S. Ward Casscells

Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies.

In the United States, 12 400 000 people live with a history of heart attack, angina pectoris, or both. Of this population, an estimated 1 100 000 will suffer a new or recurrent coronary attack this year.1 According to the World Health Organization, cardiovascular disease (CVD) will be the leading cause of death worldwide by 2020.2 Infectious agents have been implicated in the etiology of atherosclerosis and its complications since the early 1900s.3 Clinicians have long noticed that ≈30% of myocardial infarctions (MIs) are preceded by an upper respiratory infection.4,5 Agents implicated in atherosclerosis include cytomegalovirus (CMV), Chlamydia pneumoniae , Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Helicobacter pylori , Mycoplasma pneumoniae , Porphyromonas gingivalis , and Enterovirus.6–13 Antibiotic therapy for C. pneumoniae in CVD patients has been tried with transient or no benefit to date.14,15 Ongoing studies may give a definitive answer by late 2003.16 Here, we review recent studies suggesting influenza may play a role in atherogenesis or atherothrombosis. In 2000, we reported a case-control study in patients with known coronary artery disease; influenza vaccination was associated with a 67% reduction (OR 0.33, 95% CI 0.13 to 0.82, P =0.017) in risk of MI in the subsequent influenza season.17 In a simultaneous population-based case-control study, Siscovick et al18 found that after adjusting for demographic, clinical, and behavioral risk factors, influenza vaccination was associated with a 49% reduction (OR 0.51, 95% CI 0.33 to 0.79) in risk of out-of-hospital primary cardiac arrest. Another case-control study reported a 50% risk reduction (OR 0.50, 95% CI 0.26 to 0.94, P =0.033) in stroke risk in subjects vaccinated during the year of the study and a 48% (OR 0.42, 95% CI 0.21 to 0.81, P =0.009) risk reduction in those vaccinated …

Superparamagnetic Iron Oxide–Based Method for Quantifying Recruitment of Monocytes to Mouse Atherosclerotic Lesions In Vivo Enhancement by Tissue Necrosis Factor-α, Interleukin-1β, and Interferon-γ

Background—It has been found recently that the MRI contrast agent superparamagnetic iron oxide (SPIO) localizes to aortic atherosclerotic plaques. We therefore asked whether SPIO might be used to monitor monocyte recruitment into aortic atherosclerotic plaques. Methods and Results—Eleven female apo E knockout (K/O) mice, each 11 months old, were divided into 2 groups. Six mice received tissue necrosis factor-&agr; (0.2 &mgr;g IP once), interleukin-1&bgr; (0.2 &mgr;g IP once), and interferon-&ggr; (100 U/g per day IP for 5 days); 5 received 0.5 mL saline containing1% BSA and served as sham-treated atherosclerotic controls. Two wild-type C57BL/6 mice served as sham-treated nonatherosclerotic controls. Three hours after initial cytokine or sham treatment, all mice received SPIO by intravenous injection (1 mmol/kg iron). Six days later, all mice were euthanized, the hearts and aortas were perfused under physiological pressure, and the entire aortas were studied histologically. Atherosclerotic plaques in cytokine-treated mice contained more iron-positive macrophages per cross section than did those in sham-treated apo E K/O control mice (42±11.8 versus 11.6±5.9) (P <0.0001). Iron-laden macrophages were present either in subendothelial plaque surfaces or in thin layers overlying the internal elastic lamina, often at the edges of atherosclerotic plaques. No iron deposition was seen in aortas of the wild-type nonatherosclerotic control mice. Immunocytochemistry showed mostly macrophages and few T lymphocytes in atherosclerotic plaques of cytokine-treated mice. Conclusions—SPIO allows detection of iron-laden macrophages in the aortic subendothelium of apo E–deficient mice under basal conditions and monitoring of monocyte recruitment after cytokine injection.

The role of periadventitial fat in atherosclerosis.

CONTEXT It has become increasingly evident that adipose tissue is a multifunctional organ that produces and secretes multiple paracrine and endocrine factors. Research into obesity, insulin resistance, and diabetes has identified a proinflammatory state associated with obesity. Substantial differences between subcutaneous and omental fat have been noted, including the fact that omental fat produces relatively more inflammatory cytokines. Periadventitial fat, as a specific adipose tissue subset, has been overlooked in the field of atherosclerosis despite its potential diagnostic and therapeutic implications. OBJECTIVE To review (1) evidence for the role of adventitial and periadventitial fat in vessel remodeling after injury, (2) the relationship between adventitial inflammation and atherosclerosis, (3) the association between periadventitial fat and plaque inflammation, and (4) the diagnostic and therapeutic implications of these roles and relationships for the progression of atherosclerosis. DATA SOURCES We present new data showing greater uptake of iron, administered in the form of superparamagnetic iron oxide, in the periadventitial fat of atherosclerotic mice than in control mice. In addition, macrophage density in the periadventitial fat of lipid-rich plaques is increased compared with fibrocalcific plaques. CONCLUSIONS There is a striking paucity of data on the relationship between the periadventitial fat of coronary arteries and atherosclerosis. Greater insight into this relationship might be instrumental in making strides into the pathophysiology, diagnosis, and treatment of coronary artery disease.

Influenza virus directly infects, inflames, and resides in the arteries of atherosclerotic and normal mice

OBJECTIVE Influenza can trigger heart attacks, and vaccination against influenza reduces the risk of cardiovascular events. Currently, it is believed that influenza virus in general does not disseminate to extra-pulmonary tissues. We assessed the vascular effects of influenza infection and whether the virus can directly infect atherosclerotic arteries in mice. METHODS/RESULTS We intranasally infected 4 different types of mice--atherosclerotic apo E-deficient (our primary model), LDL receptor knockout, C57BL/6, and outbred Swiss--with influenza A/HK (H3/N2) virus. On day 7 after infection, we cultured viable virus from lung, aorta, and heart tissue, but not from the blood of apo E-deficient mice. Immunofluorescence studies showed influenza A virus NP1 protein and real time polymerase chain reaction (PCR) assay showed RNA in the aorta of infected apo E-deficient mice. Infected mice had significantly higher blood levels of chemokines and cytokines than control mice. At the local level, gene expression for several chemokines and cytokines was increased and eNOS expression was decreased. Infected mice had a higher density of macrophages in plaque than did control mice. CONCLUSIONS We have shown for the first time that influenza virus can directly infect and reside in atherosclerotic arteries and that infection was associated with systemic and arterial-level pro-inflammatory changes.

Thermography basket catheter: in vivo measurement of the temperature of atherosclerotic plaques for detection of vulnerable plaques.

We have developed an intravascular thermography basket catheter to measure the temperature of the vessel wall to locate foci of inflammation. Our 3 Fr thermography basket catheter is a thermocouple‐based catheter made of a nitinol expandable and externally controllable basket system loaded with nine small and flexible built‐in thermosensors. It is equipped with real‐time data acquisition software with a thermal resolution of 0.0001°C and a sampling rate of 20 readings per second. In 10 inbred cholesterol‐fed dogs with femoral (but not carotid) atherosclerosis, we found foci of warmth on the surface of atherosclerotic but not disease‐free regions (P < 0.05). Marked temperature heterogeneity was also observed in the aortas of atherosclerotic Watanabe rabbits but not in normal rabbits. The catheters showed satisfactory accuracy, reproducibility, and safety. If confirmed in further studies, it has the potential to be utilized in detection of vulnerable plaques. Cathet Cardiovasc Intervent 2003;59:52–59.

Cholesterol crystallization and macrophage apoptosis: implication for atherosclerotic plaque instability and rupture.

The presence of abundant cholesterol crystals symbolizes the disorder of cholesterol metabolism during the development of atherosclerosis. Examination of cultured human THP-1 macrophages treated with the cholesterol oxide, 7-ketocholesterol, revealed a concentration- and time-dependent increase in formation of cholesterol crystals in the cells. Radioisotope labeling and X-ray diffraction confirmed the presence of 7-ketocholesterol crystalline domains (d space 35.8A). Under the normal cell culture condition (5% CO(2), 37 degrees ), incubation with 7-ketocholesterol induced moderate levels of apoptosis. Elevating temperature from 37 to 40 degrees markedly reduces formation of the crystals in the macrophages. Meanwhile, at high temperatures, significantly increased numbers of apoptotic cells were detected in the cells treated with 7-ketocholesterol but not in those with native free cholesterol. These results suggest that hyperthermia inhibits cholesterol crystallization and promotes apoptotic effects of oxysterols on macrophages.

Use of Oseltamivir After Influenza Infection Is Associated With Reduced Incidence of Recurrent Adverse Cardiovascular Outcomes Among Military Health System Beneficiaries With Prior Cardiovascular Diseases

Background—Influenza infection has been associated with increased risk of adverse cardiac and cerebral vascular outcomes. Oseltamivir, a treatment for influenza, has been shown to decrease the severity of an influenza episode, but few data exist regarding its potentially protective effect against recurrent vascular outcomes among influenza patients with a history of vascular disease. Methods and Results—Electronic healthcare service and pharmacy records for 37 482 TRICARE beneficiaries, aged 18 and older, with a coded history of cardiovascular (CV) disease and a subsequent diagnosis of influenza from October 1, 2003, through September 30, 2007, were examined. Subjects were grouped according to whether they had filled a prescription for oseltamivir within 2 days of their influenza diagnosis. The incidence of recurrent CV events within 30 days after the influenza diagnosis among oseltavmivir-treated and untreated subjects was 8.5% and 21.2%, respectively (P<0.005). Subject age was a persistent and significant contributor to the likelihood of recurrent CV outcomes. After controlling for the differences in demographics among treated and untreated cohorts using a propensity-scored logistic regression model, a statistically significant protective effect was associated with oseltamivir treatment (odds ratio, 0.417; 95% CI, 0.349 to 0.498). Conclusions—Our findings suggests that oseltamivir treatment for influenza is associated with significant decrease in the risk of recurrent CV events in subjects with a history of CV disease. These findings merit confirmation in further prospective and controlled studies. Meanwhile, in patients with CV disease, strict adherence with current practice guidelines for prevention and treatment of influenza is recommended.

Decreasing Body Temperature Predicts Early Rehospitalization in Congestive Heart Failure

BACKGROUND In congestive heart failure (CHF), a low body temperature at hospital admission predicts in-hospital mortality. We hypothesized that a postdischarge reduction in body temperature predicts early CHF rehospitalization and death. METHODS We reviewed the records of 198 patients discharged after CHF hospitalization. We categorized the patients as hypothermic or normothermic (cutoff point, 36.3 degrees C/97.4 degrees F) according to body temperature at discharge. We classified the 2 groups according to the direction of temperature change between discharge and the first follow-up visit: normothermic/non-decreasing temperature (N+), normothermic/decreasing temperature (N-), hypothermic/non-decreasing temperature (H+), and hypothermic/decreasing temperature (H-). RESULTS Ninety-three patients (47%) had decreasing temperatures, and 105 patients (53%) had non-decreasing temperatures. Kaplan-Meier analysis revealed a significant intergroup difference in survival (P = .01) and rehospitalization time (P = .005). On logistic regression, a decreasing temperature was significantly associated with rehospitalization within 180 days (odds ratio, 4.01; 95% confidence interval, 1.63-10.02; P = .003). On Cox regression, the hazard ratios for death were 3.19 (P = .07), 6.49 (P = .004), and 5.17 (P = .07), for the N-, H+, and H- groups, respectively, versus the N+ group. For rehospitalization time, the hazard ratios were 7.02 (P = .01), 4.24 (P = .08), and 13.43 (P = .005) for the N-, H+, and H- groups, respectively, versus the N+ group. CONCLUSION Decreasing body temperatures can predict readmission, decreased time to rehospitalization, and (in combination with hypothermia) decreased survival.

Telephone survey to assess influenza-like illness, United States, 2006.

This method offers a potentially feasible means to monitor patients at home.

Association of low body temperature and poor outcomes in patients admitted with worsening heart failure: a substudy of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial

Risk stratification in patients admitted with worsening heart failure (HF) is essential for tailoring therapy and counselling. Risk models are available but rarely used, in part because many require laboratory and imaging results that are not routinely available. Body temperature is associated with prognosis in other illnesses, and we hypothesized that low body temperature would be associated with worse outcomes in patients admitted with worsening HF.