Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR). RESULTS: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors. CONCLUSIONS: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors.

Overcoming barriers to implementation: Improving incidental coronary calcium reporting on non-EKG gated chest CT scans.

BACKGROUND: Current guidelines recommend the reporting of incidental CAC on non-EKG-gated CT scans of the chest. The finding of incidental moderate or severe CAC on non-cardiac non-contrast chest CT correlates with a CAC score ≥ 100 Agatston units, a guideline-based indication for a clinician-patient discussion regarding the initiation of statin therapy. In contemporary practice, whether the presence and severity of incidental CAC are routinely reported on such CT scans of the chest is unknown. METHODS: At a major university hospital, we collected a one-month convenience sample of 297 patients who had chest CT imaging for indications other than lung cancer screening (OICT) and 42 patients who underwent lung cancer chest CT screening (LSCT). We evaluated reporting patterns of incidental CAC in the body and impression of the reports as compared to the overreading of such studies by a board-certified CT chest radiologist. We hypothesized and demonstrated that there was underreporting of incidental CAC on these scans. We then undertook an initiative to educate reporting radiologists on the importance of reporting CAC and implemented a reporting template change to encourage routine reporting. Then we repeated another one-month sample (n= 363 for the OICT and n= 63 for the LSCT groups) to evaluate reporting patterns following our intervention. RESULTS: The presence of incidental moderate and severe CAC was systematically underreported in the OICT group (0 and 4.8 %) and the severity was never mentioned in the impression of reports. In the LSCT group, the presence of incidental moderate and severe CAC was also underreported (66.7 % and 75 %) and the severity of CAC was mentioned 50 % of the time in the impression of the reports. Following the initiation of an educational program and radiology reporting template change, there was a significant increase in reporting of moderate or severe CAC in the OICT group (0 vs. 80.0 %, p < 0.001) and (4.8 vs. 93.5 %, p < 0.001) respectively and a significant increase in the reporting of the severity of incidental CAC for those with severe CAC in the LSCT group (50 vs. 94.1 %, p=0.006). CONCLUSION: Despite guideline recommendations, Incidental CAC was underreported at a large academic center. We implemented a system that significantly improved reporting patterns of incidental CAC. Failure to report incidental CAC represents a missed opportunity to initiate preventive therapies. Hospital systems interested in improving the quality of their radiology reporting procedures should examine their practices to assure that CAC quantification is routinely performed.

A historical, evidence-based, and narrative review on commonly used dietary supplements in lipid-lowering.

Dietary supplements augment the nutritional value of everyday food intake and originate from the historical practices of ancient Egyptian (Ebers papyrus), Chinese (Pen Ts'ao by Shen Nung), Indian (Ayurveda), Greek (Hippocrates), and Arabic herbalists. In modern-day medicine, the use of dietary supplements continues to increase in popularity with greater than 50% of the US population reporting taking supplements. To further compound this trend, many patients believe that dietary supplements are equally or more effective than evidence-based therapies for lipoprotein and lipid-lowering. Supplements such as red yeast rice, omega-3 fatty acids, garlic, cinnamon, plant sterols, and turmeric are marketed to and believed by consumers to promote "cholesterol health." However, these supplements are not subjected to the same manufacturing scrutiny by the Food and Drug Administration as pharmaceutical drugs and as such, the exact contents and level of ingredients in each of these may vary. Furthermore, supplements do not have to demonstrate efficacy or safety before being marketed. The holistic approach to lowering atherosclerotic cardiovascular disease risk makes dietary supplements an attractive option to many patients; however, their use should not come at the expense of established therapies with proven benefits. In this narrative review, we provide a historical and evidence-based approach to the use of some dietary supplements in lipoprotein and lipid-lowering and provide a framework for managing patient expectations.

Coronary and Extra-coronary Subclinical Atherosclerosis to Guide Lipid-Lowering Therapy.

PURPOSE OF REVIEW: To discuss and review the technical considerations, fundamentals, and guideline-based indications for coronary artery calcium scoring, and the use of other non-invasive imaging modalities, such as extra-coronary calcification in cardiovascular risk prediction. RECENT FINDINGS: The most robust evidence for the use of CAC scoring is in select individuals, 40-75 years of age, at borderline to intermediate 10-year ASCVD risk. Recent US recommendations support the use of CAC scoring in varying clinical scenarios. First, in adults with very high CAC scores (CAC ≥ 1000), the use of high-intensity statin therapy and, if necessary, guideline-based add-on LDL-C lowering therapies (ezetimibe, PCSK9-inhibitors) to achieve a ≥ 50% reduction in LDL-C and optimally an LDL-C < 70 mg/dL is recommended. In patients with a CAC score ≥ 100 at low risk of bleeding, the benefits of aspirin use may outweigh the risk of bleeding. Other applications of CAC scoring include risk estimation on non-contrast CT scans of the chest, risk prediction in younger patients (< 40 years of age), its value as a gatekeeper for the decision to perform nuclear stress testing, and to aid in risk stratification in patients presenting with low-risk chest pain. There is a correlation between extra-coronary calcification (e.g., breast arterial calcification, aortic calcification, and aortic valve calcification) and incident ASCVD events. However, its role in informing lipid management remains unclear. Identification of coronary calcium in selected patients is the single best non-invasive imaging modality to identify future ASCVD risk and inform lipid-lowering therapy decision-making.

Strategies for Improving Enrollment of Diverse Populations with a Focus on Lipid-Lowering Clinical Trials.

PURPOSE OF REVIEW: We review under-representation of key demographic groups in cardiovascular clinical trials, focusing on lipid-lowering trials. We outline multilevel strategies to recruit and retain diverse populations in cardiovascular trials. RECENT FINDINGS: Barriers to participation in trials occur at the study, participant, health system, sponsor, and policy level, requiring a multilevel approach to effectively increase participation of under-represented groups in research. Increasing the representation of marginalized and under-represented groups in leadership positions in clinical trials can ensure that their perspectives and experiences are considered. Trial design should prioritize patient- and community-indicated needs. Women and individuals from racially/ethnically diverse populations remain under-represented in lipid-lowering and other cardiovascular clinical trials relative to their disease burden in the population. This limits the generalizability of trial results to the broader population in clinical practice. Collaboration between community stakeholders, researchers, and community members can facilitate shared learning about trials and build trust.

Inclisiran: A New Strategy for LDL-C Lowering and Prevention of Atherosclerotic Cardiovascular Disease.

Multiple lines of evidence confirm that the cumulative burden of low-density lipoprotein cholesterol (LDL-C) is causally related to the development of atherosclerotic cardiovascular disease (ASCVD). As such, lowering LDL-C is a central tenet in all ASCVD prevention guidelines, which recommend matching the intensity of LDL-C lowering with the absolute risk of the patient. Unfortunately, issues such as difficulty with long-term adherence to statin therapy and inability to achieve desired LDL-C thresholds with statins alone results in residual elevated ASCVD risk. Non-statin therapies generally provide similar risk reduction per mmol/L of LDL-C reduction and are included by major society guidelines as part of the treatment algorithm for managing LDL-C. Per the 2022 American College of Cardiology Expert Consensus Decision Pathway, patients with ASCVD are recommended to achieve both an LDL-C reduction ≥50% and an LDL-C threshold of <55 mg/dL in patients at very high-risk and <70 mg/dL in those not at very high risk. Patients with familial hypercholesterolemia (FH) but without ASCVD should lower LDL-C to <100 mg/dL. For patients who remain above LDL-C thresholds with maximally tolerated statin therapy plus lifestyle changes, non-statin therapy warrants strong consideration. While several non-statin therapies have been granted FDA approval for managing hypercholesterolemia (eg, ezetimibe, Proprotein Convertase Subtilisin/Kexin 9 [PCSK9] monoclonal antibodies, and bempedoic acid), the focus of the current review is on inclisiran, a novel small interfering RNA therapy that inhibits the production of the PCSK9 protein. Inclisiran is currently FDA approved as an adjunct to statin therapy in patients with clinical ASCVD or heterozygous FH who require additional LDL-lowering. The drug is administered by subcutaneous injection twice a year, after an initial baseline and 3 month dose. In this review, we sought to provide an overview of the use of inclisiran, review current trial data, and outline an approach to potential patient selection.

Trends and In-Hospital Outcomes of Patients With Baseline Right Bundle Branch Block Who Underwent Transcatheter Aortic Valve Implantation.

This study aimed to explore contemporary in-hospital outcomes and trends of transcatheter aortic valve implantation (TAVI) outcomes in patients with baseline right bundle branch block (RBBB) using data collected from a nationwide sample. Using the National Inpatient Sample, we identified patients hospitalized for an index TAVI procedure from 2016 to 2019. Primary outcomes included in-hospital all-cause mortality, complete heart block, and permanent pacemaker (PPM) implantation. A total of 199,895 hospitalizations for TAVI were identified. RBBB was present in 10,495 cases (5.3%). Patients with RBBB were older (median age 81 vs 80 years, p <0.001) and less likely to be female (35% vs 47.4%, p <0.001). After adjusting for differences in baseline characteristics and elective versus nonelective admission, patients with RBBB had a higher incidence of complete heart block (adjusted odds ratio [aOR] 4.77, confidence interval [CI] 4.55 to 5.01, p <0.001) and PPM implantation (aOR 4.15, CI 3.95 to 4.35, p <0.001) and no difference in-hospital mortality rate (aOR 0.85, CI 0.69 to 1.05, p = 0.137). Between 2016 and 2019, there was a 3.5% and 2.9% decrease in in-hospital PPM implantation in patients with and without RBBB, respectively. In conclusion, from 2016 to 2019, the rate of in-hospital PPM implantation decreased during index TAVI hospitalization in both patients with and without RBBB. However, in those with baseline RBBB, complete heart block complication rates requiring PPM implantation remain relatively high. Further research and advances are needed to continue to reduce complication rates and the need for PPM implantation.

Bempedoic Acid: Lipid Lowering for Cardiovascular Disease Prevention.

The management of low-density lipoprotein cholesterol (LDL-C) levels is a central strategy for the prevention of atherosclerotic cardiovascular disease. Current United States (2018 American Heart Association/American College of Cardiology/Multisociety) and European (2019 European Society of Cardiology/European Atherosclerosis Society) guidelines endorse statin therapy as the first-line therapy for pharmacologic LDL-C lowering. However, in clinical practice up to 30% of patients report partial or complete intolerance to statin therapy. While the nocebo effect with statins is well described, perceived statin intolerance prevents many patients from achieving LDL-C thresholds associated with clinical benefit. Bempedoic acid is a novel, oral, non-statin lipid-l owering therapy that works by inhibiting adenosine triphosphate-citrate lyase, an enzymatic reaction upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the hepatic cholesterol synthesis pathway. Bempedoic acid confers reduction in LDL-C of ~18% on background statin therapy,~21% in patients with statin intolerance, and ~38% when given in fixed-dose combination with ezetimibe. The CLEAR Outcomes trial, which enrolled high-risk primary and secondary prevention patients with reported statin intolerance and LDL-C levels ≥100 mg/dL, showed that bempedoic acid compared with placebo reduced 4-component major adverse cardiovascular events (MACE) by 13% (hazard ratio 0.87, 95% confidence interval 0.79-0.96). Bempedoic acid also reduced 3-component MACE by 15%, myocardial infarction by 23% and coronary revascularization by 19%. The benefit was even greater in the primary prevention cohort (hazard ratio 0.70, 95% confidence interval 0.55-0.89) for 4-component MACE. Bempedoic acid was associated with increases in uric acid levels and cholelithiasis, but numerically fewer events of myalgia and new-onset diabetes. These findings confirm that bempedoic acid is an effective approach to reduce cardiovascular outcomes in high-risk patients with statin intolerance who require further reduction in LDL-C.

The association of pre-transplant atrial fibrillation with in-hospital outcomes in patients undergoing orthotopic liver transplantation: A propensity score matching analysis.

INTRODUCTION: In this study, we sought to evaluate the prevalence and association of pre-transplant atrial fibrillation (AF) on 30-day postoperative outcomes in patients undergoing orthotopic liver transplant (OLT). METHOD: The National Inpatient Sample Database was queried from 2011 to 2017 for relevant ICD-9 and ICD-10 procedural and diagnostic codes. Baseline characteristics and in-hospital outcomes were compared in patients who underwent OLT with AF and those without. RESULTS: Among 45,357 patients who underwent OLT, women made up 35.8% of the overall population. The prevalence of AF before transplant was 2932 (6.5%) with a trend toward increasing prevalence, with an average annual change rate of 4.19%. Applying propensity score matching to control for potential confounding factors, there was no association between pre-transplant AF and in-hospital mortality in patients undergoing OLT, however there was a higher incidence of perioperative complications including: acute kidney injury, ventricular tachycardia, major bleeding, blood product transfusion, and septic shock. CONCLUSION: In patients undergoing OLT, pre-transplant AF is increasing in prevalence and appears to be associated with similar in-hospital mortality but worse perioperative outcomes. Greater emphasis should be placed on AF in the preoperative cardiovascular risk stratification of patients undergoing OLT.

Under-reporting and under-representation of non-Hispanic Black subjects in lipid-lowering atherosclerotic cardiovascular disease outcomes trials: A systematic review.

BACKGROUND: Non-Hispanic (NH) Black participants have been under-represented in studies of cardiovascular disease. OBJECTIVE: We sought to determine the trends of reporting and representation of NH Black subjects in randomized controlled trials (RCTs) of lipid-lowering therapies demonstrating atherosclerotic cardiovascular disease (ASCVD) risk reduction benefit. METHODS: The electronic databases of MEDLINE, EMBASE and ClinicalTrials.gov were searched from 1990-2020. Studies of lipid-lowering therapies (i.e., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9], and icosapent ethyl) with proven ASCVD benefit, sample sizes of at least 1000 subjects and follow-up of at least 1 year were included (40 RCTs, N=306 747 total participants). We examined articles and supplementary material for participant-level race data. Using United States disease prevalence data, the participation-to-prevalence ratio (PPR) metric was used to estimate the representation of NH Black subjects compared with their reported disease burden (i.e., < 0.8 indicated under-representation; > 1.2, over-representation; and 0.8 to <1.2, adequate representation). RESULTS: The median (interquartile range) number of participants per trial was 4871 (2434-10077). NH Black enrollees comprised 7.3% (95% CI, 0.9%-15.4%) of the total number of subjects reported. During the time intervals 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015 and 2016-2020, NH Black participation was 0%, 1.1%, 4.4%, 4.8%, 0.2% and 0.7% respectively (P for trend <0.001). For statin trials, the participation of NH Black subjects was reported in 0 studies between 1990-1995 and in 9 of 28 trials from 1996-2020. For ezetimibe and icosapent ethyl, NH Black participants were reported in 0 of 3 and 0 of 1 studies, respectively. For trials of PCSK9 inhibitors, NH Black subjects were reported in 2 of 5 (40%). NH Black participants were under-represented compared with their disease burden in studies evaluating subjects with diabetes, hypercholesterolemia, stable coronary artery disease, and acute coronary syndrome (PPR < 0.8 for all). CONCLUSION: NH Black participants are markedly under-represented, and results are under-reported. The inclusion of population and disease specific representation of NH Black persons and their related social determinants of health will help to address the disparity in preventive care for this historically undertreated population.

A Review of Statin Intolerance: a Focus on Statin-Attributed Muscle Symptoms.

PURPOSE OF REVIEW: To provide a systematic approach to management of the patient with statin-attributed muscle symptoms. RECENT FINDINGS: We examined the prevalence of statin intolerance, the role of the nocebo effect, key findings in the patient's history and laboratory studies, the potential value of coronary calcium scoring, and the importance of shared decision-making in considering statin re-initiation. Most patients with statin-attributed muscle symptoms can be successfully treated with statins or a combination of statins and non-statins to achieve successful ASCVD risk reduction.

Lipid-Lowering Therapy in Women of Childbearing Age: a Review and Stepwise Clinical Approach.

PURPOSE OF REVIEW: Women are less often recognized to have cardiovascular disease (CVD) risk and are underrepresented in randomized trials of lipid-lowering therapy. Here, we summarize non-pharmacologic and pharmacologic strategies for lipid-lowering in women of childbearing age, lipid changes during pregnancy and lactation, discuss sex-specific outcomes in currently available literature, and discuss future areas of research. RECENT FINDINGS: While lifestyle interventions form the backbone of CVD prevention, some women of reproductive age have an indication for pharmacologic lipid-lowering. Sex-based evidence is limited but suggests that both statin and non-statin lipid-lowering agents are beneficial regardless of sex, especially at high cardiovascular risk. Pharmacologic lipid-lowering therapies, both during the pregnancy period and during lactation, have historically been and continue to be limited by safety concerns. This oftentimes limits lipid-lowering options in women of childbearing age. In this review, we summarize lipid-lowering strategies in women of childbearing age and the impact of therapies during pregnancy and lactation. The limited sex-specific data regarding efficacy, adverse events, and cardiovascular outcomes underscore the need for a greater representation of women in randomized controlled trials. More data on lipid-lowering teratogenicity are needed, and through increased clinician awareness and reporting to incidental exposure registries, more data can be harvested.

A comprehensive review of coronary artery disease in patients with end-stage liver disease.

The prevalence of coronary artery disease has increased in patients with end stage liver disease. In the near future, non-alcoholic steatohepatitis is expected to be the leading cause of end stage liver disease and shares common risk factors with coronary artery disease such as hypertension, hyperlipidemia, obesity and diabetes mellitus. At present, liver transplantation is the only definitive treatment for end stage liver disease, with post-operative mortality associated with the presence of coronary artery disease. Given the high prevalence of cardiovascular disease and the unique balance of pro-thrombotic and antithrombotic factors in patients with end stage liver disease, we sought to discuss the non-invasive and invasive diagnosis, medical and procedural management considerations and pre-transplant evaluation of coronary artery disease in patients with end stage liver disease.

Comparison of In-Hospital Outcomes and Readmission Rates of Transcatheter Aortic Valve Implantation in Mixed Aortic Valve Disease Versus Pure Aortic Stenosis.

Recently, transcatheter aortic valve implantation (TAVI) has been performed in patients with combined aortic stenosis (AS) and aortic regurgitation. We sought to evaluate in-hospital outcomes and readmission rates after TAVI in patients with mixed aortic valve disease (MAVD). A total of 100,573 TAVI procedures were identified between 2011 and 2017 using International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision procedure codes the from Nationwide Readmissions Database. We separated patients into 2 cohorts, those with MAVD and those with pure AS. The primary outcome was all-cause inpatient mortality after TAVI, and secondary outcomes included rates of 30- and 90-day readmissions and postprocedural complications. A total of 3,260 patients had MAVD (median age 83 years, 43.5% women). In-hospital mortality (2.5% vs 2.6%, p = 0.531) and rates of paravalvular leak (1.0% vs 1.3%, p = 0.056) were similar between the MAVD and pure AS groups. Major bleeding (7.4% vs 9.6%, p <0.001), 30-day readmission (0.5% vs 8.8%, p <0.001) and 90-day readmission rates (0.8% vs 16.0%, p <0.001), acute kidney injury (12.9% vs 15.1%, p <0.001), postoperative ischemic stroke (2.0% vs 5.7%, p <0.001), and mechanic circulatory support use (1.9% vs 4.5%, p <0.001) were less prevalent in the MAVD cohort. Using a multivariate logistic regression model to adjust for confounding factors, MAVD was not predictive of mortality in patients who underwent TAVI (adjusted odds ratio [adjOR] 1.25, 95% confidence interval [CI] 0.99 to 1.57, p = 0.056); however, MAVD was associated with: decreased odds of 30-day readmission (adjOR 0.05, 95% CI 0.03 to 0.08, p <0.001), 90-day readmission rates (adjOR 0.04, 95% CI 0.03 to 0.06, p <0.001), and higher odds of pacemaker implantation (adjOR 1.46, 95% CI 1.29 to 1.65, p <0.001). In conclusion, despite differences in the aortic valve and left ventricular anatomy (pressure vs volume-related adaptive changes) in patients with MAVD and pure AS, TAVI appears safe and feasible. However, patients with MAVD were more likely to have permanent pacemakers implanted. The results of our study warrant further randomized controlled studies to confirm these findings.