JCL Roundtable: Global Think Tank on Lipoprotein(a).

Lipoprotein(a) operates in causal pathways to promote atherosclerosis, arterial thrombosis, and aortic stenosis. It has been associated with rare cases of nonatherosclerotic arterial thrombotic stroke at any age. Inherited variation of lipoprotein(a) levels substantially increases cardiovascular risk in 20% of people worldwide. Recent progress in identifying the risk associated with lipoprotein(a) and in pursuing effective treatment has led to a recent Global Think Tank including representatives from the European Atherosclerosis Society, American Heart Association, Preventive Cardiovascular Nurses Association, National Lipid Association, and other groups. The need for standardized laboratory measurement in nanomoles per liter met with unanimous consensus. Atherosclerotic risk is linearly associated with plasma lipoprotein(a) levels, so that persons with the highest levels may have risk similar to other severe inherited lipoprotein disorders. Universal once-in-lifetime screening has been recommended by European and Canadian cardiovascular societies, but not by U.S. organizations. Current pharmacologic therapies are limited to 20-30% lowering of lipoprotein(a) levels, and no pharmacologic treatment for lowering lipoprotein(a) has yet been proven to reduce risk in a cardiovascular outcomes trial. Treatment for high-risk patients focuses on reducing low density lipoprotein cholesterol and other risk factors. New therapies targeting messenger RNA for apolipoprotein(a) can achieve 80-90% reduction of lipoprotein(a) levels. One such therapy using a liver-directed antisense oligonucleotide is currently being tested in a large cardiovascular outcomes trial. Increased recognition of lipoprotein(a)-associated risk and emergence of potentially effective therapy together lead to a mandate for a unified global effort on education, standardization, and clinical management.

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial.

Importance: Current guidelines for atherosclerotic cardiovascular disease focus on high-intensity statins and targeting or using a threshold low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL for the highest-risk patients. Whether further reduction of LDL-C beyond these boundaries would be beneficial is unknown. Objective: To compare outcomes of evolocumab vs placebo in patients with stable atherosclerotic cardiovascular disease and a baseline LDL-C of less than 70 mg/dL and in those receiving background treatment with a maximal-potency statin. Design, Setting, and Participants: This secondary ad hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial compared randomized treatments in 2 subgroups of patients with stable atherosclerotic cardiovascular disease currently receiving statin. Patients were classified by a baseline LDL-C of less than 70 or at least 70 mg/dL and by statin intensity (maximal: atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d; submaximal: all other dosages). Patients with baseline LDL of less than 70 mg/dL either had a final screening LDL-C of at least 70 mg/dL or a final screening non-high-density lipoprotein cholesterol level of at least 100 mg/dL. Data were retrieved from 2013 to 2016 and analyzed in 2017 based on intention to treat. Main Outcomes and Measures: The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. Safety outcomes included adverse events and events of interest identified in the FOURIER trial. Interaction testing was used to assess the consistency of results in patients who did vs did not satisfy the above criteria. Results: A total of 27 564 patients (75.4% men and 24.6% women; mean [SD] age, 62.5 [9.0] years) were included in the analysis. Of 2034 patients (7.4%) who had a baseline LDL-C of less than 70 mg/dL, evolocumab reduced the risk for the primary endpoint (hazard ratio [HR], 0.80; 95% CI, 0.60-1.07) to a similar degree as in the 25 529 patients who had baseline LDL-C of at least 70 mg/dL (HR 0.86; 95% CI, 0.79-0.92; P = .65 for interaction; 1 patient was missing baseline LDL-C data). Of 7533 patients (27.3%) receiving maximal-potency statins, evolocumab significantly reduced the primary endpoint (HR, 0.86; 95% CI, 0.75-0.98) to a similar degree as in the 20 031 patients not receiving a maximal-potency statin (HR, 0.85; 95% CI, 0.78-0.93; P = .88 for interaction). The key secondary endpoint was reduced to a similar degree in both analyses. No major safety concerns were identified. Conclusions and Relevance: Evolocumab was equally effective in reducing cardiovascular events in patients with stable atherosclerotic cardiovascular disease regardless of whether the baseline LDL-C was less than 70 or at least 70 mg/dL and whether the background statin was of maximal or submaximal potency.

Serum PON-1 activity but not Q192R polymorphism is related to the extent of atherosclerosis.

AIM: Paraoxonase-1 (PON1) is an antioxidant enzyme located in high density lipoprotein (HDL). PON1 was defined as a protective factor against atherosclerosis. The aim of this study was to investigate the possible relationship between serum paraoxonase (PONase), homocysteine thiolactonase (HTase) activities and PON1 Q192R polymorphism, and the extent and severity of atherosclerosis. METHODS: Blood specimens were collected from 142 individuals who had no coronary artery lesions angiographically (control group) and 128 individuals who had angiographically documented coronary artery disease of several degrees (patient group). The extent and severity of arterial lesions were evaluated by the Gensini scoring system. PONase and HTase activities were measured in serum using a spectrophotometric method. PON1 Q192R polymorphism was evaluated using PCR-RFLP after DNA isolation from blood. RESULTS: Serum PONase and HTase activities were significantly lower in the patient group than in healthy controls (135.7±56.0U/mL vs 153.8±62.0U/mL, p< 0.05; 36.0±6.1 U/mL vs 43.0±4.04 U/mL, p< 0.01; respectively). In the patient group, there was a negative correlation between PONase, HTase activities and the Gensini score (r=-0.168, p= 0.039; r=-0.164, p= 0.006, respectively). In both groups, there was no significant difference in the distribution of PON1 Q192R polymorphism. In the patient group, the distribution of Gensini scores according to genotypes was not significant. CONCLUSION: It has been concluded that serum PONase and HTase activities might be a more relevant marker than PON1 genotype in evaluating the extent and severity of atherosclerosis.

Evaluation of the impact of treatment on endothelial function and cardiac performance in acromegaly.

OBJECTIVE: To evaluate the effects of treatment on left ventricular (LV) performance and endothelial function in patients with acromegaly. METHOD: Nineteen patients with active acromegaly (AA), 18 patients with cured/well-controlled acromegaly (CA), and 25 healthy control subjects were studied. LV performance was evaluated by two-dimensional/Doppler echocardiography and Doppler tissue imaging (TDI). Flow-mediated dilatation (FMD) was measured by B-mode ultrasound. Endothelial cell markers; thrombomodulin (TM), and P-selectin were also measured. RESULTS: Tei index was higher than the control subjects in both acromegaly groups. The ratio of early and late diastolic annular velocities (Em'/Am') was significantly lower in the AA group than the other groups (P < 0.05). FMD in both acromegaly groups was significantly lower than the controls (P < 0.001) but difference between acromegaly groups was not significant (P > 0.05). In the CA group, P-selectin was higher than the controls and was even higher in the AA (P < 0.05). TM was significantly higher in the active group (P < 0.05) and not different than the controls in the CA group. CONCLUSION: TDI determine LV performance changes in acromegaly earlier than conventional echocardiographic methods. Endothelial function both in the form of FMD and endothelial cell markers is impaired in acromegaly. While in cured acromegaly endothelial cell injury, as evidenced by TM levels, is decreased, endothelial dysfunction still persists.

Plasma myeloperoxidase is related to the severity of coronary artery disease.

OBJECTIVE: It has been shown that the main apolipoprotein of HDL, Apo A-1, is subjected to nitration by myeloperoxidase (MPO) and this oxidative modification renders HDL proatherogenic. The aim of this study is to evaluate the relationship between plasma MPO levels, and the severity of coronary artery disease. METHODS AND RESULTS: Forty-eight patients with coronary artery narrowing and 30 control subjects were enrolled in this study. The severity of the disease was assessed by Gensini scoring after angiography. MPO concentrations were determined by using an enzyme immunoassay. A subgroup of 30 patients underwent computerized tomography to determine the calcium load of coronary arteries. Plasma MPO levels were found significantly higher in patients with coronary artery disease than controls (4.27 [1.60 to 42.43] ng/mL vs. 2.93 [1.00 to 9.25] ng/mL, P = 0.002). MPO was positively correlated with both Gensini (r = 0.228, P = 0.044) and coronary calcium scores (r = 0.433, P = 0.017). The atherosclerotic burden was more strongly correlated with MPO levels than the traditional markers such as total cholesterol and HDL. CONCLUSIONS: We found that MPO levels were elevated in patients with coronary artery disease and this increase correlated with the extent and severity of atherosclerosis. Although it is a preliminary study with a relatively small group of subjects, we suggest that MPO might be evaluated as a new marker indicating the presence and severity of coronary artery disease.

Hyperhomocysteinemia is associated with the presence of left atrial thrombus in stroke patients with nonvalvular atrial fibrillation.

BACKGROUND AND PURPOSE: Blood stasis is the fundamental mechanism leading to thrombus formation in the venous system. Homocysteine also poses a significant risk for venous thrombosis through its endothelial toxic and prothrombotic properties. In the present study, we hypothesized that high homocysteine might be associated with thrombus formation in another stasis-related condition, atrial fibrillation. METHODS: Forty-two consecutive patients with ischemic stroke caused by nonvalvular atrial fibrillation and admitted within the first day of symptom onset were included. Total fasting plasma homocysteine, serum folic acid, and vitamin B12 levels were measured. All patients were evaluated by transesophageal echocardiography for the presence of a left atrial (LA) thrombus. Homocysteine and vitamin levels were compared between groups with or without LA thrombus. RESULTS: Transesophageal echocardiography revealed LA thrombus in 20 patients. Mean homocysteine levels were significantly higher in patients with LA thrombus (20.75 versus 13.34 micromol/L, P<0.001). Multivariate logistic regression analysis showed that the effect of high homocysteine was independent of other clinical or echocardiographic variables known to increase LA thrombus (P=0.017). There was no difference in vitamin B12 levels between groups (P=0.118), whereas the mean folic acid level was significantly lower in patients with LA thrombus (P=0.004). CONCLUSIONS: High plasma homocysteine conveys an independent risk for LA thrombus formation in patients with stroke caused by nonvalvular atrial fibrillation. This finding further supports the thrombogenic role of high homocysteine in conditions associated with blood stasis.

Angiotensin-converting enzyme genotype predicts valve damage in acute rheumatic fever.

BACKGROUND AND AIM OF THE STUDY: The genetic basis for host susceptibility to subsequent valve damage and scarring is not well defined in patients with a history of acute rheumatic fever (ARF). A high angiotensin-converting enzyme (ACE) activity has been demonstrated in valve tissue; hence, the study aim was to determine whether the ACE-DD genotype was a predisposing factor to heart valve damage after ARF attack. METHODS: A total of 165 patients diagnosed previously (16 +/- 5 years ago) with ARF was evaluated. Diagnoses were conducted according to Jones' criteria, and all received similar treatment and remain on regular penicillin prophylaxis. The ACE genotype was determined using polymerase chain reaction methods. RESULTS: Echocardiography showed that 39 patients (11 males, 28 females; mean age 25 +/- 6 years) had completely normal valves, and 126 patients (38 males, 88 females; mean age 21 +/- 6 years) had valve disease. The mitral valve was involved in 93% of patients (stenosis 86%, regurgitation 69%), and the aortic valve in 50% (stenosis 19%, regurgitation 48%). The ACE-DD genotype is associated with a significantly greater risk of valve involvement (risk ratio 2.7, 95% CI 1.15-6.5, p = 0.02). The distribution of genotypes was similar between aortic and mitral valve involvement. CONCLUSION: In patients with acute rheumatic fever the ACE-DD genotype is associated with an increased risk of subsequent heart valve damage.