AimsAtrial fibrillation (AF) is one of the commonest sustained arrhythmias in chronic heart failure (CHF), although the prognostic implications of the presence of AF in CHF remain controversial. We have therefore performed this meta-analysis to study the effects of the presence of AF on mortality in CHF patients. Methods and resultsA systematic MEDLINE search for all randomized trials and observational studies in which the influence of AF on CHF mortality was investigated and meta-analysis of the mortality data was performed. A total of 16 studies were identified of which 7 were randomized trials and 9 were observational studies including 30 248 and 23 721 patients, respectively. An adjusted meta-analysis of the data revealed that the presence of AF is associated with an adverse effect on total mortality with an odds ratio (OR) of 1.40 [95% confidence interval (CI) 1.32-1.48, P , 0.0001] in randomized trials and an OR of 1.14 (95% CI 1.03-1.26, P , 0.05) in observational studies. This increase in mortality associated with the presence of AF was observed in subgroups of CHF patients with both preserved and impaired left ventricular (LV) systolic function. ConclusionIn conclusion, meta-analysis of 16 studies involving 53 969 patients suggests that the presence of AF is associated with an adverse prognosis in CHF irrespective of LV systolic function.--

Background and Purpose— Many ischemic strokes or transient ischemic attacks are labeled cryptogenic but may have undetected atrial fibrillation (AF). We sought to identify those most likely to have subclinical AF. Methods— We prospectively studied patients with cryptogenic stroke or transient ischemic attack aged ≥55 years in sinus rhythm, without known AF, enrolled in the intervention arm of the 30 Day Event Monitoring Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event (EMBRACE) trial. Participants underwent baseline 24-hour Holter ECG poststroke; if AF was not detected, they were randomly assigned to 30-day ECG monitoring with an AF auto-detect external loop recorder. Multivariable logistic regression assessed the association between baseline variables (Holter-detected atrial premature beats [APBs], runs of atrial tachycardia, age, and left atrial enlargement) and subsequent AF detection. Results— Among 237 participants, the median baseline Holter APB count/24 h was 629 (interquartile range, 142–1973) among those who subsequently had AF detected versus 45 (interquartile range, 14–250) in those without AF ( P <0.001). APB count was the only significant predictor of AF detection by 30-day ECG ( P <0.0001), and at 90 days ( P =0.0017) and 2 years ( P =0.0027). Compared with the 16% overall 90-day AF detection rate, the probability of AF increased from <9% among patients with <100 APBs/24 h to 9% to 24% in those with 100 to 499 APBs/24 h, 25% to 37% with 500 to 999 APBs/24 h, 37% to 40% with 1000 to 1499 APBs/24 h, and 40% beyond 1500 APBs/24 h. Conclusions— Among older cryptogenic stroke or transient ischemic attack patients, the number of APBs on a routine 24-hour Holter ECG was a strong dose-dependent independent predictor of prevalent subclinical AF. Those with frequent APBs have a high probability of AF and represent ideal candidates for prolonged ECG monitoring for AF detection. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00846924.

We investigated whether plasma long-chain sphingoid base (LCSB) concentrations are altered by transient cardiac ischemia during percutaneous coronary intervention (PCI) in humans and examined the signaling through the sphingosine-1-phosphate (S1P) cascade as a mechanism underlying the S1P cardioprotective effect in cardiac myocytes. Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) of 31 patients at 1 and 5 min and 12 h, following induction of transient myocardial ischemia during elective PCI. Coronary sinus levels of LCSB were increased by 1,072% at 1 min and 941% at 5 min (n = 7), while peripheral blood levels of LCSB were increased by 579% at 1 min, 617% at 5 min, and 436% at 12 h (n = 24). In cultured cardiac myocytes, S1P, sphingosine (SPH), and FTY720, a sphingolipid drug candidate, showed protective effects against CoCl induced hypoxia/ischemic cell injury by reducing lactate dehydrogenase activity. Twenty-five nanomolars of FTY720 significantly increased phospho-Pak1 and phospho-Akt levels by 56 and 65.6% in cells treated with this drug for 15 min. Further experiments demonstrated that FTY720 triggered nitric oxide release from cardiac myocytes is through pertussis toxin-sensitive phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase signaling. In ex vivo hearts, ischemic preconditioning was cardioprotective in wild-type control mice (Pak1f/f), but this protection appeared to be ineffective in cardiomyocyte-specific Pak1 knockout (Pak1cko) hearts. The present study provides the first direct evidence of the behavior of plasma sphingolipids following transient cardiac ischemia with dramatic and early increases in LCSB in humans. We also demonstrated that S1P, SPH, and FTY720 have protective effects against hypoxic/ischemic cell injury, likely a Pak1/Akt1 signaling cascade and nitric oxide release. Further study on a mouse model of cardiac specific deletion of Pak1 demonstrates a crucial role of Pak1 in cardiac protection against ischemia/reperfusion injury.

Background: Ventricular tachyarrhythmias are the most common and often the first manifestation of coronary heart disease and lead to sudden cardiac death (SCD). Early detection/identification of acute myocardial ischaemic injury at risk for malignant ventricular arrhythmias in patients remains an unmet medical need. In the present study, we examined the sphingolipids level after transient cardiac ischaemia following temporary coronary artery occlusion during percutaneous coronary intervention (PCI) in patients and determined the role of sphingolipids level as a novel marker for early detection of human myocardial ischaemic injury.Methods and Results: Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) from 31 patients aged 40–73 years-old at 1, 5 min, and 12 h, following elective PCI. Plasma sphingolipids levels were assessed by HPLC. At 1 min coronary sinus levels of sphingosine 1-phosphate (S1P), sphingosine (SPH), and sphinganine (SA) were increased by 314, 115, and 614%, respectively (n = 7), while peripheral blood levels increased by 79, 68, and 272% (n = 24). By 5 min, coronary sinus S1P and SPH levels increased further (720%, 117%), as did peripheral levels of S1P alone (792%). Where troponin T was detectable at 12 h (10 of 31), a strong correlation was found with peak S1P (R2 = 0.818; P < 0.0001).Conclusion: For the first time, we demonstrate the behavior of plasma sphingolipids following transient cardiac ischaemia in humans. The observation supports the important role of sphingolipids level as a potential novel marker of transient or prolonged myocardial ischaemia.