Suppression of cardiac phosphatidate phosphohydrolase 1 activity and lipin mRNA expression in Zucker diabetic fatty rats and humans with type 2 diabetes mellitus.

Lipin functions in mammalian phospholipid biosynthesis through its phosphatidate phosphohydrolase 1 (PAP(1)) activity. Here, we studied cardiac PAP(1) activity and lipin expression ex vivo in 8-month-old Zucker diabetic fatty (ZDF) rats and humans with type 2 diabetes mellitus undergoing open heart surgery for coronary bypass grafting. Compared to non-diabetic littermates (ZDF-fa/+), left ventricular PAP(1) activity was 29% lower in diabetic ZDF-fa/fa rats. Left ventricular PAP(1) activities were 2.1-fold (ZDF-fa/fa) and 3.6-fold (ZDF-fa/+) higher than the respective atrial activities, indicating marked differences in cardiac distribution of PAP(1). PAP(1) activity was highly related with cardiac lipin-1 and lipin-3 mRNA expression in ZDF rats (r=0.99 and 0.96). Consistent with the findings in experimental animals, human atrial tissue displayed PAP(1) activity that was 33% lower in those having diabetes than in non-diabetic controls. Accordingly, atrial lipin-1 and lipin-3 mRNA expression in diabetic patients was 50% and 59% lower as in non-diabetic patients, respectively. Insulin therapy increased both PAP(1) activity and lipin mRNA expression in diabetic patients. We conclude that suppression of cardiac PAP(1) activity/lipin expression may contribute to metabolic dysfunction of the diabetic heart.

Atrioventricular node ablation is not a prerequisite for cardiac resynchronization therapy in patients with chronic atrial fibrillation.

BACKGROUND: In drug-refractory heart failure, cardiac resynchronization therapy (CRT) is an established method in patients with sinus rhythm, severe reduced ejection fraction and broad QRS. Heart failure is known as a predisposition for atrial fibrillation (AF). However, the putative impact of atrioventricular node (AVN) ablation in chronic AF and CRT remains unclear. The aim of this study was to elucidate the effects of CRT in patients with chronic AF and the requirement for AVN ablation. METHODS: A total of 100 patients were included in the retrospective study, 64 with sinus rhythm (SR) and 36 with chronic AF with a mean duration of 2.8 +/- 0.5 years. Clinical parameters, QRS duration and echocardiographic parameters were compared at baseline and after a follow-up of 11 +/- 0.34 months in patients with SR and in 27 patients with chronic AF who received optimized medication to control ventricular rate and nine patients who underwent an AVN ablation. RESULTS: Baseline characteristics between patients with SR or AF in the presence or absence of AVN ablation were comparable. In each group, a significant improvement of NYHA class, ejection fraction could be observed, with an analogous reduction of QRS duration and a diminished left ventricular end-diastolic dimension after 11 +/- 0.34 months of CRT. CONCLUSIONS: The present results demonstrate a comparable improvement in left ventricular function and functional capacity in all treated groups. In conclusion, AVN ablation is not a prerequisite for CRT in patients with severe heart failure and chronic AF.

Nearly asymptomatic left ventricular apical ballooning after a hit-and-run accident.

Tako-tsubo cardiomyopathy is a syndrome that mimics acute myocardial infarction consisting of typical chest pain with acute onset and transient left ventricular wall-motion abnormalities. We present a case of a 53-year-old woman with nearly asymptomatic apical ballooning after a hit-and-run car accident. No blunt force impact occurred over the precordial area. Typical chest pain or dyspnea was not present at any time. Electrocardiogram showed ST-segment elevation and T-wave inversion. Cardiac catheterization revealed the absence of coronary stenosis. Whereas left ventriculography and cardiac magnetic resonance imaging showed apical akinesia and hypercontractility of the basal segments (apical ballooning). Left ventricular systolic function recovered from ejection fraction 34% to 55% in ten days and echocardiographic wall abnormalities returned to normal.

Adenosine A1 receptor-mediated inhibition of myocardial norepinephrine release involves neither phospholipase C nor protein kinase C but does involve adenylyl cyclase.

Stimulation of adenosine A1 receptors in the heart exerts cardioprotective effects by inhibiting norepinephrine (NE) release from sympathetic nerve endings. The intraneuronal signal transduction triggered by presynaptic adenosine A1 receptors is still not completely understood. The objective of the present study was to determine whether phospholipase C (PLC), protein kinase C (PKC), and adenylyl cyclase (AC) are involved in the adenosine A1 receptor-mediated inhibition of endogenous (stimulation-induced) NE release in isolated Langendorff-perfused rat hearts as an approach to elucidate their role in the cardiovascular system. Activation of adenosine A1-receptors with 2-chloro-N6-cyclopentyladenosine (CCPA) decreased cardiac NE release by approximately 40%. Inhibition of PLC with 1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U 73122) as well as inhibition of PKC with 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide (GF 109203X) slightly but significantly decreased NE release; however, the suppressive effect of CCPA on NE release was not modulated by U 73122 or GF 109203X. Blockade of AC with 9-(tetrahydro-2'-furyl)adenine (SQ 22536) reversed the inhibitory effect of CCPA on sympathetic neurotransmitter release irrespective of whether PKC was pharmacologically activated by phorbol 12-myristate 13-acetate or was not activated, indicating a PKC-independent but AC-dependent mechanism. Direct stimulation of AC with forskolin increased NE release by approximately 20%; an effect that was antagonized by either CCPA or SQ 22536. These data suggest that the adenosine A1 receptor-mediated inhibition of NE release does not involve PLC or PKC but does involve AC.

Impairment of presynaptic alpha2-adrenoceptor-regulated norepinephrine overflow in failing hearts from Zucker diabetic fatty rats.

The aim of this study was to assess whether cardiac norepinephrine overflow is affected in Type 2 diabetes mellitus. Homozygous (fa/fa) Zucker diabetic fatty (ZDF) rats were used as a model of Type 2 diabetes; heterozygous (fa/+) ZDF rats served as non-diabetic controls. Cardiac performance was determined in isolated working hearts; release of endogenous norepinephrine was induced by electrical field stimulation in Langendorff-perfused hearts. At a mean age of 30 weeks, left ventricular contraction, relaxation, and developed pressure were reduced by 20% to 35% in ZDF-fa/fa rats compared with ZDF-fa/+ rats. Stepwise increase of stimulation frequency gradually increased norepinephrine overflow in isolated hearts from both rat strains. Compared to ZDF-fa/+ rats, cardiac norepinephrine overflow was suppressed by 25% to 45% in ZDF-fa/fa rats. During presynaptic alpha2-adrenoceptor blockade with rauwolscine, increase of norepinephrine overflow was significantly higher in ZDF-fa/fa rats than in ZDF-fa/+ rats whereas alpha2-adrenoceptor activation with UK 14,304 suppressed norepinephrine overflow solely in ZDF-fa/+ rats. Myocardial tissue content of norepinephrine did not differ markedly between the two groups. In conclusion, cardiac norepinephrine overflow is inhibited in failing hearts from ZDF-fa/fa rats. This inhibition may result from a hyperactive status of presynaptic alpha2-adrenoceptors.

Adenylyl cyclase-dependent inhibition of myocardial norepinephrine release by presynaptic adenosine A1-receptors.

Adenosine A1-receptor-mediated inhibition of exocytotic norepinephrine (NE) release from sympathetic nerve endings has been implicated as an endogenous cardioprotective mechanism. So far, the intraneuronal signal transduction underlying the adenosine A1-receptor-elicited inhibition of NE release is not known. In the present study, we determined in isolated Langendorff-perfused rat hearts the role of inhibitory G-proteins and of adenylyl cyclase (AC) on NE release after pharmacologic adenosine A1-receptor activation. NE release was induced by electrical field stimulation and was assessed in the coronary effluent by high-performance liquid chromatography. Adenosine A1-receptor activation with 2-chloro-N6-cyclopentyladenosine (CCPA) decreased NE release by approximately 50% in hearts from both untreated and pertussis toxin-pretreated rats. In hearts from untreated rats, suppression of NE release in response to CCPA was completely abolished by the cell-permeable AC inhibitor 9-(tetrahydro-2'-furyl)adenine (SQ 22536). Direct activation of AC with forskolin increased NE release by approximately 20%. In the presence of forskolin, stimulation of adenosine A1-receptors with CCPA or inhibition of AC with SQ 22536 decreased NE release to baseline. These findings suggest a Gi-protein-independent but AC-dependent inhibition of NE release following adenosine A1-receptor activation.

Role of neuronal KATP channels and extraneuronal monoamine transporter on norepinephrine overflow in a model of myocardial low flow ischemia.

Global myocardial low flow ischemia results in an uniform suppression of norepinephrine (NE) overflow from the heart. We hypothesized that opening of neuronal ATP-sensitive potassium (K(ATP)) channels as well as activation of the extraneuronal monoamine transporter (EMT) mediates attenuation of NE overflow during low flow ischemia. Isolated rat hearts were subjected to low coronary flow of 0.4 ml min(-1). Release of endogenous NE was induced by electrical field stimulation. EMT activity was measured as the transport rate of the substrate N-[methyl-3H]4-phenylpyridinium ([3H]MPP+). NE overflow decreased by 57 +/- 2% within 120 min of low flow. Five minutes of reperfusion at normal flow (8 ml min(-1)) restored NE overflow to baseline. K(ATP) channel blockade with glibenclamide as well as EMT blockade with corticosterone increased NE overflow 1.5- and 2-fold at 120 min of low flow, whereas neither drug affected NE overflow in the absence of flow reduction. At normal flow, K(ATP) channel opening with cromakalim suppressed NE overflow, both in the presence and absence of EMT blockade (14 +/- 4 and 9 +/- 1%). However, cromakalim had no effect on EMT activity as indicated by an unaffected [3H]MPP+ overflow. In conclusion, activation of both K(ATP) channels and EMT mediate suppression of NE overflow during low flow ischemia. K(ATP) channels impair NE release directly at presynaptic nerve endings, whereas EMT increases NE elimination in a manner independent of K(ATP) channels.