Role of Kv7 channels in responses of the pulmonary circulation to hypoxia

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K(+) channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3–5 days in an isobaric hypoxic chamber (Fi(O(2)) = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease

Validated risk score for predicting 6-month mortality in infective endocarditis

Background-Host factors and complications have been associated with higher mortality in infective endocarditis (IE). We sought to develop and validate a model of clinical characteristics to predict 6-month mortality in IE. Methods and Results-Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ICE]-Prospective Cohort Study [PCS], 2000-2006, n=4049), a model to predict 6-month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry (ICE-PLUS, 2008-2012, n=1197). The 6-month mortality was 971 of 4049 (24.0%) in the ICE-PCS cohort and 342 of 1197 (28.6%) in the ICE-PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE, causative organism, left-sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6-month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62-0.89). A simplified risk model was developed by weight adjustment of these variables. Conclusions-Six-month mortality after IE is 25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE

Infective Endocarditis in Patients on Chronic Hemodialysis

295sinoneBackground: Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). Objectives: This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. Methods: Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. Results: A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non–HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001). Conclusions: HD-IE is a health care–associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non–HD-IE patients, whereas cardiac surgery is less frequently performed.nonePericas J.M.; Llopis J.; Jimenez-Exposito M.J.; Kourany W.M.; Almirante B.; Carosi G.; Durante-Mangoni E.; Fortes C.Q.; Giannitsioti E.; Lerakis S.; Montagna-Mella R.; Ambrosioni J.; Tan R.-S.; Mestres C.A.; Wray D.; Pachirat O.; Moreno A.; Chu V.H.; de Lazzari E.; Fowler V.G.; Miro J.M.; Clara L.; Sanchez M.; Casabe J.; Cortes C.; Nacinovich F.; Oses P.F.; Ronderos R.; Sucari A.; Thierer J.; Altclas J.; Kogan S.; Spelman D.; Athan E.; Harris O.; Kennedy K.; Tan R.; Gordon D.; Papanicolas L.; Korman T.; Kotsanas D.; Dever R.; Jones P.; Konecny P.; Lawrence R.; Rees D.; Ryan S.; Feneley M.P.; Harkness J.; Post J.; Reinbott P.; Gattringer R.; Wiesbauer F.; Andrade A.R.; Passos de Brito A.C.; Guimaraes A.C.; Grinberg M.; Mansur A.J.; Siciliano R.F.; Varejao Strabelli T.M.; Campos Vieira M.L.; de Medeiros Tranchesi R.A.; Paiva M.G.; de Oliveira Ramos A.; Weksler C.; Ferraiuoli G.; Golebiovski W.; Lamas C.; Karlowsky J.A.; Keynan Y.; Morris A.M.; Rubinstein E.; Jones S.B.; Garcia P.; Cereceda M.; Fica A.; Mella R.M.; Fernandez R.; Franco L.; Gonzalez J.; Jaramillo A.N.; Barsic B.; Bukovski S.; Krajinovic V.; Pangercic A.; Rudez I.; Vincelj J.; Freiberger T.; Pol J.; Zaloudikova B.; Ashour Z.; El Kholy A.; Mishaal M.; Osama D.; Rizk H.; Aissa N.; Alauzet C.; Alla F.; Campagnac C.C.; Doco-Lecompte T.; Selton-Suty C.; Casalta J.-P.; Fournier P.-E.; Habib G.; Raoult D.; Thuny F.; Delahaye F.; Delahaye A.; Vandenesch F.; Donal E.; Donnio P.Y.; Flecher E.; Michelet C.; Revest M.; Tattevin P.; Chevalier F.; Jeu A.; Remadi J.P.; Rusinaru D.; Tribouilloy C.; Bernard Y.; Chirouze C.; Hoen B.; Leroy J.; Plesiat P.; Naber C.; Neuerburg C.; Mazaheri B.; Sophia Athanasia C.N.; Deliolanis I.; Giamarellou H.; Thomas T.; Mylona E.; Paniara O.; Papanicolaou K.; Pyros J.; Skoutelis A.; Papanikolaou K.; Sharma G.; Francis J.; Nair L.; Thomas V.; Venugopal K.; Hannan M.M.; Hurley J.P.; Wanounou M.; Gilon D.; Israel S.; Korem M.; Strahilevitz J.; Iossa D.; Orlando S.; Ursi M.P.; Pafundi P.C.; D'Amico F.; Bernardo M.; Cuccurullo S.; Dialetto G.; Covino F.E.; Manduca S.; Della Corte A.; De Feo M.; Tripodi M.F.; Cecchi E.; De Rosa F.; Forno D.; Imazio M.; Trinchero R.; Grossi P.; Lattanzio M.; Toniolo A.; Goglio A.; Raglio A.; Ravasio V.; Rizzi M.; Suter F.; Magri S.; Signorini L.; Kanafani Z.; Kanj S.S.; Sharif-Yakan A.; Abidin I.; Tamin S.S.; Martinez E.R.; Soto Nieto G.I.; van der Meer J.T.M.; Chambers S.; Holland D.; Morris A.; Raymond N.; Read K.; Murdoch D.R.; Dragulescu S.; Ionac A.; Mornos C.; Butkevich O.M.; Chipigina N.; Kirill O.; Vadim K.; Vinogradova T.; Edathodu J.; Halim M.; Liew Y.-Y.; Lejko-Zupanc T.; Logar M.; Mueller-Premru M.; Commerford P.; Commerford A.; Deetlefs E.; Hansa C.; Ntsekhe M.; Almela M.; Azqueta M.; Brunet M.; Castro P.; Falces C.; Fuster D.; Fita G.; Garcia- de- la- Maria C.; Garcia-Gonzalez J.; Gatell J.M.; Marco F.; Miro J.M.; Ortiz J.; Ninot S.; Pare J.C.; Pericas J.M.; Quintana E.; Ramirez J.; Rovira I.; Sandoval E.; Sitges M.; Tellez A.; Tolosana J.M.; Vidal B.; Vila J.; Anguera I.; Font B.; Guma J.R.; Bermejo J.; Bouza E.; Garcia Fernandez M.A.; Gonzalez-Ramallo V.; Marin M.; Munoz P.; Pedromingo M.; Roda J.; Rodriguez-Creixems M.; Solis J.; Fernandez-Hidalgo N.; Tornos P.; de Alarcon A.; Parra R.; Alestig E.; Johansson M.; Olaison L.; Snygg-Martin U.; Pachirat P.; Pussadhamma B.; Senthong V.; Casey A.; Elliott T.; Lambert P.; Watkin R.; Eyton C.; Klein J.L.; Bradley S.; Kauffman C.; Bedimo R.; Corey G.R.; Crowley A.L.; Douglas P.; Drew L.; Holland T.; Lalani T.; Mudrick D.; Samad Z.; Sexton D.; Stryjewski M.; Wang A.; Woods C.W.; Cantey R.; Steed L.; Dickerman S.A.; Bonilla H.; DiPersio J.; Salstrom S.-J.; Baddley J.; Patel M.; Peterson G.; Stancoven A.; Levine D.; Riddle J.; Rybak M.; Cabell C.H.Pericas, J. M.; Llopis, J.; Jimenez-Exposito, M. J.; Kourany, W. M.; Almirante, B.; Carosi, G.; Durante-Mangoni, E.; Fortes, C. Q.; Giannitsioti, E.; Lerakis, S.; Montagna-Mella, R.; Ambrosioni, J.; Tan, R. -S.; Mestres, C. A.; Wray, D.; Pachirat, O.; Moreno, A.; Chu, V. H.; de Lazzari, E.; Fowler, V. G.; Miro, J. M.; Clara, L.; Sanchez, M.; Casabe, J.; Cortes, C.; Nacinovich, F.; Oses, P. F.; Ronderos, R.; Sucari, A.; Thierer, J.; Altclas, J.; Kogan, S.; Spelman, D.; Athan, E.; Harris, O.; Kennedy, K.; Tan, R.; Gordon, D.; Papanicolas, L.; Korman, T.; Kotsanas, D.; Dever, R.; Jones, P.; Konecny, P.; Lawrence, R.; Rees, D.; Ryan, S.; Feneley, M. P.; Harkness, J.; Post, J.; Reinbott, P.; Gattringer, R.; Wiesbauer, F.; Andrade, A. R.; Passos de Brito, A. C.; Guimaraes, A. C.; Grinberg, M.; Mansur, A. J.; Siciliano, R. F.; Varejao Strabelli, T. M.; Campos Vieira, M. L.; de Medeiros Tranchesi, R. A.; Paiva, M. G.; de Oliveira Ramos, A.; Weksler, C.; Ferraiuoli, G.; Golebiovski, W.; Lamas, C.; Karlowsky, J. A.; Keynan, Y.; Morris, A. M.; Rubinstein, E.; Jones, S. B.; Garcia, P.; Cereceda, M.; Fica, A.; Mella, R. M.; Fernandez, R.; Franco, L.; Gonzalez, J.; Jaramillo, A. N.; Barsic, B.; Bukovski, S.; Krajinovic, V.; Pangercic, A.; Rudez, I.; Vincelj, J.; Freiberger, T.; Pol, J.; Zaloudikova, B.; Ashour, Z.; El Kholy, A.; Mishaal, M.; Osama, D.; Rizk, H.; Aissa, N.; Alauzet, C.; Alla, F.; Campagnac, C. C.; Doco-Lecompte, T.; Selton-Suty, C.; Casalta, J. -P.; Fournier, P. -E.; Habib, G.; Raoult, D.; Thuny, F.; Delahaye, F.; Delahaye, A.; Vandenesch, F.; Donal, E.; Donnio, P. Y.; Flecher, E.; Michelet, C.; Revest, M.; Tattevin, P.; Chevalier, F.; Jeu, A.; Remadi, J. P.; Rusinaru, D.; Tribouilloy, C.; Bernard, Y.; Chirouze, C.; Hoen, B.; Leroy, J.; Plesiat, P.; Naber, C.; Neuerburg, C.; Mazaheri, B.; Sophia Athanasia, C. N.; Deliolanis, I.; Giamarellou, H.; Thomas, T.; Mylona, E.; Paniara, O.; Papanicolaou, K.; Pyros, J.; Skoutelis, A.; Papanikolaou, K.; Sharma, G.; Francis, J.; Nair, L.; Thomas, V.; Venugopal, K.; Hannan, M. M.; Hurley, J. P.; Wanounou, M.; Gilon, D.; Israel, S.; Korem, M.; Strahilevitz, J.; Iossa, D.; Orlando, S.; Ursi, M. P.; Pafundi, P. C.; D'Amico, F.; Bernardo, M.; Cuccurullo, S.; Dialetto, G.; Covino, F. E.; Manduca, S.; Della Corte, A.; De Feo, M.; Tripodi, M. F.; Cecchi, E.; De Rosa, F.; Forno, D.; Imazio, M.; Trinchero, R.; Grossi, P.; Lattanzio, M.; Toniolo, A.; Goglio, A.; Raglio, A.; Ravasio, V.; Rizzi, M.; Suter, F.; Magri, S.; Signorini, L.; Kanafani, Z.; Kanj, S. S.; Sharif-Yakan, A.; Abidin, I.; Tamin, S. S.; Martinez, E. R.; Soto Nieto, G. I.; van der Meer, J. T. M.; Chambers, S.; Holland, D.; Morris, A.; Raymond, N.; Read, K.; Murdoch, D. R.; Dragulescu, S.; Ionac, A.; Mornos, C.; Butkevich, O. M.; Chipigina, N.; Kirill, O.; Vadim, K.; Vinogradova, T.; Edathodu, J.; Halim, M.; Liew, Y. -Y.; Lejko-Zupanc, T.; Logar, M.; Mueller-Premru, M.; Commerford, P.; Commerford, A.; Deetlefs, E.; Hansa, C.; Ntsekhe, M.; Almela, M.; Azqueta, M.; Brunet, M.; Castro, P.; Falces, C.; Fuster, D.; Fita, G.; Garcia- de- la- Maria, C.; Garcia-Gonzalez, J.; Gatell, J. M.; Marco, F.; Miro, J. M.; Ortiz, J.; Ninot, S.; Pare, J. C.; Pericas, J. M.; Quintana, E.; Ramirez, J.; Rovira, I.; Sandoval, E.; Sitges, M.; Tellez, A.; Tolosana, J. M.; Vidal, B.; Vila, J.; Anguera, I.; Font, B.; Guma, J. R.; Bermejo, J.; Bouza, E.; Garcia Fernandez, M. A.; Gonzalez-Ramallo, V.; Marin, M.; Munoz, P.; Pedromingo, M.; Roda, J.; Rodriguez-Creixems, M.; Solis, J.; Fernandez-Hidalgo, N.; Tornos, P.; de Alarcon, A.; Parra, R.; Alestig, E.; Johansson, M.; Olaison, L.; Snygg-Martin, U.; Pachirat, P.; Pussadhamma, B.; Senthong, V.; Casey, A.; Elliott, T.; Lambert, P.; Watkin, R.; Eyton, C.; Klein, J. L.; Bradley, S.; Kauffman, C.; Bedimo, R.; Corey, G. R.; Crowley, A. L.; Douglas, P.; Drew, L.; Holland, T.; Lalani, T.; Mudrick, D.; Samad, Z.; Sexton, D.; Stryjewski, M.; Wang, A.; Woods, C. W.; Cantey, R.; Steed, L.; Dickerman, S. A.; Bonilla, H.; Dipersio, J.; Salstrom, S. -J.; Baddley, J.; Patel, M.; Peterson, G.; Stancoven, A.; Levine, D.; Riddle, J.; Rybak, M.; Cabell, C. H

Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the international collaboration of Endocarditis-Prospective Cohort Study

Background. The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis–Prospective Cohort Study. Methods. Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. Results. EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non–S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39–1.15]; P = .15). Conclusions. In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE

Impact of early valve surgery on outcome of staphylococcus aureus prosthetic valve infective endocarditis: Analysis in the international collaboration of endocarditis-prospective cohort study

Background. The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. Methods. Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. Results. EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). Conclusions. In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE