Brian G. Choi

Normalization of platelet reactivity in clopidogrel-treated subjects.

Summary.  Background: Aspirin (ASA) + clopidogrel are commonly used in acute coronary syndrome (ACS), but persistent antiplatelet effects may complicate surgery.Methods and Results: To study the possibility of normalizing platelet reactivity after ASA + clopidogrel treatment, 11 healthy subjects received a 325‐mg ASA + clopidogrel loading dose (300 or 600 mg dependent on study arm), followed by 81 mg of ASA + 75 mg of clopidogrel daily for 2 days. Platelet reactivity was assessed by light transmittance aggregometry (LTA) [challenged by adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thrombin receptor activating peptide (TRAP)] and flow cytometry for platelet activation by GPIIb/IIIa receptor exposure pretreatment, 4 and 72 h postload. To normalize platelet reactivity, increasing amounts of pooled platelets from five untreated volunteers [volunteers (V)‐platelet‐rich plasma (PRP)] were added ex vivo to the subjects PRP (S‐PRP). At both 4 and 72 h, 40% and 50% V‐PRP were needed to overcome platelet disaggregation in the 300 or 600 mg arms, respectively, after ADP challenge; an additional 10% V‐PRP fully normalized aggregation. Recovery of function was linear with each incremental increase of V‐PRP. ADP‐induced GPIIb/IIIa activation showed the same pattern as LTA (r = 0.74). Forty percent V‐PRP was required to normalize platelet function to AA, collagen, and TRAP.Conclusion: Our results suggest that the pre‐operative transfusion of 10 platelet concentrate units (the equivalent of 40% V‐PRP) after a 300‐mg clopidogrel loading or 12.5 units (50% V‐PRP) after a 600 mg loading may adequately reverse clopidogrel‐induced platelet disaggregation to facilitate postoperative hemostasis. An additional 2.5 units fully normalized platelet function. The potential clinical implications of our observations could include shorter hospitalizations and reduced bleeding complications. But these observations should be fully explored in an in vivo clinical setting with clopidogrel‐treated patients before and after surgery.

Rapid change in plaque size, composition, and molecular footprint after recombinant apolipoprotein A-I Milano (ETC-216) administration: magnetic resonance imaging study in an experimental model of atherosclerosis

OBJECTIVES This study sought to assess the effect of short-term apolipoprotein (apo) A-I(Milano) administration on plaque size and on suspected markers of plaque vulnerability. BACKGROUND Long-term lipid-lowering interventions can regress and stabilize atherosclerotic plaques. However, the majority of recurrent events occur early after the first episode. Interventions able to acutely induce plaque regression and stabilization are lacking. Regression of human coronary lesions after 5 weeks of treatment with apoA-I(Milano) administration has been shown. However, there are no data regarding its effect on plaque vulnerability. METHODS Advanced aortic lesions were induced in New Zealand White rabbits (n = 40). Plaque size was assessed by magnetic resonance imaging (MRI) at the end of atherosclerosis induction. Animals were randomized to placebo or apoA-I(Milano) phospholipids (ETC-216), 2 infusions 4 days apart. After the last dose, another MRI study was performed and aortas were processed for cellular composition and gene protein expression of markers associated with plaque instability. RESULTS Pre-treatment MRI showed similar plaque size in both groups, whereas post-treatment MRI showed 6% smaller plaques in apoA-I(Milano)-treated animals compared with placebo (p = 0.026). The apoA-I(Milano) treatment induced a 5% plaque regression (p = 0.003 vs. pre-treatment), whereas the placebo showed no significant effect. Plaque regression by apoA-I(Milano) was associated with a reduction in plaque macrophage density and a significant down-regulation in gene and protein expression of tissue factor, monocyte chemoattractant protein-1, and cyclooxygenase-2, as well as marked decrease in gelatinolytic activity. Conversely, cyclooxygenase-1 was significantly up-regulated. CONCLUSIONS Acute plaque regression observed after short-term apoA-I(Milano) administration was associated with a significant reduction in suspected makers of plaque vulnerability in an experimental model of atherosclerosis.

Interpretation of Remotely Downloaded Pocket-Size Cardiac Ultrasound Images on a Web-Enabled Smartphone: Validation Against Workstation Evaluation

BACKGROUND Pocket-size ultrasound has increased echocardiographic portability, but expert point-of-care interpretation may not be readily available. The aim of this study was to test the hypothesis that remote interpretation on a smartphone with dedicated medical imaging software can be as accurate as on a workstation. METHODS Eighty-nine patients in a remote Honduran village underwent echocardiography by a nonexpert using a pocket-size ultrasound device. Images were sent for verification of point-of-care diagnosis to two expert echocardiographers in the United States reading on a workstation. Studies were then anonymized, randomly ordered, and reinterpreted on a smartphone with a dedicated, Health Insurance Portability and Accountability Act-compliant application. Point-of-care diagnosis was considered accurate if any abnormal finding was matched and categorized at the same level of severity (mild, moderate, or severe) by either expert interpretation. RESULTS The mean age was 54 ± 23 years, and 57% of patients were women. The most common indications for echocardiography were arrhythmia (33%), cardiomyopathy (28%), and syncope (15%). Using the workstation, point-of-care diagnoses were changed in 38% of cases by expert overread (41% left ventricular function correction, 38% valvulopathy correction, 18% poor image quality). Expert interobserver agreement was excellent at 82%, with a Cohens κ value of 0.82 (95% confidence interval, 0.70-0.94). Intraobserver agreement comparing interpretations on workstations and smartphones was 90%, with a Cohens κ value of 0.86 (95% confidence interval, 0.76-0.97), signifying excellent intertechnology agreement. CONCLUSIONS Remote expert echocardiographic interpretation can provide backup support to point-of-care diagnosis by nonexperts when read on a dedicated smartphone-based application. Mobile-to-mobile consultation may improve access in previously inaccessible locations to accurate echocardiographic interpretation by experienced cardiologists.

The Role of High-Density Lipoprotein Cholesterol in the Prevention and Possible Treatment of Cardiovascular Diseases

Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.

A novel anti-ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects.

Summary.  Background: Platelet and endothelial production of nitric oxide (NO) is known to be impaired in coronary artery disease patients. Compounds that release NO (e.g. nitrates) have antiplatelet effects, but at supratherapeutic doses with hypotensive side effects. Objectives: To investigate the antithrombotic effect on human blood of a novel NO donor (LA419) with known anti‐ischemic properties but without hypotensive side effects and to compare with abciximab. Patients/methods: Healthy subjects (n = 8; 32 ± 3 years) received daily aspirin starting three days prior to the study day. Treatments (LA419 10 and 20 μm, and abciximab 4 μm) were added ex vivo to non‐anticoagulated blood, and the antithrombotic properties were assessed by measuring changes in thrombus size from pretreatment baseline in the Badimon perfusion chamber at low and high shear rates. Platelet surface adhesion using a Cone and Platelet Analyzer (CPA) and platelet fibrinogen‐receptor activation with flow cytometry were also evaluated. Results: At low shear rates, LA419 displayed a reduction in thrombus area of 43% ± 8% (10 μm) and 56% ± 6% (20 μm), whereas at high shear rates the reductions were 44% ± 3% (10 μm) and 62% ± 6% (20 μm). Platelet surface adhesion with the CPA was also reduced. Abciximab exhibited a strong inhibitory effect on thrombus formation, platelet surface adhesion and fibrinogen receptor activation. Conclusions: The novel NO donor, LA419, shows a strong antithrombotic effect in human blood, which is comparable to abciximab, especially under high shear rate conditions. Our observations suggest that the availability of an NO donor could prove beneficial in the prevention of thrombotic complications of cardiovascular disease. Further clinical studies are warranted.

Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.

Background  Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor‐κΒ ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis.

Effect of Electronic Prescription on Attainment of Cholesterol Goals

Although recent federal mandate provides incentives for physicians to use electronic prescribing (e‐prescribing), clinical end points to support its use are lacking.

Positron emission tomography for the evaluation and treatment of cardiomyopathy.

Congestive heart failure accounts for tremendous morbidity and mortality worldwide. There are numerous causes of cardiomyopathy, the most common of which is coronary artery disease. Positron emission tomography (PET) has an established and expanding role in the evaluation of patients with cardiomyopathy. The specific application of PET to hypertrophic cardiomyopathy, cardiac sarcoidosis, and diabetic cardiomyopathy has been studied extensively and promises to be a useful tool for managing these patients. Furthermore, evaluating the efficacy of standard treatments for congestive heart failure is important as health care costs continue to rise. Recently, there have been significant developments in the field of cardiovascular stem cell research. Familiarity with the mechanisms by which stem cells benefit patients with cardiovascular disease is the key to understanding these advances. Molecular imaging techniques including PET/CT imaging play an important role in monitoring stem cell therapy in both animals and humans. These noninvasive imaging techniques will be highlighted in this paper.

Validation Study of a Semi-Automated Program for Quantification of Atherosclerotic Burden

Practical implementation of cardiovascular magnetic resonance (CMR) for the noninvasive screening of atherosclerosis is limited by inter-and intra-observer variability and labor intensity of morphometric analysis by manual planimetry (MANU). We assessed the hypothesis that a semi-automated quantification program (AUTO) for CMR would be faster and more accurate than MANU without loss of reliability. In the analysis of carotid atherosclerosis in asymptomatic hypercholesterolemic patients (n = 17), AUTO was superior to MANU in speed and histopathologic correlation without significant differences in inter-and intra-observer variability. Implementation of AUTO may facilitate CMR for the screening of the burden of atherosclerotic disease.

Estimation of right atrial and ventricular hemodynamics by CT coronary angiography

BACKGROUND Computed tomography coronary angiography (CTCA) provides an accurate noninvasive alternative to the invasive assessment of coronary artery disease. However, a specific limitation of CTCA is inability to assess hemodynamic data. OBJECTIVE We hypothesized that CTCA-derived measurements of contrast within the superior vena cava (SVC) and inferior vena cava (IVC) would correlate to echocardiographic estimations of right atrial and right ventricular pressures. METHODS Medical records of all patients who underwent both echocardiography and CTCA in our center were reviewed (n = 32). Standard CTCA was performed with a 64-detector CT using test-bolus method for image acquisition timing and iso-osmolar contrast injection through upper extremity vein. The length of the column of contrast reflux into the inferior vena cava (IVC) was correlated to echocardiographically determine tricuspid regurgitation jet velocity (TRV). SVC area change with contrast injection at the level of the bifurcation of the pulmonary artery was also correlated with IVC sniff response by echocardiogram. RESULTS The reflux column length was interpretable in 27 of 32 patients with a mean length of 10.1 ± 1.1 mm, and a significant bivariate correlation was observed between reflux column length and the tricuspid regurgitant jet velocity (r = 0.84; P < .0001). Mean SVC distensibility ratio was 0.63 ± 0.03; mean IVC sniff response ratio was 0.53 ± 0.03. SVC distensibility correlated to IVC sniff response with a Pearson r of 0.57 (P = .04). CONCLUSION Quantification of IVC and SVC contrast characteristics during CTCA provides a feasible and potentially accurate method of estimating right atrial and ventricular pressure.