in non-valvular atrial fibrillation patients. We investigated the prognostic role of CHA2DS2-VASc score in a non-selected sACHD population regardless of cardiac rhythm. Between November 2009 and June 2018, 427 sACHD patients (377 in sinus rhythm, 50 in AA) were consecutively referred to our ACHD service. Cardiovascular hospitalization and/or all-cause death were considered as composite primary end-point. Patients were divided into group A with CHA2DS2-VASc score = 0 or 1 point, and group B with a score greater than 1 point. Group B included 197 patients (46%) who were older with larger prevalence of cardiovascular risk factors than group A. During a mean follow-up of 70 months (IQR 40-93), primary end-point occurred in 94 patients (22%): 72 (37%) in group B and 22 (10%, p < 0.001) in group A. Rate of death for all causes was also significantly higher in the group B than A (22% vs 2%, respectively, p < 0.001). Multivariable Cox regression analysis revealed that CHA2DS2-VASc score was independently related to the primary end-point (HR 1.84 [1.22-2.77], p = 0.004) together with retrospective AA, stroke/TIA/peripheral thromboembolism and diabetes. Furthermore, CHA2DS2-VASc score independently predicted primary end-point in the large subgroup of 377 patients with sinus rhythm (HR 2.79 [1.54-5.07], p = 0.01). In conclusion, CHA2DS2-VASc score accurately stratifies sACHD patients with different risk for adverse clinical events in the long term regardless of cardiac rhythm.

Prediction of early- and long-term mortality in adult patients acutely admitted to internal medicine: NRS-2002 and beyond.

BACKGROUND & AIMS: In hospitalized patients malnutrition is a risk factor for adverse clinical outcomes. The Nutritional Risk Screening 2002 (NRS-2002) represents a quick and simple tool to identify malnutrition risk in this population. No study tested the predictive power of NRS-2002 on mortality adjusting for confounders related to patient's complexity, thus considering conditions such as functional status, illness-related severity and inflammation. The aim of this study was to explore the independent prognostic power and the relative weight of NRS-2002 screening tool to predict inhospital and post-discharge (up to 1 year) mortality, adjusting for variables representing the non-disease specific multidimensional complexity of patients admitted to Internal Medicine wards. METHODS: Retrospective observational study including 5698 consecutive patients acutely admitted to an Internal Medicine Department. Logistic regression models were run to test the predictive power of the NRS-2002 on patient mortality at different time intervals, adjusted for age, sex, Charlson comorbidity index, Glasgow Prognostic Score (GPS), BUN/creatinine ratio, Modified Early Warning Score (MEWS), and Norton index. The performance of the logistic models in predicting mortality was measured through the c-statistic. The different time of death between patients scored upon admission as NRS-2002 < 3 or ≥3 was evaluated through crude Kaplan-Meier curves and multivariate Cox proportional hazard analysis. RESULTS: Patients classified at high malnutrition risk (NRS-2002 ≥ 3) showed a higher and earlier mortality (Log-rank test: p < 0.001) compared to subjects in the NRS-2002 "low-risk" group. NRS-2002 ≥ 3 was an independent significant (p < 0.01) predictor of mortality in logistic regression at every time interval. Among the considered covariates, Charlson index, GPS and Norton scale showed a steadily higher OR than NRS-2002 in predicting both early and late mortality. The multivariate models demonstrated a very good discrimination for hospital and mid-term (up to 90 days) mortality. Being classified at risk for malnutrition (NRS-2002 ≥ 3) on admission independently increased the risk of one-year death (HR = 1.431; 95% CI: 1.277-1.603; p < 0.001) compared to the patients who were scored at low malnutrition risk. CONCLUSIONS: Malnutrition risk identified upon hospital admission by NRS-2002 independently contributes to early and late mortality in a population including a majority of elderly. However, risk of malnutrition has to be considered according to other factors related to comorbidities, functional status, illness severity and inflammation which reciprocally interact, concurring at worsening patient's outcome.