Extracellular vesicles in cardiomyopathies: A narrative review.

Extracellular vesicles (EVs) are membrane-bound particles released by all cells under physiological and pathological conditions. EVs constitute a potential tool to unravel cell-specific pathophysiological mechanisms at the root of disease states and retain the potential to act as biomarkers for cardiac diseases. By being able to carry bioactive cargo (such as proteins and miRNAs), EVs harness great potential as accessible "liquid biopsies", given their ability to reflect the state of their cell of origin. Cardiomyopathies encompass a variety of myocardial disorders associated with mechanical, functional and/or electric dysfunction. These diseases exhibit different phenotypes, including inappropriate ventricular hypertrophy, dilatation, scarring, fibro-fatty replacement, dysfunction, and may stem from multiple aetiologies, most often genetic. Thus, the aims of this narrative review are to summarize the current knowledge on EVs and cardiomyopathies (e.g., hypertrophic, dilated and arrhythmogenic), to elucidate the potential role of EVs in the paracrine cell-to-cell communication among cardiac tissue compartments, in aiding the diagnosis of the diverse subtypes of cardiomyopathies in a minimally invasive manner, and finally to address whether certain molecular and phenotypical characteristics of EVs may correlate with cardiomyopathy disease phenotype and severity.

A Cluster Randomized Trial of Primary Care Practice Redesign to Integrate Behavioral Health for Those Who Need It Most: Patients With Multiple Chronic Conditions.

PURPOSE: Patient outcomes can improve when primary care and behavioral health providers use a collaborative system of care, but integrating these services is difficult. We tested the effectiveness of a practice intervention for improving patient outcomes by enhancing integrated behavioral health (IBH) activities. METHODS: We conducted a pragmatic, cluster randomized controlled trial. The intervention combined practice redesign, quality improvement coaching, provider and staff education, and collaborative learning. At baseline and 2 years, staff at 42 primary care practices completed the Practice Integration Profile (PIP) as a measure of IBH. Adult patients with multiple chronic medical and behavioral conditions completed the Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey. Primary outcomes were the change in 8 PROMIS-29 domain scores. Secondary outcomes included change in level of integration. RESULTS: Intervention assignment had no effect on change in outcomes reported by 2,426 patients who completed both baseline and 2-year surveys. Practices assigned to the intervention improved PIP workflow scores but not PIP total scores. Baseline PIP total score was significantly associated with patient-reported function, independent of intervention. Active practices that completed intervention workbooks (n = 13) improved patient-reported outcomes and practice integration (P ≤ .05) compared with other active practices (n = 7). CONCLUSION: Intervention assignment had no effect on change in patient outcomes; however, we did observe improved patient outcomes among practices that entered the study with greater IBH. We also observed more improvement of integration and patient outcomes among active practices that completed the intervention compared to active practices that did not. Additional research is needed to understand how implementation efforts to enhance IBH can best reach patients.

Practice integration profile revised: Improving item readability and completion.

INTRODUCTION: The Practice Integration Profile (PIP) is a reliable, valid, and broadly used measure of the integration of behavioral health (BH) into primary care. The PIP assesses operational and procedural elements that are grounded in the AHRQ Lexicon for Behavioral Health and Primary Care Integration. Prior analyses of PIP data and feedback from users suggested the measure was in need of revisions. This article describes the process used to improve readability, clarity, and pragmatic utility of the instrument. METHOD: Two rounds of structured cognitive interviews were conducted with clinicians in primary care settings. After each round, interview transcripts were coded by an analytic team using an iterative and consensus-driven process. Themes were identified based on codes. Themes and recommendations for revisions were reviewed and modified by committee. RESULTS: Based on feedback and a prior factor analysis of the PIP, revisions were undertaken to: (a) eliminate redundant or overlapping items; (b) clarify the meaning of items; (c) standardize the response categories, and (d) place items in the most appropriate domains. The resulting measure has 28 items in five domains. DISCUSSION: PIP 2.0 will need further examination to confirm its continuing use as a foundational tool for evaluating integrated care. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Expanding interprofessional teams: Training future health care professionals in screening, brief intervention, and referral to treatment (SBIRT).

INTRODUCTION: Substance misuse persists and is undertreated across the United States (Substance Abuse and Mental Health Services Administration, 2021). Further enhancing the skill sets and capacity of interprofessional members of primary care teams to include proficiency in the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model could help to alleviate the "treatment gap" (those requiring treatment, but not receiving it) by enhancing interprofessional teams at the pregraduate level (e.g., health educators, health coaches) to expand capacity and meet the volume of patients with substance use-related needs. METHOD: In this study, SBIRT knowledge, training satisfaction, and efficacy were evaluated among undergraduate and graduate health and behavioral health students before and after exposure to a series of online training modules. RESULTS: On completion of the training, there were positive percent increases in overall mean knowledge and self-efficacy when compared with pretraining. At posttraining, graduate level students, regardless of discipline, reported greater knowledge than undergraduate students; there were no differences in efficacy or satisfaction among the groups. Additional analysis at the graduate level evaluated differences between behavioral health and medical trainees. No differences were found in knowledge or efficacy between groups at posttest, despite medical trainees reporting significantly lower efficacy at pretest. DISCUSSION: The findings of this study reinforce the need and potential to incorporate SBIRT training into higher education curricula for interprofessional health care professions to begin expanding the integrated care team's knowledge and efficacy in the provision of SBIRT to address the treatment gap. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.

Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.

Synthesis and defect characterization of hybrid ceria nanostructures as a possible novel therapeutic material towards COVID-19 mitigation.

This study reports the synthesis of hybrid nanostructures composed of cerium dioxide and microcrystalline cellulose prepared by the microwave-assisted hydrothermal route under distinct temperature and pH values. Their structural, morphological and spectroscopic behaviors were investigated by X-Rays Diffraction, Field Emission Gun Scanning Electron Microscopy, High-Resolution Transmission Electron Microscopy, and Fourier-Transform Infrared, Ultraviolet-Visible, Raman and Positron Annihilation Lifetime spectroscopies to evaluate the presence of structural defects and their correlation with the underlying mechanism regarding the biocide activity of the studied material. The samples showed mean crystallite sizes around 10 nm, characterizing the formation of quantum dots unevenly distributed along the cellulose surface with a certain agglomeration degree. The samples presented the characteristic Ce-O vibration close to 450 cm-1 and a second-order mode around 1050 cm-1, which is indicative of distribution of localized energetic levels originated from defective species, essential in the scavenging of reactive oxygen species. Positron spectroscopic studies showed first and second lifetime components ranging between 202-223 ps and 360-373 ps, respectively, revealing the presence of two distinct defective oxygen species, in addition to an increment in the concentration of Ce3+-oxygen vacancy associates as a function of temperature. Therefore, we have successfully synthesized hybrid nanoceria structures with potential multifunctional therapeutic properties to be further evaluated against the COVID-19.

Further Experience with the Practice Integration Profile: A Measure of Behavioral Health and Primary Care Integration.

Valid measures of behavioral health integration have the potential to enable comparisons of various models of integration, contribute to the overall development of high-quality care, and evaluate outcomes that are strategically aligned with standard improvement efforts. The Practice Integration Profile has proven to discriminate among clinic types and integration efforts. We continued the validation of the measure's internal consistency, intra-rater consistency, and inter-rater consistency with a separate and larger sample from a broader array of practices. We found that the Practice Integration Profile demonstrated a high level of internal consistency, suggesting empirically sound measurement of independent attributes of integration, and high reliability over time. The Practice Integration Profile provides internally consistent and interpretable results and can serve as both a quality improvement and health services research tool.

Integrating behavioral health & primary care for multiple chronic diseases: Clinical trial of a practice redesign toolkit.

Context: Most patients in need of behavioral health (BH) care are seen in primary care, which often has difficulty responding. Some practices integrate behavioral health care (IBH), with medical and BH providers at the same location, working as a team. However, it is difficult to achieve high levels of integration. Objective: Test the effectiveness of a practice intervention designed to increase BH integration. Study Design: Pragmatic, cluster-randomized controlled trial. Setting: 43 primary care practices with on-site BH services in 13 states. Population: 2,460 adults with multiple chronic medical and behavioral conditions. Intervention: 24-month practice change process including an online curriculum, a practice redesign and implementation workbook, remote quality improvement coaching services, and an online learning community. Outcomes: Primary outcomes were changes in the 8 Patient-Reported Outcomes Measurement Information System (PROMIS-29) domain scores. Secondary outcomes were changes in medication adherence, self-reported healthcare utilization, time lost due to disability, cardiovascular capacity, patient centeredness, provider empathy, and several condition-specific measures. A sample of practice staff completed the Practice Integration Profile at each time point to estimate the degree of BH integration in that site. Practice-level case studies estimated the typical costs of implementing the intervention. Results: The intervention had no significant effect on any of the primary or secondary outcomes. Subgroup analyses showed no convincing patterns of effect in any populations. COVID-19 was apparently not a moderating influence of the effect of the intervention on outcomes. The intervention had a modest effect on the degree of practice integration, reaching statistical significance in the Workflow domain. The median cost of the intervention was $18,204 per practice. In post-hoc analysis, level of BH integration was associated with improved patient outcomes independent of the intervention, both at baseline and longitudinally. Conclusions: The specific intervention tested in this study was inexpensive, but had only a small impact on the degree of BH integration, and none on patient outcomes. However, practices that had more integration at baseline had better patient outcomes, independent of the intervention. Although this particular intervention was ineffective, IBH remains an attractive strategy for improving patient outcomes.

Integrating Behavioral Health and Primary Care (IBH-PC) to improve patient-centered outcomes in adults with multiple chronic medical and behavioral health conditions: study protocol for a pragmatic cluster-randomized control trial.

BACKGROUND: Chronic diseases that drive morbidity, mortality, and health care costs are largely influenced by human behavior. Behavioral health conditions such as anxiety, depression, and substance use disorders can often be effectively managed. The majority of patients in need of behavioral health care are seen in primary care, which often has difficulty responding. Some primary care practices are providing integrated behavioral health care (IBH), where primary care and behavioral health providers work together, in one location, using a team-based approach. Research suggests there may be an association between IBH and improved patient outcomes. However, it is often difficult for practices to achieve high levels of integration. The Integrating Behavioral Health and Primary Care study responds to this need by testing the effectiveness of a comprehensive practice-level intervention designed to improve outcomes in patients with multiple chronic medical and behavioral health conditions by increasing the practice's degree of behavioral health integration. METHODS: Forty-five primary care practices, with existing onsite behavioral health care, will be recruited for this study. Forty-three practices will be randomized to the intervention or usual care arm, while 2 practices will be considered "Vanguard" (pilot) practices for developing the intervention. The intervention is a 24-month supported practice change process including an online curriculum, a practice redesign and implementation workbook, remote quality improvement coaching services, and an online learning community. Each practice's degree of behavioral health integration will be measured using the Practice Integration Profile. Approximately 75 patients with both chronic medical and behavioral health conditions from each practice will be asked to complete a series of surveys to measure patient-centered outcomes. Change in practice degree of behavioral health integration and patient-centered outcomes will be compared between the two groups. Practice-level case studies will be conducted to better understand the contextual factors influencing integration. DISCUSSION: As primary care practices are encouraged to provide IBH services, evidence-based interventions to increase practice integration will be needed. This study will demonstrate the effectiveness of one such intervention in a pragmatic, real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02868983 . Registered on August 16, 2016.

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.

Testing a Screening, Brief Intervention, and Referral to Treatment (SBIRT) interdisciplinary training program model for higher education systems.

INTRODUCTION: An estimated 21 million Americans meet the criteria for a substance use disorder (SUD), whereas 24% of the population engages in risky alcohol use leading to tremendous health and economic impacts (Substance Abuse and Mental Health Services Administration, 2017). Opioid misuse is a national public health emergency, with an estimated 46,802 opioid-related deaths occurring in 2018 (National Center for Health Statistics, 2020). Despite the high prevalence of risky substance use and SUDs, preservice education related to screening for and treating SUDs in health and behavioral health professions is inadequate (Dimoff, Sayette, & Norcross, 2017; Russett & Williams, 2015; Savage et al., 2014; Tabak et al., 2012). A critical need exists for an interdisciplinary, implementation science-informed approach for developing academic training programs in the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model within higher education systems. METHOD: We delineate a training model implemented within 5 health and behavioral health disciplines (nursing, social work, clinical psychology, counseling psychology, and integrated behavioral health), informed by prominent implementation scientists (Proctor et al., 2011; Rogers, 2003). RESULTS: Faculty surveys (n = 33), interviews (n = 24), and syllabi and training records reviews indicated the Brief Intervention, and Referral to Treatment model was infused into course content by 89.47% of trained faculty and sustained in 90.47% of course syllabi at project close. CONCLUSION: The model demonstrated successful uptake and sustainability in higher education systems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Transcultural translation and validation of Fugl-Meyer assessment to Italian.

PURPOSE: The Fugl-Meyer Assessment is the most used and highly recommended clinical assessment of sensorimotor function after stroke. A standardized use of the scale in different countries requires translation and cultural validation to the target language. The objective of the study was to develop an official Italian version of the scale by transcultural translation and validation. METHODS: A standardized multistep translation protocol was adopted to achieve optimal conceptual and semantic equivalence. The developed Italian version was validated in 10 post-stroke hemiparetic patients. Items with low intra- and interrater agreement, quantified as percentage of agreement <70% and/or statistically significant disagreement in relative position or concentration, between different raters were identified and revised. RESULTS: All motor items received a high level of agreement with values well above 70%. Disagreements were observed in 6 items in the sensory, joint range and pain domains and 1 in one reflex item. Items showing disagreements were discussed and revised to establish the final Italian version. CONCLUSIONS: The culturally validated Italian Fugl-Meyer Assessment can reliably be used in research and in clinical practice. A standardized use will improve the quality of sensorimotor assessment in stroke across Italy and allow reliable comparisons of stroke populations internationally.Implications for rehabilitationThe Fugl-Meyer Assessment is the gold standard for evaluation of sensorimotor impairment after stroke.Having access to a transculturally validated official Italian version of Fugl-Meyer Assessment will improve the quality of sensorimotor assessment after stroke among Italian health professionals and researchers. A wider standardized use of the Fugl-Meyer Assessment in Italy will allow reliable international comparison of stroke rehabilitation outcomes.

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.

Impact of Phyllantus niruri and Lactobacillus amylovorus SGL 14 in a mouse model of dietary hyperoxaluria.

Hyperoxaluria is a pathological condition which affects long-term health of kidneys. The present study evaluates the impact of the combination of Lactobacillus amylovorus SGL 14 and the plant extract Phyllantus niruri (namely Phyllantin 14™) on dietary hyperoxaluria. Safety and efficacy of Phyllantin 14 have been evaluated in vivo. Mice C57BL6 fed a high-oxalate diet were compared to mice fed the same diet administered with Phyllantin 14 by gavage for 6 weeks. Control mice were fed a standard diet without oxalate. No adverse effects were associated to Phyllantin 14 supplementation, supporting its safety. Mice fed a high-oxalate diet developed significant hyperoxaluria and those administered with Phyllantin 14 showed a reduced level of urinary oxalate and a lower oxalate-to-creatinine ratio. Soluble and insoluble caecal oxalate were significantly lower in treated group, a finding in agreement with the colonisation study, i.e. mice were colonised with SGL 14 after 3 weeks. Microbiota analysis demonstrated that both oxalate diet and Phyllantin 14 can differently modulate the microbiota. In conclusion, our findings suggest that Phyllantin 14 supplementation represents a potential supportive approach for reducing urinary oxalate and/or for enhancing the efficacy of existing treatments.

Independent Functioning in Nonagenarians Living in a Rural Italian Community: The Mugello Study.

Nonagenarians are a fast-growing population deserving specific research. We explored the prevalence and characteristics of functionally independent nonagenarians from a rural community-dwelling Italian population. Data were collected in the Mugello Study; 475 persons aged ≥90 years (median age, 92) underwent a home-based clinical and functional assessment, including psychosocial, clinical, functional, and lifestyle history and status and physical and instrumental examinations. Sixty-eight (15%) persons reported no need for help in basic and instrumental daily living activities. Among variables significantly associated with independent functionality after age- and gender-adjusted cross-sectional analysis, lower body mass index (BMI; p = .034) and depressive symptoms (p = .028), higher current physical activity (p < .001), better cognitive status (p = .033), and lower medication intake (p = .048) were associated with reporting no disability in the logistic regression analysis. Disability was mainly associated with current lifestyle-related potentially modifiable factors. Thus, lifestyle-oriented multidimensional interventions, should be developed and evaluated for their potential effects on functionality, even in the oldest old.

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.

HDL Cholesterol Is Independently Associated with Cognitive Function in Males But Not in Females within a Cohort of Nonagenarians: The MUGELLO Study.

OBJECTIVES: To investigate the possible relationship between lipid profile and cognitive functions in a cohort of nonagenarians enrolled within the Mugello Study, an epidemiological study aimed at investigating both clinically relevant geriatric items and various health issues. DESIGN: Cross-sectional survey. SETTING: This study focused on oldest old community-dwelling participants. PARTICIPANTS: Three hundred twenty-five nonagenarians (218 F, median age: 92 years). MEASUREMENTS: Participants were evaluated through laboratory, instrumental examinations and questionnaires concerning lifestyle, dietary habits and cognitive status. RESULTS: Females are older, with a lower level of education, live more prevalently on their own and have higher values for total cholesterol and high-density lipoprotein cholesterol (HDL) compared to males. With regard to functional and cognitive measures females report a significantly lower skill level in the physical activity performance, with a level of independence that is better for both basic and instrumental activities. In order to investigate whether there was an association between lipid variables and cognitive function as measured by the Mini-Mental State Examination a multiple regression analysis was performed with adjustments for confounding variables based on gender. In males, HDL cholesterol showed a significant relationship with Mini-Mental State Examination after a complete adjustment with years of education, physical activity performance and daily living activities (ß = 0.174; p=0.037). In females HDL cholesterol showed a significant association only in the model adjusted for age and body mass index, losing its associations as soon as the cohabitation state and the depression status entered the model. CONCLUSION: Our results support the hypothesis that HDL cholesterol is significantly linked to cognitive functions, especially in males of a cohort of very old people.

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.