The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 μg/g ip) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (ΔCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca(2+) decay (τCa) was prolonged, and sarcoplasmic reticulum Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca(2+)-ATPase (SERCA). L-type Ca(2+) channel current (ICa,L) was also decreased after LPS challenge, whereas Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+)-handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L, and τCa prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCα1(-/-) mice) versus WT mice. LPS did not alter the protein expression of SERCA and phospholamban in either genotype. After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP.

Background Electrical alternans is a pattern of variation in the shape of electrocardiographic waveform that occurs every other beat. In humans, alternation in ventricular repolarization, known as repolarization alternans (RA), has been associated with increased vulnerability to ventricular tachycardia/fibrillation and sudden cardiac death. Methods and Results This study investigates the spatio-temporal variability of intracardiac RA and its relationship to body surface RA in an acute myocardial ischemia model in swine. We developed a real-time multi-channel repolarization signal acquisition, display and analysis system to record electrocardiographic signals from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface prior to and following circumflex coronary artery balloon occlusion. We found that RA is detectable within 4 minutes following the onset ischemia, and is most prominently seen during the first half of the repolarization interval. Ischemia-induced RA was detectable on unipolar and bipolar leads (both in near- and far-field configurations) and on body surface leads. Far-field bipolar intracardiac leads were more sensitive for RA detection than body surface leads, with the probability of body surface RA detection increasing as the number of intracardiac leads detecting RA increased, approaching 100% when at least three intracardiac leads detected RA. We developed a novel, clinically-applicable intracardiac lead system based on a triangular arrangement of leads spanning the right ventricular (RV) and coronary sinus (CS) catheters which provided the highest sensitivity for intracardiac RA detection when compared to any other far-field bipolar sensing configurations (p < 0.0001). Conclusions In conclusion, intracardiac alternans, a complex spatio-temporal phenomenon associated with arrhythmia susceptibility and sudden cardiac death, can be reliably detected through a novel triangular RV-CS lead configuration.

We tested the hypothesis that periodic breathing (PB) at high altitude is more frequent and arterial oxygen desaturation more severe during sleep in subjects developing high altitude pulmonary edema (HAPE) or acute mountain sickness (AMS) compared with subjects remaining healthy. We registered thoraco-abdominal movement, electro-encephalogram and oxygen saturation by pulse oximeter (pSao2) in 21 subjects during the first night spent at the altitude of 4,559 m. During the subsequent stay at 4,559 m, eight subjects remained well (controls), five subjects developed AMS and eight subjects developed HAPE. PB was found in all sleep stages and the percentage PB in any sleep stage was not significantly different between groups. There was a trend towards more PB in the HAPE vs. AMS and control group lasting 80 +/- 5 (mean +/- SE), 58 +/- 7, 57 +/- 9% of analyzable time, respectively (p = 0.09). The mean nocturnal decrease of pSao2 for these groups was 8.7 +/- 1.9, 5.4 +/- 2.1, 4.8 +/- 1.2%; (p = 0.36) and the median nocturnal pSao2 was 49 +/- 3, 63 +/- 3, and 63 +/- 4% (p = 0.02). Arterial blood gas analysis before and after sleep recordings indicate that the significantly lower Sao2 in the HAPE group is secondary to gas exchange rather than ventilation. The nocturnal decrease of pSao2 did not correlate with the time of PB nor the number of desaturation events > or = 4%. These findings suggest that more frequent PB in the HAPE group is a consequence of lower Sao2 due to impairment of gas exchange.

The ability to accurately monitor tidal volume (TV) from electrocardiographic (ECG) signals holds significant promise for improving diagnosis treatment across a variety of clinical settings. The objective of this study was to develop a novel method for estimating the TV from ECG signals. In 10 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the coronary sinus (CS), left ventricle (LV), and right ventricle (RV), as well as body surface electrograms, while TV was varied between 0 and 750 ml at respiratory rates of 7–14 breaths/min. We devised an algorithm to determine the optimized respirophasic modulation of the amplitude of the ECG-derived respiratory signal. Instantaneous measurement of respiratory modulation showed an absolute error of 72.55, 147.46, 85.68, 116.62, and 50.89 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. Minute TV estimation demonstrated a more accurate estimation with an absolute error of 69.56, 153.39, 79.33, 122.16, and 48.41 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. The RV-CS and body surface leads provided the most accurate estimations that were within 7 and 10% of the true TV, respectively. Finally, the absolute error of the bipolar RV-CS lead was significantly lower than any other lead configuration ( P < 0.0001). In conclusion, we have demonstrated that ECG-derived respiratory modulation provides an accurate estimation of the TV using intracardiac or body surface signals, without the need for additional hardware.