- Differential Behaviors of Atrial Versus Ventricular Fibroblasts: A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
- Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2−/− Mice: Evidence for Independent Chemokine Functions in Atherogenesis
- Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6Chi and Ly6Clo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice
- Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality: Sixteen Years of Follow-Up in US Women
- Age-Dependent Associations Between Chronic Periodontitis/Edentulism and Risk of Coronary Heart Disease
- Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
- N-Terminal Prohormone Brain Natriuretic Peptide as a Predictor of Cardiovascular Disease and Mortality in Blacks With Hypertensive Kidney Disease: The African American Study of Kidney Disease and Hypertension (AASK)
- Interrelation of Coronary Calcification, Myocardial Ischemia, and Outcomes in Patients With Intermediate Likelihood of Coronary Artery Disease: A Combined Positron Emission Tomography/Computed Tomography Study
- Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction
- Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism: Findings From the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry
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Differential Behaviors of Atrial Versus Ventricular Fibroblasts: A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
Cardiac tissue fibrosis is important in the progression of heart disease and plays an important role in cardiac arrhythmogenesis, particularly for atrial fibrillation. In a variety of cardiac disease models, atrial fibrosis is much more prominent than fibrosis in the ventricles, even when the profibrotic stimulus appears to be operating comparably at both the atrial and ventricular levels. This study examined the hypothesis that differences between atrial and ventricular fibroblast properties contribute to the predominant atrial fibrotic phenotype. To assess this possibility, we compared morphological, secretory, and proliferative responses of canine atrial versus ventricular fibroblasts. Atrial fibroblasts showed in vitro and in vivo behaviors indicating a greater tendency to activated myofibroblast dedifferentiation. Atrial fibroblast proliferation responses were consistently greater than ventricular responses for a variety of growth factors, including fetal bovine serum, platelet-derived growth factor, basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β1. Atrial tissue showed larger myofibroblast density than ventricular tissue, particularly in the presence of congestive heart failure. Congestive heart failure atria had more active fibroblast division rates and enhanced gene expression of fibroblast-selective markers compared with ventricles. Gene microarrays revealed 225 differentially expressed transcript probe sets between paired atrial and ventricular fibroblast samples, including extracellular matrix, cell signaling, and metabolism genes, and identified platelet-derived growth factor as a potential contributor to atrial-ventricular fibroblast differences. Platelet-derived growth factor inhibition eliminated atrial-ventricular fibroblast proliferative response differences. Our results suggest that important differences exist in properties of atrial versus ventricular fibroblasts, that these differences contribute to atrium-selective fibrosis, and that platelet-derived growth factor signaling may be an interesting therapeutic target for the prevention of arrhythmogenic atrial structural remodeling. See p 1630.
Fractalkine Deficiency Markedly Reduces Macrophage Accumulation and Atherosclerotic Lesion Formation in CCR2−/− Mice: Evidence for Independent Chemokine Functions in Atherogenesis
The past decade has witnessed a dramatic increase in our understanding of the importance of inflammation in all stages of atherosclerotic heart disease. Subendothelial foam cells, the hallmark of early lesions, are derived from circulating blood monocytes, and recent evidence indicates that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Genetic deletions of monocyte chemoattractant protein-1 (MCP-1, CCL2), fractalkine (CX3CL1), or their cognate receptors, CCR2 and CX3CR1, have been shown to markedly reduce monocyte recruitment and atherosclerotic lesion size in murine models of atherosclerosis; however, whether these 2 chemokine systems were redundant or made independent contributions was unknown. To address this question, we created double knockouts of fractalkine and CCR2 (on the apolipoprotein E–null background) and performed a 4-arm atherosclerosis study. The results demonstrate that deletion of CCR2 affords significantly more protection than deletion of fractalkine. Significantly, deletion of fractalkine in CCR2-null mice further reduced monocyte recruitment and atherosclerotic lesion size, which indicates that both chemokines make independent and significant contributions to atherogenesis. These data provide the first in vivo evidence for independent roles for CCR2 and CX3CL1 in monocyte recruitment and atherosclerotic lesion formation and suggest that successful therapeutic strategies for atherosclerosis or other classic inflammatory diseases such as rheumatoid arthritis or multiple sclerosis may need to target multiple chemokines or chemokine receptors. See p 1642.
Combined Inhibition of CCL2, CX3CR1, and CCR5 Abrogates Ly6Chi and Ly6Clo Monocytosis and Almost Abolishes Atherosclerosis in Hypercholesterolemic Mice
Monocytes are critical mediators of atherogenesis and are recruited into atherosclerotic arteries in response to chemokine/chemokine receptor signaling. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking. Here, we show that combined inhibition of CCL2, CX3CR1, and CCR5 in apolipoprotein E–deficient mice almost abolishes lesion formation, indicating that these pathways play independent and additive roles in atherosclerosis. Another important finding is that the major role of chemokines and chemokine receptors in atherosclerosis may relate to their role in the modulation of monocyte number in both the bone marrow and circulating blood. Our results clearly show that inhibition of CCL2, CX3CR1, and CCR5 abolishes hypercholesterolemia-associated blood monocytosis, identifying a critical role for chemokine signaling in this process. It is remarkable that the reduction in lesion size in mice with defective CCL2, CX3CR1, and/or CCR5 signaling strongly correlated with the reduction in circulating monocyte number, particularly the CD11b+ Ly6G− 7/4lo subset. Thus, in addition to their roles in leukocyte recruitment from the blood into the vessel wall, which is the prevailing paradigm to explain the proatherogenic effects of several chemokine/chemokine receptor pathways, signals mediated through CCL2, CX3CR1, and CCR5 critically determine the frequency of circulating monocyte subsets and cooperate to promote full macrophage accumulation within atherosclerotic vessels. It will be important to examine in future studies whether particular blood monocyte subsets are associated with the extent of atherosclerosis in humans. See p 1649.
Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality: Sixteen Years of Follow-Up in US Women
In parallel with the increase in overall body adiposity in the US population, the prevalence of abdominal obesity increased substantially during the past decades. Evidence is growing that abdominal obesity is particularly detrimental to health. Greater abdominal adiposity is strongly related to an increased risk for cardiovascular disease and some other diseases independently of overall adiposity. In this study, we investigated several measures of abdominal adiposity, including waist circumference, waist-to-hip ratio, and waist-to-height ratio in relation to all-cause, cardiovascular disease, and cancer mortality during 16 years of follow-up in the Nurses’ Health Study. With >600 000 person-years of follow-up and 3507 deaths, ours is one of the largest studies with the longest follow-up on abdominal adiposity and mortality. Our data indicate that anthropometric measures of abdominal adiposity were strongly and positively associated with all-cause, cardiovascular disease, and cancer mortality independently of body mass index. Elevated waist circumference and waist-to-hip ratio were associated with significantly increased cardiovascular disease mortality even among normal-weight women (body mass index, 18.5 to <25 kg/m2). Although maintaining a healthy weight should continue to be a cornerstone in the prevention of chronic diseases and premature death, it is equally important to maintain a healthy waist size and to prevent abdominal obesity. See p 1658.
Age-Dependent Associations Between Chronic Periodontitis/Edentulism and Risk of Coronary Heart Disease
Chronic periodontitis is a highly prevalent inflammatory disease of the periodontium and an important cause of tooth loss. More recently, periodontitis has been implicated as a putative cardiovascular risk factor. We studied the association between periodontitis/edentulism and incident coronary heart disease (CHD) in the VA Normative Aging/Dental Longitudinal Study, an ongoing long-term closed-cohort study of men in the greater Boston (Massachusetts) area that performed comprehensive medical and dental examinations triennially. A total of 1203 men free of CHD at baseline were followed up for up to 35 years (median 24 years). Of these, a total of 364 men were diagnosed with CHD (either fatal or nonfatal), and 109 men died of CHD. We found a dose-dependent association between chronic periodontitis and incidence of CHD among men <60 years of age. Compared with men with no or minimal periodontal bone loss, men with severe periodontal bone loss had more than twice the risk of developing CHD (hazard ratio 2.12, 95% confidence interval 1.26 to 3.60). No association was found among men >60 years of age. Edentulous men ≥60 years of age tended to be more likely to develop any CHD and were significantly more likely to develop fatal CHD than dentate and periodontally healthy men. In summary, chronic periodontitis is associated with incident CHD among younger men. See p 1668.
Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
Recent studies exploring the entire genome identified the chromosomal locus 9p21.3 as being associated with the risk of coronary artery disease and myocardial infarction. To use this information for clinical risk prediction, the present study investigated close to 10 000 individuals. The findings consistently replicated the significant association between the 9p21.3 locus and coronary artery disease in 7 case-control studies. The chromosomal locus was further investigated by genotyping of 31 additional single-nucleotide polymorphisms and detailed haplotypes that further characterized the genomic structure of the chromosomal locus and its association with coronary artery disease. Moreover, the present study revealed that an autosomal-additive mode of inheritance best explained the underlying association. This information is essential for appropriate incorporation of the genotypic information into algorithms for risk prediction. Indeed, the present study can be considered an important step for using genomic information to better predict risk of coronary artery disease. See p 1675.
N-Terminal Prohormone Brain Natriuretic Peptide as a Predictor of Cardiovascular Disease and Mortality in Blacks With Hypertensive Kidney Disease: The African American Study of Kidney Disease and Hypertension (AASK)
Individuals with chronic kidney disease are at an elevated risk of adverse cardiovascular outcomes. This study found that among hypertensive blacks with a glomerular filtration rate of 20 to 65 mL · min−1 · 1.73 m−2 and no other identified cause of kidney disease, higher levels of N-terminal prohormone brain-type natriuretic peptide strongly predicted the occurrence of coronary artery disease, heart failure, and cardiovascular death. These results extend previous findings demonstrating that N-terminal prohormone brain-type natriuretic peptide was a cardiovascular risk marker for blacks and for individuals with chronic kidney disease in whom it had been suggested that N-terminal prohormone brain-type natriuretic peptide may not be predictive of future events because of confounding by reduced renal clearance. Higher N-terminal prohormone brain-type natriuretic peptide levels did not predict progression of renal disease. See p 1685.
Interrelation of Coronary Calcification, Myocardial Ischemia, and Outcomes in Patients With Intermediate Likelihood of Coronary Artery Disease: A Combined Positron Emission Tomography/Computed Tomography Study
The measurement of coronary artery calcification (CAC) by computed tomography (CT) has received considerable attention for diagnosis and risk stratification of patients with suspected coronary artery disease. The decision of whether and when myocardial perfusion imaging should be coupled with CAC scoring is becoming increasingly relevant because hybrid single-photon emission computed tomography/CT and positron-emission tomography/CT scanners are becoming more widely available. The goals of the present study were to assess the relationship between CAC scoring and stress-induced myocardial ischemia, as assessed by combined positron-emission tomography CT, and to define the incremental prognostic information added by the integration of CAC scoring and myocardial perfusion imaging in patients with intermediate likelihood of coronary artery disease. The frequency of ischemia among patients with a CAC score ≥400 was high (48%), and multivariable analysis supported the concept of a threshold CAC score ≥400 governing this relationship. Conversely, the absence of CAC only afforded a negative predictive value of 84% to rule out ischemia. Survival analysis demonstrated a stepwise increase in event rates (death and myocardial infarction) with increasing CAC scores. Among patients with normal myocardial perfusion, the annualized event rate in patients with no CAC was lower than in those with a CAC score ≥1000 (2.6% versus 12.3%). Similar differences were observed in patients with inducible ischemia. The study suggests that imaging approaches that combine quantitative information on the anatomic burden of coronary artery disease with its physiological consequences offer improved risk stratification over conventional approaches that use myocardial perfusion alone. If confirmed in larger prospective studies, it is possible that the use of combined imaging technologies may offer improved risk assessment and a more rational risk-based approach to management. See p 1693.
Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction
Pharmacological inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) has been proposed as an alternative to inhibition of cyclooxygenase-2 in the management of patients with pain and inflammatory diseases. Here, we examined the role of prostaglandin E2 (PGE2) in postinfarction cardiac remodeling by taking advantage of homozygote mPGES-1 knockout mice, which have low basal and induced PGE2 synthesis. Contrary to our original hypothesis, we found that deletion of mPGES-1 did not affect the size of the infarct after coronary ligation. However, the mPGES-1 knockout animals had worse left ventricular systolic and left ventricular diastolic function, more ventricular dilation, and markedly attenuated cardiomyocyte hypertrophy in the region remote from the infarction compared with wild-type mice. Coupled with the observation that the bulk of PGE2 biosynthesis in the infarct was carried out by inflammatory cells, these findings suggest that diffusion of PGE2 from the infarct and peri-infarct regions influences the hypertrophy of cardiomyocytes remote from the infarction. These data imply that hypertrophy in the region remote from the infarct is not regulated purely by mechanical forces but also by inflammatory mediators such as PGE2. The potential clinical importance of these observations is significant because the millions of patients who previously took cyclooxygenase-2 inhibitors are potential candidates to take pharmacological inhibitors of mPGES-1, which are currently in development. Our findings emphasize the importance of carefully evaluating cardiac function in patients at risk for myocardial infarction who are treated with agents that selectively block PGE2 biosynthesis, which have been proposed to have less cardiovascular toxicity than inhibitors of cyclooxygenase-2. See p 1701.
Clinical Predictors for Fatal Pulmonary Embolism in 15 520 Patients With Venous Thromboembolism: Findings From the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry
Pulmonary embolism (PE) remains a potentially fatal disease in patients with venous thromboembolism. Its incidence varies widely in the literature, from <1% to 7%. Identifying patients at increased risk of fatal PE is therefore important for optimally adapting treatment to the level of risk. This is all the more important because the use of generally recommended treatments in high-risk patients, such as administration of fibrinolytic drugs or placement of vena cava filters, may be complicated by severe adverse events. Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about 15 520 patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Symptomatic nonmassive PE was observed in 40.4%, and massive PE in 1.6%. At 3 months, the cumulative rate of fatal PE was 1.68%. On multivariable analysis, compared to patients with deep-vein thrombosis at presentation, the risk of fatal PE was multiplied by 5.42 in patients with symptomatic nonmassive PE and by 17.5 in patients presenting a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilisation for neurological disease (4.90-fold higher), age >75 years (2.54-fold higher), and cancer (2.04-fold higher). The clinical factors predicting a fatal PE identified in this study can be routinely identified and could therefore easily be included in a risk stratification scheme for daily practice. These results may help to improve the management of patients with PE and therefore increase survival rates. See p 1711.
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