Statins are the most-effective therapy currently available for lowering the LDL-cholesterol (LDL-C) level and preventing cardiovascular events. Additional therapies are necessary for patients who cannot reach the target LDL-C level when taking the maximum-tolerated dose of a statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme with an important role in lipoprotein metabolism. Rare gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature coronary heart disease, whereas loss-of-function variants lead to a low LDL-C level and a reduced incidence of coronary heart disease. Furthermore, the PCSK9 level is increased with statin therapy through negative feedback, which promotes LDL-receptor degradation and decreases the efficacy of LDL-C lowering with statins. PCSK9 inhibition is, therefore, a rational therapeutic target, and several approaches are being pursued. In phase I, II, and III trials, inhibition of PCSK9 with monoclonal antibodies has produced an additional 50-60% decrease in the LDL-C level when used in combination with statin therapy, compared with statin monotherapy. In short-term trials, PCSK9 inhibitors were well tolerated and had a low incidence of adverse effects. Ongoing phase III trials will provide information about the long-term safety of these drugs, and their efficacy in preventing cardiovascular events.

Compared to controls, individuals with obesity and MS had increased fasting and postprandial monocyte lipid accumulation and activation.

Background and purpose Cerebrovascular and cardiovascular disease share common risk factors. Our goal was to determine if levels of N-terminal brain natriuretic peptide (NT-proBNP) and cardiac troponin T measured with a highly sensitive assay (hs-cTnT) are associated with silent brain infarcts (BI) and white matter lesions (WML) on magnetic resonance imaging (MRI) in the Atherosclerosis Risk In Communities (ARIC) study. Methods 1920 participants had brain MRI at ARIC visit 3 (1993–1995). NT-proBNP and hs-cTnT were measured in all individuals at ARIC visit 4 (1996-1998). Of 1920 individuals, 1112 had a follow-up MRI in 2004-2006. We analyzed the association of NT-proBNP and hs-cTnT with MRI-defined BI and WML on the initial MRI and incident BI and WML progression on the follow-up MRI in participants without heart failure, coronary heart disease, or stroke. Results In the adjusted model, individuals in the highest NT-proBNP quartile had significantly more BI (odds ratio [OR] 3.50, 95% confidence interval [CI]2.03-6.20) and WML (β-coefficient 0.09[standard error](SE) 0.03]) on the baseline MRI and more incident BI (OR 2.18, 95% CI [1.38-3.47]) and WML progression (β-coefficient 0.22 (SE 0.10)] on the follow-up MRI. Individuals in the highest hs-cTnT category had more BI (OR 3.03, 95% CI [1.57-5.82) and WML (β-coefficient 0.11 [SE 0.04]) on the initial MRI and more WML progression (β-coefficient 0.43 [0.17]) on the follow-up MRI. Conclusion NT-proBNP and hs-cTnT are independently associated with silent MRI-defined BI and WML suggesting that cardiovascular biomarkers may be useful to identify individuals with subclinical cerebral injury.

Background Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the association between Cp and incident heart failure (HF), death and CVD in the Atherosclerosis Risk in Communities (ARIC) Study. Methods and Results Cp was measured at ARIC visit 4 (1996–1998). We studied 9,240 individuals without HF or CVD at ARIC visit 4, and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF. Cp levels (mean±standard deviation) were higher in women vs men (335±79 vs 258±44 mg/L, p<0.0001), women on vs not on hormone-replacement therapy (398±89 vs 291±60 mg/L, p<0.0001) and African Americans vs Caucasians (299±63 vs 293±74 mg/L, p=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.13–1.83) and mortality (HR 1.38, 95% CI 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60mg/L, heterozygote 316.72±88.02mg/L; homozygote 331.04±85.40mg/L, p=8.3×10−) but not with incident HF. After adjustment for traditional risk factors Cp levels were also weekly associated with CVD. Conclusions Cp was associated with incident, HF mortality and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.

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Background:The ventriculophasic response (VR) refers to shortening of atrial cycle length during heart block when a QRS complex is interposed between P waves. No formal quantitative definition has heretofore been proposed, nor have its potential clinical correlations been studied. Hypothesis: We hypothesized that VR is present in selected patients who are distinguished by clinical features from those who lack VR. Methods: Pacing devices were temporarily programmed to VVI mode at 30 ppm as electrocardiogram and intracardiac electrograms were recorded at 50 mm/sec paper speed. We measured the percentage decrease in a P-P interval (A-A interval on the atrial electrogram) containing a QRS, compared to the preceding P-P interval. Left ventricular ejection fraction (LVEF) was measured by echocardiogram. Results: Shortening of P-P interval was observed chiefly when the interposed QRS occurred early in the anticipated P-P interval (as judged by the preceding P-P interval). P-P shortening of 0% to 3% occurred randomly. Defining VR as being a >3% P-P interval shortening when an interposed QRS occurred in the first 60% of the anticipated P-P interval, we found that VR was present in 28 (55%) of our patients. It was quite reproducible, was more common in women (81% vs 37% of men; P = 0.004), and positively correlated with LVEF (r = 0.41, P = 0.004). It did not correlate with age, diabetes, or β-blocker use. Conclusions: Using our newly derived definition of VR, we found the phenomenon was present in 55% of our patients. It was reproducible and more commonly seen in women and patients with LVEF ≥40%.

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VR, like SA, increases with deep breathing and likely reflects intact parasympathetic nervous system function. Its increase in the presence of narrower beats suggests it may reflect ventricular synchrony.