The type VI adenylyl cyclase protects cardiomyocytes from ß-adrenergic stress by a PKA/STAT3-dependent pathway.

BACKGROUND: The type VI adenylyl cyclase (AC6) is a main contributor of cAMP production in the heart. The amino acid (aa) sequence of AC6 is highly homologous to that of another major cardiac adenylyl cyclase, AC5, except for its N-terminus (AC6-N, aa 1-86). Activation of AC6, rather than AC5, produces cardioprotective effects against heart failure, while the underlying mechanism remains to be unveiled. Using an AC6-null (AC6-/-) mouse and a knockin mouse with AC6-N deletion (AC6 ΔN/ΔN), we aimed to investigate the cardioprotective mechanism of AC6 in the heart. METHODS: Western blot analysis and immunofluorescence staining were performed to determine the intracellular distribution of AC6, AC6-ΔN (a truncated AC6 lacking the first 86 amino acids), and STAT3 activation. Activities of AC6 and AC6-ΔN in the heart were assessed by cAMP assay. Apoptosis of cardiomyocytes were evaluated by the TUNEL assay and a propidium iodine-based survival assay. Fibrosis was examined by collagen staining. RESULTS: Immunofluorescence staining revealed that cardiac AC6 was mainly anchored on the sarcolemmal membranes, while AC6-ΔN was redistributed to the sarcoplasmic reticulum. AC6ΔN/ΔN and AC6-/- mice had more apoptotic myocytes and cardiac remodeling than WT mice in experimental models of isoproterenol (ISO)-induced myocardial injury. Adult cardiomyocytes isolated from AC6ΔN/ΔN or AC6-/- mice survived poorly after exposure to ISO, which produced no effect on WT cardiomyocytes under the condition tested. Importantly, ISO treatment induced cardiac STAT3 phosphorylation/activation in WT mice, but not in AC6ΔN/ΔN and AC6-/- mice. Pharmacological blockage of PKA-, Src-, or STAT3- pathway markedly reduced the survival of WT myocytes in the presence of ISO, but did not affect those of AC6ΔN/ΔN and AC6-/- myocytes, suggesting an important role of AC6 in mediating cardioprotective action through the activation of PKA-Src-STAT3-signaling. CONCLUSIONS: Collectively, AC6-N controls the anchorage of cardiac AC6 on the sarcolemmal membrane, which enables the coupling of AC6 with the pro-survival PKA-STAT3 pathway. Our findings may facilitate the development of novel therapies for heart failure.

Association of white blood cell count and peripheral arterial disease in patients with and without traditional risk factors.

Peripheral arterial disease (PAD) is an inflammatory process. The association between white blood cell (WBC) count and PAD in those with and without traditional risk factors is not clear. We examined data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. A total of 5260 participants were included. The result showed that the prevalence of PAD rose from 2.8% +/- 0.5% in the lowest quartile of plasma WBC count to 8.0% +/- 1.2% in the highest quartile. In subgroup analysis, the graded association between WBC count and PAD was significant in patients without hypertension, diabetes, smoking, chronic kidney disease (CKD), and in patients with or without hypercholesterolemia but not significant in patients with hypertension, smoking, diabetes, or CKD. In those without hypertension, diabetes, smoking, or CKD, the cutoff value for WBC count was 6.75 x 10(9)/L. We concluded that the positive association between WBC count and PAD can be demonstrated in this national survey.

Analysis of the outcome for patients experiencing myocardial infarction and cardiopulmonary resuscitation refractory to conventional therapies necessitating extracorporeal life support rescue.

OBJECTIVE: To analyze the results of acute myocardial infarction (AMI) complicated with refractory shock necessitating extracorporeal life support (ECLS) rescue and to search for associated risk factors. DESIGN: Retrospective review of our 9-yr experience with patients initially presenting with AMI with shock necessitating ECLS rescue; analysis of patient outcomes. SETTING: A university-affiliated tertiary referral medical center. PATIENTS: Between 1994 and 2003 inclusively, 36 consecutive patients (age [mean +/- sd], 57 +/- 10 yrs) with AMI complicated by refractory shock and undergoing cardiopulmonary resuscitation (CPR) necessitating emergent ECLS rescue were enrolled in this study. INTERVENTION: All patients underwent CPR before ECLS, although 30 patients (83.3%) received ECLS during CPR because spontaneous circulation failed to return. All patients underwent intraaortic counterpulsation either before or following rescue. Seven patients underwent angioplasty only, and one underwent heart transplantation without any intervention. Twenty-eight patients underwent coronary artery bypass grafting (CABG), in which the beating-heart technique was used for 20 patients. MEASUREMENTS AND MAIN RESULTS: The pre-ECLS blood lactate level was high (13.4 +/- 8.5 mmol/L), as was the inotropic score (121.4 +/- 117.3 microg/kg/min). Twenty-five patients (69.4%) were successfully weaned off ECLS, and 12 (48%) survived to discharge (one had a neurologic deficit). The overall mortality rate was 66.7%. A lower inotropic score, reduced blood lactate level, shorter CPR duration, surgical revascularization, and a reduced total maximal Sepsis-related Organ Failure Assessment (SOFA) score were noted among survivors. Liver failure, central nervous system failure, and renal failure mainly occurred in nonsurvivors after ECLS. The technique used for surgical revascularization (beating heart or arrested heart) did not influence the outcome. ECLS is associated with a lower mortality rate than that expected (>90%) from the resultant total maximal SOFA score (16.6 +/- 3.0). CONCLUSIONS: : AMI complicated with refractory shock remains associated with a high mortality rate, even following ECLS rescue, although ECLS might afford a better chance of survival. The SOFA score can be applied to ECLS condition as a reference point for predicting outcome.

Experience and result of extracorporeal membrane oxygenation in treating fulminant myocarditis with shock: what mechanical support should be considered first?

BACKGROUND: Extracorporeal membrane oxygenation (ECMO), instead of ventricular assist device (VAD), could work as the first-line treatment of choice for fulminant myocarditis (FM) with profound shock if intraaortic balloon pumping was inadequate. We reviewed our experience in treating FM with ECMO and compared it with the literature that described the use of VAD. METHODS: Fifteen consecutive patients (age 27.1 +/- 19.3 years) who had FM with profound shock were rescued with ECMO emergently. Hypotension, depressed left ventricular ejection fraction (19.1% +/- 6.1%), and oliguria occurred in all patients with high-dose catecholamine (inotropic equivalents: 69.0 +/- 37.7 microg/kg/min) and ventilator support. Before ECMO support, 6 patients received intraaortic balloon pumping support, 5 received external cardiac massage, 5 needed a temporary pacemaker, and 4 needed continuous hemofiltration. The pre-ECMO cardiac enzyme and liver enzyme levels were abnormally high. RESULTS: Fourteen patients (93.3%) could be weaned off mechanical support. Three of 14 successfully weaned patients died later as a result of complications. Survival to discharge was 73.3%, and none of survivors needed heart transplantation. The ECMO duration was 137.7 +/- 74.5 hours. The ECMO-related neurological complication (6.7%) and the reexploration rate for hemostasis (8.9%) were lower than the myocarditis group supported by VAD from the literature review. The 11 survivors exhibited no cardiac dysfunction during the follow-up period. CONCLUSIONS: Owning to advantages of fewer complications, easier application, and biventricular support, ECMO can be considered as the first-line treatment of mechanical support for FM with profound shock when intraaortic balloon pumping is inadequate or infeasible.