Amir H. Najafi

Insights into the role of infection in atherogenesis and in plaque rupture.

The potential contribution of infection to the induction and progression of atherosclerosis has been characterized by profound controversy, continuing to the present time. Controversy also surrounds the concept that infection can precipitate plaque rupture, an event complicating the course of atherosclerosis and clinically characterized by acute myocardial infarction and death. The purpose of this article is (1) to review what we believe are the most compelling data that either are compatible with or refute the concept that infection plays a role in atherogenesis or plaque rupture; (2) to present the mechanisms that may contribute to such effects; and (3) to discuss the impact on the infection/atherosclerosis paradigm of the recent negative therapeutic trials examining the effects of macrolide antibiotics on cardiovascular end points in patients with coronary artery disease (CAD). Although anecdotal information existed for many years suggesting that acute infection can trigger an acute myocardial infarction,1,2 it was the groundbreaking work by Minick and Fabricant and their coworkers3,4 in the1970s that began the serious scientific exploration of the relation between infection and atherosclerosis. These investigators demonstrated that Marek’s disease virus, an avian herpesvirus, caused atherosclerotic-like lesions in multiple arteries of chickens and that infection of smooth muscle cells (SMCs) with the virus in vitro caused cholesterol accumulation. Evidence was subsequently published extending the infection/atherosclerosis paradigm to humans. Thus, pathogens were found to reside in human atherosclerotic vessels,5–8 and seroepidemiological studies demonstrated an association between pathogen-specific antibodies and atherosclerosis. Such associations were found with multiple pathogens, including cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, Chlamydia pneumonia , Helicobacter pylori , and hepatitis A virus, as well as periodontal pathogens.9–16 However, other studies failed to show such associations,17,18 leading to discussions of the limitations of seroepidemiological studies in evaluating a causal role between …

Aging Causes Collateral Rarefaction and Increased Severity of Ischemic Injury in Multiple Tissues

Objective—Aging is a major risk factor for increased ischemic tissue injury. Whether collateral rarefaction and impaired remodeling contribute to this is unknown. We quantified the number and diameter of native collaterals and their remodeling in 3-, 16-, 24-, and 31-month-old mice. Methods and Results—Aging caused an “age-dose-dependent” greater drop in perfusion immediately after femoral artery ligation, followed by a diminished recovery of flow and increase in tissue injury. These effects were associated with a decline in collateral number, diameter, and remodeling. Angiogenesis was also impaired. Mechanistically, these changes were not accompanied by reduced recruitment of T cells or macrophages to remodeling collaterals. However, endothelial nitric oxide synthase signaling was dysfunctional, as indicated by increased protein nitrosylation and less phosphorylated endothelial nitric oxide synthase and vasodilator-stimulated phosphoprotein in collateral wall cells. The cerebral circulation exhibited a similar age-dose-dependent loss of collateral number and diameter and increased tortuosity, resulting in an increase in collateral resistance and infarct volume (eg, 6- and 3-fold, respectively, in 24-month-old mice) after artery occlusion. This was not associated with rarefaction of similarly sized arterioles. Collateral remodeling was also reduced. Conclusion—Our findings demonstrate that aging causes rarefaction and insufficiency of the collateral circulation in multiple tissues, resulting in more severe ischemic tissue injury.

Outcomes and Quality of Life in Patients ≥85 Years of Age With ST-Elevation Myocardial Infarction

The oldest old comprise the fastest growing segment of the US population. However, data are limited regarding the treatment and outcomes of ST-segment elevation myocardial infarction (STEMI) in this age group. We analyzed consecutive patients with STEMI>or=85 years old at a single center. Quality of life was assessed using the EQ-5D Index (range -0.11 to 1.00) and EQ-VAS (range 0 to 100). Of 1,847 patients admitted from 2002 to 2007 with STEMI, 73 (4%) were >or=85 years old (range 85 to 94). Median time from symptom onset to hospital arrival was 3 hours. Cardiogenic shock occurred in 33%. Primary percutaneous coronary intervention (PCI) was performed in 70% of patients, and the procedural success rate was 94%. Evidenced-based therapy included aspirin (97%), clopidogrel (93%), beta blockers (82%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (74%), and statins (86%). The in-hospital mortality rate was 32%, and it was 54% in those with cardiogenic shock. Long-term follow-up was obtained in 96% of hospital survivors at a median of 429 days. Survival rates in patients discharged alive were 75% at 1 year and 65% at 2 years. Cardiogenic shock was the only independent predictor of in-hospital mortality (odds ratio 3.8, 95% confidence interval 1.2 to 11.7, p=0.02), and primary PCI was the only independent predictor of long-term survival (hazard ratio 0.3, 95% confidence interval 0.1 to 0.8, p=0.02). Mean EQ-5D Index was 0.78 and mean EQ-VAS was 70.5. In conclusion, in the oldest old with STEMI, aggressive treatment is associated with reasonable long-term survival and excellent quality of life. The exception may be patients presenting with cardiogenic shock, for whom short-term mortality remains exceedingly high.

Gender differences affect blood flow recovery in a mouse model of hindlimb ischemia.

Blood flow restoration to ischemic tissue is affected by various risk factors. The aim of this study was to examine gender effects on arteriogenesis and angiogenesis in a mouse ischemic hindlimb model. C57BL/6J mice were subjected to unilateral hindlimb ischemia. Flow recovery was less and hindlimb use impairment was greater in females. No gender difference in vessel number was found at baseline, although 7 days postsurgery females had fewer α-smooth muscle actin-positive vessels in the midpoint of the adductor region. Females had higher hindlimb vascular resistance, were less responsive to vasodilators, and were more sensitive to vasoconstrictors postligation. Western blotting showed that females had higher baseline levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in the calf, while 7 days postligation males had higher levels of VEGF, eNOS, and phosphorylated vasodilator stimulated phosphoprotein. Females had less angiogenesis in a Matrigel plug assay and less endothelial cell proliferation in vitro. Females have impaired recovery of flow, a finding presumably caused by multiple factors including decreased collateral remodeling, less angiogenesis, impaired vasodilator response, and increased vasoconstrictor activity; our results also suggest the possibility that new collateral formation, from capillaries, is impaired in females.

Metallothionein Enhances Angiogenesis and Arteriogenesis by Modulating Smooth Muscle Cell and Macrophage Function

Objective—In a previous study we identified metallothionein (MT) as a candidate gene potentially influencing collaterogenesis. In this investigation, we determined the effect of MT on collaterogenesis and examined the mechanisms contributing to the effects we found. Methods and Results—Collateral blood flow recovery was assessed using laser Doppler perfusion imaging, and angiogenesis was measured using a Matrigel plug assay. Smooth muscle cells were isolated from MT knockout (KO) mice for functional assays. Gene expression of matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, and Fat cadherin in smooth muscle cells was measured by real-time polymerase chain reaction, and protein levels of vascular endothelial growth factor and matrix metalloproteinase-9 were determined using enzyme-linked immunosorbent assay and Western blot. CD11b+ macrophages were tested for invasiveness using a real-time impedance assay. Both flow recovery and angiogenesis were impaired in MT KO mice. Proliferation, migration, and invasion were decreased in MT KO smooth muscle cells, and matrix metalloproteinase-9, platelet-derived growth factor, and vascular endothelial growth factor expression were also decreased, whereas FAT-1 cadherin expression was elevated. MT KO CD11b+ cells were more invasive than wild-type cells. Conclusion—MT plays an important role in collateral flow recovery and angiogenesis, an activity that appears to be mediated, in part, by the effects of MT on the functionality of 3 cell types essential for these processes: endothelial cells, smooth muscle cells, and macrophages.

Diagnosis of cardiogenic shock without the use of a pulmonary artery catheter

Background: Current diagnostic criteria for cardiogenic shock (CS) require the use of a pulmonary artery catheter (PAC), which is time-consuming and may cause complications. A set of simple yet accurate noninvasive diagnostic criteria would be of significant utility. Methods: Candidate components for the Noninvasive Parameters for Assessment of Cardiogenic Shock (N-PACS) criteria were required to be objective, readily available, and noninvasive. Variables encompassing hypotension, hypoperfusion, predisposing conditions, and elevated intracardiac filling pressures were optimized versus a PAC-based standard in a retrospective developmental cohort of 122 patients with acute myocardial infarction (AMI). The finalized criteria were validated in a prospective cohort of coronary care unit patients in whom a PAC was placed for clinical indications. Results: According to invasive criteria, CS was present in 32 of 217 consecutive patients undergoing PAC. Compared to the PAC-based standard, the N-PACS criteria had a sensitivity of 96.9% (95% confidence interval (CI) 82.0–99.8), specificity of 90.8% (95% CI 85.5–94.4), positive predictive value of 64.6% (95% CI 49.4–77.4), negative predictive value of 99.4% (95% CI 96.2–100), positive likelihood ratio of 10.5 (95% CI 6.7–16.7), negative likelihood ratio of 0.03 (95% CI 0.00–0.24), and diagnostic odds ratio of 306.4. Results were similar among patients with and without AMI. Conclusion: A simple, echocardiography-based set of noninvasive diagnostic criteria can be used to accurately diagnose CS.

The Role of Infection in Atherosclerosis and in Plaque Stability

The concept that infection may trigger the initiation and progression of atherosclerosis has been the subject of much debate, which continues to the present time. The potential contribution of infection to plaque rupture is also the subject of controversy. Here we provide an overview of this continuing controversy, and present the mechanisms through which infection may alter disease progression and lesion stability.