Patrick R. Lawler

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

Thrombospondins TSP-1 and TSP-2 are potent endogenous inhibitors of angiogenesis. They inhibit angiogenesis through direct effects on endothelial cell migration, proliferation, survival, and apoptosis and by antagonizing the activity of VEGF. Several of the membrane receptor systems and signal transduction molecules that mediate the effects of TSP-1 and TSP-2 have been elucidated. TSP-1 and TSP-2 exert their direct effects through CD36, CD47, and integrins. Recent data indicate that CD36 and β1 integrins collaborate to transmit the signals that are initiated by TSP-1 and TSP-2. Furthermore, these receptors appear to associate with VEGFR2 to form a platform for the integration of positive and negative signals for angiogenesis. Cross talk between pro- and antiangiogenic signal transduction pathways may enable TSP-1 and TSP-2 to inhibit angiogenesis by antagonizing survival pathways while also activating apoptotic pathways. CD36 and CD47 are both involved in the suppression of nitric oxide (NO). Advances in understanding of the molecular regulation of angiogenesis by TSP have paved the way for innovations in experimental treatment of cancers and will likely continue to offer vast avenues for discovery in other disease processes as well.

Relations of Change in Plasma Levels of LDL-C, Non-HDL-C and apoB With Risk Reduction From Statin Therapy: A Meta-Analysis of Randomized Trials

Background Identifying the best markers to judge the adequacy of lipid‐lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid‐lowering therapies are in development. Reductions in LDL‐C, non‐HDL‐C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. Methods and Results We performed a random‐effects frequentist and Bayesian meta‐analysis of 7 placebo‐controlled statin trials in which LDL‐C, non‐HDL‐C, and apoB values were available at baseline and at 1‐year follow‐up. Summary level data for change in LDL‐C, non‐HDL‐C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta‐analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL‐C; 20.0% (15.2%, 24.7%) for non‐HDL‐C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL‐C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non‐HDL‐C (P<0.001). Similarly, in Bayesian meta‐analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL‐C or non‐HDL‐C (BFs ranging from 484 to 2380). Conclusions Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo‐controlled statin trials was more closely related to reductions in apoB than to reductions in either non‐HDL‐C or LDL‐C.

Cancer risk related to low-dose ionizing radiation from cardiac imaging in patients after acute myocardial infarction

Background Patients exposed to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction may be at increased risk of cancer. Methods Using an administrative database, we selected a cohort of patients who had an acute myocardial infarction between April 1996 and March 2006 and no history of cancer. We documented all cardiac imaging and therapeutic procedures involving low-dose ionizing radiation. The primary outcome was risk of cancer. Statistical analyses were performed using a time-dependent Cox model adjusted for age, sex and exposure to low-dose ionizing radiation from noncardiac imaging to account for work-up of cancer. Results Of the 82 861 patients included in the cohort, 77% underwent at least one cardiac imaging or therapeutic procedure involving low-dose ionizing radiation in the first year after acute myocardial infarction. The cumulative exposure to radiation from cardiac procedures was 5.3 milliSieverts (mSv) per patient-year, of which 84% occurred during the first year after acute myocardial infarction. A total of 12 020 incident cancers were diagnosed during the follow-up period. There was a dose-dependent relation between exposure to radiation from cardiac procedures and subsequent risk of cancer. For every 10 mSv of low-dose ionizing radiation, there was a 3% increase in the risk of age- and sex-adjusted cancer over a mean follow-up period of five years (hazard ratio 1.003 per milliSievert, 95% confidence interval 1.002–1.004). Interpretation Exposure to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction is associated with an increased risk of cancer.

Genetically Determined Resistance to Collagenase Action Augments Interstitial Collagen Accumulation in Atherosclerotic Plaques

Background—We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques. Methods and Results—To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE−/−) that express collagenase-resistant collagen-I (ColR/R/apoE−/−, n=12) or wild-type collagen-expressing mice (Col+/+/apoE−/−, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE−/− mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE−/− mice contained significantly more intimal collagen than did those of Col+/+/apoE−/− mice. Conclusion—These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.

Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk

RATIONALE Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus. OBJECTIVE Using a plasma glycan biosignature (GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals. METHODS AND RESULTS We quantified GlycA by 400 MHz (1)H nuclear magnetic resonance spectroscopy in 27,524 participants in the Womens Health Study (NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12,527 individuals in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681). We also undertook secondary examination of cardiovascular disease and cancer mortality in the Womens Health Study. In the Womens Health Study, during 524,515 person-years of follow-up (median, 20.5 years), there were 3523 deaths. Risk factor-adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per SD increment in GlycA for all-cause mortality was significantly increased at 5 years (1.21 [1.06-1.40]) and during maximal follow-up (1.14 [1.09-1.16]). Similar risk for all-cause mortality was observed in the replication cohort (1.33 [1.21-1.45]). In the Womens Health Study, risk of cardiovascular disease mortality was increased at 5 years (1.43 [1.05-1.95]) and during maximal follow-up (1.15 [1.04-1.26]) and of cancer mortality at 5 years (1.23 [1.02-1.47]) and during maximal follow-up (1.08 [1.01-1.16]). Examination of correlations and mortality associations adjusted for high-sensitivity C-reactive protein, fibrinogen, and intercellular adhesion molecule-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation. CONCLUSIONS Among initially healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all-cause, cardiovascular, and cancer mortality.

Red blood cell transfusion and mortality among patients hospitalized for acute coronary syndromes: A systematic review

BACKGROUND Observational studies have suggested a relationship between anemia and adverse outcomes among patients presenting with acute coronary syndromes (ACS). However, the hemoglobin level at which packed red blood cell (PRBC) transfusion is beneficial remains unclear as available data are conflicting. We therefore performed a systematic review of all relevant observational studies, with a particular focus on examining optimum hemoglobin thresholds for transfusion among patients hospitalized for ACS. METHODS We systematically searched MEDLINE, as well as relevant bibliographies, to identify all observational studies examining the effects of PRBC transfusion among post-ACS patients. Inclusion was restricted to English language studies that reported data for the risk of mortality, congestive heart failure (CHF), or recurrent myocardial infarction (MI). RESULTS We identified 11 studies that met our inclusion criteria, involving a total of 290,847 patients. When reported, the main indication for transfusion appeared to be major bleeding. Overall, patients who received transfusions were at greater unadjusted risk of mortality (range of odds ratio [OR]: 1.9 to 11.2). When hemoglobin-stratified analyses were examined, a graded association between PRBC transfusion and mortality was seen, wherein transfusion had beneficial or neutral effects on mortality below 8.0g/dL, and harmful or neutral effects above 11.0g/dL. CONCLUSIONS PRBC transfusion in patients post-ACS undertaken at hemoglobin levels below 8.0g/dL was found to be beneficial or, at worst, neutral. Conversely, there was suggestion of harm when transfusion was undertaken at hemoglobin levels above 11.0g/dL, supporting a more conservative transfusion strategy.

Extracorporeal Membrane Oxygenation in Adults With Cardiogenic Shock

A 28-year-old previously healthy woman was brought to the hospital after out-of-hospital resuscitated cardiac arrest attributable to ventricular fibrillation. On the evening of presentation, she was found unconscious at home by family members. Bystander cardiopulmonary resuscitation (CPR) was immediately initiated. The patient was defibrillated in the field by emergency medical response providers with return of spontaneous circulation. She aspirated during intubation in the field, and arrived to the hospital in shock, with blood pressure 88/71 mm Hg on norepinephrine 20 μg/min and vasopressin 0.04 U/min. She did not have purposeful movements, and therapeutic hypothermia was initiated in the Emergency Department. She had a metabolic acidosis and concomitant type I acute respiratory failure, with PaO2 66 mm Hg on volume-cycled assist/control mode with tidal volumes of 400 cc, FiO2 1.0, positive end-expiratory pressure 10 cm H2O, and a respiratory rate of 26 breaths/min. Her ECG did not demonstrate stigmata of ischemia or infarction. However, a type I Brugada pattern was noted in leads V1 and V2 before cooling. Over the ensuing several hours, vasopressor requirements escalated. A Swan-Ganz catheter demonstrated severely depressed cardiac index and elevated pulmonary capillary wedge pressure. She remained severely hypoxic despite maximal ventilator support. Chest x-ray showed diffuse bilateral pulmonary infiltrates, consistent with severe aspiration pneumonitis. PaO2 decreased to 49 mm Hg despite increased positive end-expiratory pressure and chemical paralysis, meeting Berlin criteria for severe acute respiratory distress syndrome.1 Options for percutaneous hemodynamic support were considered (including extracorporeal membrane oxygenation [ECMO] or percutaneous ventricular assist device [VAD], such as Impella and TandemHeart), and the patient was placed on veno-arterial ECMO (VA ECMO) for both hemodynamic and respiratory rescue 6 hours after presentation. Cardiopulmonary bypass was first developed in 1954 to facilitate open-heart surgery and used successfully 1 year later.2,3 …

Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low‐Density Lipoprotein Cholesterol

Background Levels of LDL (low‐density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid‐related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. Methods and Results We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low‐density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo‐allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non–high‐density lipoprotein cholesterol, and triglycerides, but not LDL‐c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On‐statin levels of the smallest VLDL particle subclass were associated with a 68% per‐SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk—this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C‐index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein‐related risk were observed. Conclusions Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures in Patients With Congenital Heart Disease: 15-Year Data From a Population-Based Longitudinal Cohort

Background— The burden of low-dose ionizing radiation (LDIR) exposure from medical procedures among individuals with congenital heart disease (CHD) is unknown. In this longitudinal population-based study, we sought to determine exposure to LDIR-related cardiac imaging and therapeutic procedures in children and adults with CHD. Methods and Results— In an analysis of the Quebec CHD database, exposure to the following LDIR-related cardiac procedures was recorded: catheter-based diagnostic procedures, structural heart interventions, coronary interventions, computed tomography scans of the chest, nuclear procedures, and pacemaker/implantable cardioverter-defibrillator insertion and repair. From 1990 to 2005, there were 16 253 LDIR-exposed patients with CHD with 317 988 patient-years of available follow-up. The total number of LDIR-related procedures increased from 18.5 to 51.9 per 1000 CHD patients per year ( P <0.0001). This increase was attributable to increases in rates per 1000 CHD patients in diagnostic cardiac catheterizations (11.7 to 13.7 per 1000), structural heart interventions (1.0 to 5.2 per 1000), coronary interventions (1.0 to 2.4 per 1000), pacemaker/implantable cardioverter-defibrillator insertions (1.6 to 4.4 per 1000), nuclear procedures (4.2 to 13.8 per 1000), and computed tomography scans of the chest (2.5 to 12.3 per 1000). Over time, among children with CHD, the median age at first LDIR procedure decreased from 5.0 years to 9.6 months. Severity of CHD significantly predicted extent of exposure. Conclusions— From 1990 to 2005, patients with CHD were exposed to increasing numbers of LDIR-emitting cardiac procedures. This exposure occurred at progressively younger ages. These findings provide an important perspective on longitudinal LDIR exposure in this at-risk population. # CLINICAL PERSPECTIVE {#article-title-22}Background— The burden of low-dose ionizing radiation (LDIR) exposure from medical procedures among individuals with congenital heart disease (CHD) is unknown. In this longitudinal population-based study, we sought to determine exposure to LDIR-related cardiac imaging and therapeutic procedures in children and adults with CHD. Methods and Results— In an analysis of the Quebec CHD database, exposure to the following LDIR-related cardiac procedures was recorded: catheter-based diagnostic procedures, structural heart interventions, coronary interventions, computed tomography scans of the chest, nuclear procedures, and pacemaker/implantable cardioverter-defibrillator insertion and repair. From 1990 to 2005, there were 16 253 LDIR-exposed patients with CHD with 317 988 patient-years of available follow-up. The total number of LDIR-related procedures increased from 18.5 to 51.9 per 1000 CHD patients per year (P<0.0001). This increase was attributable to increases in rates per 1000 CHD patients in diagnostic cardiac catheterizations (11.7 to 13.7 per 1000), structural heart interventions (1.0 to 5.2 per 1000), coronary interventions (1.0 to 2.4 per 1000), pacemaker/implantable cardioverter-defibrillator insertions (1.6 to 4.4 per 1000), nuclear procedures (4.2 to 13.8 per 1000), and computed tomography scans of the chest (2.5 to 12.3 per 1000). Over time, among children with CHD, the median age at first LDIR procedure decreased from 5.0 years to 9.6 months. Severity of CHD significantly predicted extent of exposure. Conclusions— From 1990 to 2005, patients with CHD were exposed to increasing numbers of LDIR-emitting cardiac procedures. This exposure occurred at progressively younger ages. These findings provide an important perspective on longitudinal LDIR exposure in this at-risk population.

Discordance between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Coronary Events in Women

BACKGROUND It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non-HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant. METHODS Among 27533 initially healthy women in the Womens Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models. RESULTS Although all 3 biomarkers were correlated (r ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both P < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56-2.00) for apo B and 1.70 (1.50-1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07-1.39) for apo B and 1.13 (0.99-1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk. CONCLUSIONS Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.