Subclavian venoplasty may reduce implant times and implant failures in the era of increasing device upgrades.

BACKGROUND: The incidence of subclavian venous occlusions (SCVOs) may be an increasing problem in the era of device upgrades, especially to cardiac resynchronization therapy. Venoplasty (VP) performed by the electrophysiologist as a way of managing SCVOs may be advantageous. METHODS: We reviewed the implantable cardioverter defibrillator (ICD) implants of the past 5 years at Montefiore Medical Center and searched for SCVOs that required intervention and compared cases where VP was performed with cases where it was not. RESULTS: Of 1,853 ICD implants, 41 SCVOs (2.2%) requiring intervention were identified. Its incidence increased seven-fold from 0.7% in 2005 to 5.2% in 2009. Twenty-seven of the 41 SCVOs were found during a device upgrade. Of these 41 SCVOs, 18 underwent VP and 23 did not. In the VP group, there was a trend towards a shorter total procedure time, 2:31 hours versus 3:28 hours (P=0.37), and the total fluoroscopy time was 30 minutes versus 27 minutes (P=0.55). VP was successful in all 18 patients. Among the non-VP group (n=23), five (21.5%) had a failed implantation because of the inability to gain venous access and 10 (42.7%) had to be implanted on the contralateral side. CONCLUSION: The incidence of SCVOs requiring intervention is increasing in the era of device upgrades. VP performed by an electrophysiologist appears to be a safe and efficient approach to manage these SCVOs. VP seems to reduce the implant time and the need to implant on the other side as well as implant failure due to the inability to gain venous access.

Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation.

OBJECTIVES: This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction. BACKGROUND: Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability. METHODS: Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 µg/kg), BRL-37344 (1 µg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels. RESULTS: Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR (-/-), eNOS(-/-), and in nNOS(-/-) mice. CONCLUSIONS: Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.

Exercise protects against myocardial ischemia-reperfusion injury via stimulation of ß(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

RATIONALE: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. OBJECTIVE: To determine the role of ß(3)-adrenergic receptors (ß(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. METHODS AND RESULTS: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by ß(3)-AR stimulation and that in response to exercise a deficiency of ß(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. CONCLUSIONS: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of ß(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).

Gene therapy for ischemic heart disease.

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".

Left ventricular apical ballooning syndrome after pacemaker implantation in a male.

Left apical ballooning syndrome, also known as Takotsubo cardiomyopathy (TTC), characterized by transient left ventricular dysfunction is increasingly recognized worldwide. Predominantly affecting females, this condition mimics myocardial infarction and often occurs in the setting of emotional or physical stress. We report the case of a 77-year-old male who was admitted to the hospital for complete heart block and developed TTC after pacemaker implantation. To our knowledge, this is the first report of TTC development after pacemaker implantation in a male.

Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.

OBJECTIVE: Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. CONCLUSIONS: These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

Genetic and pharmacologic hydrogen sulfide therapy attenuates ischemia-induced heart failure in mice.

BACKGROUND: Hydrogen sulfide (H(2)S) is an endogenous signaling molecule with potent cytoprotective effects. The present study evaluated the therapeutic potential of H(2)S in murine models of heart failure. METHODS AND RESULTS: Heart failure was induced by subjecting mice either to permanent ligation of the left coronary artery for 4 weeks or to 60 minutes of left coronary artery occlusion followed by reperfusion for 4 weeks. Transgenic mice with cardiac-restricted overexpression of the H(2)S-generating enzyme cystathione gamma-lyase (alphaMHC-CGL-Tg(+)) displayed a clear protection against left ventricular structural and functional impairment as assessed by echocardiography in response to ischemia-induced heart failure, as well as improved survival in response to permanent myocardial ischemia. Exogenous H(2)S therapy (Na(2)S; 100 microg/kg) administered at the time of reperfusion (intracardiac) and then daily (intravenous) for the first 7 days after myocardial ischemia also protected against the structural and functional deterioration of the left ventricle by attenuating oxidative stress and mitochondrial dysfunction. Additional experiments aimed at elucidating some of the protective mechanisms of H(2)S therapy found that 7 days of H(2)S therapy increased the phosphorylation of Akt and increased the nuclear localization of 2 transcription factors, nuclear respiratory factor 1 and nuclear factor-E2-related factor (Nrf2), that are involved in increasing the levels of endogenous antioxidants, attenuating apoptosis, and increasing mitochondrial biogenesis. CONCLUSIONS: The results of the present study suggest that either the administration of exogenous H(2)S or the modulation of endogenous H(2)S production may be of therapeutic benefit in the treatment of ischemia-induced heart failure.

Hydrogen sulfide mediates cardioprotection through Nrf2 signaling.

RATIONALE: The recent emergence of hydrogen sulfide (H(2)S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. OBJECTIVE: The present study evaluated potential mechanisms of H(2)S-mediated cardioprotection using an in vivo model of pharmacological preconditioning. METHODS AND RESULTS: H(2)S (100 microg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H(2)S. Initial studies revealed that H(2)S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H(2)S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Cepsilon and STAT-3. During the late preconditioning period, H(2)S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad. CONCLUSIONS: These results reveal that the cardioprotective effects of H(2)S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.

Developmental programming resulting from maternal obesity in mice: effects on myocardial ischaemia-reperfusion injury.

A comprehensive number of epidemiological and animal studies suggest that prenatal and early life events are important determinants for disorders later in life. Among them, prenatal stress (i.e. stress experienced by the pregnant mother with impact on the fetal ontogeny) has clear programming effects on the cardiovascular system. A fetus developing in adverse conditions becomes an adult who is susceptible to disease, which may include hypertension, insulin resistance, altered blood lipid levels and cardiovascular disease. Recent evidence demonstrates that maternal programming can occur in the absence of other adverse environmental factors. Obesity, which is becoming a problem of large proportions in Western countries, is a possible cause of programming. With over 30% of the population of the USA currently obese, many mothers suffer from obesity during their child-bearing years (in fact, these conditions are often aggravated during pregnancy). One of the targets of programming is the cardiovascular system, and reported consequences include hypertension, endothelial dysfunction and vascular abnormalities. The overall goal of our study was to investigate the susceptibility of the heart to ischaemia-reperfusion in an animal model of maternal obesity. Our data demonstrate that normal (non-mutant) offspring from obese agouti mouse dams had an increased susceptibility to ischaemia-reperfusion injury. These data may provide insights into the long-term cardiovascular consequences of programming.

Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure.

Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure. The mechanisms by which metformin exerts these cardioprotective effects remain unclear and may be independent of antihyperglycemic effects. We tested the hypothesis that chronic activation of AMP-activated protein kinase (AMPK) with low-dose metformin exerts beneficial effects on cardiac function and survival in in vivo murine models of heart failure. Mice were subjected to permanent left coronary artery occlusion or to 60 minutes left coronary artery occlusion followed by reperfusion for 4 weeks. High-resolution, 2D echocardiography was performed at baseline and 4 weeks after myocardial infarction to assess left ventricular dimensions and function. Metformin (125 microg/kg) administered to mice at ischemia and then daily improved survival by 47% (P<0.05 versus vehicle) at 4 weeks following permanent left coronary artery occlusion. Additionally, metformin given at reperfusion and then daily preserved left ventricular dimensions and left ventricular ejection fraction (P<0.01 versus vehicle) at 4 weeks. The improvement in cardiac structure and function was associated with increases in AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation, as well as increased peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha expression in cardiac myocytes. Furthermore, metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis compared to vehicle. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS. This study demonstrates that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1alpha, in a murine model of heart failure.

Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide.

Endothelial NOS (eNOS)-derived NO has long been considered a paracrine signaling molecule only capable of affecting nearby cells because of its short half-life in blood and relatively limited diffusion distance in tissues. To date, no studies have demonstrated that endogenously generated NO possesses a clearly defined endocrine function. Therefore, we evaluated whether enzymatic generation of NO in the heart is capable of modulating remote physiological actions and cell signaling. Mice with cardiac-specific overexpression of the human eNOS gene (CS-eNOS-Tg) were used to address this hypothesis. Cardiac-specific eNOS overexpression resulted in significant increases in nitrite, nitrate, and nitrosothiols in the heart, plasma, and liver. To examine whether the increase in hepatic NO metabolites could modulate cytoprotection, we subjected CS-eNOS-Tg mice to hepatic ischemia-reperfusion (I/R) injury. CS-eNOS-Tg mice displayed a significant reduction in hepatic I/R injury (4.2-fold reduction in the aminotransferase and a 3.5-fold reduction in aspartate aminotransferase) compared with WT littermates. These findings demonstrate that endogenously derived NO is transported in the blood, metabolized in remote organs, and mediates cytoprotection in the setting of I/R injury. This study presents clear evidence for an endocrine role of NO generated endogenously from eNOS and provides additional evidence for the profound cytoprotective actions of NO in the setting of I/R injury.

Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice.

Endothelial production of nitric oxide (NO) is critical for vascular homeostasis. Nitrite and nitrate are formed endogenously by the stepwise oxidation of NO and have, for years, been regarded as inactive degradation products. As a result, both anions are routinely used as surrogate markers of NO production, with nitrite as a more sensitive marker. However, both nitrite and nitrate are derived from dietary sources. We sought to determine how exogenous nitrite affects steady-state concentrations of NO metabolites thought to originate from nitric oxide synthase (NOS)-derived NO as well as blood pressure and myocardial ischemia-reperfusion (I/R) injury. Mice deficient in endothelial nitric oxide synthase (eNOS-/-) demonstrated decreased blood and tissue nitrite, nitrate, and nitroso proteins, which were further reduced by low-nitrite (NOx) diet for 1 week. Nitrite supplementation (50 mg/L) in the drinking water for 1 week restored NO homeostasis in eNOS-/- mice and protected against I/R injury. Nitrite failed to alter heart rate or mean arterial blood pressure at the protective dose. These data demonstrate the significant influence of dietary nitrite intake on the maintenance of steady-state NO levels. Dietary nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a novel prevention/treatment modality for disease associated with NO insufficiency.

Role of sulfonylurea receptor type 1 subunits of ATP-sensitive potassium channels in myocardial ischemia/reperfusion injury.

BACKGROUND: Opening of cardiac ATP-sensitive potassium channels (K(ATP) channels) is a well-characterized protective mechanism against ischemia and reperfusion injury. Evidence exists for an involvement of both sarcolemmal and mitochondrial K(ATP) channels in such protection. Classically, cardiac sarcolemmal K(ATP) channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2) and SUR2A (sulfonylurea receptor type 2A) subunits; however, the evidence is strong that SUR1 (sulfonylurea receptor type 1) subunits are also expressed in the heart and that they may have a functional role. The aim of this study, therefore, was to examine the role of SUR1 in myocardial infarction. METHODS AND RESULTS: We subjected mice lacking SUR1 subunits to in vivo myocardial ischemia/reperfusion injury. Interestingly, the SUR1-null mice were markedly protected against the ischemic insult, displaying a reduced infarct size and preservation of left ventricular function, which suggests a role for this K(ATP) channel subunit in cardiovascular function during conditions of stress. CONCLUSIONS: SUR1 subunits have a high sensitivity toward many sulfonylureas and certain K(ATP) channel-opening drugs. Their potential role during ischemic events should therefore be considered both in the interpretation of experimental data with pharmacological agents and in the clinical arena when the cardiovascular outcome of patients treated with antidiabetic sulfonylureas is being considered.

Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling.

OBJECTIVE: Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury. RESEARCH DESIGN AND METHODS: Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 microg/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion. RESULTS: Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177. CONCLUSIONS: These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection.

Sphingolipid therapy in myocardial ischemia-reperfusion injury.

Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia-reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia-reperfusion injury and their possible mechanisms of cardioprotection.

Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury.

Nitrite has emerged as an endogenous signaling molecule with potential therapeutic implications for cardiovascular disease. Steady-state levels of nitrite are derived in part from dietary sources; therefore, we investigated the effects of dietary nitrite and nitrate supplementation and deficiency on NO homeostasis and on the severity of myocardial ischemia-reperfusion (MI/R) injury. Mice fed a standard diet with supplementation of nitrite (50 mg/liter) in their drinking water for 7 days exhibited significantly higher plasma levels of nitrite, exhibited significantly higher myocardial levels of nitrite, nitroso, and nitrosyl-heme, and displayed a 48% reduction in infarct size (Inf) after MI/R. Supplemental nitrate (1 g/liter) in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced Inf. A time course of ischemia-reperfusion revealed that nitrite was consumed during the ischemic phase, with an increase in nitroso/nitrosyl products in the heart. Mice fed a diet deficient in nitrite and nitrate for 7 days exhibited significantly diminished plasma and heart levels of nitrite and NO metabolites and a 59% increase in Inf after MI/R. Supplementation of nitrite in the drinking water for 7 days reversed the effects of nitrite deficiency. These data demonstrate the significant influence of dietary nitrite and nitrate intake on the maintenance of steady-state tissue nitrite/nitroso levels and illustrate the consequences of nitrite deficiency on the pathophysiology of MI/R injury. Therefore, nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a treatment modality for cardiovascular disease.

Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury.

Exocytosis of endothelial granules promotes thrombosis and inflammation and may contribute to the pathophysiology of early reperfusion injury following myocardial ischemia. TAT-NSF700 is a novel peptide that reduces endothelial exocytosis by inhibiting the ATPase activity and disassembly activity of N-ethylmaleimide-sensitive factor (NSF), a critical component of the exocytic machinery. We hypothesized that TAT-NSF700 would limit myocardial injury in an in vivo murine model of myocardial ischemia/reperfusion injury. Mice were subjected to 30 minutes of ischemia followed by 24 hours of reperfusion. TAT-NSF700 or the scrambled control peptide TAT-NSF700scr was administered intravenously 20 minutes before the onset of ischemia. Myocardial ischemia/reperfusion caused endothelial exocytosis, myocardial infarction, and left ventricular dysfunction. However, TAT-NSF700 decreased von Willebrand factor levels after myocardial ischemia/reperfusion, attenuated myocardial infarct size by 47%, and preserved left ventricular structure and function. These data suggest that drugs targeting endothelial exocytosis may be useful in the treatment of myocardial injury following ischemia/reperfusion.

Cytoprotective effects of N,N,N-trimethylsphingosine during ischemia- reperfusion injury are lost in the setting of obesity and diabetes.

N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analog, has been shown to modulate protein kinase C (PKC) activity and exert a number of important biological effects, including inhibition of tumor cell growth and metastasis, inhibition of leukocyte migration and respiratory burst, and inhibition of platelet aggregation. We hypothesized that TMS would be cytoprotective in clinically relevant in vivo murine models of myocardial and hepatic ischemia-reperfusion (I/R) injury. Wild-type, obese (ob/ob), and diabetic (db/db) mice were subjected to 30 min of left coronary artery occlusion followed by 24 h of reperfusion in the myocardial I/R model. In additional studies, mice were subjected to 45 min of hepatic artery occlusion followed by 5 h of reperfusion. TMS was administered intravenously at the onset of ischemia. Myocardial infarct size, cardiac function, and serum liver enzymes were measured to assess the extent of tissue injury. TMS attenuated myocardial infarct size by 66% in the wild type and by 36% in the ob/ob mice. Furthermore, TMS reduced serum alanine transaminase levels by 43% in wild-type mice. These benefits did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. A likely mechanism is the failure of TMS to inhibit PKC-delta translocation in the diseased heart. These data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals.

Severe left ventricular systolic dysfunction increases atrial fibrillation after ablation of atrial flutter.

BACKGROUND: Atrial fibrillation (Afib) that occurs after a successful atrial flutter (AFL) ablation may negate the potential benefits of the ablation. Afib occurs more often when severe left ventricular systolic dysfunction (LVSD) is present. We hypothesized that even after a successful AFL ablation, the incidence of postablation Afib is increased when severe LVSD is present. METHODS: Ninety consecutive patients with LVSD who underwent ablation for AFL at Montefiore Medical Center from August 2001 to January 2005 were classified according to the severity of LVSD. Group 1 (n = 36) consisted of patients with EF < or = 35%, and group 2 (n = 54) consisted of patients with EF 36-55%. There were no statistically significant differences in baseline patient characteristics between the two groups. RESULTS: During a mean follow up of 350 days, Afib occurred in 31% (n = 11; 8 with prior history of AFib) in group 1, and 7.4% (n = 4; all with prior history of Afib) in group 2. Cumulative probability of remaining Afib-free in group 1 versus group 2 was 75% versus 96% at 365 days, and 69% versus 91% at 600 days (P = 0.01). A prior history of Afib did not interact with EF when analyzed with a logistic regression analysis. CONCLUSION: After an AFL ablation, the incidence of Afib is increased, and the probability of remaining free of Afib is decreased, when severe LVSD is present, independent of a prior history of Afib. This finding may have implications for optimal patient selection for AFL ablation, and the use of adjunctive therapies.