Razvan T. Dadu

Lipid lowering with PCSK9 inhibitors

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.

Cardiovascular Biomarkers and Subclinical Brain Disease in the Atherosclerosis Risk in Communities Study

Background and Purpose— Cerebrovascular and cardiovascular disease share common risk factors. Our goal was to determine whether 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 (BIs) and white matter lesions (WMLs) on MRI in the Atherosclerosis Risk in Communities (ARIC) study. Methods— At ARIC visit 3 (1993–1995), 1920 participants had brain MRI. 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 [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, 3.50; 95% confidence interval, 2.03–6.20), and WML (&bgr;-coefficient, 0.09; SE, 0.03) on the baseline MRI and more incident BI (odds ratio, 2.18; 95% confidence interval, 1.38–3.47) and WML progression (&bgr;-coefficient, 0.22; SE, 0.10) on the follow-up MRI. Individuals in the highest hs-cTnT category had more BI (odds ratio, 3.03; 95% confidence interval, 1.57–5.82) and WML (&bgr;-coefficient, 0.11; SE, 0.04) on the initial MRI and more WML progression (&bgr;-coefficient, 0.43; SE, 0.17) on the follow-up MRI. Conclusions— 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.

Developing and assessing cardiovascular biomarkers

Atherosclerosis is a slow process that over time can lead to fatal events. Early identification and prediction of future risk can allow for preventive strategies to be instituted. There is an increasing interest in utilizing novel biomarkers in cardiovascular disease screening and management. These novel biomarkers may help in cardiovascular disease risk assessment and treatment monitoring, and some may be treatment targets. To be useful for risk prediction, novel biomarkers need to show a significant association with cardiovascular disease events and bring additional value in risk stratification when added to known risk prediction models. Biomarkers used for treatment monitoring need to show that they can serve as good surrogates of cardiovascular disease status. In this article, we present 3 biomarkers that are currently approved by the U.S. Food and Drug Administration for use in cardiovascular disease management and risk assessment: C-reactive protein, lipoprotein-associated phospholipase A2, and myeloperoxidase. Other new biomarkers have also been shown recently to help in cardiovascular disease risk prediction and management. In this article, we will review 2 of these new biomarkers: cardiac troponin T measured by a highly sensitive assay and brain natriuretic peptide.

Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities Study

Background—Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the associations 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 9240 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 in ARIC participants. Cp levels (mean±SD) were higher in women versus men (335±79 versus 258±44 mg/L; P<0.0001), women on versus not on hormone-replacement therapy (398±89 versus 291±60 mg/L; P<0.0001), and African Americans versus whites (299±63 versus 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, 1.44; 95% confidence interval, 1.13–1.83) and mortality (hazard ratio, 1.38; 95% confidence interval, 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60 mg/L; heterozygote 316.72±88.02 mg/L; homozygote 331.04±85.40 mg/L; P=8.3×10–13) 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.

Isolated Perforation of Left Coronary Cusp after Blunt Chest Trauma

Left coronary cusp perforation is an extremely rare consequence of blunt chest trauma. A 22-year-old male presented after a motor vehicle accident with dyspnea. Transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) showed moderate to severe aortic regurgitation with prolapsing right coronary cusp. In the operating room he was found to have a left coronary cusp tear near the annulus and an enlarged right cusp. The patient recovered well after successful aortic valve replacement with a mechanical valve. Traumatic aortic regurgitation with left cusp perforation is serious and surgical intervention may be lifesaving if performed timely.

IMPACT OF GENDER ON DOOR TO BALLOON TIME IN STEMI

Delay in door to balloon time (DTBT) is generally associated with worse morbidity and mortality. Women have longer DTBT compared to men. This study aimed to assess system and clinical factors associated with this disparity in care. A cohort of STEMI patients presenting to a large tertiary hospital

Medical Management of Serum Lipids and Coronary Heart Disease

Hypercholesterolemia is a well-known risk factor for atherosclerosis. Atherosclerosis and its consequences have a global impact on health and the economy. Recognizing patients at risk for cardiovascular disease (CVD) is the initial and critical step in the management of dyslipidemia. Many prospective randomized clinical trials have shown that lowering of cholesterol levels, specifically low-density lipoprotein cholesterol levels, offers a clear benefit for preventing future CVD events. Statins, fibric acid derivatives, nicotinic acid, cholesterol absorption inhibitors, bile acid sequestrants, and omega-3 fatty acids are the major classes of medications used in the management of dyslipidemia. Statins are the cornerstone of therapy for the primary and secondary prevention of CVD. Other therapies have also been shown to have beneficial effects on lipoproteins. The United States Food and Drug Administration recently approved two new agents, mipomersen and lomitapide, for use in individuals with homozygous familial hypercholesterolemia.

Integration of Biomarkers with Plaque Imaging

The clinical utility of a biomarker in cardiovascular disease prediction depends on its ability to identify high-risk individuals for optimal patient management. While circulating biomarkers are relatively inexpensive and easy to measure repeatedly and monitor for changes, they are not as specific and reliable for identifying high-risk plaques as imaging techniques. Data are now accumulating on the potential clinical utility of integrating imaging technologies and circulating biomarkers for the identification of patients at high risk for future cardiovascular events. The combination of biomarkers that are already used in cardiovascular disease prevention with imaging data may improve our ability to identify high-risk patients. Molecular imaging is a new approach that uses biomarkers as target for imaging. Molecular imaging may help in identification of new cellular processes that are closer to the mechanism of a therapeutic intervention than other biomarkers or clinical endpoints and, therefore, facilitate the in vivo evaluation of drugs with novel mechanisms in small, rapid trials.