J Heart Lung Transplant. 2009 Jul; 28(7): 710-7Manginas A, Tsiavou A, Sfyrakis P, Giamouzis G, Tsourelis L, Leontiadis E, Degiannis D, Cokkinos DV, Alivizatos PABACKGROUND: Bone marrow-derived circulating progenitor cells possess tissue repair potential, improving perfusion, left ventricular remodeling, and contractility in experimental models. We quantified and investigated the kinetics of 4 circulating progenitor cell sub-populations on the basis of CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2) antigen expression. METHODS: CD34+, CD34+/CD133+/VEGFR-2-, CD34+/CD133+/VEGFR-2+, and CD34+/CD133-/VEGFR-2+ cells were counted in 10 male patients with end-stage congestive heart failure. Five underwent left ventricular/biventricular assist device (LVAD/BiVAD) implantation (VAD group), and 5 were ineligible for VAD implantation (no-VAD group). Peripheral blood was collected at 3 time points for each patient: before, 15, and 60 days after VAD placement in the VAD group and at the same time points in the no-VAD group. Purified CD34+ cells were stained with anti-CD34, anti-CD133, and anti-VEGFR-2 monoclonal antibodies and analyzed by flow cytometry. Serum levels of granulocyte-colony stimulating factor (G-CSF), interleukin-8, vascular endothelial growth factor-alpha (VEGF-alpha), and B-type natriuretic peptide (BNP) were also measured. RESULTS: In the VAD group the number of CD34+ cells/ml of blood tended to increase, from 159.6 +/- 137.0 at baseline to 428.9 +/- 224.3 at 15 days, and decreased to 343.8 +/- 165.7 at 60 days (p = 0.05 vs no-VAD group). In the other 3 cell populations, no significant differences occurred over time or between groups. A significant interaction between BNP levels and VAD status was observed (p = 0.005): BNP levels decreased over time in VAD patients vs no-VAD patients. G-CSF levels tended to decrease over time in both groups, but without a significant difference (p = 0.3). Serum levels of interleukin-8 and VEGF-alpha over time or between VAD and no-VAD patients were not significantly different. CONCLUSIONS: After VAD implantation, a transient increase occurs in the number of circulating CD34+ cells, in parallel to a reduction in BNP levels. Release of these cells from the bone marrow may contribute to the improvement of tissue perfusion and cardiac recovery occasionally seen after VAD placement.

Curr Med Chem. 2009 Sep 1; Tóth A, Kiss L, Varró A, Nánási PPThe Na(+)/Ca(2+) exchanger (NCX) has a pivotal role in cardiac Na(+) and Ca(2+) homeostasis and is an essential pathway for Ca(2+) extrusion from cardiomyocytes. Altered NCX function may result in abnormal Ca(2+) release from the sarcoplasmic reticulum (SR) and impaired cardiac electrical activity and contractility in several diseases, like arrhythmias, ischemia/reperfusion injury, hypertrophy and heart failure. This review focuses on the role of the exchanger and the major effects of partial NCX blockade in normally functioning and diseased hearts. In healthy cardiac cells consequences of a partial NCX blockade were found to be moderate and species dependent. In rabbit and dog practically no change in the magnitude of the calcium transients and mechanical activity was observed, while elevation of systolic calcium levels and a concomitant positive inotropic action were demonstrated in rat and murine hearts. On the other hand, NCX inhibition represents a novel potential therapeutic strategy in case of a variety of cardiac dysfunctions. Partial NCX blockade was shown to have beneficial effects in animal models of ischemia/reperfusion injury and also antiarrhythmic and positive inotropic actions in the failing heart. Further progress in this field is seriously hampered by the absence of really selective NCX inhibitors. KB-R7943 and SEA0400 are widely used NCX blockers, both drugs, however, have limited selectivity and efficacy, properties required to initiate relevant clinical trials. In summary, there is an increasing demand by both researchers and clinicians for new NCX inhibitors with significantly enhanced selectivity and functionality.

Europace. 2009 Jun 25; Bortone A, Boveda S, Pasquié JL, Pujadas-Berthault P, Marijon E, Appetiti A, Albenque JPAims In the setting of congestive heart failure (CHF), atrial fibrillation (AF) ablation can improve clinical status and the left ventricular ejection fraction (LVEF) value. However, the impact of AF ablation on the implantable cardioverter defibrillator (ICD) indication has never been specifically addressed. Methods and results Study subject were six CHF (mean age 61.1 +/- 6.9 years, mean LVEF 25.8 +/- 7.3%) patients refractory to conventional medical treatment with long-lasting AF unresponsive to external cardioversion. Five patients had an idiopathic dilated cardiomyopathy (DCM) and one had an ischaemic cardiomyopathy (ICM). Their New York Heart Association (NYHA) class was III-IV. Two patients had renal insufficiency. No patient had left ventricular delay. All patients underwent AF ablation. LVEF and NYHA class were dramatically improved in the five DCM patients. New York Heart Association class, but not the LVEF, was improved in the ICM patient. A redo ablative procedure was undertaken in four of five DCM patients and in the ICM patient due to arrhythmia recurrence. Left ventricular ejection fraction and NYHA were improved again in the DCM patients (56 +/- 4.4%, I-II, respectively) and led to ICD indication preclusion. The LVEF remained low in the ICM patient (30%) and led to ICD insertion. Sinus rhythm has been stable during the 18.1 +/- 5.7 months follow-up period. Conclusion Atrial fibrillation ablation in CHF patients can improve both the clinical status of patients and their LVEF, especially among those affected by DCM. The LVEF improvement has the potential to preclude the indication for a primary prevention ICD insertion.

Europace. 2009 Jun 25; Bortone A, Boveda S, Pasquié JL, Pujadas-Berthault P, Marijon E, Appetiti A, Albenque JPAims In the setting of congestive heart failure (CHF), atrial fibrillation (AF) ablation can improve clinical status and the left ventricular ejection fraction (LVEF) value. However, the impact of AF ablation on the implantable cardioverter defibrillator (ICD) indication has never been specifically addressed. Methods and results Study subject were six CHF (mean age 61.1 +/- 6.9 years, mean LVEF 25.8 +/- 7.3%) patients refractory to conventional medical treatment with long-lasting AF unresponsive to external cardioversion. Five patients had an idiopathic dilated cardiomyopathy (DCM) and one had an ischaemic cardiomyopathy (ICM). Their New York Heart Association (NYHA) class was III-IV. Two patients had renal insufficiency. No patient had left ventricular delay. All patients underwent AF ablation. LVEF and NYHA class were dramatically improved in the five DCM patients. New York Heart Association class, but not the LVEF, was improved in the ICM patient. A redo ablative procedure was undertaken in four of five DCM patients and in the ICM patient due to arrhythmia recurrence. Left ventricular ejection fraction and NYHA were improved again in the DCM patients (56 +/- 4.4%, I-II, respectively) and led to ICD indication preclusion. The LVEF remained low in the ICM patient (30%) and led to ICD insertion. Sinus rhythm has been stable during the 18.1 +/- 5.7 months follow-up period. Conclusion Atrial fibrillation ablation in CHF patients can improve both the clinical status of patients and their LVEF, especially among those affected by DCM. The LVEF improvement has the potential to preclude the indication for a primary prevention ICD insertion.

Europace. 2009 Jun 25; Bortone A, Boveda S, Pasquié JL, Pujadas-Berthault P, Marijon E, Appetiti A, Albenque JPAims In the setting of congestive heart failure (CHF), atrial fibrillation (AF) ablation can improve clinical status and the left ventricular ejection fraction (LVEF) value. However, the impact of AF ablation on the implantable cardioverter defibrillator (ICD) indication has never been specifically addressed. Methods and results Study subject were six CHF (mean age 61.1 +/- 6.9 years, mean LVEF 25.8 +/- 7.3%) patients refractory to conventional medical treatment with long-lasting AF unresponsive to external cardioversion. Five patients had an idiopathic dilated cardiomyopathy (DCM) and one had an ischaemic cardiomyopathy (ICM). Their New York Heart Association (NYHA) class was III-IV. Two patients had renal insufficiency. No patient had left ventricular delay. All patients underwent AF ablation. LVEF and NYHA class were dramatically improved in the five DCM patients. New York Heart Association class, but not the LVEF, was improved in the ICM patient. A redo ablative procedure was undertaken in four of five DCM patients and in the ICM patient due to arrhythmia recurrence. Left ventricular ejection fraction and NYHA were improved again in the DCM patients (56 +/- 4.4%, I-II, respectively) and led to ICD indication preclusion. The LVEF remained low in the ICM patient (30%) and led to ICD insertion. Sinus rhythm has been stable during the 18.1 +/- 5.7 months follow-up period. Conclusion Atrial fibrillation ablation in CHF patients can improve both the clinical status of patients and their LVEF, especially among those affected by DCM. The LVEF improvement has the potential to preclude the indication for a primary prevention ICD insertion.

Europace. 2009 Jun 25; Bortone A, Boveda S, Pasquié JL, Pujadas-Berthault P, Marijon E, Appetiti A, Albenque JPAims In the setting of congestive heart failure (CHF), atrial fibrillation (AF) ablation can improve clinical status and the left ventricular ejection fraction (LVEF) value. However, the impact of AF ablation on the implantable cardioverter defibrillator (ICD) indication has never been specifically addressed. Methods and results Study subject were six CHF (mean age 61.1 +/- 6.9 years, mean LVEF 25.8 +/- 7.3%) patients refractory to conventional medical treatment with long-lasting AF unresponsive to external cardioversion. Five patients had an idiopathic dilated cardiomyopathy (DCM) and one had an ischaemic cardiomyopathy (ICM). Their New York Heart Association (NYHA) class was III-IV. Two patients had renal insufficiency. No patient had left ventricular delay. All patients underwent AF ablation. LVEF and NYHA class were dramatically improved in the five DCM patients. New York Heart Association class, but not the LVEF, was improved in the ICM patient. A redo ablative procedure was undertaken in four of five DCM patients and in the ICM patient due to arrhythmia recurrence. Left ventricular ejection fraction and NYHA were improved again in the DCM patients (56 +/- 4.4%, I-II, respectively) and led to ICD indication preclusion. The LVEF remained low in the ICM patient (30%) and led to ICD insertion. Sinus rhythm has been stable during the 18.1 +/- 5.7 months follow-up period. Conclusion Atrial fibrillation ablation in CHF patients can improve both the clinical status of patients and their LVEF, especially among those affected by DCM. The LVEF improvement has the potential to preclude the indication for a primary prevention ICD insertion.

Am J Physiol Heart Circ Physiol. 2009 Jun 19; Casals G, Ros J, Sionis A, Davidson MM, Morales-Ruiz M, Jimenez WB-type natriuretic peptide (BNP) is a peptide hormone of myocardial origin with significant cardioprotective properties. Patients with myocardial ischemia present with high levels of BNP in plasma and elevated expression in the myocardium. However, molecular mechanisms of BNP induction in the ischemic myocardium are not well understood. The aim of the investigation was to assess whether myocardial hypoxia induces the production of BNP in human ventricular myocytes. To test the hypothesis that reduced oxygen tension can directly stimulate BNP gene expression and release in the absence of hemodynamic or neurohormonal stimuli, we used an in vitro model system of cultured human ventricular myocytes (AC16 cells). Cells were cultured under normoxic (21% O2) or hypoxic (5% O2) conditions for up to 48 hours. Then, accumulation of BNP, Atrial Natriuretic Peptide (ANP) and Vascular Endothelial Growth Factor (VEGF) was measured. Hypoxia stimulated protein release of BNP and VEGF but not of ANP. In concordance, increased mRNA levels of BNP and VEGF but not of ANP were found on culturing AC16 cells under hypoxic conditions. The analysis of the transcriptional activity of the hypoxia inducible factor 1 (HIF-1) in nuclear extracts showed that HIF-1 activity was induced under hypoxic conditions. Finally, treatment of AC16 cells with the HIF-1 inhibitor rotenone in hypoxia inhibited BNP and VEGF release. In conclusion, these data indicate that hypoxia induces the synthesis and secretion of BNP in human ventricular myocytes, likely through HIF-1 enhanced transcriptional activity. Key words: natriuretic peptides, HIF-1, myocardial ischemia, heart failure.

J Am Coll Cardiol. 2009 Jun 30; 54(1): 36-46Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JEOBJECTIVES: The purpose of this study was to test the hypothesis that in heart failure with normal ejection fraction (HFNEF) exercise limitation is due to combined systolic and diastolic abnormalities, particularly involving ventricular twist and deformation (strain) leading to reduced ventricular suction, delayed untwisting, and impaired early diastolic filling. BACKGROUND: A substantial proportion of patients with heart failure have a normal left ventricular ejection fraction. Currently the pathophysiology is considered to be due to abnormal myocardial stiffness and relaxation. METHODS: Patients with a diagnosis of HFNEF and proven cardiac limitation by cardiopulmonary exercise testing were studied by standard, tissue Doppler, and speckle tracking echocardiography at rest and on submaximal exercise. RESULTS: Fifty-six patients (39 women; mean age 72 +/- 7 years) with a clinical diagnosis of HFNEF and 27 age-matched healthy control subjects (19 women; mean age 70 +/- 7 years) had rest and exercise images of sufficient quality for analysis. At rest, systolic longitudinal and radial strain, systolic mitral annular velocities, and apical rotation were lower in patients, and all failed to rise normally on exercise. Systolic longitudinal functional reserve was also significantly lower in patients (p < 0.001). In diastole, patients had reduced and delayed untwisting, reduced left ventricular suction at rest and on exercise, and higher end-diastolic pressures. Mitral annular systolic and diastolic velocities, systolic left ventricular rotation, and early diastolic untwist on exercise correlated with peak VO(2)max. CONCLUSIONS: In HFNEF there are widespread abnormalities of both systolic and diastolic function that become more apparent on exercise. HFNEF is not an isolated disorder of diastole.

Horm Metab Res. 2009 Jun 19; Sivukhina EV, Poskrebysheva AS, Smurova IV, Dolzhikov AA, Morozov IE, Jirikowski GF, Grinevich VNeuroendocrine factors play an important role in the pathogenesis of chronic heart failure. Despite numerous clinical and experimental studies, the role of the hypothalamic-pituitary-adrenal axis and glucocorticoid hormones is not fully characterised. Here we present a study of plasma cortisol concentration in 74 chronic heart failure patients, divided into four groups based on NYHA functional classes I-IV, and in 17 control subjects. In parallel, we performed morphological analysis of the hypothalamic-pituitary-adrenal axis components from 8 male patients who had died from chronic heart failure, and 9 male controls. In our study we applied immunohistochemical method and quantitative analysis to investigate an expression of hypothalamic neurohormones (corticotropin-releasing hormone, vasopressin) and adrenocorticotropin hormone in the pituitary, as well as performed general histological examination of the adrenal cortex. Measurement of morning cortisol concentration in plasma of chronic heart failure patients revealed neither difference compared to controls nor with the severity of the disease. Despite this, a two-fold increase in the density of corticotropin-releasing hormone-immunoreactive neurons as well as a two-fold increase in the number of corticotropin-releasing hormone neurons co-expressing vasopressin in the hypothalamic paraventricular nucleus were found. In the anterior pituitary the density of adrenocorticotropin hormone-immunoreactive cells was significantly increased. General histological analysis of the adrenal cortex revealed a drastic thinning of the zona fasciculata and dystrophic changes in corticocytes. Structural changes, observed in the adrenal cortex, suggest a relative glucocorticoid deficiency, which may contribute to corticotropin-releasing hormone and adrenocorticotropin hormone upregulation in hypothalamus and pituitary of chronic heart failure patients.

J Am Coll Cardiol. 2009 Jun 30; 54(1): 36-46Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JEOBJECTIVES: The purpose of this study was to test the hypothesis that in heart failure with normal ejection fraction (HFNEF) exercise limitation is due to combined systolic and diastolic abnormalities, particularly involving ventricular twist and deformation (strain) leading to reduced ventricular suction, delayed untwisting, and impaired early diastolic filling. BACKGROUND: A substantial proportion of patients with heart failure have a normal left ventricular ejection fraction. Currently the pathophysiology is considered to be due to abnormal myocardial stiffness and relaxation. METHODS: Patients with a diagnosis of HFNEF and proven cardiac limitation by cardiopulmonary exercise testing were studied by standard, tissue Doppler, and speckle tracking echocardiography at rest and on submaximal exercise. RESULTS: Fifty-six patients (39 women; mean age 72 +/- 7 years) with a clinical diagnosis of HFNEF and 27 age-matched healthy control subjects (19 women; mean age 70 +/- 7 years) had rest and exercise images of sufficient quality for analysis. At rest, systolic longitudinal and radial strain, systolic mitral annular velocities, and apical rotation were lower in patients, and all failed to rise normally on exercise. Systolic longitudinal functional reserve was also significantly lower in patients (p < 0.001). In diastole, patients had reduced and delayed untwisting, reduced left ventricular suction at rest and on exercise, and higher end-diastolic pressures. Mitral annular systolic and diastolic velocities, systolic left ventricular rotation, and early diastolic untwist on exercise correlated with peak VO(2)max. CONCLUSIONS: In HFNEF there are widespread abnormalities of both systolic and diastolic function that become more apparent on exercise. HFNEF is not an isolated disorder of diastole.

Am J Crit Care. 2009 Jul; 18(4): 310-318Dekker RL, Peden AR, Lennie TA, Schooler MP, Moser DKBackground Patients with heart failure often experience depressive symptoms that affect health-related quality of life, morbidity, and mortality. Researchers have not described the experience of patients with heart failure living with depressive symptoms. Understanding this experience will help in developing interventions to decrease depressive symptoms. Objective To describe the experience of patients with heart failure living with depressive symptoms. Methods This study was conducted by using a qualitative descriptive design. The sample consisted of 10 outpatients (50% female, mean age 63 [SD, 13] years, 70% New York Heart Association class III or IV) with heart failure who were able to describe depressive symptoms. Data were collected via taped, individual, 30- to 60-minute interviews. ATLAS ti (version 5) was used for content analysis. Results Participants described emotional and somatic symptoms of depression. Negative thinking was present in all participants and reinforced their depressed mood. The participants experienced multiple stressors that worsened depressive symptoms. The overarching strategy for managing depressive symptoms was "taking my mind off of it." Patients managed depressive symptoms by engaging in activities such as exercise and reading, and by using positive thinking, spirituality, and social support. Conclusions Patients with heart failure experience symptoms of depression that are similar to those experienced by the general population. Clinicians should assess patients with heart failure for stressors that worsen depressive symptoms. Strategies that researchers and clinicians can use to reduce depressive symptoms in patients with heart failure include engaging patients in activities, positive thinking, and spirituality. Helping patients find enhanced social support may also be important.

J Am Coll Cardiol. 2009 Jun 30; 54(1): 36-46Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JEOBJECTIVES: The purpose of this study was to test the hypothesis that in heart failure with normal ejection fraction (HFNEF) exercise limitation is due to combined systolic and diastolic abnormalities, particularly involving ventricular twist and deformation (strain) leading to reduced ventricular suction, delayed untwisting, and impaired early diastolic filling. BACKGROUND: A substantial proportion of patients with heart failure have a normal left ventricular ejection fraction. Currently the pathophysiology is considered to be due to abnormal myocardial stiffness and relaxation. METHODS: Patients with a diagnosis of HFNEF and proven cardiac limitation by cardiopulmonary exercise testing were studied by standard, tissue Doppler, and speckle tracking echocardiography at rest and on submaximal exercise. RESULTS: Fifty-six patients (39 women; mean age 72 +/- 7 years) with a clinical diagnosis of HFNEF and 27 age-matched healthy control subjects (19 women; mean age 70 +/- 7 years) had rest and exercise images of sufficient quality for analysis. At rest, systolic longitudinal and radial strain, systolic mitral annular velocities, and apical rotation were lower in patients, and all failed to rise normally on exercise. Systolic longitudinal functional reserve was also significantly lower in patients (p < 0.001). In diastole, patients had reduced and delayed untwisting, reduced left ventricular suction at rest and on exercise, and higher end-diastolic pressures. Mitral annular systolic and diastolic velocities, systolic left ventricular rotation, and early diastolic untwist on exercise correlated with peak VO(2)max. CONCLUSIONS: In HFNEF there are widespread abnormalities of both systolic and diastolic function that become more apparent on exercise. HFNEF is not an isolated disorder of diastole.

J Cardiothorac Vasc Anesth. 2009 Jun 24; Archan S, Roscher CR, Fairman RM, Fleisher LAOBJECTIVE: To determine if the Revised Cardiac Risk Index (Lee) is useful for stratification of patients by risk of both perioperative cardiac morbidity and long-term all-cause mortality in the setting of endovascular repair of abdominal aortic aneurysms. DESIGN: This study was designed as a retrospective review. SETTING: It was conducted at a single academic medical institution. PARTICIPANTS: The analysis included 225 patients with abdominal aortic aneurysms admitted to the authors' institution from 1999 to 2006. INTERVENTIONS: All patients underwent endovascular aortic aneurysm repair. MEASUREMENTS AND MAIN RESULTS: Data were collected from medical records, office charts, and physician quality-assurance databases. There were no in-hospital cardiac deaths. The major adverse cardiac event rate in the perioperative period was 6.2%. Long-term all-cause mortality was 23%. Univariate analysis showed that a history of coronary artery disease (CAD) (likelihood ratio [LR] = 8.7, p = 0.023), history of congestive heart failure (LR = 4, p = 0.042), and a Revised Cardiac Risk Index (RCRI) >/=3 (LR = 8.6, p = 0.004) were significant predictors for perioperative major adverse cardiac events. A history of CAD (LR = 10.7, p = 0.002), echocardiographic evidence of myocardial infarction (LR = 8.5, p = 0.006), exercise tolerance of only 1 block (LR = 8.4, p = 0.005), RCRI >/=3 (LR = 5.6, p = 0.022), and perioperative cardiac events (LR = 15.9, p < 0.0001) were significantly associated with long-term all-cause mortality. Perioperative cardiac events remained highly significant in predicting long-term mortality within the RCRI >/=3 subgroup (LR = 6.1, p = 0.019). CONCLUSIONS: The results of this study confirm that long-term mortality remains high after endovascular repair of abdominal aortic aneurysms. The Lee index may be a useful tool for stratification of high-risk patients from both a short- and long-term perspective in the setting of endoluminal graft repair.

J Am Coll Cardiol. 2009 Jun 30; 54(1): 36-46Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, Sanderson JEOBJECTIVES: The purpose of this study was to test the hypothesis that in heart failure with normal ejection fraction (HFNEF) exercise limitation is due to combined systolic and diastolic abnormalities, particularly involving ventricular twist and deformation (strain) leading to reduced ventricular suction, delayed untwisting, and impaired early diastolic filling. BACKGROUND: A substantial proportion of patients with heart failure have a normal left ventricular ejection fraction. Currently the pathophysiology is considered to be due to abnormal myocardial stiffness and relaxation. METHODS: Patients with a diagnosis of HFNEF and proven cardiac limitation by cardiopulmonary exercise testing were studied by standard, tissue Doppler, and speckle tracking echocardiography at rest and on submaximal exercise. RESULTS: Fifty-six patients (39 women; mean age 72 +/- 7 years) with a clinical diagnosis of HFNEF and 27 age-matched healthy control subjects (19 women; mean age 70 +/- 7 years) had rest and exercise images of sufficient quality for analysis. At rest, systolic longitudinal and radial strain, systolic mitral annular velocities, and apical rotation were lower in patients, and all failed to rise normally on exercise. Systolic longitudinal functional reserve was also significantly lower in patients (p < 0.001). In diastole, patients had reduced and delayed untwisting, reduced left ventricular suction at rest and on exercise, and higher end-diastolic pressures. Mitral annular systolic and diastolic velocities, systolic left ventricular rotation, and early diastolic untwist on exercise correlated with peak VO(2)max. CONCLUSIONS: In HFNEF there are widespread abnormalities of both systolic and diastolic function that become more apparent on exercise. HFNEF is not an isolated disorder of diastole.

Eur Heart J. 2009 Jun 25; Moukarbel GV, Signorovitch JE, Pfeffer MA, McMurray JJ, White HD, Maggioni AP, Velazquez EJ, Califf RM, Scheiman JM, Solomon SDAims The risk of gastrointestinal (GI) bleeding limits the use of antiplatelet and anticoagulant drugs. Risk factors for GI bleeding in post- myocardial infarction (MI) patients have not been well defined. We sought to identify risk factors for GI bleeding in patients following MI. Methods and results The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) enrolled 14 703 post-MI patients with left ventricular dysfunction and/or heart failure and followed them for a median of 24.7 months. In the present secondary analysis, times from baseline to first GI bleeding were identified from the VALIANT serious adverse event database. Potential risk factors were explored from medical history, demographics, clinical profile, and medications, both at baseline and during follow-up. We also explored the relationship between the occurrence of GI bleeding and subsequent mortality. During follow-up, 98 (0.7%) patients had a serious GI bleeding event. These patients were older, had more comorbidities, were more likely to be taking additional antiplatelet drugs, and had worse left ventricular systolic and renal function. The Kaplan-Meier estimated rate of GI bleeding at 6 months was 0.37% (95% CI 0.27-0.47). In a multivariable Cox model, dual antiplatelet therapy was the most powerful predictor of GI bleeding, with an adjusted hazard ratio of 3.18 (95% CI 1.91-5.29). Other predictors were non-white race, history of alcohol abuse, increasing age, worse New York Heart Association class, anticoagulant therapy, diabetes, lower estimated glomerular filtration rate, and male sex. Gastrointestinal bleeding was associated with increased risk of death [adjusted hazard ratio 2.54 (95% CI 1.66-3.89)]. Conclusion Following MI, clinical characteristics can identify patients with increased risk of GI bleeding. The use of dual antiplatelet agents appears to be the most profound risk factor. Whether these patients would benefit from GI prophylaxis therapy remains unknown.

Circ Res. 2009 Jun 25; Liu Q, Chen X, Macdonnell SM, Kranias EG, Lorenz JN, Leitges M, Houser SR, Molkentin JDProtein kinase (PK)Calpha, PKCbeta, and PKCgamma comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKCalpha show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonize failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking PKCalpha, PKCbeta, and PKCgamma for effects on cardiac contractility and heart failure susceptibility. PKCalpha(-)(/)(-) mice, but not PKCbetagamma(-/-) mice, showed increased cardiac contractility, myocyte cellular contractility, Ca(2+) transients, and sarcoplasmic reticulum Ca(2+) load. PKCalpha(-)(/)(-) mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas PKCbetagamma(-/-) mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKCalpha/beta/gamma inhibitor, increased cardiac contractility in wild-type and PKCbetagamma(-/-) mice, but not in PKCalpha(-)(/)(-) mice. More importantly, ruboxistaurin prevented death in wild-type mice throughout 10 weeks of pressure-overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to PKCbetagamma(-/-) mice subjected to pressure overload, resulting in less death and heart failure, implicating PKCalpha as the primary target of this drug in mitigating heart disease. As an aside, PKCalphabetagamma(-/-) triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKCalpha functions distinctly from PKCbeta and PKCgamma in regulating cardiac contractility and heart failure, and broad-acting PKC inhibitors such as ruboxistaurin could represent a novel therapeutic approach in treating human heart failure.

J Am Coll Cardiol. 2009 Jun 30; 54(1): 79-86Meyns B, Klotz S, Simon A, Droogne W, Rega F, Griffith B, Dowling R, Zucker MJ, Burkhoff DOBJECTIVES: The purpose of this study was to test the hemodynamic effects of partial ventricular support in patients with advanced heart failure. BACKGROUND: The use of current left ventricular assist devices (VADs) that provide full circulatory support is restricted to critically ill patients because of associated risks. Smaller, less-invasive devices could expand VAD use to a larger pool of less-sick patients but would pump less blood, providing only partial support. METHODS: The Synergy Pocket Micro-pump device (CircuLite, Inc., Saddle Brook, New Jersey) pumps approximately 3.0 l/min, is implanted (off pump) via a mini-thoracotomy, and is positioned in a right subclavicular subcutaneous pocket (like a pacemaker). The inflow cannula inserts into the left atrium; the outflow graft connects to the right subclavian artery. RESULTS: A total of 17 patients (14 men), age 53 +/- 9 years with ejection fraction 21 +/- 6%, mean arterial pressure 73 +/- 7 mm Hg, pulmonary capillary wedge pressure 29 +/- 6 mm Hg, and cardiac index 1.9 +/- 0.4 l/min/m(2) received an implant. Duration of support ranged from 6 to 213 (median 81) days. In addition to demonstration of significant acute hemodynamic improvements in the first day of support, 9 patients underwent follow-up right heart catheterization at 10.6 +/- 6 weeks. These patients showed significant increases in arterial pressure (67 +/- 8 mm Hg vs. 80 +/- 9 mm Hg, p = 0.01) and cardiac index (2.0 +/- 0.4 l/min/m(2) vs. 2.8 +/- 0.6 l/min/m(2), p = 0.01) with large reductions in pulmonary capillary wedge pressure (30 +/- 5 mm Hg vs. 18 +/- 5 mm Hg, p = 0.001). CONCLUSIONS: Partial support appears to interrupt the progressive hemodynamic deterioration typical of late-stage heart failure. If proven safe and durable, this device could be used in a relatively large population of patients with severe heart failure who are not sick enough to justify use of currently available full support VADs. (Safety and Performance Evaluation of CircuLite Synergy; NCT00878527).

Eur J Pharmacol. 2009 Jun 20; Zheng J, Ma J, Zhang P, Hu L, Fan X, Tang QMuch evidence indicates that increased persistent sodium current (I(Na.P)) is associated with cellular calcium overload and I(Na.P) is considered to be a potential target for therapeutic intervention in ischaemia and heart failure. By inhibiting type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate (cAMP), with a positive inotropic effect. However, the effect of milrinone on increased I(Na.P) under pathological conditions remains unknown. Accordingly, we investigated the effect of milrinone on increased I(Na.P) induced by hypoxia or hydrogen dioxide in guinea pig ventricular myocytes. While milrinone (0.01 mM or 0.1 mM) or cAMP (0.1 mM) decreased I(Na.P) respectively in control condition, application of 1 muM H-89, a selective cAMP-dependant protein kinase inhibitor, prevented the effect of 0.1 mM milrinone in control condition. Milrinone (0.1 mM) reduced the increased I(Na.P) induced by hypoxia. Furthermore, 0.01 mM or 0.1 mM milrinone reduced the enhanced I(Na.P) induced by 0.3 mM hydrogen peroxide. In addition, 0.01 mM or 0.1 mM milrinone shortened action potential duration at 90% repolarization (APD(90)). Bath application of 0.3 mM hydrogen dioxide markedly prolonged APD(90), while 2 muM tetrodotoxin (TTX) reversed the prolonged APD(90). In the other two groups, 0.01 mM or 0.1 mM milrinone shortened the prolonged APD(90) induced by 0.3 mM hydrogen peroxide, ultimately 2 muM TTX causing a further decurtation of APD(90). These findings demonstrate that milrinone inhibited I(Na.P) under normal condition, hypoxia or hydrogen dioxide-induced I(Na.P), and the APD(90) prolonged by hydrogen dioxide-induced I(Na.P) in ventricular myocytes, which is associated with the mechanism of milrinone increasing intracellular cAMP.

J Indian Med Assoc. 2008 Oct; 106(10): 650-4Achari V, Prakash S, Sinha AK, Thakur AKThe mortality rate of acute myocardial infarction has declined considerably in the past three decades. In view of paucity of literature from different centres from India on this issue, the present study was undertaken to determine the in-hospital mortality with acute ST segment elevation myocardial infarction presenting to a tertiary care cardiac centre in India. Consecutive patients (n=862) with the diagnosis of acute ST segment elevation myocardial infarction admitted in Heart Hospital, Patna between June 2003 and July 2006 were included in this study. The in-hospital mortality and event rates (reinfarction, recurrent angina and heart failure) were analysed. The mean age of study population was 56 +/- 13 years. There were 690 males (80.05%) and 172 females (19.95%); 468 patients (54.29%) had hypertension, 384 patients (44.55%) were diabetic, 415 (48.14%) were smokers/tobacco chewers and 154 patients (17.86%) had past history of myocardial infarction. Anterior wall infarction was present in 435 patients (50.46%), 408 patients (47.33%) had inferior wall infarction, 115 patients (13.34%) had associated right ventricular or posterior wall infarction and 19 (2.20%) had antero-inferior infarction; 346 patients (40.14%) received thrombolytic therapy while the other patients were not thrombolysed due to various reasons (usually late arrival). The mean duration between symptom onset and hospital admission was 29.2. +/- 10.8 hours in the entire group (8.6 +/- 2.8 hours in the thrombolysed group). Of the total 862 patients, 107 patients (12.41%) died during in-hospital stay while 755 patients were discharged from the hospital in stable condition after a mean stay of 7.1 +/- 1.8 days. The in-hospital mortality rate of acute ST segment elevation myocardial infarction in this study was 12.41%, which is comparable to reports from the west. However the revascularisation rate (thrombolysis or PTCA) remained low and most patients received thrombolysis late.

N Engl J Med. 2009 Jun 25; 360(26): 2705-18Cantor WJ, Fitchett D, Borgundvaag B, Ducas J, Heffernan M, Cohen EA, Morrison LJ, Langer A, Dzavik V, Mehta SR, Lazzam C, Schwartz B, Casanova A, Goodman SG, BACKGROUND: Patients with a myocardial infarction with ST-segment elevation who present to hospitals that do not have the capability of performing percutaneous coronary intervention (PCI) often cannot undergo timely primary PCI and therefore receive fibrinolysis. The role and optimal timing of routine PCI after fibrinolysis have not been established. METHODS: We randomly assigned 1059 high-risk patients who had a myocardial infarction with ST-segment elevation and who were receiving fibrinolytic therapy at centers that did not have the capability of performing PCI to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within 6 hours after fibrinolysis. All patients received aspirin, tenecteplase, and heparin or enoxaparin; concomitant clopidogrel was recommended. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days. RESULTS: Cardiac catheterization was performed in 88.7% of the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% of the patients assigned to routine early PCI a median of 2.8 hours after randomization. At 30 days, the primary end point occurred in 11.0% of the patients who were assigned to routine early PCI and in 17.2% of the patients assigned to standard treatment (relative risk with early PCI, 0.64; 95% confidence interval, 0.47 to 0.87; P=0.004). There were no significant differences between the groups in the incidence of major bleeding. CONCLUSIONS: Among high-risk patients who had a myocardial infarction with ST-segment elevation and who were treated with fibrinolysis, transfer for PCI within 6 hours after fibrinolysis was associated with significantly fewer ischemic complications than was standard treatment. (ClinicalTrials.gov number, NCT00164190.)

Proc Natl Acad Sci U S A. 2009 Jun 23; Harzheim D, Movassagh M, Foo RS, Ritter O, Tashfeen A, Conway SJ, Bootman MD, Roderick HLCardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca(2+) signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca(2+) fluxes significantly impact on cardiac output and facilitate the development of arrhythmias. Using cardiomyocytes from spontaneously hypertensive rats (SHRs), we demonstrate that an increase in Ca(2+) release through inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) contributes to the larger excitation contraction coupling (ECC)-mediated Ca(2+) transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECC-mediated Ca(2+) transients and contraction elicited by InsP(3) or endothelin-1 (ET-1). Responsible for this is an increase in InsP(3)R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca(2+) release through InsP(3)Rs served to sensitize RyRs, thereby increasing diastolic Ca(2+) levels, the incidence of extra-systolic Ca(2+) transients, and the induction of ECC-mediated Ca(2+) elevations. Unlike the increase in InsP(3)R expression and Ca(2+) transient amplitude in the cytosol, InsP(3)R expression and ECC-mediated Ca(2+) transients in the nucleus were not altered during hypertrophy. Elevated InsP(3)R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. Our data establish that increased InsP(3)R expression is a general mechanism that underlies remodeling of Ca(2+) signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.

Arch Bronconeumol. 2009; 45 Suppl 1: 3-10Hernández C, Durán-Cantolla J, Lloberes P, González MThe following review summarises the most important articles published on sleep apnea-hypopnea syndrome (SAHS) during the current year. The analysis of the many factors implicated in the risk of cardiovascular diseases associated with SAHS is currently of great interest to the scientific community. There are many studies on this subject that demonstrate the role of inflammatory and immunological mediators, their relationship with endothelial damage and their influence in the genesis of cardiovascular disease in patients with SAHS. The role of CPAP in preventing this cardiovascular risk has had varied results. Although there is no evidence of benefit or harm in its use in heart failure, in cerebrovascular accidents SAHS has been confirmed as a predisposing factor and the reported increase in mortality would justify the intention to treat SAHS in these patients. Likewise, the reduction in blood pressure found with CPAP treatment could reduce the risk of cardio-cerebrovascular disease. The recent knowledge that there is expression of multiple phenotypes of SAHS gives a glimpse in the future of a disease based on different specific phenotypes, where the traditional symptomatology that defined the syndrome does not limit its treatment. To obtain a reliable and cost-effective diagnostic method that responds to the demands of the public health problem that is SAHS, particularly in sectors of the population that remain under-diagnosed and less well known, such as children, women and the elderly population is another one of the challenges reflected in published studies. In short, the growing knowledge on the biology of SAHS, its cardiovascular implications and its effect on the morbidity and mortality of the population will enable us to understand the true dimension of this disease in the next few years.

Curr Med Chem. 2009 Sep 1; Malm J, Färnegârdh M, Grover GJ, Ladenson PWThyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T(3), 1) and 3,5,3',5'-tetraiodo-L-thyronine (L-T(4), 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TRalpha-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix (helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.

Acad Emerg Med. 2009 Jun 22; Pines JM, Pollack CV, Diercks DB, Chang AM, Shofer FS, Hollander JEObjectives: While emergency department (ED) crowding is a worldwide problem, few studies have demonstrated associations between crowding and outcomes. The authors examined whether ED crowding was associated with adverse cardiovascular outcomes in patients with chest pain syndromes (chest pain or related complaints of possible cardiac origin). Methods: A retrospective analysis was performed for patients >/=30 years of age with chest pain syndrome admitted to a tertiary care academic hospital from 1999 through 2006. The authors compared rates of inpatient adverse outcomes from ED triage to hospital discharge, defined as delayed acute myocardial infarction (AMI), heart failure, hypotension, dysrhythmias, and cardiac arrest, which occurred after ED arrival using five separate crowding measures. Results: Among 4,574 patients, 251 (4%) patients developed adverse outcomes after ED arrival; 803 (18%) had documented acute coronary syndrome (ACS), and of those, 273 (34%) had AMI. Compared to less crowded times, ACS patients experienced more adverse outcomes at the highest waiting room census (odds ratio [OR] = 3.7, 95% confidence interval [CI] = 1.3 to 11.0) and patient-hours (OR = 5.2, 95% CI = 2.0 to 13.6) and trended toward more adverse outcomes during time of high ED occupancy (OR = 3.1, 95% CI = 1.0 to 9.3). Adverse outcomes were not significantly more frequent during times with the highest number of admitted patients (OR = 1.6, 95% CI = 0.6 to 4.1) or the highest trailing mean length of stay (LOS) for admitted patients transferred to inpatient beds within 6 hours (OR = 1.5, 95% CI = 0.5 to 4.0). Patients with non-ACS chest pain experienced more adverse outcomes during the highest waiting room census (OR = 3.5, 95% CI = 1.4 to 8.4) and patient-hours (OR = 4.3, 95% CI = 2.6 to 7.3), but not occupancy (OR = 1.8, 95% CI = 0.9 to 3.3), number of admitted patients (OR = 0.6, 95% CI 0.4 to 1.1), or trailing LOS for admitted patients (OR = 1.2, 95% CI = 0.6 to 2.0). Conclusions: There was an association between some measures of ED crowding and a higher risk of adverse cardiovascular outcomes in patients with both ACS-related and non-ACS-related chest pain syndrome. ACADEMIC EMERGENCY MEDICINE 2009; 16:1-9 (c) 2009 by the Society for Academic Emergency Medicine.

J Cell Biochem. 2009 Jun 18; Venardos KM, Zatta AJ, Marshall T, Ritchie R, Kaye DMMyocardial injury due to ischemia-reperfusion (I-R) damage remains a major clinical challenge. Its pathogenesis is complex including endothelial dysfunction and heightened oxidative stress although the key driving mechanism remains uncertain. In this study we tested the hypothesis that the I-R process induces a state of insufficient L-arginine availability for NO biosynthesis, and that this is pivotal in the development of myocardial I-R damage. In neonatal rat ventricular cardiomyocytes (NVCM), hypoxia-reoxygenation significantly decreased L-arginine uptake and NO production (42 +/- 2% and 71 +/- 4%, respectively, both P < 0.01), maximal after 2 h reoxygenation. In parallel, mitochondrial membrane potential significantly decreased and ROS production increased (both P < 0.01). NVCMs infected with adenovirus expressing the L-arginine transporter, CAT1, and NVCMs supplemented with L-arginine both exhibited significant (all P < 0.05) improvements in NO generation and mitochondrial membrane potentials, with a concomitant significant fall in ROS production and lactate dehydrogenase release during hypoxia-reoxygenation. In contrast, L-arginine deprived NVCM had significantly worsened responses to hypoxia-reoxygenation. In isolated perfused mouse hearts, L-arginine infusion during reperfusion significantly improved left ventricular function after I-R. These improved contractile responses were not dependent on coronary flow but were associated with a significant decrease in nitrotyrosine formation and increases in phosphorylation of both Akt and troponin I. Collectively, these data strongly implicate reduced L-arginine availability as a key factor in the pathogenesis of I-R injury. Increasing L-arginine availability via increased CAT1 expression or by supplementation improves myocardial responses to I-R. Restoration of L-arginine availability may therefore be a valuable strategy to ameliorate I-R injury. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc.

J Artif Organs. 2009; 12(2): 90-7Ueno A, Tomizawa YRecently, cardiac rehabilitation has gained popularity in Japan because beneficial effects on patients' prognosis have been reported. Another reason is that cardiac rehabilitation has been covered by health insurance since 1988 in Japan. Currently, cardiac rehabilitation is covered for the diseases of angina pectoris, acute myocardial infarction, chronic heart failure (CHF), peripheral arterial disease, and diseases of the aorta and after open-heart surgery. Left ventricular assist devices (LVADs) are sometimes used in patients with progressive CHF symptoms to provide circulatory support, because in most of these patients heart failure does not improve with application of medical therapy, intra-aortic balloon pumping, or a percutaneous cardiopulmonary system. Modern VAD control systems are compact, allowing patients to carry them around without difficulty. Since patient management at the outpatient clinic has become possible, patients are able to expand the scope of their activities. Early active rehabilitation in patients implanted with a LVAD improves their condition, favorably impacts the clinical course while they await heart transplantation, and also improves posttransplant recovery. Exercise therapy is one of the important components in comprehensive cardiac rehabilitation. Exercise therapy is important to improve the quality of life of patients with LVADs. Appropriate exercise therapy is effective for patients with various cardiac conditions who undergo diverse treatments and is practiced actively by many patients. In order to facilitate cardiac rehabilitation safely and effectively for patients with serious conditions, education for health care professionals is essential. In this review, we describe the concept of rehabilitation followed by cardiac rehabilitation for patients with heart failure, patients after open-heart surgery, and patients with implanted LVADs.

Peptides. 2009 Jun 18; Del Ry S, Cabiati M, Lionetti V, Simioniuc A, Caselli C, Prescimone T, Emdin M, Giannessi DHigh-frequency pacing of the left ventricle (LV) free wall causes a dyssynchronous pattern of contraction that leads to progressive heart failure (HF) with pronounced differences in regional contractility. Aim of this study was to evaluate possible changes in brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) mRNA expression in the anterior/anterior lateral region (pacing site, PS) as compared to the infero-septal region (opposite site, OS) and to explore possible association between the contractiling pattern and biomarker expression. Cardiac tissue was collected from minipigs with pacing-induced HF (n=8) and without (control, n=6). The samples were selectively harvested from the anterior left ventricular (LV) wall, (PS), and from an area remote to the pacing-site, (OS). BNP and CNP mRNA expression was evaluated by semiquantitative polymerase chain reaction (PCR). A significant difference in BNP expression was found in the PS between HF animals and controls (BNP/GAPDH: 0.65+/-0.11 vs. 0.35+/-0.04, p=0.02), but not in the OS (BNP/GAPDH: 0.36+/-0.05, ns vs. controls). CNP expression was not different compared to controls, although higher levels were observed in the PS and in the OS with respect to the controls (CNP/GAPDH: controls 0.089+/-0.036, PS 0.289+/-0.23, OS 0.54+/-0.16). This finding was in tune with an increase of CNP tissue concentration (controls: 0.69+/-0.13; PS=1.56+/-0.19; OS=1.70+/-0.42 pg/mg protein; p=0.039 controls vs. OS). Higher BNP mRNA expression in the PS is consistent with a reduction in contractile function in this region, while higher CNP mRNA expression in the OS suggests the presence of concomitant endothelial dysfunction in the remote region.

Proc Natl Acad Sci U S A. 2009 Jun 18; Pan S, Chen HH, Dickey DM, Boerrigter G, Lee C, Kleppe LS, Hall JL, Lerman A, Redfield MM, Potter LR, Burnett JC, Simari RDAlternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.

CMAJ. 2009 Jun 23; 180(13): E118-E125Tu JV, Nardi L, Fang J, Liu J, Khalid L, Johansen H, BACKGROUND: Rates of death from cardiovascular and cerebrovascular diseases have been steadily declining over the past few decades. Whether such declines are occurring to a similar degree for common disorders such as acute myocardial infarction, heart failure and stroke is uncertain. We examined recent national trends in mortality and rates of hospital admission for these 3 conditions. METHODS: We analyzed mortality data from Statistic Canada's Canadian Mortality Database and data on hospital admissions from the Canadian Institute for Health Information's Hospital Morbidity Database for the period 1994-2004. We determined age- and sex-standardized rates of death and hospital admissions per 100 000 population aged 20 years and over as well as in-hospital case-fatality rates. RESULTS: The overall age- and sex-standardized rate of death from cardiovascular disease in Canada declined 30.0%, from 360.6 per 100 000 in 1994 to 252.5 per 100 000 in 2004. During the same period, the rate fell 38.1% for acute myocardial infarction, 23.5% for heart failure and 28.2% for stroke, with improvements observed across most age and sex groups. The age- and sex-standardized rate of hospital admissions decreased 27.6% for stroke and 27.2% for heart failure. The rate for acute myocardial infarction fell only 9.2%. In contrast, the relative decline in the inhospital case-fatality rate was greatest for acute myocardial infarction (33.1%; p < 0.001). Much smaller relative improvements in case-fatality rates were noted for heart failure (8.1%) and stroke (8.9%). INTERPRETATION: The rates of death and hospital admissions for acute myocardial infarction, heart failure and stroke in Canada changed at different rates over the 10-year study period. Awareness of these trends may guide future efforts for health promotion and health care planning and help to determine priorities for research and treatment.

Heart Surg Forum. 2009 Jun; 12(3): E137-40Kassai I, Mihalcz A, Foldesi C, Kardos A, Szili-Torok TBackground: Coronary sinus lead placement for transvenous left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) has a significant failure rate at implant and a considerable dislocation rate during follow-up. For these patients epicardial pacing lead implantation is the most frequently used alternative. Recent data support endocardial lead implantation through the atrial septum and the mitral valve, because this method provides further hemodynamic advantages. On the other hand transseptal CRT carries a significant risk for device related infective endocarditis of the mitral valve. The aim of this prospective, nonrandomized study was to demonstrate the feasibility of a fundamentally new approach for endocardial LV lead implantation.Methods: We performed 12 transapical LV lead implantations in 10 end-stage heart failure patients. In each operation an active fixation lead was placed into the LV cavity using standard Seldinger technique through the LV apex. By use of a J-shaped guide wire, the tip of the lead was positioned and fixed into the basal-lateral segment of the LV under fluoroscopy guidance. Pacing parameters were assessed and found to be optimal in all patients. The lead was conducted through the chest wall near the apex into a subcutaneous tunnel up to the pocket of the previously implanted device. After surgery the patients are anticoagulated with target anticoagulation level identical to mechanical valve prostheses.Results: In 8 patients there were no major or minor complications related to this new technique. During the follow-up period (mean 7.2 +/- 4.1 months) all patients responded favorably to the treatment. One lead dislocation and 1 pocket infection were detected; the lead repositioning and replacing could be performed without reopening of the pleural cavity.Conclusions: The potential advantages of this new technique are that it is minimally invasive, endocardial, and does not involve the mitral valve. LV lead repositioning can also be performed minimally invasively.

Eur J Pediatr Surg. 2009 Jun 22; Raboei EHBACKGROUND: Dysganglionosis and aganglionosis have been frequently described in biopsies of the distal bowel in patients with anorectal malformation (ARM). They are interpreted as a developmental disorder of the anorectum. The true association of total colonic aganglionosis and anorectal malformation has not been reported before. The aim of this study was to explore the true association of anorectal malformation and Hirschsprung's disease with or without trisomy 21. MATERIAL & METHODS: A retrospective study of all patients diagnosed with anorectal malformation in our institute from 1986-2008 was performed. All patients with anorectal malformation and Hirschsprung's disease were included in the study. Rectal biopsies were taken from multiple sites, including the rectum, left, transverse, right colon and appendix. The diagnosis of aganglionosis was proven histopathologically by the absence of ganglion cells with or without acetylcholinesterase staining. Specimens were examined by at least two experienced consultant pathologists. RESULTS: Aganglionosis was confirmed in three patients out of 53 patients with anorectal malformation. Two had Down's syndrome. All were males and presented with high anorectal malformation without fistula. The clinical presentation was intestinal obstruction, necrotizing enterocolitis and failure to thrive. The level of aganglionosis was up to the left colon in two and total colonic with ileal involvement in one. One of the children with Down's syndrome and total colonic aganglionosis died. Another had correction of a congenital heart disease, colostomy and is awaiting definitive surgery. The third case is continent at the age of 22 years with a Malone stoma after pull-through of ARM and a subsequent Duhamel procedure. CONCLUSIONS: The association between ARM and intestinal dysganglionosis is not rare. We recommend not using the distal rectal pouch and parts of the fistula in the reconstruction of anorectal malformations as this may solve the constipation if the pathology is limited. In cases of aganglionosis beyond the rectal pouch and fistula, surgical intervention is needed. Delay in diagnosis may lead to morbidity or even mortality.

Clin J Am Soc Nephrol. 2009 Jun 18; Lash JP, Go AS, Appel LJ, He J, Ojo A, Rahman M, Townsend RR, Xie D, Cifelli D, Cohan J, Fink JC, Fischer MJ, Gadegbeku C, Hamm LL, Kusek JW, Landis JR, Narva A, Robinson N, Teal V, Feldman HI, BACKGROUND AND OBJECTIVES: The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. RESULTS: A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. CONCLUSIONS: Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.

J Gerontol A Biol Sci Med Sci. 2009 Jun 17; Hajjar I, Yang F, Sorond F, Jones RN, Milberg W, Cupples LA, Lipsitz LABACKGROUND: Our objectives were to investigate the existence of a group of nondemented elderly individuals who simultaneously have impairments in cognition, mobility, and mood, and to examine the association between being a member of this group and elevated blood pressure and other cardiovascular conditions. METHODS: The Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston study is an ongoing prospective observational study of community-dwelling individuals. We analyzed the cross-sectional data collected at baseline (N = 580, mean age = 77.8 years, 64% women, 14% African American, mean Mini-Mental State Examination = 27.2). Using latent profile analysis, we investigated the existence of a group of elderly participants with impairments in executive function (Trail Making Test Part B [TMT-B]), gait speed (two 4-m walk tests), and depressive symptoms (Center for Epidemiological Studies-Depression scale [CES-D]). RESULTS: We identified a group (n = 99 [17%]) with prolonged TMT-B, slow gait speed, and high CES-D scores. This group did not exist when we used a memory measure. Hypertension (p = .001), diabetes (p = .0002), congestive heart failure (p = .006), stroke (p = .005), and higher Framingham cardiovascular risk score (p = .0001) were associated with an increased likelihood of being a member in this group. This association with elevated systolic and pulse pressure, and stroke remained significant after multiple covariate adjustments. CONCLUSIONS: There exists a group of elderly individuals in whom poor executive function, slow gait speed, and depressive symptoms occur simultaneously. Memory measures did not identify such a grouping. Elevated blood pressure and other cardiovascular diseases are independently associated with being a member of this group. Assessing these domains is an important part of the evaluation of the elderly patients with high vascular risk.

Eur Heart J. 2009 Jun 17; Kirchhof P, Bax J, Blomstrom-Lundquist C, Calkins H, John Camm A, Cappato R, Cosio F, Crijns H, Diener HC, Goette A, Israel CW, Kuck KH, Lip GY, Nattel S, Page RL, Ravens U, Schotten U, Steinbeck G, Vardas P, Waldo A, Wegscheider K, Willems S, Breithardt GAtrial fibrillation (AF) causes important mortality and morbidity on a population-level. So far, we do not have the means to prevent AF or AF-related complications adequately. Therefore, over 70 experts on atrial fibrillation convened for the 2nd AFNET/EHRA consensus conference to suggest directions for research to improve management of AF patients (Appendix 1). The group defined three main areas in need for research in AF: 1. better understanding of the mechanisms of AF; 2. Improving rhythm control monitoring and management; and 3. comprehensive cardiovascular risk management in AF patients. The group put forward the hypothesis that successful therapy of AF and its associated complications will require comprehensive therapy. This applies e.g. to the "old" debate of "rate versus rhythm control", since rhythm control is generally added to underlying (continued) rate control therapy, but also to the emerging debate of "antiarrhythmic drugs versus catheter ablation", of which both may be needed in most patients to maintain sinus rhythm, but also to therapy of conditions that predispose to AF and contribute to cardiovascular complications such as stroke, cognitive decline, heart failure, and acute coronary syndromes. We call for research initiatives aiming at a better understanding of the different causes of AF and its complications, and at development and validation of mechanism-based therapies. The future of AF therapy may require a combination of management of underlying and concomitant conditions, early and comprehensive rhythm control therapy, adequate control of ventricular rate and cardiac function, and continuous therapy to prevent AF-associated complications (e.g. antithrombotic therapy). The reasons for these suggestions are detailed in this paper.

Am J Kidney Dis. 2009 Jun 16; Nishimura M, Tokoro T, Nishida M, Hashimoto T, Kobayashi H, Imai R, Yamazaki S, Okino K, Iwamoto N, Takahashi H, Ono TBACKGROUND: Survival after invasive coronary revascularization is worse in patients with chronic kidney disease than in patients without chronic kidney disease. We examined whether oral administration of nicorandil, a hybrid nitrate and adenosine triphosphate-sensitive potassium channel opener, could improve outcome after coronary revascularization in hemodialysis patients. STUDY DESIGN: Open-labeled prospective randomized trial. SETTING & PARTICIPANTS: Maintenance hemodialysis patients who underwent percutaneous coronary artery intervention and had complete coronary revascularization (absence of both restenosis and de novo coronary lesion) at coronary arteriography 6 months later. Enrollment occurred between January 1, 2002, and December 31, 2004. INTERVENTIONS: Treatment with or without oral administration of nicorandil, 15 mg/d. OUTCOMES & MEASUREMENTS: The primary end point was cardiac death (sudden cardiac death or death from acute myocardial infarction or congestive heart failure). The secondary end point was all-cause death. End-point adjudication was performed masked to the intervention. RESULTS: 129 patients (91 men, 38 women) with a mean age of 66 +/- 9 (SD) years. During a 2.7 +/- 1.5-year follow-up, 26 died of cardiac events (acute myocardial infarction, 6; congestive heart failure, 5; sudden cardiac death, 15), and 12 died of noncardiac causes. Cardiac death-free survival rates were greater in the nicorandil group than in the control group (P = 0.009; at 3 years, 86.6% in the nicorandil group and 70.7% in the control group). All-cause death-free survival rates were also greater in the nicorandil group than in the control group (P = 0.01; at 3 years, 79.2% in the nicorandil group versus 60.5% in the control group). Additional percutaneous coronary artery intervention was performed in 6 participants in the nicorandil group and 2 participants in the control group. No serious side effects of nicorandil were reported during the course of the study. LIMITATIONS: Small sample size and open-label design. CONCLUSIONS: Oral administration of nicorandil may reduce cardiac death and improve the survival of hemodialysis patients after coronary revascularization.

J Artif Organs. 2009; 12(2): 67-72Kenmoku KThe artificial heart-lung system is a device that replaces the patient's respiratory and circulatory function during surgery on the heart and great vessels. Users must operate the system by properly recognizing and appropriately evaluating various types of information and by providing feedback to the machine; inappropriate interaction between humans and the machine can cause failures. A questionnaire survey showed that the incidence of problem events during the operation of heart-lung machines was 1/300 to 1/100, both within and outside Japan, and that severe events such as permanent disability or death occurred at an incidence of 1/1000 to 1/500. It has been generally reported that the following measures are effective ways of reducing errors: (1) reducing the number of high-risk operations (risk minimization), (2) reducing the probability of occurrence of errors during each operation (probability minimization), (3) implementing multiple error-detecting measures (multiple detection of errors), and (4) having the capacity to minimizing damage (damage limitation). This article discusses effective countermeasures as a result of a questionnaire answered in Japan. The first measure to be taken is to provide both software (i.e., manuals that describe safety measures, checklists, and troubleshooting approaches that are not otherwise readily available) and hardware (i.e., necessary monitoring devices that enhance safety). Second, a standard heart-lung circuit needs to be designed. Third, safety management of medical engineering equipment for cardiac surgery must be strictly performed. Fourth, simulations of practical problems are necessary. People make mistakes, machines can fail, the electricity supply can be cut, consumables may be defective, or consumables may break. The higher the number of people involved, the more easily problems can occur due to the complexity of the system. Failures inevitably occur at a certain frequency. In other words, efforts can reduce the probability of a failure but cannot reduce it to zero. It is an empirical fact that the reliability of judgment and human responses become transiently impaired to a large degree during a state of panic. Extracorporeal technologists are required to be able to deal with such emergency situations without making errors or becoming flustered and must retain a sense of composure while working through a checklist and engaging in troubleshooting. This is a situation that demands a higher level of ability than is normally required, and this ability needs to be exercised in an intensive, timely, and precise manner. To properly acquire and maintain this ability, it is essential to undergo practical training that involves problem simulations. We must carry out simulations of problems based on this undeniable fact.

South Med J. 2009 May 7; Garcia S, Canoniero M, Young LBACKGROUND:: Little information is available to measure the impact of new trainees in the process of care and outcomes of patients with acute cardiovascular conditions. The objective of this investigation is to assess whether physicians' experience has an impact on the quality of health care delivery. METHODS:: Two cohorts of hospitalized patients with acute coronary syndromes (ACS) (n = 764) and decompensated heart failure (HF) (n = 590) were included in this study. Utilization of life-saving medications, diagnostic and therapeutic procedures, and in-hospital outcomes were compared between patients admitted during July-September (J-S) vs. October-June (O-J). Independent predictors of optimal medical management (OMM) were determined by logistic regression analysis. RESULTS:: During O-J, 573 (75%) patients were admitted with an ACS and 516 (84%) with decompensated HF. Among patients with acute coronary syndromes, utilization of beta blockers, aspirin, and statins was similar in the two groups (all P NS). In multivariate analysis, the only independent predictor of optimal medical management was the performance of coronary angioplasty (OR = 1.5, 95% CI = 1.05-2.14, P = 0.02). Among patients with decompensated HF, no difference was found in utilization of beta blockers, ACEI/ARB, length of stay and in-hospital mortality. In multivariate analysis, age >65, atrial fibrillation, admission during J-S, and disease severity were all independent predictors of not receiving optimal medical management (all P < 0.05). These differences were explained exclusively on the basis of EF measurement and not on different utilization rates of pharmacological therapy. CONCLUSIONS:: Our results do not support the concept of a "July phenomenon" in patients presenting with acute cardiovascular conditions.

Ther Adv Cardiovasc Dis. 2009 Jun 16; Jessup JA, Westwood BM, Chappell MC, Groban LBACKGROUND: Hypertension and left ventricular (LV) hypertrophy often precede diastolic dysfunction and are risk factors for diastolic heart failure. Although pharmacologic inhibition of the renin-angiotensin system (RAS) improves diastolic function and functional capacity in hypertensive patients with LV hypertrophy, the effects of combination therapy with an angiotensin converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) are unclear. METHOD: We assessed the effects of the combined 10-week administration of lisinopril (10 mg/kg/day, p.o.) and losartan (10 mg/kg/day, p.o.) (LIS/LOS) on diastolic function and LV structure in seven young (5 weeks), prehypertensive congenic mRen2.Lewis male rat, a model of tissue renin overexpression and angiotensin II (Ang II)-dependent hypertension compared to vehicle (VEH) treated (n = 7), age-matched rats. RESULTS: : Systolic blood pressures were 64% lower with the combination therapy (p < 0.001), but there were no differences in heart rate or systolic function between groups. RAS inhibition increased myocardial relaxation, defined by tissue Doppler mitral annular descent (e') by 2.2 fold (p < 0.001). The preserved lusitropy in the LIS/LOS-treated rats was accompanied by a reduction in phospholamban-to-SERCA2 ratio (p < 0.001). Despite lower relative wall thicknesses (VEH: 1.56 +/- 0.17 versus LIS/LOS: 0.78 +/- 0.05) and filling pressures, defined by the transmitral Doppler-to-mitral annular descent ratio (E/e', VEH: 28.7 +/- 1.9 versus LIS/LOS: 17.96 +/- 1.5), no differences in cardiac collagen were observed. CONCLUSION: : We conclude that the lusitropic benefit of early dual RAS blockade may be due to improved vascular hemodynamics and/or cardiac calcium handling rather than effects on extracellular matrix reduction.

Eur J Clin Invest. 2009 Jun 15; Huang WP, Yin WH, Chen JW, Jen HL, Young MS, Lin SJEur J Clin Invest 2009Abstract Background Inflammation is implicated in chronic heart failure (CHF). In this study, the potential inhibitory effect of peroxisome proliferator-activated receptor-alpha (PPARalpha) activator fenofibrate on monocyte adhesion in CHF patients was investigated in vitro. Materials and methods Isolated peripheral blood mononuclear cells (PBMCs) were collected from 36 patients (aged 65 +/- 8 years) with symptomatic CHF and from 12 healthy control subjects. The cultured human aortic endothelial cells (HAECs) were stimulated with or without 2 ng mL(-1) tumour necrosis factor-alpha (TNF-alpha) and the inhibitory effects of fenofibrate at 25, 50, 100 and 200 muM on endothelial mononuclear cell adhesion were tested. Furthermore, the HAECs were stimulated with 70% sera obtained from CHF patients and control individuals, respectively, with or without pretreatments with fenofibrate. The endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was then confirmed by mRNA expression and Western blot. Results We found that the increased adhesion of PBMCs to TNF-alpha-stimulated HAECs in CHF patients was reduced when the HAECs were pretreated with fenofibrate (31% inhibition, P = 0.0121). However, pretreatment of the isolated PBMCs collected from CHF patients with fenofibrate failed to suppress their adherence to TNF-alpha-stimulated HAECs. Furthermore, stimulation of cultured HAECs with CHF patient sera significantly increased VCAM-1 and ICAM-1 expression, which could also be inhibited by fenofibrate. Conclusions The fenofibrate directly inhibits monocyte binding by TNF-alpha-activated HAECs, probably through preventing up-regulation of cell adhesion molecules by endothelial cells in response to inflammatory stimuli. This PPARalpha activator may have the potential to ameliorate vascular inflammation in patients with CHF.

BMC Palliat Care. 2009 Jun 16; 8(1): 6Small N, Barnes S, Gott M, Payne S, Parker C, Seamark D, Gariballa SABSTRACT: BACKGROUND: This paper explores carers' views of dying, death and bereavement for family members who had recently died with heart failure adding to a growing literature on end of life experiences for people with conditions other than cancer. METHOD: Twenty interviews were conducted with bereaved carers of older people with heart failure (HF) who had been participating in a longitudinal study. Carers were approached in writing 3 months after the death. Interviews were transcribed verbatim and analysed thematically with the assistance of NUD*IST. RESULTS: Findings were grouped into three time periods: prior to death; the death itself and bereavement. Most carers found discussions about end of life with their family member prior to death difficult. Dissatisfaction with the manner of the death was focused around hospital care, particularly what they believed to be futile treatments. In contrast deaths in the home were considered 'good'. Carers adopted a range of coping strategies to deal with grief including 'using their faith' and 'busying themselves' with practicalities. There was some satisfaction with services accessed during the bereavement period although only a small number had taken up counselling. DISCUSSION: Our findings suggest that an absence of discussion about end of life care wishes with family members or health professionals is a barrier to advance care planning. Carers' perceptions about prioritising making the dying person comfortable can be in conflict with doctors' decisions to treat. Whilst carers report a range of strategies adopted in response to bereavement there is a need for continued support for vulnerable carers after the death of the person with HF.

Curr Opin Anaesthesiol. 2009 Jun 4; Salmenperä M, Eriksson HPURPOSE OF REVIEW: To present recent experiences and studies on the pharmacologic profile of levosimendan in the context of surgery, anesthesia and critical care. Special emphasis is on the studies that could support the use of or create novel indications for levosimendan in these patients. RECENT FINDINGS: Several controlled studies now suggest that levosimendan is efficacious in improving hemodynamics in patients after cardiac surgery. Its use as an adjunct to catecholamines instead of phosphodiesterase inhibitors can be recommended in patients with postcardiotomy heart failure and cardiogenic shock. Prophylactic administration before cardiopulmonary bypass in patients with compromised ventricular function may also be rational because levosimendan facilitates weaning from cardiopulmonary bypass without inotropes with higher myocardial oxygen cost of inotropy. This mode of administration also seems to attenuate troponin release and spares treatment resources such as duration of postoperative ventilation and ICU stay. The reported experience in patients with noncardiac surgery is meager but previous results obtained from nonsurgical patients should be largely applicable. The use of levosimendan in treating septic myocardial depression or sepsis syndrome is a promising option but remains investigational for today. SUMMARY: New practice advisories and proposals for indications to treat and prevent low-output syndrome in patients at risk are warranted for patients undergoing cardiac surgery with cardiopulmonary bypass. Levosimendan should also be considered as an adjunct drug for the treatment of cardiogenic shock. Further experience and controlled studies are needed to support the use of levosimendan for other perturbations in critical care and perioperative medicine.

JNMA J Nepal Med Assoc. 2009 Jan-Mar; 48(173): 20-3Shrestha NR, Sharma SK, Karki P, Shrestha NK, Acharya PINTRODUCTION: Diabetes mellitus is an established risk factor for congestive cardiac failure in which the diastolic function is impaired earlier than the systolic function and majority of these patients maybe asymptomatic without signs of overt heart failure. METHODS: A cross sectional hospital based study was done which included 100 asymptomatic patients with type 2 diabetes without evidence of coronary artery disease, congestive heart failure, thyroid or overt renal disease. LVDD was evaluated by Doppler echocardiography, which included the valsalva maneuver to unmask the pseudonormal pattern of left ventricular filling. The prevalence of LVDD and the associated risk factors were assessed. RESULTS: LVDD was found in 71 subjects (71%), of whom 60 had impaired relaxation and 11 had a pseudonormal pattern of ventricular filling. Systolic function was normal in all subjects, and there was no correlation between LVDD and indexes of metabolic control. It was also found that age > or =45 years was associated with an almost three times higher risk for the development of diastolic dysfunction in type 2 diabetes. Females were at a two times higher risk of developing diastolic dysfunction than when compared to men. Duration of diabetes > or = two years was associated with a two times higher risk for developing diastolic dysfunction. CONCLUSIONS: LVDD is much more common than previously reported in subjects with well-controlled type 2 diabetes who are free of clinically detectable heart disease. The high prevalence of this phenomenon in this high-risk population suggests that screening for LVDD in type 2 diabetes should include procedures such as the valsalva maneuver to unmask a pseudonormal pattern of ventricular filling.

J Cardiovasc Pharmacol. 2009 Jun 12; Cheng XW, Okumura K, Kuzuya M, Jin Z, Nagata K, Obata K, Inoue A, Hirashiki A, Takeshita K, Unno K, Harada K, Shi GP, Yokota M, Murohara TOBJECTIVE:: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. METHODS:: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. RESULTS:: Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. CONCLUSIONS:: The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.

Circulation. 2009 Jun 15; Poirier P, Alpert MA, Fleisher LA, Thompson PD, Sugerman HJ, Burke LE, Marceau P, Franklin BA, Abstract-Obesity is associated with comorbidities that may lead to disability and death. During the past 20 years, the number of individuals with a body mass index >30, 40, and 50 kg/m(2), respectively, has doubled, quadrupled, and quintupled in the United States. The risk of developing comorbid conditions rises with increasing body mass index. Possible cardiac symptoms such as exertional dyspnea and lower-extremity edema occur commonly and are nonspecific in obesity. The physical examination and electrocardiogram often underestimate cardiac dysfunction in obese patients. The risk of an adverse perioperative cardiac event in obese patients is related to the nature and severity of their underlying heart disease, associated comorbidities, and the type of surgery. Severe obesity has not been associated with increased mortality in patients undergoing cardiac surgery but has been associated with an increased length of hospital stay and with a greater likelihood of renal failure and prolonged assisted ventilation. Comorbidities that influence the preoperative cardiac risk assessment of severely obese patients include the presence of atherosclerotic cardiovascular disease, heart failure, systemic hypertension, pulmonary hypertension related to sleep apnea and hypoventilation, cardiac arrhythmias (primarily atrial fibrillation), and deep vein thrombosis. When preoperatively evaluating risk for surgery, the clinician should consider age, gender, cardiorespiratory fitness, electrolyte disorders, and heart failure as independent predictors for surgical morbidity and mortality. An obesity surgery mortality score for gastric bypass has also been proposed. Given the high prevalence of severely obese patients, this scientific advisory was developed to provide cardiologists, surgeons, anesthesiologists, and other healthcare professionals with recommendations for the preoperative cardiovascular evaluation, intraoperative and perioperative management, and postoperative cardiovascular care of this increasingly prevalent patient population.

Ann Intern Med. 2009 Jun 16; 150(12): 849-57, W152Warren JL, Klabunde CN, Mariotto AB, Meekins A, Topor M, Brown ML, Ransohoff DFBACKGROUND: Although use of colonoscopy has increased substantially among elderly Medicare beneficiaries, no one has described colonoscopy-related adverse events in a representative sample of Medicare patients. OBJECTIVE: To determine risk for adverse events after outpatient colonoscopy in elderly patients. DESIGN: Population-based, matched cohort study. SETTING: Surveillance, Epidemiology, and End Results cancer registry areas. PATIENTS: Random 5% sample of Medicare beneficiaries, age 66 to 95 years, who underwent outpatient colonoscopy between 1 July 2001 and 31 October 2005 (n = 53 220), matched with beneficiaries who did not have colonoscopy. MEASUREMENTS: Medicare claims were used to measure the rate of serious gastrointestinal events (bleeding and perforation), other gastrointestinal events, and cardiovascular events resulting in a hospitalization or emergency department visit within 30 days after colonoscopy compared with matched beneficiaries who did not have colonoscopy. Logistic regression was used to estimate adjusted predictive risks for adverse events and to assess whether these events varied by age, comorbid conditions, or type of colonoscopy. RESULTS: Persons undergoing colonoscopy had a higher risk for adverse gastrointestinal events than their matched group. Rates of adverse events after colonoscopy increased with age. Patients having polypectomy had higher risk for all adverse events compared with their matched group and with the screening and diagnostic colonoscopy groups. Comorbid conditions increased the risk for adverse events. Patients with a history of stroke, chronic obstructive pulmonary disease, atrial fibrillation, or congestive heart failure had significantly higher risk for serious gastrointestinal events. LIMITATION: The analysis relied on the diagnosis and procedure codes recorded on the Medicare claims. CONCLUSION: Risks for adverse events after outpatient colonoscopy among elderly Medicare beneficiaries were low; however, they increased with age with specific comorbid conditions and depending on whether polypectomy was done. These data may inform decisions on whether to perform colonoscopy in persons of advanced age or those with comorbid conditions.

Exp Mol Pathol. 2009 Jun 12; Feng W, Li W, Liu W, Wang F, Li Y, Yan WOBJECTIVE: This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model. METHODS: HF was induced in Wistar-Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 hours. After two months, the surviving rats were divided into three groups: monoclonal anti-IL-17 Ab (100 mug/day), IgG (100 mug/day) or PBS were injected five times every 48 hours (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluated myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml) +OPG (10 ng/ml), IL-17 (10 ng/ml) + Anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1. RESULTS: The expressions of MMP-1, RANKL, and type I and III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HF. IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and Anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on RANKL/OPG system to induce MMP-1 partly. CONCLUSION: Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HF. IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF.

Appl Physiol Nutr Metab. 2009 Jun; 34(3): 473-80Luiken JJCardiomyopathy and heart failure are frequent comorbid conditions in type-2 diabetic patients. However, it has become increasingly evident that insulin resistance, type-2 diabetes, and cardiomyopathy are not independent variables, and are linked through changes in metabolism. Specifically, elevated intracellular levels of long-chain fatty acid (LCFA) metabolites are a central feature in the development of cardiac insulin resistance, and their prolonged accumulation is an important cause of heart failure. In the insulin-resistant heart, the abundance of the LCFA transporters CD36 and FABPpm at the sarcolemma of cardiac myocytes appears to be markedly increased. Because circulating LCFA levels are increased in insulin resistance, the cardiac LCFA metabolizing machinery is confronted with drastic increases in substrate supply. Indeed, LCFA esterification into triacylglycerol and other lipid intermediates is increased, as is beta-oxidation and reactive oxygen species production. Therapeutic strategies to normalize the cardiac LCFA flux would be most successful when the target is the rate-limiting step in cardiac LCFA utilization. Carnitine palmitoyltransferase (CPT)-I has long been considered to be this rate-limiting site and, accordingly, pharmacological inhibition of CPT-I, or beta-oxidation enzymes, has been proposed as an insulin-resistance-antagonizing strategy. However, recent evidence indicates that, instead, sarcolemmal LCFA transport mediated by CD36 in concert with FABPpm provides a major site of flux control. In this review, it is proposed that a pharmacologically imposed net internalization of CD36 and FABPpm is the preferable strategy to limit LCFA entry and accumulation of LCFA metabolites, to regress cardiac insulin resistance and, eventually, prevent diabetic heart failure.

Am J Physiol Heart Circ Physiol. 2009 Jun 12; Chicos AB, Kannankeril PJ, Kadish AH, Goldberger JJDepressed parasympathetic activity has been proposed to be associated with an increased risk of sudden death. Parasympathetic effects (PE) on cardiac electrophysiology during exercise and recovery have not been studied in patients with left ventricular dysfunction. We performed non-invasive electrophysiologic studies (NI-EPS) and characterized the electrophysiological properties of the sinus node, atrioventricular (AV) node, and ventricle in subjects with depressed left ventricular ejection fraction (LVEF) and dual-chamber defibrillators. NI-EPS was performed during rest, exercise and recovery at baseline and after parasympathetic blockade with atropine to assess PE (the difference between parameter values in the 2 conditions). Ten subjects (9 men, age 60+/-9 years, LVEF=29+/-8%) completed the study. All NI-EPS parameters decreased during exercise, and trended toward rest values during recovery. PE at rest, during exercise, and during recovery, respectively, on sinus cycle length were 320+/-71 ms (p=0.0001), 105+/-60 ms (p=0.0003), and 155+/-82 ms (p=0.0002); on AV block cycle length 137 +/-136 ms (p=0.09), 37+/-19 ms (p=0.002), and 61+/-39 ms (p=0.006); on AV interval 58+/-32 ms (p=0.035), 22+/-13 ms (p=0.002), and 36+/-20 ms (p=0.001); on ventricular effective refractory period 15.8+/-11.3 ms (p=0.02), 4.7+/-15.2 ms (p=0.38), and 6.8+/-15.5 ms (p=0.20); on QT interval 13+/-12 ms (p=0.13), 3+/-17 ms (p=0.6), and 20+/-23 ms (p=0.04). In conclusion, we describe for the first time the changes in cardiac electrophysiology and PE during rest, exercise and recovery in subjects with left ventricular dysfunction. PE are preserved in these patients. Thus, the role of autonomic changes in the pathophysiology of sudden death requires further exploration. Key words: electrophysiology, exercise, heart failure, nervous system, autonomic.

Peptides. 2009 Jun 11; Castro-Chaves P, Pintalhao M, Fontes-Carvalho R, Cerqueira R, Leite-Moreira AFAngiotensin 1-7 is a bioactive heptapeptide of the renin-angiotensin system. Its cardiovascular actions have recently acquired growing relevance, mainly due to its counter-regulatory actions in the angiotensin cascade. The aim of the present study was to evaluate the actions of angiotensin 1-7 on myocardial function. Increasing concentrations of angiotensin 1-7 (10(-9)-10(-5)M) were added to rabbit right papillary muscles: (1) in baseline conditions with intact endocardial endothelium (EE); (2) after selective removal of the EE with Triton X-100 (1s, 0.01%); (3) with intact EE in the presence of the Mas receptor antagonist A-779, the AT(1) receptor antagonist ZD-7155, the AT(2) receptor antagonist PD-123,319 or the nitric oxide synthesis inhibitor NG-nitro-L-arginine (L-NA). Concerning the effects on contractility, we observed a significant decrease on active tension, dT/dt(max), peak shortening and dL/dt(max) of -10.5+/-3.6%, -8.0+/-3.0%, -5.3+/-2.6% and -5.7+/-2.3%, respectively. There was no change on relaxation parameters, namely dT/dt(min) or dL/dt(min). Time to half relaxation was significantly decreased. The presence of ZD-7155 or PD-123,319 did not change these effects. However, angiotensin 1-7 effects on myocardial properties were abolished after selective EE removal and in the presence of A-779 or L-NA. In conclusion, in this animal species, angiotensin 1-7 through its binding to Mas receptor induces a negative inotropic effect modulated by the EE and nitric oxide and independent of AT(1) or AT(2) receptors activation. As the effects described in the present work were influenced by the endocardial endothelium, they may be disrupted in situations associated to endothelial dysfunction, as in heart failure or myocardial ischemia.

Nature. 2009 Jun 14; Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, Ronchi AE, Rocchetti M, Mingozzi F, Foti M, Chirico G, Costa B, Zaza A, Ricciardi-Castagnoli P, Granucci FToll-like receptors (TLRs) are the best characterized pattern recognition receptors. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor kappaB, activation protein 1 and interferon regulatory factors. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca(2+)/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cgamma2 activation, influx of extracellular Ca(2+) and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.