Stephen G. Wagner

Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

BACKGROUND c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. METHODS In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. FINDINGS This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). INTERPRETATION These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. FUNDING University of Louisville Research Foundation and National Institutes of Health.

Acrolein exposure is associated with increased cardiovascular disease risk.

Background Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Methods and Results Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite—3‐hydroxypropylmercapturic acid (3‐HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3‐HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3‐HPMA levels were inversely related to levels of both early (AC133+) and late (AC133−) circulating angiogenic cells. In smokers as well as nonsmokers, 3‐HPMA levels were positively associated with both increased levels of platelet–leukocyte aggregates and the Framingham Risk Score. No association was observed between 3‐HPMA and plasma fibrinogen. Levels of C‐reactive protein were associated with 3‐HPMA levels in nonsmokers only. Conclusions Regardless of its source, acrolein exposure is associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased CVD risk.

Diastolic dysfunction is a feature of the antiphospholipid syndrome

Recurrent thrombi, thrombocytopenia, pregnancy loss, and stroke in association with medium to high concentrations of anticardiolipin antibodies are well-recognized features of antiphospholipid syndrome. Cardiac manifestations of primary antiphospholipid syndrome (PAPS) also have been documented but involve structural and valvular heart disease. Diastolic dysfunction in PAPS has not been well described. Therefore, 10 patients with PAPS (nine women and one man) of mean age 30 +/- 7 years (range 20 to 46 years) and 10 healthy age-, sex-, weight-, and height-matched control subjects were studied by echocardiography. Anticardiolipin antibody concentrations of patients with PAPS were > 80 immunoglobulin G phospholipid units as determined by enzyme-linked immunosorbent assay. Doppler-derived parameters of left ventricular filling showed a significant association between PAPS and diastolic dysfunction compared with control, as evidenced by a decrease in peak early filling velocity (52 +/- 10 cm/sec vs 67 +/- 12 cm/sec; p < 0.01), a decrease in the ratio of peak early to peak atrial filling velocities (1.03 +/- 0.40 vs 1.52 +/- 0.28; p < 0.005), a decrease in the mean deceleration rate of early filling (338 +/- 75 cm/sec2 vs 590 +/- 227 cm/sec2; p < 0.005), and an increase in the percentage of atrial contribution to filling and deceleration time. Left ventricular mass, diastolic filling time, and heart rate did not differ between groups. Left ventricular systolic function was normal and ejection fraction did not differ between patients with PAPS and control subjects (63% +/- 2% vs 65% +/- 7%; p not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells

Objectives—Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells. Approach and Results—In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31+/AC133+, AC133+, CD34+/AC133+, and CD34+/45dim/AC133+ cells) and positively associated with road segment distance (CD31+/AC133+, AC133+, and CD34+/AC133+ cells), traffic intensity (CD31+/AC133+ and AC133+ cells), and distance-weighted traffic intensity (CD31+/34+/45+/AC133+ cells). Conclusions—Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133+. This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.

Implications of reverse cholesterol transport: recent studies.

INTRODUCTION There is a strong epidemiological relationship between high density lipoproteins and atherosclerotic coronary vascular disease (ASCVD). The process of reverse cholesterol transport (RCT) has been hypothesized to help explain this relationship. The corollary that raising HDL should reduce ASCVD is also drawn from this relationship. In recent years, the metabolism of HDL has become better understood. A hypothetical process for explaining RCT has been superimposed on the currently understood HDL metabolic pathways. METHODS Outline of HDL metabolism and the superimposed RCT process. Literature review of studies of persons with genetic defects, HDL cholesterol raising clinical trials, Mendelian randomization studies and treatments with molecules that mimic HDL. CONCLUSIONS Mutation studies of ABCA1, LCAT and SR-B1 genes in humans showed expected variations in HDLC but little association with ASCVD and there was no significant association between HDLC and ASCVD in Mendelian randomization studies. Elevations in HDLC due to treatment with niacin and cholesteryl ester transport protein inhibitors in randomized trials raised HDLC but did not significantly reduce risk of ASCVD. Treatment with molecules that mimic HDL did not seem to reduce ASCVD. Thus, recent evidence does not seem to support RCT as currently proposed. This hypothesis seems to need substantial revision.

Angle of incidence does not affect accuracy of mitral stenosis area calculation by pressure half-time: Application to Doppler transesophageal echocardiography

Continuous wave Doppler transesophageal echocardiography (TEE) may allow the estimation of stenotic mitral valve area. Intuitively the posterolateral position of the transducer appears to limit the application of TEE for this purpose because of the excessive angle of incidence to mitral valve inflow. However, algebraic equations can be used to predict that the angle of incidence should not affect mitral valve area derived by using pressure half-time. To test the validity of this prediction and the potential application of Doppler TEE to estimate mitral valve area, 28 patients (21 women, 7 men) with a mean age of 59 +/- 14 years with mitral stenosis were studied by continuous wave transthoracic echocardiography (TTE) and TEE guided color flow Doppler. TTE was performed from the apical four-chamber (TEE-0) and a modified parasternal four-chamber (TTE-MAL) plane as a means of intentionally increasing the angle of incidence. TEE was done by using the horizontal (TEE-HAX) and vertical (TEE-VAX) planes. Mitral valve area was calculated by pressure half-time method. Mean mitral valve area did not differ (p = not significant [NS]) between TTE-0 (1.26 +/- 0.84 cm2), TTE-MAL (1.37 +/- 0.94 cm2), TEE-HAX (1.39 +/- 0.92 cm2), and TEE-VAX (1.35 +/- 0.89 cm2). The estimated mean angle of incidence during TTE-MAL was 45 +/- 12 degrees (range 21 to 68 degrees). Six (21%) of 28 and 9 (32%) of 28 patients had an underestimation of transmitral peak velocities with TEE from the horizontal or vertical planes, respectively. However, excellent correlations were found between mitral valve area derived by using TEE-0 versus TTE-MAL (r = 0.97; SEE = 0.25 cm2; intercept = 0.02 cm2; slope = 1.08; and p = 0.0001), TEE-HAX (r = 0.91; SEE = 0.39 cm2; intercept = 0.14 cm2; slope = 1.00; and p = 0.0001) and TEE-VAX (r = 0.92; SEE = 0.36 cm2; intercept = 0.13 cm2; slope = 0.97; and p = 0.0001). These results are directly applicable to Doppler TEE in the determination of mitral stenosis area by pressure half-time, whereby 21% to 32% of patients using the horizontal or vertical transesophageal planes may have a significant angle of incidence leading to underestimation of transmitral valve velocities. Future studies comparing Doppler TEE with cardiac catheterization are of interest. However, the present study suggests that Doppler TEE will play an important role in the hemodynamic assessment of the severity of mitral valve stenosis.

Relationships between triglycerides, lipoproteins, glucose and coronary artery disease

We examined the relationship of apolipoprotein B (apo B), glucose, triglycerides and other lipoprotein lipids to coronary artery disease (CAD). Using receiver-operating characteristic curves (ROC), we noticed that the triglyceride ROC curve crossed above other lipoprotein curves at a triglycerides level of approximately 1.4 g/l. We examined subgroups of < 1.4 g/l and > 1.4 g/l. ANOVA (F = 18.9, P < 0.0001) and stepwise logistic regression (P = 0.0002) indicated that triglycerides were the best predictor in the < 1.4 g/l group. The best markers in the > 1.4 g/l group were low density lipoprotein cholesterol and apo B. Glucose did not appear to significantly alter the predictive power of triglycerides. These data suggest that triglyceride appears to be an overall significant univariate marker for CAD because of its effect at lower concentrations. The strong relationship between CAD and triglycerides at low triglyceride levels may reflect increased levels of very low density lipoprotein metabolites in some individuals. We conclude that some triglyceride-rich particles are independently atherogenic, that glucose did not alter this relationship and that when the samples were split into those with high and low levels of triglycerides, triglycerides and apo B but not HDLC was a significant predictor of CAD.

Immunonephelometric/turbidimetric apolipoprotein B assays for the clinical laboratory

Because apolipoproteins are a part of complex macromolecular particles, modifications to the assay system may substantially alter results of immunological measurement. Accuracy as analytical recovery cannot be effectively determined by adding exogenous apolipoproteins because antibody access differs from access to endogenous apolipoproteins. Clinical studies are essential for determining accuracy in terms of clinical effectiveness. Since different kit methods use different reagent systems, the purpose of the present study was to compare total cholesterol and LDL cholesterol as markers for coronary artery disease with apo B by automated rate nephelometric, end-point nephelometric and turbidimetric kit methods. The subjects were age matched, male patients with and without angiographically documented coronary artery disease. High correlation coefficients (0.95-0.96) between the assays for both the normal and disease groups indicate that the methods are providing similar information: apo B was a better marker for coronary artery disease (CAD) than total or LDL cholesterol on the basis of univariate, multivariate and Bayesian statistics and correlated best with non-HDL cholesterol. Apo B along with HDLC could explain the variability between the CAD and normal groups without LDLC, total C, or triglycerides.