Publications

BACKGROUND

Sudden cardiac death (SCD) remains a major public health problem; however, its true burden remains unknown with widely variable estimates of its incidence. We aimed to examine the contemporary epidemiology and autopsy characteristics of SCD in an ethnically diverse community.

METHODS

Three physicians reviewed all deaths of individuals aged ≥20 years reported to the San Francisco medical examiner in 2007 for presentations fitting World Health Organization (WHO) SCD criteria-within 1 hour of symptom onset (witnessed) or within 24 hours of being observed alive and symptom free (unwitnessed). After comprehensive review of medical examiner investigation, WHO SCDs were classified as sudden arrhythmic death (SAD) or nonarrhythmic death. Coronary artery disease (CAD) and cardiac mass were evaluated in all SADs undergoing autopsy and compared with demographically similar accidental trauma control deaths.

RESULTS

We identified 252 WHO SCDs; 145 were SADs. Men had a 2.2-fold higher SAD rate (P < .0005). Blacks had a 3.15-fold higher SAD rate compared with whites (P = .003). Significant CAD was present in 38.9% of SADs and associated with higher SAD risk compared with control deaths (OR 2.58, 95% CI 1.12-5.97, P = .026). Mean cardiac mass was linearly associated with risk for SAD in cases without significant CAD (OR 2.06 per 100 g, 95% CI 1.43-2.98, P < .0005).

CONCLUSIONS

In a diverse, urban population, SAD incidence varied substantially by gender and race. Significant CAD accounted for far fewer SADs than previous studies but remained associated with a 2.6-fold higher risk as compared with control deaths. These findings may reflect the evolving contemporary epidemiology of SCD.

RATIONALE

Sepsis and acute lung injury (ALI) have devastatingly high mortality rates. Both are associated with increased vascular leak, a process regulated by complex molecular mechanisms.

OBJECTIVES

We hypothesized that integrin αvβ3 could be an important determinant of vascular leak and endothelial permeability in sepsis and ALI.

METHODS

β3 subunit knockout mice were tested for lung vascular leak after endotracheal LPS, and systemic vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. Possible contributory effects of β3 deficiency in platelets and other hematopoietic cells were excluded by bone marrow reconstitution experiments. Endothelial cells treated with αvβ3 antibodies were evaluated for sphingosine-1 phosphate (S1P)–mediated alterations in barrier function, cytoskeletal arrangement, and integrin localization.

MEASUREMENTS AND MAIN RESULTS

β3 knockout mice had increased vascular leak and pulmonary edema formation after endotracheal LPS, and increased vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. In endothelial cells, αvβ3 antibodies inhibited barrier-enhancing and cortical actin responses to S1P. Furthermore, S1P induced translocation of αvβ3 from discrete focal adhesions to cortically distributed sites through Gi- and Rac1-mediated pathways. Cortical αvβ3 localization after S1P was decreased by αvβ3 antibodies, suggesting that ligation of the αvβ3 with its extracellular matrix ligands is required to stabilize cortical αvβ3 focal adhesions.

CONCLUSIONS

Our studies identify a novel mechanism by which αvβ3 mitigates increased vascular leak, a pathophysiologic function central to sepsis and ALI. These studies suggest that drugs designed to block αvβ3 may have the unexpected side effect of intensifying sepsis- and ALI-associated vascular endothelial leak.

Increasing evidence links air pollution to the risk of cardiovascular disease. This study investigated the association between ischemic heart disease (IHD) prevalence and exposure to traffic-related air pollution (nitrogen dioxide [NO₂], fine particulate matter [PM₂.₅], and ozone [O₃]) in a population of susceptible subjects in Toronto. Local (NO₂) exposures were modeled using land use regression based on extensive field monitoring. Regional exposures (PM₂.₅, O₃) were modeled as confounders using inverse distance weighted interpolation based on government monitoring data. The study sample consisted of 2360 patients referred during 1992 to 1999 to a pulmonary clinic at the Toronto Western Hospital in Toronto, Ontario, Canada, to diagnose or manage a respiratory complaint. IHD status was determined by clinical database linkages (ICD-9-CM 412-414). The association between IHD and air pollutants was assessed with a modified Poisson regression resulting in relative risk estimates. Confounding was controlled with individual and neighborhood-level covariates. After adjusting for multiple covariates, NO₂ was significantly associated with increased IHD risk, relative risk (RR) = 1.33 (95% confidence interval [CI]: 1.2, 1.47). Subjects living near major roads and highways had a trend toward an elevated risk of IHD, RR = 1.08 (95% CI: 0.99, 1.18). Regional PM₂.₅ and O₃ were not associated with risk of IHD.