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Background: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. the primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 mu m/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 mu m/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: the extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials., Austrian Science Fund (FWF)Austrian Science Fund (FWF) [P 32488]; Dr-Johannes-and-Hertha-Tuba Foundation; German Research FoundationGerman Research Foundation (DFG) [DFG Lo 1569/2-1, DFG Lo 1569/2-3]; excellence initiative "Competence Centers for Excellent Technologies" (COMET) of the Austrian Research Promotion Agency (FFG) "Research Center of Excellence in Vascular Ageing: Tyrol, VAS-Cage" - Bundesministerium fur Verkehr, Innovation und Technologie (B [843536]; Bundesministerium fur Bildung, Wissenschaft und Forschung (BMWFW); Wirtschaftsagentur Wien; Standortagentur Tirol, This work was supported by the Austrian Science Fund (FWF; P 32488); the Dr-Johannes-and-Hertha-Tuba Foundation; the German Research Foundation (DFG Lo 1569/2-1 and DFG Lo 1569/2-3); and the excellence initiative "Competence Centers for Excellent Technologies" (COMET) of the Austrian Research Promotion Agency (FFG) "Research Center of Excellence in Vascular Ageing: Tyrol, VAS-Cage" (K-Project No. 843536), funded by Bundesministerium fur Verkehr, Innovation und Technologie (BMVIT), Bundesministerium fur Bildung, Wissenschaft und Forschung (BMWFW), Wirtschaftsagentur Wien, and Standortagentur Tirol.

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Background— Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin. Methods and Results— Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5. Conclusions— Our data elucidate a unique molecular mechanism by which ticks inhibit the host’s coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors.

Background— Although the vasculoprotective effects of apolipoprotein A-I (apoA-I), the major protein associated with high-density lipoprotein, have been universally accepted, apoA-II has been suggested to have poor antiatherogenic or even proatherogenic properties. To study this suggestion more closely, we evaluated how serum levels of apoA-II and apoA-I relate to the risk of future coronary artery disease (CAD) in a large, prospective study. Methods and Results— We performed a nested case-control study in the prospective EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition–Norfolk) cohort. Case subjects (n=912) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Control subjects (n=1635) were matched by age, gender, and enrollment time. Conditional logistic regression was used to quantify the relationship between serum apoA-II levels and risk of CAD. Serum apoA-II concentration was significantly lower in case subjects (34.5±6.3 mg/dL) than in control subjects (35.2±5.8 mg/dL) and was inversely associated with risk of CAD, such that patients in the upper quartile (>38.1 mg/dL) had an odds ratio of 0.59 (95% confidence interval 0.46 to 0.76) versus those in the lowest quartile (P for linearity P for linearity P for linearity P for linearity 0.02). Conclusions— ApoA-II is associated with a decreased risk of future CAD in apparently healthy people. These findings imply that apoA-II itself exerts effects on specific antiatherogenic pathways. On the basis of these findings, discussion of the potential proatherogenic effects of apoA-II can cease.

Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for familial hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these familial hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase N G -monomethyl- l -arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P P ≤0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.3±0.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both P ≤0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol. Conclusions— In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to by impaired basal and stimulated NO bioactivity. Strikingly, both parameters were completely restored after a single, rapid infusion of apoA-I/PC. These findings indicate that in addition to its long-term role within reverse cholesterol transport, HDL per se also exerts direct beneficial effects on the arterial wall.

Background— A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed. Methods and Results— Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol. The type of mutation did not influence HDL cholesterol levels. Patients with FH had CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95% CI, 5.29 to 13.80). The N543H/2393del9 mutation was associated with a smaller increase of risk compared with other mutations ( P Conclusions— LDL receptor mutations only partly contributed to the variation of LDL cholesterol levels and cardiovascular burden in FH. Additional, so far unidentified, familial risk factors must underlie the differences of CVD risk, most likely independent of lipids and lipoproteins.

Background— The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. Methods and Results— In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 μg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F 1+2 ), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. Conclusions— rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Background — Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results — In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity ( P P P =0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions — We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects ( P =0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

Background— Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results— A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals ( P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance ( P =0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions— The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Background— Low plasma levels of cholesteryl ester transfer protein (CETP) are associated with elevated levels of HDL cholesterol (HDL-C), but it remains unclear whether this translates into a concomitant reduction in the risk of coronary artery disease (CAD). Evidence exists that the effect of CETP depends on metabolic context, in particular on triglyceride levels. Methods and Results— A nested case-control study was performed in the prospective EPIC-Norfolk cohort study. Cases were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during follow-up. Control subjects were matched by age, sex, and enrollment time. CETP levels were not significantly different between cases and controls (4.0±2.2 versus 3.8±2.1 mg/L, P =0.07). CETP levels were significantly related to plasma levels of total cholesterol, LDL cholesterol, and HDL-C. The risk of CAD increased with increasing CETP quintiles ( P for linearity=0.02), such that subjects in the highest quintile had an adjusted OR of 1.43 (95% CI 1.03 to 1.99, P =0.03) versus those in the lowest. Among individuals with triglyceride levels below the median (1.7 mmol/L), no relationship between CETP levels and CAD risk was observed ( P for linearity=0.5), but this relationship was strong among those with high triglyceride levels ( P for linearity=0.02), such that those in the highest CETP quintile had an OR of 1.87 (95% CI 1.06 to 3.30, P =0.02). Conclusions— Elevated CETP levels are associated with an increasing risk of future CAD in apparently healthy individuals, but only in those with high triglyceride levels.

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)–TIMI 48 trial (NCT00781391) of edoxaban versus warfarin. Methods: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS 2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin. Results: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71–0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41–0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81–0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63–0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding. Conclusions: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Background: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). Methods: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C Results: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15–1.92; P -trendP P -homogeneity=0.0053); results were consistent for triglycerides ( P -homogeneity=0.0101) and directionally similar for non–high-density lipoprotein cholesterol ( P -homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86–1.00; P =0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; P =0.0008). Conclusions: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

Background: Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in cardiovascular trials and research. This study aims at a better understanding of lifestyle and genetic factors that affect LDL-C in young women. Methods: We randomly selected for every year of age 8 women with LDL-C ≤1st percentile (≤50 mg/dL) and 8 women with LDL-C ≥99th percentile (≥186 mg/dL) from 28 000 female participants aged between 25 to 40 years of a population-based cohort study. The resulting groups include 119 and 121 women, respectively, of an average 33 years of age. A gene-sequencing panel was used to assess established monogenic and polygenic origins of these phenotypes. Information on lifestyle was extracted from questionnaires. A healthy lifestyle score was allocated based on a recently developed algorithm. Results: Of the women with LDL-C ≤1st percentile, 19 (15.7%) carried mutations that are causing monogenic hypocholesterolemia and 60 (49.6%) were genetically predisposed to low LDL-C on the basis of an extremely low weighted genetic risk score. In comparison with control groups, a healthier lifestyle was not associated with low LDL-C in women without genetic predispositions. Among women with LDL-C ≥99th percentile, 20 women (16.8%) carried mutations that cause familial hypercholesterolemia, whereas 25 (21%) were predisposed to high LDL-C on the basis of a high-weighted genetic risk score. The women in whom no genetic origin for hypercholesterolemia could be identified were found to exhibit a significantly unfavorable lifestyle in comparison with controls. Conclusions: This study highlights the need for early assessment of the cardiovascular risk profile in apparently healthy young women to identify those with LDL-C ≥99th percentile for their age: first, because, in this study, 17% of the cases were molecularly diagnosed with familial hypercholesterolemia, which needs further attention; second, because our data indicate that an unfavorable lifestyle is significantly associated with severe hypercholesterolemia in genetically unaffected women, which may also need further attention.

Background: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to-day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes. Methods: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m 2 , an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes. Results: We included 574 subjects with 9776 twenty-four–hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165–170 mmol), was equal among all methods ( P =0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short-term (1-year) and long-term (5-year) follow-up instead of baseline estimations. Conclusions: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual’s sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes.

Background: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. Methods: Children with HeFH (age, 6–4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6–P values were adjusted for age, sex, carotid artery site, and family relations. Results: At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively; P =0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030–0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095–0.0192) in unaffected siblings ( P =0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively; P =0.2). Conclusions: In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01078675.

Background: Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so-called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events, and all-cause mortality in patients randomized to different SBP targets. Methods: Data from 2 large randomized trials that randomly allocated hypertensive patients at high risk for cardiovascular disease to intensive (SBP Results: The pooled data consisted of 194 875 on-treatment SBP measurements in 13 946 patients (98.9%). During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%), and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J curve was present, with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher body mass index, smoked more often, and had a higher frequency of diabetes mellitus and cardiovascular events. Conclusions: Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure–lowering treatment can be established only via randomized clinical trials. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01206062 and NCT00000620.

Supplemental Digital Content is available in the text., Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein–mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Background: Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. Methods: The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. Results: The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%–28%), varying from 30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be 30% in 9% of the patients (median, 11%; interquartile range, 7%–17%). Conclusions: Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk 20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

Background— Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients. Methods and Results— Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 μg/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%; P =0.0108) and Day 35 (7.2% versus 4.1%; P =0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 ( P =0.017) and D-dimer concentration with VTE risk up to Day 35 ( P =0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group. Conclusions— Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00571649.

Low-density lipoproteins (LDLs) are a proven causal risk factor for the development of atherosclerotic cardiovascular disease. Plasma levels of LDL cholesterol (LDL-C) and its major protein, apolipoprotein B (apoB), are positively associated with incident cardiovascular events.1 Individuals with genetic conditions of extremely high LDL-C develop premature cardiovascular disease; conversely, those with genetically low LDL-C are protected from cardiovascular disease. Interventions that reduce LDL-C, including statins and bile acid sequestrants, are proven to reduce cardiovascular risk.2 Indeed, therapy to reduce LDL-C is a cornerstone of the treatment and primary prevention of atherosclerotic cardiovascular disease. Despite the commercial availability of 3 major classes of LDL-lowering drugs (statins, bile acid sequestrants, and a cholesterol absorption inhibitor), a substantial unmet need has remained with regard to LDL-lowering treatment. Some patients are intolerant of statins because of myalgias. Others have genetic conditions that substantially elevate their LDL-C and make it challenging to achieve desirable LDL-C levels even with combination therapy. Perhaps the single best example of a genetic condition in which patients frequently fail to achieve acceptable LDL-C levels despite aggressive therapy is familial hypercholesterolemia (FH).3,4 This condition, classically caused by loss-of-function mutations in the LDL receptor,5 is associated with substantially elevated LDL-C and premature atherosclerotic cardiovascular disease. Patients with heterozygous FH typically have untreated LDL-C levels in the range of 200 to 400 mg/dL, and many cannot achieve desirable LDL-C levels on available combination therapy. Patients with 2 mutant LDL receptor alleles have homozygous FH (hoFH) with LDL-C levels usually >400 mg/dL and cannot achieve desirable LDL-C levels on available therapy. There are other causes of autosomal-dominant hypercholesterolemia4 resulting from mutations in the receptor-binding region of apoB (the ligand for the LDL receptor) and gain-of-function mutations in PCSK9 (a protein that targets the LDL receptor for degradation), …

We thank Dr Koh for his comments on our article1 and his remarks on the new 2017 American College of Cardiology/American Heart Association hypertension guideline. In this new guideline, the systolic blood pressure (SBP) target is set to

Background— It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and Results— We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38 153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72–0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels Conclusions— Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Article, see p 698 It was the Norwegian Internist Carl Muller who, almost a century ago, wrote about his observation that patients with xanthomas and lipoidosis were “at risk of dying suddenly and unexpectedly, apparently with symptoms of paralysis of the heart.”1 He was among the first not only to describe the association, but also to suggest that lipoidosis was causally related to premature cardiovascular disease (CVD). Prospective observational studies conducted in the 1950s further bolstered the hypothesis that dyslipidemia, characterized by high levels of low-density lipoprotein-cholesterol (LDL-C), are a major cause of CVD.2 Forty years later, in 1994 to be precise, another Norwegian, cardiologist Terje Pedersen, closed the loop on the LDL-hypothesis by demonstrating in the Scandinavian Simvastatin Survival Study (4S) that statin therapy decreased both total and cardiovascular mortality.3 Since that time, the pathophysiologic role of LDL-C in atherosclerosis has been defined and the molecular basis unraveled for familial hypercholesterolemia (FH), the genetic disease underlying the triad described by Muller. More recently, the heterozygous form of FH (heFH) was shown to be much more prevalent than previously anticipated, and it is remarkable to observe the similarity in these novel prevalence estimates of 1:200 to 250, irrespective of the geographic region (the United States, Denmark, or The Netherlands) or the method of defining heFH.4–6 Many studies, including our own, have shown unequivocally that coronary risk is 3.5- to 16-fold increased in patients with heFH compared with individuals without non-FH, and the severity of the underlying mutation is considered to be a major determinant of the observed variation in risk for CVD.4,5 A crucial question is whether the presence of a genetic defect per se adds to the risk prediction based on LDL-C levels and, in their seminal article, Khera and …

Background— Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this “residual risk” have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors. Methods and Results— A total of 9251 coronary patients with low-density lipoprotein cholesterol 2 ), male sex (aHR, 1.33; 95% CI, 1.07–1.65), hypertension (aHR, 1.38; 95% CI, 1.17–1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11–1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11–1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03–1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70–0.94), aspirin use (aHR, 0.67; 95% CI, 0.56–0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84–0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679). Conclusions— Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT00327691.

Background— Homozygous or double heterozygous factor V Leiden and/or prothrombin G20210A is a rare inherited thrombophilic trait. Whether individuals with this genetic background have an increased risk of recurrent venous thrombosis is uncertain. Methods and Results— A case-control design within a large cohort of families with thrombophilia was chosen to calculate the risk of recurrent venous thrombosis in individuals with homozygosity or double heterozygosity of factor V Leiden and/or prothrombin G20210A. Cases were individuals with recurrent venous thrombosis, and controls were those with only 1 venous thrombosis. The cohort consisted of 788 individuals with venous thrombosis; 357 had factor V Leiden, 137 had prothrombin G20210A, 27 had factor V Leiden and/or prothrombin G20210A homozygosity, and 49 had double heterozygosity for both mutations. We identified 325 cases with recurrent venous thrombosis and 463 controls with only 1 venous thrombosis. Compared with noncarriers, crude odds ratio for recurrence was 1.2 (95% confidence interval, 0.9 to 1.6) for heterozygous carriers of factor V Leiden, 0.7 (95% confidence interval, 0.4 to 1.2) for prothrombin G20210A, 1.2 (95% confidence interval, 0.5 to 2.6) for homozygous carriers of factor V Leiden and/or prothrombin G20210A, and 1.0 (95% confidence interval, 0.6 to 1.9) for double heterozygotes of both mutations. Adjustments for age, sex, family status, first event type, and concomitance of natural anticoagulant deficiencies did not alter the risk estimates. Conclusions— In this study, individuals with homozygous factor V Leiden and/or homozygous prothrombin G20210A or double heterozygous carriers of factor V Leiden and prothrombin G20210A did not have a high risk of recurrent venous thrombosis.

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Background— Reactive oxygen species have been implicated in the pathogenesis of ischemia/reperfusion (IR) injury. Recent studies suggest that NADPH oxidase may be a source of ROS during IR. Using an in vivo model of endothelial IR injury in the arm, we compared the response to IR in healthy volunteers with that in patients with chronic granulomatous disease. These patients have a molecular lesion in a subunit of NADPH oxidase that renders the enzyme inactive. Methods and Results— Flow-mediated dilatation was used to assess endothelial function in patients with X-linked (NOX2) or autosomal (p47) chronic granulomatous disease. IR injury was induced by 20 minutes of upper limb ischemia followed by reperfusion. Flow-mediated dilatation was determined before IR and after 20 minutes of reperfusion. The response to IR in chronic granulomatous disease patients was compared with that in age- and sex-matched healthy control subjects. Flow-mediated dilatation was expressed as mean and compared statistically with mixed linear models. IR caused a significant reduction in flow-mediated dilatation in control subjects (−5.1%; 95% confidence interval, 6.3 to 3.%; P P =0.12; n=11). Similarly, IR-induced reduction in flow-mediated dilatation was not observed in p47-chronic granulomatous disease patients (−1.5%; 95% confidence interval, −3.1 to 0.2; P =0.08; n=6) in contrast to healthy control subjects (−6.5%; 95% confidence interval, −8.2 to −4.9%; P Conclusions— These data indicate, for the first time in humans in vivo, that reactive oxygen species produced by NADPH oxidase are determinants of endothelial function after IR injury in humans. These findings have implications for the design of strategies to limit clinical IR injury.

Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P =0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Background— We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8- to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results— All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions— These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence.

There is much current interest in the potential of cholesteryl ester transfer protein (CETP) inhibition as a strategy to reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). There is also great uncertainty. On the one hand, there is a large body of circumstantial evidence suggesting that inhibition of CETP is antiatherogenic and will protect against the development of ASCVD. On the other hand, 2 human clinical outcome trials with CETP inhibitors have failed. However, as outlined below, because of major problems with these 2 human clinical trials, the hypothesis has not been refuted and it remains unknown whether or not CETP inhibition reduces ASCVD risk. This is something we really need to know. The answer will emerge with the results of 2 large ongoing clinical outcome trials designed to test the hypothesis that CETP inhibition reduces ASCVD risk. Response by Hovingh et al on p 432 There is a possibility that the current level of uncertainty about CETP inhibition may impact adversely on the retention of participants in these ongoing clinical trials and thus reduce their power to provide an answer. We believe that everything possible must be done to ensure that the ongoing clinical outcome trials are allowed to proceed to completion with minimal dropout to provide confidence in the result. The purpose of this article is to summarize the large body of evidence showing that CETP inhibition is protective and that continuation of the ongoing trials to completion is essential. To present this evidence, this article addresses a series of fundamental questions. 1. What exactly is the function of CETP? 2. What is the rationale for inhibiting CETP as a strategy to reduce ASCVD risk? 3. What is the relationship between CETP and atherosclerosis in animal studies? 4. What is the relationship between the genetics and activity of CETP and atherosclerosis …

Background— Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB. Methods and Results— This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% ( P =0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C ( P =0.001). LDL-C and apoB remained significantly below baseline ( P Conclusions— Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.

Background— The lipid-lowering effects of statin therapy show considerable interindividual variation in patients with familial hypercholesterolemia (FH). Whether the type of LDL receptor mutation predicts the response to statin treatment is not yet established. We analyzed the relationship between LDL receptor genotype and response to pravastatin treatment in children with FH using carotid intima-media thickness (IMT) to measure efficacy. Methods and Results— In a randomized, placebo-controlled, double-blind, 2-year trial with pravastatin, 193 children had genetically confirmed FH and were included in the present substudy. At baseline, children with null alleles had higher LDL cholesterol levels (difference, 0.94±0.19 mmol/L [SEM]; P P =0.02) compared with children with receptor-defective mutations. The decrease in carotid IMT during the trial was not significantly different in children with null alleles and receptor-defective mutations (0.018±0.012 and 0.012±0.010 mm; 2-way ANCOVA, P =0.7). After 2 years of treatment, the children with null alleles continued to have greater carotid IMT than children with receptor-defective mutations (difference, 0.016±0.01 mm; P =0.02). LDL cholesterol lowering tended to be less in carriers of null alleles compared with carriers of receptor-defective mutations (1.30±0.25 and 1.85±0.20 mmol/L; 2-way ANCOVA, P =0.08). Conclusions— In FH children, we found that the null allele genotype was associated with a greater carotid IMT, higher LDL cholesterol levels, and a nonsignificant tendency to attenuated LDL cholesterol lowering compared with receptor-defective mutations. Null alleles identify FH patients at the highest cardiovascular disease risk who may benefit from more aggressive treatment started in childhood.

Background— In patients with a malignant hypertension, immediate parenteral treatment with blood pressure–lowering agents such as intravenous sodium nitroprusside (SNP) is indicated. In this study, we evaluated static and dynamic cerebral autoregulation (CA) during acute blood pressure lowering with SNP in these patients. Methods and Results— In 8 patients with mean arterial pressure (MAP) >140 mm Hg and grade III or IV hypertensive retinopathy at hospital admission, middle cerebral artery blood velocity (MCA V) and blood pressure were monitored. Dynamic CA was expressed as the 0.1-Hz MCA V mean to MAP phase lead and static CA as the MCA V mean to MAP relationship during SNP treatment. Eight normotensive subjects served as a reference group. In the patients, the MCA V mean to MAP phase lead was lower (30±8° versus 58±5°, mean±SEM; P mean decrease was 22±4%, along with a 27±3% reduction in MAP (from 166±4 to 121±6 mm Hg; P −1 · % mm Hg −1 ; r =0.70±0.07). Conclusions— In patients with malignant hypertension, dynamic CA is impaired. An MCA V mean plateau was not detected during the whole SNP treatment, indicating loss of static CA as well. This study showed that during the whole rapid reduction in blood pressure with SNP, MCA V mean decreases almost one on one with MAP.

Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.

Background — After experimental carotid sinus denervation in animals, blood pressure (BP) level and variability increase markedly but normalize to preoperative levels within 10 to 14 days. We investigated the course of arterial BP level and variability after bilateral denervation of the carotid sinus baroreceptors in humans. Methods and Results — We studied 4 women (age 41 to 63 years) who were referred for evaluation of arterial baroreflex function because of clinical suspicion of carotid sinus denervation attributable to bilateral carotid body tumor resection. The course of BP level and variability was assessed from repeated office and 24-hour ambulatory measurements (Spacelabs/Portapres) during 1 to 10 years of (retrospective) follow-up. Rapid cardiovascular reflex adjustments to active standing and Valsalva’s maneuver were assessed. Office BP level increased from 132/86 mm Hg (range, 118 to 148/80 to 92 mm Hg) before bilateral surgery to 160/105 mm Hg (range, 143 to 194/90 to 116 mm Hg) 1 to 10 years after surgery. During continuous 24-hour noninvasive BP recording (Portapres), a marked BP variability was apparent in all 4 patients. Initial symptomatic hypotension on change to the upright posture and abnormal responses to Valsalva’s maneuver were observed. Conclusions — Acute carotid sinus denervation, as a result of bilateral carotid body tumor resection, has a long-term effect on the level, variability, and rapid reflex control of arterial BP. Therefore, in contrast to earlier experimental observations, the compensatory ability of the baroreceptor areas outside the carotid sinus seems to be of limited importance in the regulation of BP in humans.

Most acute coronary syndromes are caused by intracoronary thrombus superimposed on disrupted atherosclerotic plaque. Platelets adhere to subendothelial proteins exposed at sites of plaque disruption where they become activated, release vasoactive and procoagulant substances, and aggregate.1 Tissue factor in the lipid-rich core of the plaque initiates coagulation, which leads to thrombin generation. A potent platelet agonist, thrombin recruits additional platelets to the site of vascular injury. Thrombin also converts fibrinogen to fibrin, which serves to stabilize platelet-rich thrombi formed at sites of plaque disruption. Depending on the extent and duration of coronary artery obstruction, clinical manifestations range from unstable angina to acute myocardial infarction.1 Aspirin and heparin, the cornerstones of therapy for acute coronary syndromes, reduce the risk of myocardial infarction and death.2,3⇓ Despite the widespread use of these treatments, however, patients with unstable angina or acute myocardial infarction remain at risk for recurrent ischemic events, suggesting that intracoronary thrombus formation is incompletely attenuated by aspirin and heparin. High concentrations of thrombin are generated by tissue factor exposed at sites of arterial injury.4 When bound to fibrin,5,6⇓ fibrin degradation products,7 or subendothelial matrix,8 thrombin is resistant to inactivation by the heparin/antithrombin complex. Bound thrombin, which remains enzymatically active, triggers thrombus growth by activating factors V, VIII, and XI,9 thereby amplifying thrombin generation. Bound thrombin also activates platelets,10 at least in part, via thromboxane A2-independent pathways that are not blocked by aspirin. Because thrombin plays a central role in arterial thrombogenesis, the goal of most treatment regimens is to block thrombin generation or inhibit its activity. Direct thrombin inhibitors were developed to overcome the inability of the heparin/antithrombin complex to inactivate bound thrombin. In contrast to heparin and low-molecular-weight heparin, which catalyze the inactivation of thrombin by antithrombin, …

Background— A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol–lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). Methods and Results— A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (−41%), total cholesterol (−31%), apolipoprotein B (−34%), VLDL cholesterol (−21%), and triglyceride (−9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. Conclusions— Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

Over the past 3 decades, we have witnessed in the Western world a remarkable reduction in morbidity and mortality resulting from coronary heart disease (CHD). For example, in Finland, the dramatic decrease in CHD mortality is estimated to be ≈50%, at least one third of which can be accredited to a reduction in cholesterol levels in the general population.1 An even more impressive reduction in the incidence of cardiovascular events has been observed among patients with prevalent CHD, as can be deduced from a comparison between the control arm of one of the earliest statin trials, the Scandinavian Simvastatin Survival Study (4S),2 and the aggressive lipid-lowering arm of one of the latest intervention trials, the Treating to New Targets (TNT) study.3 Major cardiovascular events occurred in 36.2% of patients in the placebo arm of 4S and in 8.7% of patients in the intensive lipid-lowering arm of TNT, an astounding 76% relative risk reduction that occurred in the last 15 years. Among patients with type 2 diabetes, another highly prevalent and high-risk population, a similarly impressive risk reduction was achieved with an intensified multifactorial intervention.4 However, a cursory glance at the event rates in the experimental arms of these trials alerts us to the fact that even under current state-of-the-art treatment, cardiovascular events are still common. This leaves us with a large and unmet medical need to develop new strategies to combat atherosclerotic vascular disease, and this quest often starts with the identification of novel cardiovascular risk factors as potential targets. In the mid 1990s, inflammation was introduced as a novel dimension in atherogenesis. Since then, we have seen an impressive range of publications about inflammatory molecules as novel risk markers, most prominently C-reactive protein, myeloperoxidase, and lipoprotein-associated phospholipase A2 (Lp-PLA2). The development of small molecules specifically …

Background— Clinicians need to identify coronary artery disease patients for whom the benefits of high-dose versus usual-dose statin therapy outweigh potential harm. We therefore aimed to develop and validate a model for prediction of the incremental treatment effect of high-dose statins for individual patients in terms of reduction of 5-year absolute risk for myocardial infarction, stroke, coronary death, or cardiac resuscitation. Methods and Results— Based on data from the Treating to New Targets trial (TNT; n=10 001), a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (ie, atorvastatin 80 mg or 10 mg). External validation in the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL; n=8888) confirmed adequate goodness-of-fit and calibration, but moderate discrimination (C-statistic, 0.63; 95% confidence interval, 0.62–0.65). Still, among participants of both trials combined, the model identified a group of 11.7% whose predicted 5-year number needed to treat was ≤25 and a group of 41.9% whose predicted needed to treat was ≥50. A decision curve shows that making treatment decisions on the basis of predictions using our model may improve net benefit. Conclusions— Estimation of the incremental treatment effect of high-dose versus usual-dose statin therapy in individual coronary artery disease patients enables selection of high-risk patients that benefit most from more aggressive therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00327691 and NCT00159835.

Background— Despite effective treatment with anticoagulants, 2% to 7% of patients with pulmonary embolism will die as a result of their disease. Methods and Results— We examined in 110 consecutive patients with pulmonary embolism whether plasma brain natriuretic peptide (BNP), a novel marker of (right) ventricular dysfunction, is a predictor of fatal pulmonary embolism. The relationship between BNP concentration measured at presentation and clinical outcome was assessed by comparing the proportion of outcome events among tertiles. Positive and negative predictive values of BNP levels in the highest and lowest tertiles were calculated. The risk of death related to pulmonary embolism if the BNP level is >21.7 pmol/L is 17% (95% CI, 6% to 33%). The negative predictive value for uneventful outcome of a BNP value Conclusion— This is the first study to show that plasma BNP levels seem to predict adverse outcome in patients with acute pulmonary embolism.

Background— Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD. Methods and Results— To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; P P = 0.001). Conclusion— The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P P P =0.002) and normalized with PCC (114±26%; P Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR2272.

Background— High-density lipoproteins have antidiabetic properties in vitro. Furthermore, elevated high-density lipoprotein levels accompanying a genetic deficiency of cholesteryl ester transfer protein are associated with decreased levels of plasma glucose. We now investigate effects on glucose homeostasis of inhibiting cholesteryl ester transfer protein with torcetrapib. Methods and Results— A post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was conducted to investigate effects of the cholesteryl ester transfer protein inhibitor torcetrapib on glycemic control in the 6661 diabetic patients in the trial. At baseline, there were no differences between the 2 treatment arms with respect to plasma glucose, insulin, hemoglobin A 1c , or the homeostasis model assessment of insulin resistance. After 3 months, the diabetic subjects taking the combination of torcetrapib plus atorvastatin had plasma glucose levels 0.34 mmol/L lower ( P P P 1c level in the atorvastatin arm was 7.29% compared with 7.06% in the torcetrapib/atorvastatin arm ( P Conclusions— Treatment with torcetrapib improves glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus. It remains to be determined whether this effect is the consequence of raising high-density lipoprotein.at Clinical Trial Registration— http:www.clinicaltrials.gov . Unique identifier: NCT00134264.

Background— Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non–high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and Results— A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 (“Treating to New Targets”) and 8888 (“Incremental Decrease in End Points through Aggressive Lipid Lowering”) patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. Conclusions— In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.

To the Editor: Kashani et al1 report that in randomized trials, statin therapy (with the exclusion of cerivastatin) did not result in significant absolute increases in myalgias (risk difference per 1000 patients, 2.7 (95% CI, −3.2 to 8.7), or mild creatine kinase …

Background— The patency of AV expanded polytetrafluoroethylene (ePTFE) grafts for hemodialysis is impaired by intimal hyperplasia (IH) at the venous outflow tract. The absence of a functional endothelial monolayer on the prosthetic grafts is an important stimulus for IH. In the present study, we evaluated the feasibility of capturing endothelial progenitor cells in vivo using anti-CD34 antibodies on ePTFE grafts to inhibit IH in porcine AV ePTFE grafts. Methods and Results— In 11 pigs, anti-CD34–coated ePTFE grafts were implanted between the carotid artery and internal jugular vein. Bare ePTFE grafts were implanted at the contralateral side. After 3 (n=2) or 28 (n=9) days, the pigs were terminated, and the AV grafts were excised for histological analysis and SEM. At 3 and 28 days after implantation, 95% and 85% of the coated graft surface was covered by endothelial cells. In contrast, no cell coverage was observed in the bare graft at 3 days, whereas at 28 days, bare grafts were partly covered with endothelial cells (32%; P =0.04). Twenty-eight days after implantation, IH at the venous anastomosis was strongly increased in anti-CD34–coated grafts (5.96±1.9 mm 2 ) compared with bare grafts (1.70±0.4 mm 2 ; P =0.03). This increase in IH coincided with enhanced cellular proliferation at the venous anastomosis. Conclusions— Autoseeding with anti-CD34 antibodies results in rapid endothelialization within 72 hours. Despite persistent endothelial graft coverage, IH at the outflow tract is increased profoundly at 4 weeks after implantation. Further modifications are required to stimulate the protective effects of trapped endothelial cells.

Background— The patency of arteriovenous (AV) expanded polytetrafluoroethylene (ePTFE) hemodialysis grafts is severely compromised by intimal hyperplasia (IH) at the venous anastomosis and in the venous outflow tract. We addressed the potential of primary placement of a sirolimus-eluting stent (SES) in a validated porcine model. Methods and Results— In 25 pigs, ePTFE AV grafts were created bilaterally between the carotid artery and the jugular vein, whereupon a self-expandable nitinol stent (14 SESs and 11 bare-metal stents) was implanted over the venous anastomosis in 1 of the 2 grafts. After exclusion of technical failures and 1 unilateral occlusion, 16 pigs (9 SESs and 7 bare-metal stents) were included for further analysis. After 28 days, we measured graft flow and performed quantitative angiography. The pigs were then euthanized, and grafts with adjacent vessels were excised for histological analysis. Minimal luminal diameter was substantially larger in the SES group compared with unstented controls (5.9±0.2 versus 3.8±0.4 mm, respectively, P =0.01), which was accompanied by more prominent graft flow (SES, 1360±89 mL/min versus unstented, 861±83 mL/min, P =0.05). IH at the venous anastomosis was 77% less in the SES group compared with unstented controls (0.44±0.05 versus 1.92±0.5 mm 2 , respectively, P =0.01), whereas IH increased markedly when bare-metal stents were used (5.7±1.4 mm 2 , P =0.05). Conclusions— SESs in the venous outflow of AV grafts significantly reduce IH and increase vessel diameter and graft flow compared with unstented grafts. These findings suggest that SESs have the potential to improve primary patency of AV grafts in hemodialysis patients.

To the Editor: Juul et al1 describe the interesting observation that low serum insulin-like growth factor-I (IGF-I) and high IGF-binding protein-3 (IGFBP-3) are associated with an increased occurrence of cardiovascular disease. In line with their observation, we recently demonstrated that low plasma IGF-I levels were associated with postprandial dyslipidemia and insulin resistance. Postprandial dyslipidemia is an atherogenic risk factor, and this postprandial period is dominated by triglyceride-rich particles (TRPs) and high atherogenic TRP remnants, such as the remnant-like particle (RLP). Fasting and postprandial plasma RLP cholesterol (RLP-C) levels in heterozygous familial hypercholesterolemia have been reported by our group to be an additional factor in the atherogenic lipoprotein.2,3 The postprandial accumulation of RLP-C in adult growth hormone (GH)-deficient subjects is inversely associated with pretreatment plasma IGF-I levels; consequently, the lower the serum IGF-I level, the higher the postprandial RLP-C load.4 It is established that GH directly affects the expression of the hepatic low-density lipoprotein receptors and of key enzymes implicated in bile acid metabolism with effects on the intracellular cholesterol homeostasis in the liver; such homeostasis is linked to metabolism of TRPs. Consequently, the question arises whether the pituitary GH secretion capacity in the participants of the report by Juul et al1 may be impaired. Additionally, knowledge about free IGF-I levels, and thus the biological active form, in the population studied by Juul et al is of major importance to more precisely understand their reported positive associations. Most circulating IGF-I is bound to IGFBP-3. Consequently, proteolysis of IGFBP-3 modulates the IGF bioavailability. In insulin-resistant subjects, the proteolysis of IGFBP-3 is increased, and this regulation mechanism for free exchangeable IGF-I in circulation keeps the IGF/intact IGFBP-3 ratio constant. A low total IGF level in insulin resistance may therefore have no …