Qiangjun Cai

Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice

Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/+ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid–metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element–binding protein and nuclear factor-κB, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/+. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a “preactivated” and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis.

Coronary Artery Disease in Patients with Chronic Kidney Disease: A Clinical Update

Chronic kidney disease (CKD) is an independent risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of morbidity and mortality in patients with CKD. The outcomes of CAD are poorer in patients with CKD. In addition to traditional risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, coronary artery calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis. A number of uremia-related biomarkers are identified as predictors of cardiac outcomes in CKD patients. The symptoms of CAD may not be typical in patients with CKD. Both dobutamine stress echocardiography and radionuclide myocardial perfusion imaging have moderate sensitivity and specificity in detecting obstructive CAD in CKD patients. Invasive coronary angiography carries a risk of contrast nephropathy in patients with advanced CKD. It should be reserved for those patients with a high risk for CAD and those who would benefit from revascularization. Guideline-recommended therapies are, in general, underutilized in renal patients. Medical therapy should be considered the initial strategy for clinically stable CAD. The effects of statins in patients with advanced CKD have been neutral despite a lipid-lowering effect. Compared to non-CKD population, percutaneous coronary intervention (PCI) is associated with higher procedure complications, restenosis, and future cardiac events even in the drug-eluting stent era in patients with CKD. Compared with PCI, coronary artery bypass grafting (CABG) reduces repeat revascularizations but is associated with significant perioperative morbidity and mortality. Screening for CAD is an important part of preoperative evaluation for kidney transplant candidates.

Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways

Objective—Vascular smooth muscle cells (VSMCs) may regulate monocyte functions within atherosclerotic lesions. We investigated the impact of VSMC/monocyte interactions on monocyte apoptosis and scavenger receptor CD36 expression, key events related to monocyte survival and differentiation. Methods and Results—Serum deprivation significantly increased THP-1 and human peripheral blood monocyte apoptosis. However, this was significantly reversed by physical binding to human VSMCs (HVSMCs). On binding to HVSMCs, antiapoptotic kinase Akt and its downstream targets were phosphorylated, and Bcl-2 expression was enhanced. Binding-mediated suppression of apoptosis and Akt phosphorylation were attenuated by a phosphoinositide 3-kinase inhibitor and also by an antibody to vascular cell adhesion molecule-1. CD36 expression was also significantly increased in THP-1 cells and in human peripheral blood monocytes after binding to HVSMCs, and this was mediated by both direct contact and soluble factors. Extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase phosphorylation was increased in THP-1 cells after HVSMC coculture. Furthermore, an ERK1/2 inhibitor blocked monocyte CD36 upregulation. Contact-dependent CD36 induction and ERK1/2 phosphorylation in monocytes were inhibited by blocking vascular cell adhesion molecule-1 on HVSMC, whereas soluble factor–induced CD36 expression was attenuated by a monocyte chemoattractant protein-1 neutralizing antibody. Conclusions—These data provide evidence of novel VSMC-dependent local regulation mechanisms for monocyte survival and differentiation in atherosclerosis.

Molecular Characterization and Antimicrobial Susceptibility of Nasal Staphylococcus aureus Isolates from a Chinese Medical College Campus

Staphylococcus aureus colonization and infection occur more commonly among persons living or working in crowded conditions, but characterization of S. aureus colonization within medical communities in China is lacking. A total of 144 (15.4%, 144/935) S. aureus isolates, including 28 (3.0%, 28/935) MRSA isolates, were recovered from the nares of 935 healthy human volunteers residing on a Chinese medical college campus. All S. aureus isolates were susceptible to vancomycin, quinupristin/dalfopristin and linezolid but the majority were resistant to penicillin (96.5%), ampicillin/sulbactam (83.3%) and trimethoprim/sulfamethoxazole (93.1%). 82%, (23/28) of the MRSA isolates and 66% (77/116) of the MSSA isolates were resistant to multiple antibiotics, and 3 MRSA isolates were resistant to mupirocin—an agent commonly used for nasal decolonization. 16 different sequence types (STs), as well as SCCmec genes II, III, IVd, and V, were represented among MRSA isolates. We also identified, for the first time, two novel STs (ST1778 and ST1779) and 5 novel spa types for MRSA. MRSA isolates were distributed in different sporadic clones, and ST59-MRSA-VId- t437 was found within 3 MRSA isolates. Moreover, one isolate with multidrug resistance belonging to ST398-MRSA-V- t571 associated with animal infections was identified, and 3 isolates distributed in three different clones harbored PVL genes. Collectively, these data indicate a high prevalence of nasal MRSA carriage and molecular heterogeneity of S. aureus isolates among persons residing on a Chinese medical college campus. Identification of epidemic MRSA clones associated with community infection supports the need for more effective infection control measures to reduce nasal carriage and prevent dissemination of MRSA to hospitalized patients and health care workers in this community.

Diabetic conditions promote binding of monocytes to vascular smooth muscle cells and their subsequent differentiation

Diabetes is associated with significantly accelerated rates of atherosclerosis, key features of which include the presence of excessive macrophage-derived foam cells in the subendothelial space. We examined the hypothesis that enhanced monocyte-vascular smooth muscle cell (VSMC) interactions leading to subendothelial monocyte retention and differentiation to macrophages under diabetic conditions may be underlying mechanisms. Human aortic VSMCs (HVSMCs) treated with diabetic stimuli high glucose (HG) or S100B, a ligand of the receptor for advanced glycation end products, exhibited significantly increased binding of THP-1 monocytic cells. Diabetic stimuli increased the expression of the adhesive chemokine fractalkine (FKN) in HVSMCs. Pretreatment of HVSMCs with FKN or monocyte chemoattractant protein-1 (MCP-1) neutralizing antibodies significantly inhibited monocyte-VSMC binding, whereas monocytes treated with FKN showed enhanced binding to VSMC. Mouse aortic VSMCs (MVSMCs) derived from type 2 diabetic db/db mice exhibited significantly increased FKN levels and binding to mouse WEHI78/24 monocytic cells relative to nondiabetic control db/+ cells. The enhanced monocyte binding in db/db cells was abolished by both FKN and MCP-1 antibodies. Endothelium-denuded aortas from db/db mice and streptozotocin-induced diabetic mice also exhibited enhanced FKN expression and monocyte binding, relative to respective controls. Coculture with HVSMCs increased CD36 expression in THP-1 cells, and this was significantly augmented by treatment of HVSMCs with S100B or HG. CD36 mRNA and protein levels were also significantly increased in WEHI78/24 cells after coincubation with db/db MVSMCs relative to control MVSMCs. These results demonstrate that diabetic conditions may accelerate atherosclerosis by inducing key chemokines in the vasculature that promote VSMC-monocyte interactions, subendothelial monocyte retention, and differentiation.

The left bundle-branch block puzzle in the 2013 ST-elevation myocardial infarction guideline: From falsely declaring emergency to denying reperfusion in a high-risk population. Are the Sgarbossa Criteria ready for prime time?

Prompt and accurate identification of ST-elevation myocardial infarction (STEMI) in the presence of left bundle-branch block (LBBB) remains difficult. The 2004 STEMI guideline recommended emergent reperfusion therapy to patients with suspected ischemia and new or presumably new LBBB. These recommendations have led to frequent false catheterization laboratory activation and inappropriate fibrinolytic therapy because most patients with suspected ischemia and new or presumably new LBBB do not have acute coronary artery occlusion on angiography. The new 2013 STEMI guideline makes a drastic change by removing previous recommendations. Therefore, patients with suspected ischemia and new or presumably new LBBB would no longer be treated as STEMI equivalent. The new guideline fails to recognize that some patients with suspected ischemia and LBBB do have STEMI, and denying reperfusion therapy could be fatal. The Sgarbossa electrocardiography criteria are the most validated tool to aid in the diagnosis of STEMI in the presence of LBBB. A Sgarbossa score of ≥3 has a superb specificity (98%) and positive predictive value for acute myocardial infarction and angiography-confirmed acute coronary occlusion. Thus, we propose a diagnosis and triage algorithm incorporating the Sgarbossa criteria to quickly and accurately identify, among patients presenting with chest pain and new or presumably new LBBB, those with acute coronary artery occlusion. This is a high-risk population in which reperfusion therapy would be denied by the 2013 STEMI guideline. Our algorithm will also significantly reduce false catheterization laboratory activation and inappropriate fibrinolytic therapy, the inevitable consequence of the 2004 STEMI guideline.

Cardiac allograft vasculopathy: advances in diagnosis.

Cardiac allograft vasculopathy (CAV), characterized by diffuse intimal thickening and luminal narrowing in the arteries of the allograft, is the leading cause of morbidity and mortality in cardiac transplant recipients. Many transplant centers perform routine annual surveillance coronary angiography. However, angiography can underdiagnose or miss CAV due to its diffuse nature. Intravascular ultrasound (IVUS) is more sensitive than angiography. IVUS provides not only accurate information on lumen size, but also quantification of intimal thickening, vessel wall morphology, and composition. IVUS has evolved as a valuable adjunct to angiography and the optimal diagnostic tool for early detection. Noninvasive testing such as dobutamine stress echocardiography and nuclear stress test have shown considerable accuracy in diagnosing significant CAV. Computed tomographic imaging and cardiac magnetic resonance imaging are promising new modalities but require further study. This article reviews the diagnostic methods that are currently available.

Use of impella ventricular assist device in patients with severe coronary artery disease presenting with cardiac arrest.

Impella (Abiomed, Danvers, MA) is a percutaneously inserted ventricular assist device (VAD). It has been increasingly used in patients with severe heart failure, cardiogenic shock, and high-risk percutaneous intervention (PCI). However, the use and efficacy of Impella in patients with severe coronary artery disease (CAD) presenting with cardiac arrest has rarely been reported.The objective of this study is to report our center experience in using Impella VAD in CAD patients presenting with cardiac arrest. From December 2010 to March 2011, three patients with severe CAD presented to our center with cardiac arrest underwent PCI with Impella support. We reported three cases of severe CAD presenting with cardiac arrest successfully treated with PCI and Impella support. Our experience demonstrated that Impella VAD may play an adjunctive role in obtaining hemodynamic stability in these high-risk patients undergoing PCI. One of the patients was supported to left VAD implantation, and the other two had excellent neurological and functional recovery. Our reports suggest an important role of Impella in cardiac arrest population. Earlier Impella implantation after cardiac arrest might provide cardiac support and tissue perfusion until recovery or high-risk PCI.

Three‐Dimensional Echocardiography in Valvular Heart Disease

Two‐dimensional echocardiography (2DE) with color Doppler has been the standard tool for assessing valvular heart disease. However, this requires conceptualizing three‐dimensional (3D) valvular anatomy from individual 2D slices, which is inadequate for complex valvular abnormalities. Similarly, Doppler‐based methods are inherently limited by several assumptions and are influenced by hemodynamics and concomitant valvular disease. 3DE has improved both morphological and functional assessment of valvular heart disease. It provides additional morphological information, which leads to better understanding of the mechanism of valvular dysfunction and surgical planning. 3D planimetry has proven to be accurate in the evaluation of valvular stenosis. This direct assessment eliminates measurement errors and could potentially serve as new gold standard. The continuity equation for aortic stenosis can be simplified by directly measuring left ventricular outflow tract area and stroke volume. In patients with valvular regurgitation, vena contracta area can be directly measured by using 3D color Doppler which is more accurate than the standard 2D methods. By applying hemi‐elliptical formula or directly measuring isovelocity surface area, 3DE has significantly improved the accuracy in regurgitant severity assessment. This is particularly useful in patients with eccentric jets. 3DE has an advantage over 2DE in assessment of tricuspid valve due to its complex geometry. Direct planimetry of orifice area in tricuspid stenosis, or vena contracta area in tricuspid regurgitation are promising although validation studies are needed before they can be applied for clinical decision making. 3DE has not been widely studied in pulmonic valve disease but preliminary data indicate that it is feasible. (Echocardiography 2012;29:88‐97)

Monocyte retention in the pathology of atherosclerosis

Atherosclerosis is a type of chronic inflammatory disease characterized by the presence of monocyte-derived cells in all stages. Monocytes, macrophages, dendritic and foam cells play important roles in the uptake of oxidized lipids, lesion development, and ultimate plaque disruption. Much is known about the mechanisms of monocyte recruitment in the lumen; however, the fate of monocytes after they enter the artery wall is not well understood. In this review, some of the interesting recent results related to monocyte retention after their migration across the endothelium in the pathology of atherosclerosis will be highlighted. The authors have focused on monocyte inside-out equilibrium, apoptosis and proliferation regulation, and the role of vascular smooth muscle cells in monocyte retention in atherosclerosis. They have also proposed potential treatments for atherosclerosis that target inflammation and monocyte/macrophage retention.