Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Interaction of Impaired Coronary Flow Reserve and Cardiomyocyte Injury on Adverse Cardiovascular Outcomes in Patients Without Overt Coronary Artery Disease
- Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease Phenotypes
- Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction
- Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8+ Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development
- Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets
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Interaction of Impaired Coronary Flow Reserve and Cardiomyocyte Injury on Adverse Cardiovascular Outcomes in Patients Without Overt Coronary Artery Disease
Very low levels of serum cardiac troponin are associated with increased mortality, even among subjects without acute coronary syndromes or overt coronary artery disease. Although impaired hemodynamics, endothelial dysfunction, and coronary vasomotor stiffness, all of which may lead to chronic myocardial ischemia and injury, have been invoked as potential mechanisms of mild elevations in cardiac troponin, the pathophysiology of this process in the absence of acute coronary syndromes remains unclear. Coronary vascular dysfunction, as assessed by a reduced coronary flow reserve (calculated as the ratio of hyperemic to rest absolute myocardial blood flow), identifies patients at high risk for major adverse cardiac events even absent overt obstructive coronary artery disease. In these patients, diffuse atherosclerosis or microvascular dysfunction likely contributes to adverse outcomes. This study sought to explore the relationship between biomarkers of coronary flow reserve and low-level myocardial injury and their contributions to cardiovascular outcomes in patients without overt coronary artery disease. These data demonstrated that impaired coronary flow reserve, as quantified noninvasively by positron emission tomography, was associated independently with low-level cardiomyocyte injury and adverse cardiovascular outcomes in patients without flow-limiting coronary artery disease, with a highly significant interaction demonstrated between coronary flow reserve and troponin positivity. Thus, impaired coronary flow reserve, reflecting microvascular dysfunction, modified the effect of a positive troponin on adverse outcomes in an otherwise low-risk population. Investigations of coronary flow reserve may have implications for risk stratification and management of this relatively common clinical scenario. See p 528.
Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease Phenotypes
Cardiovascular diseases (CVDs) reflect a highly coordinated complex of traits. Although thousands of single nucleotide polymorphisms have been found to be associated with CVD traits, a key question that remains unanswered is as follows: How does DNA sequence variation cause disease? Answers to this question can be translated into new drug targets to improve patient care. In this study, we built a CVD network using single nucleotide polymorphism–CVD phenotype associations. The shared single nucleotide polymorphisms between CVD risk factors provide evidence of a genetic explanation for the clustering of metabolic risk factors in the same individuals. We incorporated transcriptomic data into genetic and phenotype network analysis using data from 5257 Framingham Heart Study participants to dissect the relationships between genetic variants, gene expression, and CVD phenotypes. We identified several putatively causal genetic variants that appear to exert their function by altering expression of associated genes that in turn appear to promote interindividual variation in CVD phenotypes. These variants and pathways identified by this approach point toward novel therapeutic targets for the treatment and prevention of CVD. See p 536.
Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction
Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has lagged behind because of the limited availability of human cardiac tissue specimens. Alterations in the cardiomyocytes, coronary microcirculation, or the extracellular matrix may contribute to HFpEF pathophysiology. In this study, we defined structural changes in full-thickness left ventricular myocardial autopsy specimens from 124 subjects with HFpEF and 104 age-appropriate controls dying of noncardiac causes. HFpEF subjects had similar clinical characteristics to observational studies. We found more cardiac hypertrophy, epicardial coronary artery atherosclerosis, coronary microvascular rarefaction, and myocardial fibrosis in HFpEF patients than in controls. The differences in microvascular density were independent of the severity of epicardial coronary artery stenosis or history of hypertension. Myocardial fibrosis was inversely associated with microvessel density, but was not associated with the severity of epicardial coronary artery disease. These data support a role of coronary microvascular endothelial inflammation and microvascular rarefaction in the pathophysiology of HFpEF. Both microvascular rarefaction and myocardial fibrosis may uniquely contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment in HFpEF. See p 550.
Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8+ Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development
B cells can modulate the development of atherosclerotic plaques. Their maturation into antibody-secreting cells is determined by T follicular helper cells. Here, we show that newly identified CD8+ T regulatory cells control the activity of T follicular helper and B cells and consequently atherogenesis. We have identified the adventitial layer as a critical location for atherosclerosis-associated immune activity. Indeed, we show that lymphoid aggregates develop around human atherothrombotic arteries, particularly aortas affected by atherothrombotic aneurysms, are enriched in T follicular helper and B cells, and release immune effectors. Using mouse models, we demonstrate that disrupting the T follicular helper–B-cell axis with an anti-ICOSL antibody is a strategy that suppresses the formation of lymphoid aggregates around diseased arteries. Importantly, the use of this strategy also limits lesion development. Given the specificity of action of anti-ICOSL antibodies, they are good candidates for human translational trials. Indeed, they are currently being tested in lupus patients (http://www.ClinicalTrials.gov; NCT00774943). This approach could be considered to stop aneurysm progression. See p 560.
Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets
Infective endocarditis is characterized by the formation of septic thrombus, called vegetation, with embedded pathogens such as viridans streptococci that form biofilms. However, controversy remains on the most effective regimens for either the prophylaxis or treatment of bacterial endocarditis. With the use of a rat endocarditis model, our previous study demonstrated that infective endocarditis–inducing pathogens, such as Streptococcus mutans or Streptococcus godornii, could hijack host immune effectors (including antibacteria-specific immunoglobulin G and platelets) to protect phagocytosis and form a biofilm in situ at damaged heart valves. In the present study, we extended these findings and show that streptococci-platelet aggregates can induce neutrophil extracellular trap formation, thus providing the framework necessary for entrapping streptococci-platelet aggregates into well-organized biofilms, and for activating the coagulation system to expand the size of the vegetation, as well. These findings provide sound rationale to support the prophylactic prescription of antiplatelet agents in addition to antibiotics to patients at high risk of endocarditis. However, for those patients requiring dental extraction or other surgical interventions, the disturbance of hemostasis by antiplatelet agents is contraindicated. In this context, we provide direct evidence to indicate that the disruption of neutrophil extracellular traps with agents such as DNase I alone could significantly diminish vegetation formation. Moreover, the concomitant administration of penicillin and DNase I provided a synergistic antimicrobial effect on preventing bacteremia and the formation of vegetation more efficiently. Therefore, targeting neutrophil extracellular traps by agents such as DNase I may provide an efficient alternative to antiplatelet agents for the prophylaxis of endocarditis in patients undergoing surgery in clinics. See p 571.
- © 2014 American Heart Association, Inc.
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