Primary Prevention Setting Research Articles

Cardiovascular disease in women: Do we need new diagnostic and therapeutic strategies?

Cardiovascular disease (CVD) is the leading cause of death worldwide affecting both genders equally. However, in comparison to men, in women it often is underrecognized and undertreated in both the primary and secondary prevention settings. It is clear, that in the healthy population, there are profound differences both anatomically and biochemically between woman and men and this may impact how both groups present when they become ill. Therefore, there are some diseases that affect more frequently in women than in men such us myocardial ischemia or infarction without obstructive coronary disease, Tako-subo syndrome, some atrial arrhythmias or the appearance of heart failure with preserved ejection fraction. Therefore, the diagnostic and therapeutic strategies that have been established based largely on clinical studies with a predominant male population must be adapted before being applied to women. There is a paucity of data regarding cardiovascular disease in women. It is inadequate to only perform a subgroup analysis evaluating a specific treatment or invasive technique, when women constitute fifty percent of the population. In this regard, this may affect the time of clinical diagnosis and severity assessments of some valvulopathies. In this review, we will focus on the differences in the diagnosis, management, and outcomes of woman with the most frequent cardiovascular pathologies including coronary artery disease, arrythmias, heart failure and valvopathies. In addition, we will describe diseases that exclusively affect to women related with the pregnancy some of them are life treating. Although the lack of research in women plays a role in the poorer outcomes in women specially in ischemic heart disease the results of some techniques such as transcathether aortic valve implantation and transcatheter edge to edge therapy seem to have better outcome in women.

Major hurdles to the use of tyrosine kinase inhibitors in clinical prevention/interception studies: Do preclinical studies with EGFR inhibitors suggest approaches to overcome some of the limitations.

There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth factor receptor (EGFR) inhibitors as examples, both in a primary prevention setting, where agent(s) are administered to individuals with no cancer but who might be considered at higher risk due to a variety of factors, and in anti-progression/interception studies, where agent(s) are administered to persons with known preinvasive lesions (e.g., colon adenomas, lung nodules, ductal carcinoma in situ (DCIS), or pancreatic intraepithelial neoplasia (PanIN) lesions in the pancreas) in an attempt to reverse or inhibit progression of these lesions. Multiple potential hurdles will be examined, including: a) toxicity of agents, b) the likely range of subtypes of cancers affected by a given treatment (e.g., EGFR inhibitors against EGFR mutant lung adenocarcinomas), c) the availability of practical endpoints besides the blocking of cancer formation or pharmacokinetics related to the agents administered in a primary prevention study, and d) the interpretation of the regression or blockage of new preinvasive lesions in the anti-progression study. Such an anti-progression approach may help address some of the factors commented on regarding primary prevention (toxicity, potential target organ cancer subtypes) but still leaves major questions regarding interpretation of modulation of preinvasive endpoints when it may not be clear how frequently they progress to clinical cancer. Additionally, we address whether certain recent preclinical findings might be able to reduce the toxicities associated with these agents and perhaps even increase their potential efficacy. Antibodies and TKIs other than the EGFR inhibitors are not discussed because few if any had been tested as monotherapies in humans, making their efficacy harder to predict, and because a number have relatively rare but quite striking toxicities. Furthermore, most of the practical hurdles raised regarding the EGFR inhibitors are relevant to the other TKIs. Finally, we briefly discuss whether early detection employing blood or serum samples may allow identification of high-risk groups more amenable to agents with greater toxicity.

Attainment of the low-density lipoprotein cholesterol treatment target and prognosis of heterozygous familial hypercholesterolemia

Background and aimsNo previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (<100 mg/dL) and secondary (<70 mg/dL) prevention settings. MethodsThe data of patients with FH who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. ResultsThe median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1000 person-years for LDL cholesterol levels of <100 and ≥100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1000 person-years for LDL cholesterol levels of <70 and ≥70 mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. ConclusionsAttainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.

An open-label study on the short-term effects of a novel EFSA-compliant nutraceutical combination in mild-to-moderate hypercholesterolemia.

Recently, the European Food Safety Authority (EFSA) has recommended to limit the use of total monacolins in red yeast rice (RYR) products to a dose <3 mg/day. However, data concerning the lipid lowering efficacy of the reduced dosage remain limited. A monacolin dose reduced due to safety issues may be expected to be less effective as a lipid lowering strategy and, for this reason, nutraceutical combinations with other active compounds may offer a viable solution as they can act synergistically through different mechanisms. This 8-week open-label study was designed to investigate the safety and efficacy of a novel ESFA-compliant lipid lowering nutraceutical combination (Colestarmony Plus®; containing total monacolins from RYR at a dose of 2.9 mg/day, a highly bioavailable berberine formulation, and pomegranate extract) in subjects (n=40) with mild-to-moderate hypercholesterolemia and no history of cardiovascular disease. After 8 weeks of supplementation, Colestarmony Plus® significantly reduced total cholesterol (-10.4%, p<0.05), low-density lipoprotein cholesterol (-14.8%, p<0.05), oxidized low-density lipoprotein cholesterol (-12.0%, p<0.05), and high-sensitivity C-reactive protein (-14.0%, p<0.05) compared with baseline values. A subgroup of 22 patients underwent measurements of flow-mediated dilation, with values increasing by 18.0% at 8 weeks with respect to baseline (p<0.05). The supplement was generally well-tolerated. Our short-term results indicate that the tested ESFA-compliant nutraceutical is effective in a primary prevention setting, even by providing only <3 mg/day of monacolins.

Carotid and femoral bruits as cardiovascular risk indicators in a middle-aged Finnish population: A 20-year prospective study.

Effective treatment and prevention of cardiovascular (CV) diseases requires reliable methods of assessing individual CV event risk. Although standardized risk calculators like Systematic Coronary Risk Evaluation (SCORE) are sufficient in most instances, sometimes more specific clinical examination is needed to determine the most optimal intervention and its intensity. To study whether carotid and femoral bruits provide prognostic information on CV events, CV mortality and all-cause mortality beyond traditional CV risk factors. 1045 subjects (49.8% men), aged 51.3 ± 5.97 years were clinically examined in the beginning of 1990's. The subjects were followed for over 20 years and data on CV events and causes of deaths was collected. During the follow-up period, 241 (23.1%) of the subjects died and 82 (34.6%) of the deaths were of CV origin. Carotid bruits were a significant risk factor for CV deaths only if subjects with previous CV events were included. After adjusting for age, sex, systolic blood pressure, smoking, diabetes, LDL cholesterol, coronary artery disease and stroke, carotid bruits posed a hazard ratio (HR) (95% confidence interval) of 4.15 (2.39-8.52) p<0.001 for CV deaths. After excluding subjects with previous CV events (after which n = 941) neither carotid nor femoral bruits were statistically associated with CV events or all-cause mortality. Adding carotid or femoral bruits in the baseline risk model with traditional CV risk factors did not improve C-statistic, reclassification, or discrimination of the subjects. Carotid and femoral bruits do not provide clinically useful information in a pure primary prevention setting. Carotid bruits might be useful in evaluating the overall CV risk in a population where recurrent CV events may occur.

Prolonged cardiac monitoring for stroke prevention: A systematic review and meta-analysis of randomized-controlled clinical trials.

Prolonged cardiac monitoring (PCM) substantially improves the detection of subclinical atrial fibrillation (AF) among patients with history of ischemic stroke (IS), leading to prompt initiation of anticoagulants. However, whether PCM may lead to IS prevention remains equivocal. In this systematic review and meta-analysis, randomized-controlled clinical trials (RCTs) reporting IS rates among patients with known cardiovascular risk factors, including but not limited to history of IS, who received PCM for more than 7 days versus more conservative cardiac rhythm monitoring methods were pooled. Seven RCTs were included comprising a total of 9048 patients with at least one known cardiovascular risk factor that underwent cardiac rhythm monitoring. PCM was associated with reduction of IS occurrence compared to conventional monitoring (Risk Ratio: 0.76; 95% CI: 0.59-0.96; I 2 = 0%). This association was also significant in the subgroup of RCTs investigating implantable cardiac monitoring (Risk Ratio: 0.75; 95% CI: 0.58-0.97; I 2 = 0%). However, when RCTs assessing PCM in both primary and secondary prevention settings were excluded or when RCTs investigating PCM with a duration of 7 days or less were included, the association between PCM and reduction of IS did not retain its statistical significance. Regarding the secondary outcomes, PCM was related to higher likelihood for AF detection and anticoagulant initiation. No association was documented between PCM and IS/transient ischemic attack occurrence, all-cause mortality, intracranial hemorrhage, or major bleeding. PCM may represent an effective stroke prevention strategy in selected patients. Additional RCTs are warranted to validate the robustness of the reported associations.

Abstract 10476: Impact of C-Reactive Protein Levels on Lipoprotein(a)-Associated Coronary Artery Disease and Aortic Stenosis Risk in Apparently Healthy Individuals

Introduction: Elevated Lipoprotein(a) (Lp[a]) levels are strongly and linearly associated with coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies in primary and secondary prevention settings revealed that Lp(a) and other CAD risk factors such as C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS risk is unknown. Methods: We investigated the long-term associations of Lp(a) with CAD and CAVS according to CRP levels in the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk study. Lp(a) and CRP levels were measured in 18,459 participants who were followed for 20 years. During the follow-up, 3915 and 418 participants had incident CAD and CAVS, respectively. Results: As presented in Figure 1, in comparison to individuals with low Lp(a) levels (&lt;30 mg/dL) and low CRP levels (&lt;2.0 mg/dL), those with elevated Lp(a) (&gt;30 mg/dL) and low CRP levels (&lt;2.0 mg/dL) and those with elevated Lp(a) (&gt;30 mg/dL) and elevated CRP levels (&gt;2.0 mg/dL) had a higher CAD risk (hazard ratio [HR] = 1.38 [95% CI, 1.28-1.49] and 1.93 [95% CI, 1.74-2.13] , respectively), and a higher CAVS risk (HR = 1.46 [95% CI, 1.08-1.98] and 1.87 [95% CI, 1.40-2.49], respectively). Conclusions: Results of this study confirm the joint association of high Lp(a) and CRP levels on incident CAD and extend these joint associations to valvular diseases such as CAVS. Lowering Lp(a) levels may warrant further investigation in the prevention of CAD and CAVS, especially in the context of systemic inflammation.

Increased residual cardiovascular risk in U.S. veterans with moderately-elevated baseline triglycerides and well-controlled LDL-C levels on statins

Recent studies have demonstrated a causal role for elevated triglycerides (TG) in incident cardiovascular (CV) events in patients with established coronary heart disease (CHD) and those with CV risk factors alone, particularly diabetes. Using a large cohort of U.S. veterans with statin-controlled LDL-C levels (40-100 mg/dL), we explored residual CV risk among patients with elevated baseline TG levels (150-499 mg/dL) vs. those with normal TG levels (<150 mg/dL). We identified veterans receiving a statin but not a TG-lowering agent from the VA electronic health records database, from 2010 to 2015. We compared composite CV event rates (MI, stroke, unstable angina, coronary revascularization, and CV death) between the elevated TG and normal TG groups. We stratified the study cohort according to 3 CV risk groups: (1) no diabetes and no prior CV event, (2) diabetes and no prior CV event, and (3) prior CV event. We calculated crude event rates, rate ratios, and event rate ratios adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. The cohort included 396,189 veterans (predominantly male and white) of whom 109,195 (28%) had elevated TG levels. Those with elevated TG were younger (age 73 vs. 77 years) and had a higher body mass index (31.3 vs. 28.3 Kg/M2). The overall composite crude and adjusted rate ratios comparing the elevated and normal TG groups were 1.10 (1.09, 1.12) and 1.05 (1.03, 1.06), respectively. For CV risk groups 1, 2 and 3, the adjusted rate ratios comparing the elevated and normal TG groups were 0.99 (0.96, 1.02), 1.05 (1.02, 1.08), and 1.07 (1.04, 1.10), respectively. An association of increased rate ratios did not hold for fatal events. Those with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in CV events compared to those with normal TG. Elevated TG levels were associated with increased CV events in patients with established CV disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.

Cardio-Ankle Vascular Index as an Arterial Stiffness Marker Improves the Prediction of Cardiovascular Events in Patients without Cardiovascular Diseases.

Several studies have reported that the cardio-ankle vascular index (CAVI), a non-invasive measurement of arterial stiffness, is associated with the incidence of cardiovascular events. We investigated whether adding CAVI to a risk score improves the prediction of cardiovascular events in the setting of primary prevention. This retrospective observational study included consecutive 554 outpatients with cardiovascular disease risk factors but without known cardiovascular disease (68 ± 9 years, 64% men). The CAVI was measured using the VaSera vascular screening system. Major adverse cardiovascular events (MACE) included cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization. During a median follow-up of 4.3 years, cardiovascular events occurred in 65 patients (11.7%). Multivariate Cox analysis showed that abnormal CAVI (&gt;9.0) was significantly associated with the incidence of MACE (hazard ratio 2.31, 95% confidence interval 1.27-4.18). The addition of CAVI to the Suita score, a conventional risk score for coronary heart disease in Japan, significantly improved the C statics from 0.642 to 0.713 (p = 0.04). In addition to a conventional risk score, CAVI improved the prediction of cardiovascular events in patients with cardiovascular disease risk factors but without known cardiovascular diseases.

Cardiometabolic characterization in metabolic dysfunction-associated fatty liver disease.

To better understand the patient's heterogeneity in fatty liver disease (FLD), metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed by international experts as a new nomenclature for nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the cardiovascular risk, assessed through coronary artery calcium (CAC) and epicardial adipose tissue (EAT), of patients without FLD and patients with FLD and its different subtypes. Cross sectional study of 370 patients. Patients with FLD were divided into 4 groups: FLD without metabolic dysfunction (non-MD FLD), MAFLD and the presence of overweight/obesity (MAFLD-OW), MAFLD and the presence of two metabolic abnormalities (MAFLD-MD) and MAFLD and the presence of T2D (MAFLD-T2D). MAFLD-OW included two subgroups: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). The patients without FLD were divided into 2 groups: patients without FLD and without MD (non-FLD nor MD; reference group) and patients without FLD but with MD (non-FLD with MD). EAT and CAC (measured through the Agatston Score) were determined by computed tomography. Compared with the reference group (non-FLD nor MD), regarding EAT, patients with MAFLD-T2D and MAFLD-MUHO had the highest risk for CVD (OR 15.87, 95% CI 4.26-59.12 and OR 17.60, 95% CI 6.71-46.20, respectively), patients with MAFLD-MHO were also at risk for CVD (OR 3.62, 95% CI 1.83-7.16), and patients with non-MD FLD did not have a significantly increased risk (OR 1.77; 95% CI 0.67-4.73). Regarding CAC, patients with MAFLD-T2D had an increased risk for CVD (OR 6.56, 95% CI 2.18-19.76). Patients with MAFLD-MUHO, MAFLD-MHO and non-MD FLD did not have a significantly increased risk compared with the reference group (OR 2.54, 95% CI 0.90-7.13; OR 1.84, 95% CI 0.67-5.00 and OR 2.11, 95% CI 0.46-9.74, respectively). MAFLD-T2D and MAFLD-OW phenotypes had a significant risk for CVD. MAFLD new criteria reinforced the importance of identifying metabolic phenotypes in populations as it may help to identify patients with higher CVD risk and offer a personalized therapeutic management in a primary prevention setting.

Ultra-sensitive troponin-I and incident coronary heart disease, stroke, heart failure, cardiac arrhythmias, arterial aneurysms and venous thromboembolism hospitalizations

Abstract Background Cardiac troponin I (cTnI) as measured by high-sensitive assays has been related to incident cardiovascular disease events (CVD) in the community. With the advent of ultra-sensitive assays, it is now possible to detect troponin I at very low concentration, far below the classical threshold of 1.9 pg/mL. However, the clinical relevance of these low concentrations for predicting CVD is largely unknown. Purpose To examine the association of cTnI as low as 0.013 pg/mL with incident cardiovascular disease events (CVDs) in the primary prevention setting. Methods cTnI was analyzed in the baseline plasma (2008–2012) of CVD free volunteers from the Paris Prospective Study III using for the first time a novel ultra-sensitive immunoassay (Simoa Troponin-I 2.0 Kit, Quanterix, Lexington) with a limit of detection (LOD) of 0.013 pg/mL. Incident CVD hospitalizations for coronary heart disease, stroke, arrhythmias, venous thromboembolism, arterial aneurysms and heart failure were validated by critical review of the hospital records. Hazard ratios were estimated per log-transformed standard deviation (SD) increase of cTnI in Cox models using age as the time scale. The added value (gain in discriminatory capacity) of cTnI for CVD risk prediction was examined by calculating the Harell's C-index boostraped difference of the SCORE 2 risk model with and without cTnI. Results There were 9503 CVD free participants (40% women) aged 59.6 (6.3) years at baseline. cTnI was detected in 99.6% of the participants (median value = 0.63 pg/mL, interquartile range [IQR] 0.39–1.09). After a median follow-up of 8.34 years (IQR, 8.0–10.07), 516 participants suffered 612 events. In fully-adjusted analysis, higher cTnI (per 1 SD increase of log cTnI) was significantly associated with CVD events combined (n=516, HR= 1.21; 1.06; 1.39). In univariate Cox analysis and compared to each single established risk factor, cTnI had the highest discrimination capacity for incident CVD events (C-index=0.6349) (Figure 1). Adding log cTnI to the SCORE 2 algorithm increased significantly albeit moderately discriminatory capacity (C-index 0.698 vs. 0.685; boostraped C index difference: 0.0135 (95% CI: 0.0131; 0.0138)). Conclusion cTnI concentrations as measured by a novel ultra-sensitive immunoassay is associated with a significant increased risk of incident CVD events in the primary prevention setting. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): ANR: French National Research AgencyEurope: Horizon 2020

The effect of achieving LDL-C &amp;lt;1.8 mmol/L to prevent the first atherosclerotic cardiovascular events in the primary prevention settings of severe heterozygous familial hypercholesterolemia

Abstract Introduction The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. LDL-C &amp;lt;2.5 mmol/l is a recommended therapeutic goal for the primary prevention settings of severe FH. However, given that ESC guidelines recommends LDL-C &amp;lt;1.8 mmol/l in FH patients, this stricter goal may be better to prevent the first atherosclerotic cardiovascular disease (ASCVD) in severe FH patients. Purpose To determine whether achieving LDL-C&amp;lt;1.8 mg/dl is more beneficial to reduce the first ASCVD events. Methods A total of 148 severe FH subjects without any history of ASCVD were analyzed. Severe FH was defined as untreated LDL-C &amp;gt;10.3 mmol/l, LDL-C &amp;gt;8.0 mmol/l+ 1 high-risk feature, LDL-C &amp;gt;4.9 mmol/l + 2 high-risk features according to IAS proposed statement. The occurrence of ASCVD (all-cause death, CAD, ischemic stroke and lower extremity artery disease (LEAD)) were compared in those with on-treatment LDL-C &amp;lt; and ≥1.8 mmol/L. Results 10.1% (=15/148) of study subjects achieved on-treatment LDL-C &amp;lt;1.8 mmol/l. They were more likely to receive PCSK9 inhibitor (15.0 vs. 66.7%, p&amp;lt;0.01), whereas there was no significant difference in FH-related physical characteristics (tendon xanthomas: 72.2 vs. 93.3%, p=0.12) and causative genotypes (LDLR: 68.4 vs. 66.7%, p=1.00, PCSK9: 8.3 vs. 6.7%, p=1.00, LDLR/PCSK9: 3.8 vs. 6.7%, p=0.48), untreated LDL-C (7.3±1.7 vs. 7.9±1.8 mmol/l, p=0.22) and lipoprotein(a) (23 [11–42] vs. 25 [15–70] mg/dl, p=0.41) levels between two groups. During the observational period (median=7.0 years), severe FH achieving on-treatment LDL-C &amp;lt;1.8 mmol/l was associated with a lower likelihood of experiencing ASCVD events (Figure 1). Of note, any cardiovascular events did not occur in severe FH who achieved on-treatment LDL-C &amp;lt;1.8 mmol/l. In those with on-treatment LDL ≥1.8 mmol/L, CAD (76.5%=26/34) was more dominant component of ASCVD, followed by ischemic stroke (17.6%=6/34) and LEAD (5.9%=2/34). Conclusions A significantly lower frequency of ASCVD was observed in severe FH who achieved LDL-C &amp;lt;1.8 mmol/L in the primary prevention settings. Given that only 10.1% of severe FH patients achieved LDL-C &amp;lt;1.8 mmol/l, more actions are required to motivate physicians for further intensified management of LDL-C in severe FH patients in the primary prevention settings. Funding Acknowledgement Type of funding sources: None.

C-reactive protein as a possible modifier of Lipoprotein(a)-related risk for coronary heart disease in Europe: results from the BiomarCARE project

Abstract Background Lipoprotein(a) (Lp(a)) represents a unique proatherogenic lipoprotein with potent pro-thrombotic and pro-inflammatory properties. Recent studies demonstrated that Lp(a)-associated risk for cardiovascular disease (CVD) was significantly increased only in individuals with a high inflammatory burden (i.e. hsCRP levels &amp;gt;2 mg/L). However, these results have been either based on a post-hoc analysis in a highly selected study population with a high/very high CVD risk, or conducted within a multi-ethnic population with significant variation in Lp(a) levels. Purpose The main aim was to investigate whether hsCRP concentration modulates the predictive value of Lp(a) for coronary heart disease (CHD) events in the general population across Europe. Methods Data of 87,760 participants from 10 European prospective population-based cohorts, participating in the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, were used for the present analysis (79,958 subjects without and 7,189 individuals with established CHD at baseline (primary/secondary prevention cohorts, respectively)). All Lp(a) measurements were performed in the central BiomarCaRE laboratory. Fine and Gray competing risk-adjusted models stratified by study cohort were calculated to assess the association between Lp(a) levels and future CHD events stratified according to hsCRP levels (&amp;lt;1 mg/l, ≥1–&amp;lt;2 mg/l and ≥2 mg/l). Results During a median follow-up of 11.3 years, 4,928 events occurred in the CHD-free subpopulation and 1,772 events occurred in the CHD subpopulation. In the primary prevention cohort, increased Lp(a) was significantly associated with future CHD events irrespective of hsCRP: Hazard ratios (HRs) for future CHD events (top vs bottom quintile (Q) of Lp(a) distribution) were 1.46 (95% CI: 1.21–1.78; p&amp;lt;0.001) in those having a hsCRP concentration &amp;lt;1 mg/l; 1.32 (95% CI: 1.09–1.61; p=0.0052) for a hsCRP group of ≥1-&amp;lt;2 mg/l and 1.40 (95% CI: 1.22–1.61; p&amp;lt;0.001) in subjects with a hsCRP concentration ≥2 mg/l, after multivariable adjustment for traditional CV risk factors including LDL-Ccorr and lipid-lowering medication. In contrast, in the secondary prevention, we found no association between increased Lp(a) levels and CHD events in individuals with a very low inflammatory burden (HR for hsCRP &amp;lt;1 mg/l 0.92 (95% CI 0.63–1.34), p=0.66, Q5 vs Q1)), whereas the association was significant among subjects with a hsCRP concentration ≥1 mg/l (HRs: 1.43 (95% CI: 1.01–2.03; p=0.045) for hsCRP group ≥1-&amp;lt;2 mg/l and 1.35 (95% CI: 1.07–1.71; p=0.013) for hsCRP group ≥2 mg/l (both for Q5 vs Q1)). Conclusion In a primary prevention setting, Lp(a) was associated with incident CHD irrespective of the inflammatory burden. In contrast, among subjects with known CHD, the association of Lp(a) and future CHD events was only present in those with hsCRP levels &amp;gt;1 mg/l. These findings might guide target population selection for upcoming Lp(a)-targeting compounds. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the 7th Framework Programme Collaborative Project (grant agreement no. HEALTH-F2-2011-278913). The MORGAM Project has received funding from EU projects MORGAM (Biomed, BMH4-CT98-3183), GenomEUtwin (Fifth Framework Programme FP5, QLG2-CT-2002-01254), ENGAGE (FP7, HEALTH-F4-2007-201413), CHANCES (FP7, HEALTH-F3-2010-242244), BiomarCaRE (FP7, HEALTH-F2-2011-278913), euCanSHare (Horizon 2020, No. 825903) and AFFECT-EU (Horizon 2020, No. 847770); and Medical Research Council, London (G0601463, No. 80983: Biomarkers in the MORGAM Populations).

Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes

BackgroundThe role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established. ObjectivesThis study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention. MethodsThe study analyzed 12,815 genotyped individuals ≥70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately. ResultsDuring a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P = 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk. ConclusionsAspirin may benefit older individuals with elevated lipoprotein(a) genotypes in primary prevention.

The burden of severe hypercholesterolemia and familial hypercholesterolemia in a population-based setting in the US

BackgroundContemporary prevalence, awareness, and control of severe hypercholesterolemia (SH) and familial hypercholesterolemia (FH) and the associated atherosclerotic cardiovascular disease risk in the US are unknown. MethodUsing electronic health records, we assessed the burden of SH and FH in Olmsted County, Minnesota, US, between 2004 and 2015. We defined SH as low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dl without secondary causes of hypercholesterolemia and FH as a Dutch Lipid Clinic Network score ≥6. Controls were age- and sex-matched individuals with LDL-C level <190 mg/dl. ResultsThe age- and sex-adjusted point and period prevalence (age-recursive method) of SH was 4.44% and 8.95%, respectively; 1 in 21 had FH (∼1:233 adults), and 46.2% had a recorded diagnosis. Guideline recommended targets (LDL-C <100 mg/dl and <70 mg/dl in the primary and secondary prevention settings, respectively) were achieved in 33.1% and 21.2% of SH cases, with less women overall achieving the target than men (18.6% vs. 23.7%, p=0.022). After adjustment for conventional risk factors, the hazard ratio for incident coronary heart disease (CHD) in those with SH was 1.21 (1.05-1.39; p=0.010), in those with SH and a family history of CHD was 2.16 (1.57-2.96; p<0.001) and in those with FH was 4.61 (2.66-7.97; p<0.001). The association of SH with CHD was modified by age (p-interaction = 0.015), such that the risk was greater at younger ages. ConclusionsSH was prevalent and an independent risk factor for incident CHD. Awareness and control were low, highlighting a treatment gap (more prominent in women) that needs to be addressed.

Analysis Of Physiological Determinants During A Single Bout Of German Volume Training

While resistance training (RT) has been proposed as a useful adjunct in a primary prevention setting and rehabilitation context, the exact application of training intensity and volume for maximal therapeutic effects is still unclear. In this regard, German Volume Training (GVT), or the 10 sets method, has been utilized by athletes for decades and may prove a safe and effective method in improving strength and cardiorespiratory endurance, and modifying coronary risk factors. PURPOSE: To determine the physiological determinants during a single bout of German Volume Training. METHODS: Using a within-group design, untrained healthy males (n = 19; mean age: 22 ± 1 years) served as their own inactive controls prior to engaging in a single one-hour bout of GVT consisting of leg press, chest press, latissimus dorsi pull-downs and shoulder press for 10 sets of 10 repetitions each with a 60-second rest between sets and a three-minute rest period between exercises. Differences from pre- to post-test were examined using t-tests with alpha levels set at p ≤ 0.05. RESULTS: An acute bout of GVT significantly (p ≤ 0.05) decreased systolic blood pressure (SPB) (from 119 ± 9 mmHg to 110 ± 9 mmHg; p = 0.042), diastolic BP (DBP) (from 77 ± 10 mmHg to 68 ± 10 mmHg; p = 0.037) and mean arterial pressure (MAP) (from 91 ± 9 mmHg to 82 ± 8 mmHg; p = 0.028), but increased rate pressure product (RPP) (from 8370 ± 826 to 12332 ± 1602; p = 0.008). Increases were observed in carbon dioxide production (VCO2) (from 0.34 ± 0.09 L.min-1 to 0.65 ± 0.32 L.min-1; p = 0.021). No changes were found in any of the measured spirometry parameters. CONCLUSION: This study suggests that GVT is of sufficient safety and provides the appropriate intensity to be included in general primary prevention and rehabilitation settings.

Clinical utility of simple subjective gait speed for the risk stratification of heart failure in a primary prevention setting

Little is known regarding the relationship between self-reported gait speed and the subsequent risk of heart failure (HF) and cardiovascular disease (CVD). We sought to clarify the clinical utility of self-reported gait speed in primary CVD prevention settings. This is an observational cohort study using the JMDC Claims Database, which is an administrative health claims database. Data were collected between January 2005 and April 2020. Medical records of 2,655,359 participants without a prior history of CVD were extracted from the JMDC Claims Database. Gait speed was assessed using information from questionnaires provided at health check-ups, and study participants were categorized into fast or slow gait speed groups. The primary outcome was HF. The secondary outcomes included myocardial infarction (MI), angina pectoris (AP), and stroke. The median age was 45.0 years, and 55.3% of participants were men. 46.1% reported a fast gait speed. The mean follow-up period was 1180 ± 906 days. HF, MI, AP, and stroke occurred in 1.9%, 0.2%, 1.9%, and 1.0% of participants, respectively. Multivariable Cox regression analyses showed that, compared with slow gait speed, fast gait speed was associated with a lower incidence of HF, MI, AP, and stroke. The discriminative predictive ability for HF significantly improved by adding self-reported gait speeds to traditional risk factors (net reclassification improvement 0.0347, p < 0.001). In conclusion, our analysis demonstrated that subjective gait speed could be a simple method to stratify the risk of HF and other CVD events in the general population. Further investigations are required to clarify the underlying mechanism of our results and to develop a novel approach for primary CVD prevention.

Standardized measurement of abdominal muscle by computed tomography: association with cardiometabolic risk in the Framingham Heart Study

ObjectivesTo provide a standard for total abdominal muscle mass (TAM) quantification on computed tomography (CT) and investigate its association with cardiovascular risk in a primary prevention setting.MethodsWe included 3016 Framingham Heart Study participants free of cardiovascular disease (CVD) who underwent abdominal CT between 2002 and 2005. On a single CT slice at the level of L3/L4, we segmented (1) TAM-Area, (2) TAM-Index (= TAM-Area/height) and, (3) TAM-Fraction (= TAM-Area/total cross-sectional CT-area). We tested the association of these muscle mass measures with prevalent and incident cardiometabolic risk factors and incident CVD events during a follow-up of 11.0 ± 2.7 years.ResultsIn this community-based sample (49% women, mean age: 50.0 ± 10.0 years), all muscle quantity measures were significantly associated with prevalent and incident cardiometabolic risk factors and CVD events. However, only TAM-Fraction remained significantly associated with key outcomes (e.g., adj. OR 0.68 [0.55, 0.84] and HR 0.73 [0.57, 0.92] for incident hypertension and CVD events, respectively) after adjustment for age, sex, body mass index, and waist circumference. Moreover, only higher TAM-Fraction was associated with a lower risk (e.g., adj. OR: 0.56 [0.36–0.89] for incident diabetes versus TAM-Area: adj. OR 1.26 [0.79–2.01] and TAM-Index: 1.09 [0.75–1.58]).ConclusionTAM-Fraction on a single CT slice at L3/L4 is a novel body composition marker of cardiometabolic risk in a primary prevention setting that has the potential to improve risk stratification beyond traditional measures of obesity.Key Points• In this analysis of the Framingham Heart Study (n = 3016), TAM-F on a single slice CT was more closely associated with prevalent and incident cardiometabolic risk factors as compared to TAM alone or TAM indexed to body surface area.• TAM-F on a single abdominal CT slice at the level of L3/L4 could serve as a standard measure of muscle mass and improve risk prediction

Dietary influence on physical functioning in the Women’s Health Initiative (WHI) randomized Dietary Modification (DM) trial.

10552 Background: In the WHI DM randomized trial, randomization to the dietary intervention group was associated with a 21% lower breast cancer mortality (P = 0.02) (JCO 2020), and while not an intervention target, with higher physical activity as well. Therefore, we examined whether these lifestyle changes attenuate age-related physical functioning decline. Methods: From 1993-1998, 48,835 postmenopausal women, aged 50-79 years, were randomized to dietary intervention or usual diet comparison groups through 8 years intervention and 19 years cumulative follow-up. Breast cancer findings, as primary outcome, have been reported. Physical functioning was assessed using the RAND 36-Item Short Form Health Survey (SF-36), which assessed limitations of 10 hierarchical physical activities, scored from 0 to 100, with a higher score indicating less limited physical function. The trajectory of longitudinal physical functioning was the primary study outcome, assessed by comparing findings in the two randomization groups, overall, and by baseline physical activity and age decade. Additionally, findings were reported against a disability threshold (when assistance in daily activities is required). Results: Physical functioning was assessed nearly half a million times during the study (n = 495,317) with 11.0 (median) assessments per participant. Physical functioning score was significantly better in the intervention versus comparison groups during the 8-year intervention and extended follow-up through 12 years (median) (P = 0.001), representing a reduction in age-related functional decline. The intervention effect subsequently lost significance at 19 years and both randomization groups crossed the disability threshold at similar times. Differences between randomization groups in physical functioning emerged after stratification by physical activity and age decade (P-interaction = 0.007). Among all participants physically active at entry, the intervention initially had a statistically significant, favorable influence on physical functioning which attenuated post-intervention. In contrast, among younger, physically inactive women 50-59 years of age, the intervention had a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold. Conclusions: In the primary prevention setting of the WHI DM randomized trial, with long-term follow-up, a dietary intervention which has been shown to reduce breast cancer mortality also significantly reduced age-related functional decline through 12 years. Among all participants, the intervention effect was attenuated with longer follow-up. However, reduction in age-related functional decline was sustained in younger women in the intervention group who were inactive at entry, a potential target population for future behavior interventions. Clinical trial information: NCT00000611.

More Than Just the Target: Blood Pressure, Stroke, and Vascular Cognitive Impairment.

Despite effective treatments, hypertension remains a leading risk factor of any stroke, stroke recurrence, and vascular cognitive impairment. Hypertension is underdiagnosed and undertreated, both in the primary and secondary prevention setting. The current issue of Stroke includes a Focused Update series of 6 review articles covering differing aspects of hypertension and cerebrovascular disease. Traditionally, the goal of antihypertensive treatment has been risk reduction through reaching defined targets, a "one-size-fits-all" approach, both in the acute stroke and in secondary prevention. In this series, there is a shift toward a more individualized approach to blood pressure management in patients suffering from stroke or vascular cognitive impairment, taking several factors in addition to a defined target into account.