Updates in Small Interfering RNA for the Treatment of Dyslipidemias.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Cholesterol Lowering Biotechnological Strategies: From Monoclonal Antibodies to Antisense Therapies. A Pre-Clinical Perspective Review.

In recent years, the increase in available genetic information and a better understanding of the genetic bases of dyslipidemias has led to the identification of potential new avenues for therapies. Additionally, the development of new technologies has presented the key for developing novel therapeutic strategies targeting not only proteins (e.g., the monoclonal antibodies and vaccines) but also the transcripts (from antisense oligonucleotides (ASOs) to small interfering RNAs) or the genomic sequence (gene therapies). These pharmacological advances have led to successful therapeutic improvements, particularly in the cardiovascular arena because we are now able to treat rare, genetically driven, and previously untreatable conditions (e.g, familial hypertriglyceridemia or hyperchylomicronemia). In this review, the pre-clinical pharmacological development of the major biotechnological cholesterol lowering advances were discussed, describing facts, gaps, potential future steps forward, and therapeutic opportunities.

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

A new dawn for managing dyslipidemias: The era of rna-based therapies.

The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.

Cam morphology and inguinal pathologies: is there a possible connection?

BACKGROUND: To analyse the prevalences of the cam and pincer morphologies in a cohort of patients with groin pain syndrome caused by inguinal pathologies. MATERIALS AND METHODS: Forty-four patients (40 men and 4 women) who suffered from groin pain syndrome were enrolled in the study. All the patients were radiographically and clinically evaluated following a standardised protocol established by the First Groin Pain Syndrome Italian Consensus Conference on Terminology, Clinical Evaluation and Imaging Assessment in Groin Pain in Athlete. Subsequently, all of the subjects underwent a laparoscopic repair of the posterior inguinal wall. RESULTS: The study demonstrated an association between the cam morphology and inguinal pathologies in 88.6% of the cases (39 subjects). This relationship may be explained by noting that the cam morphology leads to biomechanical stress at the posterior inguinal wall level. CONCLUSIONS: Athletic subjects who present the cam morphology may be considered a population at risk of developing inguinal pathologies. LEVEL OF EVIDENCE: Level IV, Observational cross-sectional study.

Aorto-septal angle, isolated basal septal hypertrophy, and systolic murmur in 122 cats.

INTRODUCTION/OBJECTIVES: Systolic murmurs in the absence of cardiac structural abnormalities are common in cats. Narrow aorto-septal angle (AoSA) and septal remodeling can be a cause of a systolic murmur in elderly human beings. The aim of this study was to measure the AoSA in cats and to investigate the association between the AoSA and the presence of a murmur and isolated basal septal hypertrophy (IBSH). ANIMALS: The study population comprised 122 cats. MATERIALS AND METHODS: A physical exam, blood pressure measurement, chest radiographs, and echocardiography were performed. RESULTS: A systolic murmur was audible in 39/122 cats. A difference between cats with and without a murmur was found for age (P=0.0001), interventricular basal septal thickness (BIVSd) (P=0.004), AoSA (P=0.003), aortic (P<0.0001), and pulmonic (P=0.021) flow velocity, the presence of IBSH (P<0.0001), and systolic anterior motion of the mitral valve (P=0.0002). More than 50% of cats with a murmur had an AoSA ≤122°. Less than 25% of the cats with an AoSA ≥137° had a murmur. The AoSA narrowed 0.55°/year of age (P<0.001), whereas the BIVSd increased 0.11 mm/year of age (P<0.0001); the BIVSd increased as the AoSA narrowed. In all cats with AoSA < 120°, IBSH was present. CONCLUSIONS: This study demonstrates that the probability of having a systolic murmur in cats is increased by the presence of a narrow AoSA. Aging was associated with a narrower AoSA and a thicker basal septum; these findings might represent an age-related heart remodeling.

Global cardiovascular risk management in different Italian regions: an analysis of the Evaluation of Final Feasible Effect of Control Training and Ultra Sensitisation (EFFECTUS) educational program.

BACKGROUND AND AIM: The Final Evaluation Feasible Effect of Ultra Control Training and Sensitization (EFFECTUS) is an educational program, aimed at improving global CV risk stratification and management in Italy. The present study evaluates differences on clinical approach to global CV risk among physicians involved in the EFFECTUS program and stratified in three geographical macro-areas (North, Center, South) of our Country. METHODS AND RESULTS: Physicians were asked to submit data already available in their medical records, covering the first 10 adult outpatients, consecutively seen in the month of May 2006. Overall, 1.078 physicians (27% females, aged 50 ± 7 years) collected data of 9.904 outpatients (46.5% females, aged 67 ± 9 years), among which 3.219 (32.5%) were residents in Northern, 3.652 (36.9%) in Central and 3.033 (30.6%) in Southern Italy. A significantly higher prevalence of major CV risk factors, including obesity, physical inactivity, hypertension and diabetes, was recorded in Southern than in other areas. Accordingly, Southern physicians more frequently prescribed antihypertensive, glucose and lipid lowering agents than other physicians, who paid significantly more attention to life-style changes in their clinical practice. CONCLUSIONS: This analysis of the EFFECTUS study demonstrates a high prevalence of CV risk factors in Italy, particularly in Southern areas, and indicates some important discrepancies in the clinical management of global CV risk among physcians working in different Italian regions.

[Biological monitoring of exposure to carcinogenic metallic elements and polycyclic aromatic hydrocarbons in four secondary metallurgical sectors]. / Monitoraggio biologico dell'esposizione ad elementi metallici cancerogeni e ad idrocarburi policiclici aromatici in quattro settori metallurgici secondari.

This cross-sectional study was aimed at evaluating in a large sample of male foundry workers the current exposure levels to carcinogenic compounds, including metallic elements [arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), nickel (Ni)] and aromatic polycyclic hydrocarbons (PAH) by a biological monitoring approach, using validated biomarkers of exposure. Workers were recruited from 15 aluminium, copper alloy, electric steel and cast iron foundries and provided an end-of-shift urine sample to determine urinary concentrations of As, Be, Cd, Cr, Ni and 1-hydroxypyrene (1-OHP). Metallic elements were determined either by inductively coupled plasma mass spectrometry (Be, Cd and Cr) or by atomic absorption spectrometry (As, Ni), whereas 1-OHP was determined by high pressure liquid chromatography with fluorimetric detection. Most of the determinations fell within the laboratory's reference values. Age and lifestyle habits (smoking, alcohol, diet) played a significant interfering role.

Author Correction: Antihypertensive treatment with calcium channel blockers and renal protection: focus on lercanidipine and lercanidipine/enalapril.

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (20): 7482-7492. DOI: 10.26355/eurrev_202210_30018-PMID: 36314318, published online on October 28, 2022. After publication, the authors applied some corrections to the text: - The section "Clinical Oharmacology of Lercanidipine" has been corrected into "Clinical Pharmacology of Lercanidipine" - The Legend of Figure 2 has been corrected as follows: Ca T-type channels vs. Ca L-type channels selectivity ratio. LAC, lacidipine, AML, amlodipine; MIB, mibefradil; LER, lercanidipine; *p<0.05, ** p<0.01 vs. LAC (low concentrations); †p<0.01 LAC vs. all other CCBs (high concentrations). Source: Modified from 25. - The reference 25 has been changed into: Hart P, Bakris GL. Calcium antagonists: Do they equally protect against kidney injury? Kidney Int 2008; 73: 795-796. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30018.

Antihypertensive treatment with calcium channel blockers and renal protection: focus on lercanidipine and lercanidipine/enalapril.

OBJECTIVE: The aim of the study was to review the literature on clinical pharmacology of lercanidipine and experimental and clinical evidence and evaluate its ability to reduce proteinuria and preserve renal function when used as monotherapy or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril. MATERIALS AND METHODS: MEDLINE/PubMed was searched for appropriate keywords. RESULTS: Lercanidipine, a third-generation calcium channel blocker, has been shown to have a unique pharmacological and clinical profile, which translates into favorable renal hemodynamic changes. The fixed-dose combination lercanidipine/enalapril has been proposed to overcome unmet therapeutic needs, often as the initial treatment in the high-risk patient. CONCLUSIONS: Lercanidipine may be regarded as an ideal antihypertensive drug for patients at renal risk and possibly the preferred choice among calcium channel blocker drugs.

Impact of physicians' age on the clinical management of global cardiovascular risk: analysis of the results of the Evaluation of Final Feasible Effect of Control Training and Ultra Sensitisation Educational Programme.

AIM: To evaluate the potential impact of physicians' age on global cardiovascular (CV) risk management in the population of the Evaluation of Final Feasible Effect of Ultra Control Training and Sensitisation (EFFECTUS) study. METHODS: Involved physicians were stratified into three age groups (≤ 45, 46-55 and > 55 years), and asked to provide clinical data covering the first 10 adult outpatients, consecutively seen in May 2006. RESULTS: Overall 1078 physicians, among whom 219 (20%) were aged ≤ 45, 658 (61%) between 46 and 55, and 201 (19%) > 55 years, collected data of 9904 outpatients (46.5% female patients, aged 67 ± 9 years), who were distributed into three corresponding groups: 2010 (20%), 6111 (62%) and 1783 (18%), respectively. A higher prevalence of myocardial infarction and stroke was recorded by younger physicians rather than those aged > 46 years. Older physicians frequently recommended life-style changes, whereas a higher number of antihypertensive, antiplatelet, glucose and lipid-lowering prescriptions was prescribed by physicians aged ≤ 45 years. CONCLUSIONS: This analysis of the EFFECTUS study indicates a higher prevalence of vascular diseases among outpatients who were followed by younger physicians, who prescribed a higher number of CV drugs than older physicians. These older physicians have more attitude for prescribing favourable life-style changes than younger physicians.

Recombinant human thyrotropin stimulation test in 114 dogs with suspected hypothyroidism: a cross-sectional study.

OBJECTIVE: To evaluate the performance and define cut-offs for the interpretation of a thyroid-stimulating hormone (TSH) stimulation test with a recombinant human TSH dose of 75 µg/dog administered intravenously in dogs with suspected hypothyroidism. MATERIALS AND METHODS: Cross-sectional study. Medical records of dogs presented for suspected hypothyroidism were retrospectively reviewed. Animals were included if a TSH stimulation test with a recombinant human TSH dose of 75 µg/dog was performed and follow-up was available. Dogs with a post-TSH serum total thyroxine (T4) level of ≥2.2 µg/dL were considered euthyroid. Dogs with a post-TSH T4 level of <2.2 µg/dL were classified as hypothyroid or euthyroid based on follow-up, including response to levothyroxine supplementation. A receiver operating characteristic curve analysis was used to define the performance of the test. RESULTS: One hundred and fourteen dogs were included. Forty were classified as hypothyroid and 74 as euthyroid. Post-TSH T4 cut-offs of 1.3 and 1.7 µg/dL showed sensitivities of 92.5 and 100% and specificities of 97.3 and 93.2%, respectively. Post-TSH T4 levels of >1.7 µg/dL had a negative predictive value of 100%. Post-TSH T4 levels of <1.3 µg/dL showed a positive predictive value of 94.9%. Area under the ROC curve for post-TSH T4 was 0.99. CLINICAL SIGNIFICANCE: A TSH stimulation test performed with a recombinant human TSH dose of 75 µg/dog is highly reliable to discriminate between hypothyroid and euthyroid dogs, even in cases of concurrent non-thyroidal illness or administration of medications. A post-stimulation T4 concentration of >1.7 µg/dL is suggestive of normal thyroid function.

Symmetric dimethylarginine concentrations in dogs with hypothyroidism before and after treatement with levothyroxine.

OBJECTIVES: To evaluate the serum symmetric dimethylarginine (SDMA) and serum creatinine concentrations in a population of hypothyroid dogs at the time of diagnosis and after treatment. MATERIALS AND METHODS: Serum SDMA and serum creatinine were measured in serum samples of 24 healthy dogs and 24 hypothyroid dogs, at the time of diagnosis (T0) and after supplementation with levothyroxine (T1). RESULTS: The mean SDMA concentrations (reference intervals [RI] <18 µg/dL and <14 µg/dL depending on the source) were 11.7 ± 3.5 µg/dL, 13.8 ± 3.1 µg/dL and 11.83 ± 2.87 µg/dL in healthy dogs, and in the hypothyroid dogs at T0 and T1, respectively. The SDMA concentrations were higher in the hypothyroid dogs at T0 in comparison with the healthy dogs. Of the hypothyroid dogs, 1 out of 24 had an SDMA concentration above 18 µg/dL and 12 out of 24 above 14 µg/dL at T0. At T1, none of the hypothyroid dogs had SDMA concentrations above 18 µg/dL and two of them had SDMA concentrations above 14 µg/dL. The serum creatinine concentration was higher in the hypothyroid dogs at T0 as compared to the healthy dogs. At T0, 8 out of 24 hypothyroid dogs had serum creatinine concentrations above the RI (>1.4 mg/dL). In all but one dog, serum creatinine normalised after treatment. CLINICAL SIGNIFICANCE: The SDMA and serum creatinine concentrations were higher in hypothyroid dogs at diagnosis as compared to healthy dogs. Serum creatinine concentrations were increased in one-third of the hypothyroid dogs and in the majority of cases normalised after levothyroxine supplementation. SDMA concentrations were rarely above the upper limit of the RI when the higest (<18 µg/dL) cut-off was employed. The diagnostic accuracy of SDMA in dogs with thyroid dysfunction requires additional evaluation.

Maternal exposure to air pollutants, PCSK9 levels, fetal growth and gestational age - An Italian cohort.

OBJECTIVE: Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. DESIGN: A cohort of 134 healthy women during early pregnancy (11-12 weeks of gestational age) was studied. RESULTS: A significant association between circulating PCSK9 levels and three tested air pollutants (PM10, PM2.5, nitric oxide (NO2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22-6.57), similar trends being obtained for PM10 and NO2. CONCLUSIONS: The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders.

Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels - experimental and clinical approaches with lipid-lowering agents.

Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.

ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials.

INTRODUCTION: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.

Fluvastatin synergistically improves the antiproliferative effect of everolimus on rat smooth muscle cells by altering p27Kip1/cyclin E expression.

Multiple intracellular signaling pathways stimulate quiescent smooth muscle cells (SMCs) to exit from G(0) and re-enter the cell cycle. Thus, a combination of two drugs with different mechanisms of action may represent a suitable approach to control SMC proliferation, a prominent feature of in-stent restenosis. In the present study, we investigated the effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on proliferation of rat SMCs. The antiproliferative action of everolimus was amplified by 2.5-fold by the addition of subliminal concentrations of fluvastatin (5 x 10(-7) M), lowering the IC(50) value from 2.5 x 10(-9) to 1.0 x 10(-9) M. The increased antiproliferative effect of everolimus by fluvastatin was prevented in the presence of mevalonate, farnesol, or geranylgeraniol, suggesting the involvement of prenylated proteins. Cell cycle analysis and [3H]thymidine incorporation assay demonstrated that the two drugs synergistically interfered with the progression of G(1) phase. In particular, the drug combination significantly up-regulated p27(Kip1) levels by 47.0%, suppressed cyclin E by 43.0%, and it reduced retinoblastoma (Rb) hyperphosphorylation by 79.0%, compared with everolimus alone. Retroviral overexpression of cyclin E conferred a significant resistance of rat SMCs to the antiproliferative action of the drug combination, measured by cell counting, [3H]thymidine incorporation, and cell cycle analysis, with higher levels of hyperphosphorylated form of Rb. Taken together, these results demonstrated that everolimus acts synergistically with fluvastatin to inhibit SMC proliferation by altering the expression of cyclin E and p27(kip1), which affects Rb phosphorylation and leads to G(1) phase arrest.

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

Appropriateness of statin prescription in the elderly.

Statins, the most widely used drugs in the Western world, have become a pivotal component in the primary and secondary prevention of vascular diseases. Although benefits have been well documented in younger-than-75-year-old individuals, the value of statins in people aged >75years and over is controversial. The CTT meta-analysis calculated an absolute risk reduction of 0.6%/year per 38.7mg/dl reduction in LDL-C levels in patients aged >75years, that would translate into a number needed to treat of 167. However, the absolute effect of a 38.7mg/dl cholesterol lowering on the rate of annual ischemic heart disease mortality is 10-fold larger in older vs younger patients. In order to advise physician prescription, three major Guidelines have been published over the last few years, i.e. the AHA/ACC and the NLA in the US, and the ESC/EAS in Europe. Moreover, statin prescription in the elderly should also consider the cardiovascular outcomes of elderly patients reported in classical statin preventive trials which give important clues on adherence and persistence of use, as well as on drug safety. The present review discusses benefits of intensive vs moderate statin therapy, justifications for the use of aggressive lipid management in the very old and the use of statins in frail elderlies. The final decision on the therapeutic strategy with statins in elderlies at higher risk to develop cardiovascular events should be always based on a careful analysis of the patient's general health and on the presence of metabolic abnormalities or drug interactions potentially leading to risk.

Basin-scale analysis of the geomorphic effectiveness of flash floods: A study in the northern Apennines (Italy).

Large floods may produce remarkable channel changes, which determine damages and casualties in inhabited areas. However, our knowledge of such processes remains poor, as is our capability to predict them. This study analyses the geomorphic response of the Nure River (northern Italy) and nine tributaries to a high-magnitude flood that occurred in September 2015. The adopted multi-disciplinary approach encompassed: (i) hydrological and hydraulic analysis; (ii) analysis of sediment delivery to the stream network by means of landslides mapping; (iii) assessment of morphological modifications of the channels, including both channel width and bed elevation changes. The spatial distribution of rainfall showed that the largest rainfall amounts occur in the upper portions of the catchment, with cumulative rainfall reaching 300 mm in 12 h, and recurrence intervals exceeding 100-150 years. The unit peak discharge ranged between 5.2 and 25 m3 s-1 km-2. Channel widening was the most evident effect. In the tributaries, the ratio between post-flood and pre-flood channel width averaged 3.3, with a maximum approaching 20. Widening was associated with channel aggradation up to 1.5 m and removal of riparian vegetation. New islands formed due to the fragmentation of the former floodplain. In the Nure River, the average width ratio was 1.7, and here widening occurred mainly at the expenses of islands. Bed level dynamics in the Nure were varied, including aggradation, incision, and overall stability. The flood geomorphic effectiveness was more pronounced in the middle-higher portions of the basin. Planimetric and elevation changes were well correlated. Regression analysis of the relationship between widening and morphological/ hydraulic controlling factors indicated that unit stream power and confinement index were the most relevant variables. The study provides useful insights for river management, especially with regard to the proportion of the valley floor subject to erosion and/or deposition during large events.