Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

New tatt? We're ok with that! Relaxing the tattoo deferral for plasmapheresis donors maintains safety and increases donations.

BACKGROUND AND OBJECTIVES: Tattooing is one of the leading donor deferral reasons in Australia. Until September 2020, donors were deferred from all donation types for 4 months after a tattoo. At this time, our guideline changed such that donations of plasma for further manufacture were accepted immediately, provided the tattoo was administered in a licensed or regulated Australian establishment. We examined the effects of this change. MATERIALS AND METHODS: Donors with a tattoo deferral in the 2 years before or after the guideline change were identified and followed up until 3 November 2022. Between the two periods, we compared blood-borne virus (BBV) incidence, donor return, and the number of donors and donations regained after deferral. RESULTS: The incidence of BBV infection in donors after a tattoo deferral was zero in both periods. To exceed a residual risk of 1 in 1 million for hepatitis C virus, 190 donors would need to be infected yearly from a tattoo. Donors returned to donate significantly faster after the change (median return 85 days compared with 278 days). An extra 187 donations per 10,000 person-years of observation were gained, yielding a total of 44,674 additional plasma donations nationally 0-4 months after getting a tattoo. CONCLUSION: Allowing plasma donations immediately post-tattoo resulted in a substantial donation gain with no adverse safety effect. Lifeblood subsequently reduced the deferral for transfusible component donations to 7 days for tattoos in Australian licensed/regulated establishments.

Residual Seizure Rate of Intermittent Inpatient EEG Compared to a Continuous EEG Model.

BACKGROUND: Subclinical seizures are common in hospitalized patients and require electroencephalography (EEG) for detection and intervention. At our institution, continuous EEG (cEEG) is not available, but intermittent EEGs are subject to constant live interpretation. As part of quality improvement (QI), we sought to estimate the residual missed seizure rate at a typical quaternary Canadian health care center without cEEG. METHODS: We calculated residual risk percentages using the clinically validated 2HELPS2B score to risk-stratify EEGs before deriving a risk percentage using a MATLAB calculator which modeled the risk decay curve for each recording. We generated a range of estimated residual seizure rates depending on whether a pre-cEEG screening EEG was simulated, EEGs showing seizures were included, or repeat EEGs on the same patient were excluded. RESULTS: Over a 4-month QI period, 499 inpatient EEGs were scored as low (n = 125), medium (n = 123), and high (n = 251) seizure risk according to 2HELPS2B criteria. Median recording duration was 1:00:06 (interquartile range, IQR 30:40-2:21:10). The model with highest residual seizure rate included recordings with confirmed electrographic seizures (median 20.83%, IQR 20.6-26.6%), while the model with lowest residual seizure rate was in seizure-free recordings (median 10.59%, IQR 4%-20.6%). These rates were significantly higher than the benchmark 5% miss-rate threshold set by 2HELPS2B (p<0.0001). CONCLUSIONS: We estimate that intermittent inpatient EEG misses 2-4 times more subclinical seizures than the 2HELPS2B-determined acceptable 5% seizure miss-rate threshold for cEEG. Future research is needed to determine the impact of potentially missed seizures on clinical care.

Residual risk of cardiovascular complications in statin-using patients with type 2 diabetes: the Taiwan Diabetes Registry Study.

BACKGROUND: The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. METHODS: Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged < 25 or > 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. RESULTS: The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log-alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. CONCLUSION: This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

The residual risk of inflammation and remnant cholesterol in acute coronary syndrome patients on statin treatment undergoing percutaneous coronary intervention.

BACKGROUND: Residual risk assessment for acute coronary syndrome (ACS) patients after sufficient medical management remains challenging. The usefulness of measuring high-sensitivity C-reactive protein (hsCRP) and remnant cholesterol (RC) in assessing the level of residual inflammation risk (RIR) and residual cholesterol risk (RCR) for risk stratification in these patients needs to be evaluated. METHODS: Patients admitted for ACS on statin treatment who underwent percutaneous coronary intervention (PCI) between March 2016 and March 2019 were enrolled in the analysis. The included patients were stratified based on the levels of hsCRP and RC during hospitalization. The primary outcome was ischemic events at 12 months, defined as a composite of cardiac death, myocardial infarction, or stroke. The secondary outcomes included 12-month all-cause death and cardiac death. RESULTS: Among the 5778 patients, the median hsCRP concentration was 2.60 mg/L and the median RC concentration was 24.98 mg/dL. The RIR was significantly associated with ischemic events (highest hsCRP tertile vs. lowest hsCRP tertile, adjusted hazard ratio [aHR]: 1.52, 95% confidence interval [CI]: 1.01-2.30, P = 0.046), cardiac death (aHR: 1.77, 95% CI:1.02-3.07, P = 0.0418) and all-cause death (aHR: 2.00, 95% CI: 1.24-3.24, P = 0.0048). The RCR was also significantly associated with these outcomes, with corresponding values for the highest tertile of RC were 1.81 (1.21-2.73, P = 0.0043), 2.76 (1.57-4.86, P = 0.0004), and 1.72 (1.09-2.73, P = 0.0208), respectively. The risks of ischemic events (aHR: 2.80, 95% CI: 1.75-4.49, P < 0.0001), cardiac death (aHR: 4.10, 95% CI: 2.18-7.70, P < 0.0001), and all-cause death (aHR: 3.00, 95% CI, 1.73-5.19, P < 0.0001) were significantly greater in patients with both RIR and RCR (highest hsCRP and RC tertile) than in patients with neither RIR nor RCR (lowest hsCRP and RC tertile). Notably, the RIR and RCR was associated with an increased risk of ischemic events especially in patients with adequate low-density lipoprotein cholesterol (LDL-C) control (LDL-C < 70 mg/dl) (Pinteraction=0.04). Furthermore, the RIR and RCR provide more accurate evaluations of risk in addition to the GRACE score in these patients [areas under the curve (AUC) for ischemic events: 0.64 vs. 0.66, P = 0.003]. CONCLUSION: Among ACS patients receiving contemporary statin treatment who underwent PCI, high risks of both residual inflammation and cholesterol, as assessed by hsCRP and RC, were strongly associated with increased risks of ischemic events, cardiac death, and all-cause death.

Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

PURPOSE OF REVIEW: What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials. RECENT FINDINGS: Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction. If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%. What are the clinical implications? Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed. HYPOTHESIS: failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients. Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.

Effect of dual residual risk of cholesterol and inflammation on all-cause mortality in patients with cardiovascular disease.

BACKGROUND: Randomized controlled trials confirm that risks of residual cholesterol and residual inflammation remains in patients with cardiovascular disease (CVD) even after lipid-lowering therapy. This study aims to investigate the association between dual residual risk of cholesterol and inflammation and all-cause mortality in a real-world population with CVD. METHODS: Patients with a CVD history who first took statins between 1 January 2010 and 31 December 2017 in the Kailuan Study were selected as study participants. According to low-density lipoprotein cholesterol (LDL-C) and hypersensitive C-reactive protein levels, patients were divided into those with no residual risk, residual inflammatory risk (RIR), residual cholesterol risk (RCR), and residual cholesterol and inflammatory risk (RCIR). Cox proportional hazard model was conducted to determine hazard ratio (HR) of all-cause mortality for RIR, RCR, and RCIR. Stratified analysis was conducted according to good medication adherence and 75% of the percentage LDL-C decline, high SMART 2 risk score, and blood pressure and blood glucose at standard levels. RESULTS: After 6.10 years of follow-up, 377 all-cause deaths occurred in 3509 participants (mean age 63.69 ± 8.41 years, 86.78% men). After adjusting for related risk factors, the HR and (95% confidence interval [CI]) of all-cause mortality in the RIR, RCR, and RCIR was 1.63 (1.05, 2.52), 1.37 (0.98, 1.90), and 1.75 (1.25, 2.46), compared with no residual risk. Similar associations were observed in participants with moderate or low statin compliance, a lower percentage of LDL-C decline, high SMART 2 risk score, uncontrolled blood pressure, and uncontrolled blood glucose, in the RCIR had a 1.66-fold, 2.08-fold, 1.69-fold, 2.04-fold, and 2.05-fold higher risk of all-cause mortality, respectively, than the reference. CONCLUSION: Risks of residual cholesterol and residual inflammation remain in patients with CVD after receiving statins, and their combined effect significantly increases the risk of all-cause mortality. Here, this increased risk was dependent on statin compliance, LDL-C reduction, SMART 2 risk score, and blood pressure and blood glucose control.

Low risk of human T-lymphotropic virus infection in U.S. blood donors; Is it time to consider a one-time selective testing approach?

BACKGROUND: U.S. blood donors are tested at each donation for human T-lymphotropic virus (HTLV) antibodies. Depending on donor incidence and other mitigation/removal technologies, a strategy of one-time selective donor testing should be considered. METHODS: Antibody seroprevalence was calculated for HTLV-confirmed-positive American Red Cross allogeneic blood donors from 2008 to 2021. Incidence was estimated for seven 2-year time periods using confirmed-positive repeat donors having seroconverted in 730 days. Leukoreduction failure rates were obtained from internal data from July 1, 2008-June 30, 2021. Residual risks were calculated using a 51-day window period. RESULTS: Between 2008 and 2021, >75 million donations (>18 million donors) yielded 1550 HTLV seropositives. HTLV seroprevalence was 2.05 antibody-positives per 100,000 donations (0.77 HTLV-1, 1.03 HTLV-2, 0.24 HTLV-1/2), and 10.32 per 100,000 among >13.9 million first-time donors. Seroprevalence differed significantly by virus type, sex, age, race/ethnicity, donor status, and U.S. census region. Over 14 years and 24.8 million person-years of observation, 57 incident donors were identified (25 HTLV-1, 23 HTLV-2, and 9 HTLV-1/2). Incidence decreased from 0.30 (13 cases) in 2008-2009 to 0.25 (7 cases) in 2020-2021. Female donors accounted for most incident cases (47 vs. 10 males). In the last 2-year reporting period, the residual risk was 1 per 2.8 million donations and 1 per 3.3 billion donations when coupled with successful leukoreduction (0.085% failure rate). CONCLUSIONS: HTLV donation seroprevalence for the years 2008-2021 varied by virus type and donor characteristics. Low HTLV residual risk and use of leukoreduction processes support the conclusion that a selective one-time donor testing strategy should be considered.

Residual risks and evolving atherosclerotic plaques.

Atherosclerotic disease of the coronary and carotid arteries is the primary global cause of significant mortality and morbidity. The chronic occlusive diseases have changed the epidemiological landscape of health problems both in developed and the developing countries. Despite the enormous benefit of advanced revascularization techniques, use of statins, and successful attempts of targeting modifiable risk factors, like smoking and exercise in the last four decades, there is still a definite "residual risk" in the population, as evidenced by many prevalent and new cases every year. Here, we highlight the burden of the atherosclerotic diseases and provide substantial clinical evidence of the residual risks in these diseases despite advanced management settings, with emphasis on strokes and cardiovascular risks. We critically discussed the concepts and potential underlying mechanisms of the evolving atherosclerotic plaques in the coronary and carotid arteries. This has changed our understanding of the plaque biology, the progression of unstable vs stable plaques, and the evolution of plaque prior to the occurrence of a major adverse atherothrombotic event. This has been facilitated using intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the clinical settings to achieve surrogate end points. These techniques are now providing exquisite information on plaque size, composition, lipid volume, fibrous cap thickness and other features that were previously not possible with conventional angiography.

Genetic diversity of the human immunodeficiency virus of type 1 in Gabonese transfusional settings.

BACKGROUND: The high endemicity of transfusion-transmissible infections (TTIs) in sub-Saharan Africa is a real public health problem. To reduce the risk of HIV transmission through blood donation, the NBTC of Gabon has launched in recent years a reorganization of its blood transfusion system. This study aims to characterize the molecular strains of HIV-1 circulating in donors and to estimate the risk of viral transmission. MATERIALS AND METHODS: A cross-sectional study was carried out during the period from August 2020 to August 2021 among 381 donors who had agreed to donate blood at the National Blood Transfusion Center (NBTC). Viral load was determined by Abbott Real-Time (Abbott m2000®, Abbott) and sequencing by the Sanger method (ABI 3500 Hitachi®). The phylogenetic tree was constructed by MEGA X software. Data were checked, entered, and analyzed using SPSS version 21.0 software, with p ≤ 0.05 considered statistically significant. RESULTS: A total of 381 donors were enrolled in the study. Among the 359 seronegative donors, five (5) seronegative donors were detected positive for HIV-1 using Real-Time PCR. The residual risk was 648 per 1,000,000 donations. The prevalence of residual infection was 1.4% [0,01; 0,03]. Sixteen (16) samples were sequenced. The strains obtained were CRF02_AG (50%), subtype A1 (18.8%), subtype G (12.5%), CRF45_cpx (12.5%) and subtype F2 (6.2%). Six sequences clustered with A1, G, CRF02_AG, and CRF45_cpx subtypes. CONCLUSION: The residual risk of HIV-1 transmission by blood transfusion remains a concern in the Gabonese transfusional settings. A policy based on improving the current screening strategy would involve the implementation of the nucleic acid test (NAT) in order to optimize the safety of the donation by detecting the HIV-1 subtypes in circulation in the donors.

Low-grade inflammation is associated with a heterogeneous lipoprotein subclass profile in an apparently healthy population sample.

BACKGROUND AND AIMS: Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. METHODS: We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. RESULTS: APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. CONCLUSION: Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Role of Soluble Urokinase-Type Plasminogen Activator Receptor in Cardiovascular Disease.

PURPOSE OF REVIEW: Chronic inflammation is a major contributor to cardiovascular disease (CVD) risk. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived glycoprotein that is strongly associated with atherosclerotic disease. This review summarizes evidence on suPAR's role in CVD pathogenesis and its potential as a prognostic indicator and therapeutic target. RECENT FINDINGS: Clinical, genetic, and experimental evidence supports suPAR's role as a pathogenic factor in atherosclerosis. suPAR promotes atherosclerosis through modulation of monocyte activation and function. Clinically, elevated suPAR levels are linked to increased cardiovascular risk across diverse populations. Ongoing clinical trials are evaluating therapies targeting suPAR signaling. Current evidence positions suPAR as a regulator of myeloid cell function that contributes to vascular inflammation and subsequent cardiovascular events. Additional research is needed to determine whether suPAR measurement can improve CVD risk prediction and enable personalized management. Overall, suPAR is a promising immune-derived biomarker and target for reducing inflammation and cardiovascular risk.

Multi-proteomic Biomarker Risk Scores for Predicting Risk and Guiding Therapy in Patients with Coronary Artery Disease.

PURPOSE OF REVIEW: Patients with established coronary artery disease (CAD) are at high residual risk for adverse events, despite guideline-based treatments. Herein, we aimed to determine whether risk scores based on multiple circulating biomarkers that represent activation of various pathophysiologically important pathways involved in atherosclerosis and myocardial dysfunction help identify those at greatest residual risk. RECENT FINDINGS: Numerous circulating proteins, representing dysregulation of the pathways involved in the development and stability of coronary and myocardial diseases, have been identified. When aggregated together, biomarker risk scores (BRS) more accurately stratify patients with established CAD that may help target interventions in those individuals who are at elevated risk. Moreover, intensification of guideline-based therapies has been associated with parallel improvements in both BRS and outcomes, indicating that these risk scores may be employed clinically to target therapy. Multi-protein BRS are predictive of risk, independent of, and in addition to traditional risk factor assessments in patients with CAD. Those with elevated risk may benefit from optimization of therapies, and improvements in the BRS will identify those with improved outcomes.

Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease: the updated SMART2 algorithm.

AIMS: The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations. METHODS AND RESULTS: Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options. CONCLUSION: The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk.

Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation.

Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. This paper aims to conduct a literature review on pharmacotherapy for PAD, specifically focusing on how different drug classes target pro-inflammatory pathways. The goal is to enhance the choice of therapeutic plans by considering their impact on the chronic subclinical inflammation that is associated with PAD development and progression. We conducted a comprehensive review of currently published original articles, narratives, systematic reviews, and meta-analyses. The aim was to explore the relationship between PAD and inflammation and evaluate the influence of current pharmacological and nonpharmacological interventions on the underlying chronic subclinical inflammation. Our findings indicate that the existing treatments have added anti-inflammatory properties that can potentially delay or prevent PAD progression and improve outcomes, independent of their effects on traditional risk factors. Although inflammation-targeted therapy in PAD shows promising potential, its benefits have not been definitively proven yet. However, it is crucial not to overlook the pleiotropic properties of the currently available treatments, as they may provide valuable insights for therapeutic strategies. Further studies focusing on the anti-inflammatory and immunomodulatory effects of these treatments could enhance our understanding of the mechanisms contributing to the residual risk in PAD and pave the way for the development of novel therapies.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID-REAL registry.

BACKGROUND: Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so-called lipid residual risk, is unknown. METHODS: Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on-treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides-to-glucose index (TGGi). RESULTS: Six hundred fifty-two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On-treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity. CONCLUSIONS: This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.

HIV residual risk in Canada for apheresis source plasma donation without deferral for men who have sex with men.

BACKGROUND AND OBJECTIVES: In Canada, men having sex with men (MSM) are deferred for 3 months from last sexual contact to reduce human immunodeficiency virus (HIV) risk to recipients. The aim of this paper was to model the Canadian residual risk of HIV-positive source plasma incorporating pathogen inactivation (PI) under no MSM deferral scenarios for apheresis plasma donations. MATERIALS AND METHODS: A combined Bayesian network (BN) and Monte Carlo approach were implemented to estimate the HIV residual risk under 3-month deferral compared with no deferral without quarantine scenarios for MSM donors. Models involve the stochastic generation of donation and its infection status based on its corresponding simulated donor profile. Viral load reduction conferred by PI used by source plasma fractionators was simulated. Model parameters were derived from Héma-Québec and Canadian Blood Services data, viral loads in a large sample of HIV-positive US blood donors, CSL Behring documentation and from published data. RESULTS: In the most likely scenario for the 3-month deferral model, there were 2.71 positive donations per 1,000,000 donations (95% confidence interval [CI] 2.63-2.78). For the no-deferral model, there were 3.01 positive donations per 1,000,000 donations (95% CI 2.94-3.09). For both scenarios, the risk of having an infectious pool was 0 in 300,000 pools (95% CI 0-0.0000123) after consideration of PI. CONCLUSION: Based on simulation results, there would be a negligible HIV residual risk associated with the removal of a time-based MSM deferral without quarantine for source plasma incorporating PI.

Should a Statin be Given to All Hypertensive Patients?

PURPOSE OF REVIEW: To review the milestone trials and recent literature supporting statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) and to provide rationale for more generalized use of statin therapy among patients treated for hypertension. RECENT FINDINGS: Hypertension is a leading modifiable risk factor for ASCVD worldwide. Randomized controlled trial evidence supports initiation of antihypertensive medication for stage 2 hypertension regardless of ASCVD risk. The HOPE-3 trial tested statin therapy in intermediate-risk individuals (defined as an annual risk of major cardiovascular events of approximately 1%) for primary prevention of ASCVD and reported significant reductions in cardiovascular events in all statin treatment arms, with the greatest benefit observed in patients in the highest tertile of systolic blood pressure. Based on the current data, patients with stage 2 hypertension with an indication for antihypertensive therapy may benefit from the addition of statin therapy in the primary prevention setting. Patients with hypertension have an elevated risk for ASCVD that appears to be modifiable beyond implementation of antihypertensive therapy. The addition of statin therapy in patients treated with antihypertensive therapy may further help to lower risk of future cardiovascular events.

Does the Naked Emperor Parable Apply to Current Perceptions of the Contribution of Renin Angiotensin System Inhibition in Hypertension?

PURPOSE OF REVIEW: To address contemporary hypertension challenges, a critical reexamination of therapeutic accomplishments using angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, and a greater appreciation of evidence-based shortcomings from randomized clinical trials are fundamental in accelerating future progress. RECENT FINDINGS: Medications targeting angiotensin II mechanism of action are essential for managing primary hypertension, type 2 diabetes, heart failure, and chronic kidney disease. While the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to control blood pressure is undisputed, practitioners, hypertension specialists, and researchers hold low awareness of these drugs' limitations in preventing or reducing the risk of cardiovascular events. Biases in interpreting gained knowledge from data obtained in randomized clinical trials include a pervasive emphasis on using relative risk reduction over absolute risk reduction. Furthermore, recommendations for clinical practice in international hypertension guidelines fail to address the significance of a residual risk several orders of magnitude greater than the benefits. We analyze the limitations of the clinical trials that have led to current recommended treatment guidelines. We define and quantify the magnitude of the residual risk in published hypertension trials and explore how activation of alternate compensatory bioprocessing components within the renin angiotensin system bypass the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to achieve a significant reduction in total and cardiovascular deaths. We complete this presentation by outlining the current incipient but promising potential of immunotherapy to block angiotensin II pathology alone or possibly in combination with other antihypertensive drugs. A full appreciation of the magnitude of the residual risk associated with current renin angiotensin system-based therapies constitutes a vital underpinning for seeking new molecular approaches to halt or even reverse the cardiovascular complications of primary hypertension and encourage investigating a new generation of ACE inhibitors and ARBs with increased capacity to reach the intracellular compartments at which Ang II can be generated.