Publications

PURPOSE

The effect of the heart failure substrate on the initiation of ventricular fibrillation (VF) and its resulting mechanism is not known. The objective of this study was to determine the effects of substrate on VF initiation and its spatiotemporal organization in the heart failure model.

METHODS

Optical action potentials were recorded from LV wedge preparations either from structurally normal hearts (control, n = 11) or from congestive heart failure (CHF; n = 7), at the epicardial surface, endocardial surface which included a papillary muscle, and a transmural cross section. Action potential duration (APD(80)) was determined, and VF was initiated. A fast Fourier transform was calculated, and the dominant frequency (DF) was determined.

RESULTS

The CHF group showed increased VF vulnerability (69 vs 26 %, p < 0.03), and every mapped surface showed an APD(80) gradient which included islands of higher APDs on the transmural surface (M cells) which was not observed in controls. VF in the CHF group was characterized by stable, discrete, high-DF areas that correlated to either foci or spiral waves located on the transmural surface at the site of the papillary muscle. Overall, the top 10 % of DFs correlated to an APD of 101 ms while the bottom 10 % of DFs correlated to an APD of 126 ms (p < 0.01).

CONCLUSIONS

In the CHF model, APD gradients correlated with an increased vulnerability to VF, and the highest stable DFs were located on the transmural surface which was not seen in controls. This indicates that the CHF substrate creates unique APD and DF characteristics.

Despite the equipoise regarding alcohol's cardiovascular effects and absence of relevant rigorous controlled trials, the lay press frequently portrays alcohol as "heart healthy." The public perception of alcohol's heart effects, the sources of those perceptions, and how they may affect behavior are unknown. We performed a cross-sectional analysis of data obtained from March 2013 to September 2014 from consecutive participants enrolled in the Health eHeart Study. Of 5,582 participants, 1,707 (30%) viewed alcohol as heart healthy, 2,157 (39%) viewed it as unhealthy, and 1,718 (31%) were unsure. Of those reporting alcohol as heart healthy, 80% cited lay press as a source of their knowledge. After adjustment, older age (odds ratio 1.11), higher education (odds ratio 1.37), higher income (odds ratio 1.07), US residence (odds ratio 1.63), and coronary artery disease (odds ratio 1.51) were associated with perception of alcohol as heart healthy (all p <0.003). Ever smokers (odds ratio 0.76, p = 0.004) and those with heart failure (odds ratio 0.5, p = 0.01) were less likely to cite alcohol as heart healthy. Those perceiving alcohol as heart healthy consumed on average 47% more alcohol on a regular basis (95% confidence interval 27% to 66%, p <0.001). In conclusion, of >5,000 consecutive Health eHeart participants, approximately 1/3 believed alcohol to be heart healthy, and the majority cited the lay press as the origin of that perception. Those with a perception of alcohol as heart healthy drink substantially more alcohol.

Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific αβTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific αβTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of αβTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RβVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that αβTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease.