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Background: We describe the association between longitudinal hemodynamic changes and clinical outcomes in patients with cardiogenic shock (CS) receiving acute mechanical circulatory support devices (AMCS) at a single center. We hypothesized that improved right atrial pressure is associated with better survival in CS. Methods: Retrospective analysis of patients from Tufts Medical Center that received AMCS for CS. Baseline characteristics and invasive hemodynamics were collected, analyzed, and correlated against outcomes. Hemodynamics were recorded at different time intervals during index admission [pre-AMCS, 24 h after AMCS (post AMCS), and last available set of hemodynamics (final-AMCS)]. Logistic regression was performed to determine variables associated with in-hospital mortality. Results: A total of 76 patients had longitudinal hemodynamics available. In hospital mortality occurred in 46% of the cohort. Mean baseline right atrial pressure (RAP) was significantly higher among non-survivors vs. survivors (19.5+6.6 vs. 16.4+5.3 mmHg). Change in right atrial pressure from baseline to before device removal (ΔRA:final AMCS-pre AMCS) was significantly different between survivors and non survivors (-6.5 ± 6.9 mmHg vs. -2.5 ± 6.2 mmHg p = 0.03). Unadjusted logistic regression revealed baseline RAP (OR: 1.1 95% CI: 1.0-1.2), 24 h post device implant RAP (OR: 1.3 95% CI: 1.1-1.4), and final RAP (OR: 1.3 95% CI: 1.1-1.5) to be significant predictors of in-hospital mortality. In a multivariate logistic regression baseline RAP was no longer significantly associated with mortality in the overall cohort, while 24 h (OR: 1.26 95% CI: 1.1-1.5) and final RAP (OR: 1.3 95% CI: 1.1-1.6) remained statistically significant. Conclusion: We report a novel retrospective analysis of hemodynamic changes in patients with CS receiving AMCS. Our findings identify the potential importance of venous congestion as a prognostic marker of mortality. Furthermore, early decongestion or reduced RA pressure is associated with better survival in these critically ill CS patients. These observations suggest the need for further study in larger retrospective and prospective cohorts of patients with varying degrees of CS severity.

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BACKGROUND: Heart failure after an acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a transvalvular axial-flow pump in the left ventricle and delaying myocardial reperfusion, known as primary unloading, limits infarct size after AMI. The mechanisms underlying the cardioprotective benefit of primary unloading and whether the acute decrease in infarct size results in a durable reduction in LV scar and improves cardiac function remain unknown. OBJECTIVES: This study tested the importance of LV unloading before reperfusion, explored cardioprotective mechanisms, and determined the late-term impact of primary unloading on myocardial function. METHODS: Adult male swine were subjected to primary reperfusion or primary unloading after 90 min of percutaneous left anterior descending artery occlusion. RESULTS: Compared with primary reperfusion, 30 min of LV unloading was necessary and sufficient before reperfusion to limit infarct size 28 days after AMI. Compared with primary reperfusion, primary unloading increased expression of genes associated with cellular respiration and mitochondrial integrity within the infarct zone. Primary unloading for 30 min further reduced activity levels of proteases known to degrade the cardioprotective cytokine, stromal-derived factor (SDF)-1α, thereby increasing SDF-1α signaling via reperfusion injury salvage kinases, which limits apoptosis within the infarct zone. Inhibiting SDF-1α activity attenuated the cardioprotective effect of primary unloading. Twenty-eight days after AMI, primary unloading reduced LV scar size, improved cardiac function, and limited expression of biomarkers associated with heart failure and maladaptive remodeling. CONCLUSIONS: The authors report for the first time that first mechanically reducing LV work before coronary reperfusion with a transvalvular pump is necessary and sufficient to reduce infarct size and to activate a cardioprotective program that includes enhanced SDF-1α activity. Primary unloading further improved LV scar size and cardiac function 28 days after AMI.

Asunto(s)

Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Reperfusión Miocárdica/métodos , Recuperación de la Función/fisiología , Función Ventricular Izquierda/fisiología , Animales , Masculino , Reperfusión Miocárdica/tendencias , Porcinos

RESUMEN

BACKGROUND: Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-ß1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-ß1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFß family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFß coreceptor that promotes TGF-ß1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. METHODS: We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction-induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. RESULTS: BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9-/- mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction-induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. CONCLUSIONS: Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.

Asunto(s)

Factor 2 de Diferenciación de Crecimiento/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Modelos Animales de Enfermedad , Endoglina/deficiencia , Endoglina/genética , Endoglina/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Factor 2 de Diferenciación de Crecimiento/deficiencia , Factor 2 de Diferenciación de Crecimiento/genética , Factores de Diferenciación de Crecimiento/genética , Haploinsuficiencia , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/patología , Fosforilación , Recuperación de la Función , Transducción de Señal , Proteína Smad1/metabolismo , Proteína smad3/metabolismo

RESUMEN

INTRODUCTION: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFß1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1+/-) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1+/- mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and ß-myosin heavy chain were increased similarly in Alk1+/- and WT mice after TAC. Alk-1 mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 collagen mRNA and protein levels were higher in Alk1+/- mice. LV fractional shortening was lower in Alk1+/- mice after TAC. CONCLUSIONS: Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Asunto(s)

Receptores de Activinas Tipo II/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocardio/patología , Remodelación Ventricular/fisiología , Receptores de Activinas Tipo I/metabolismo , Adulto , Animales , Femenino , Fibrosis/metabolismo , Insuficiencia Cardíaca/patología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Miocardio/metabolismo

RESUMEN

Community hospitals with limited resources struggle to engage physicians in Quality improvement initiatives. We introduced Quality Improvement (QI) curriculum for residents in response to ACGME requirements and surveyed the residents understanding of QI and their involvement in QI projects before and after the introduction of the curriculum. The current article describes our experiences with the process, the challenges and possible solutions to have a successful resident led QI initiative in a community hospital. Methods: A formal QI curriculum was introduced in the Department of Internal Medicine from September to October 2015 using the Model for Improvement from Institute for Health care Improvement (IHI). Learners were expected to read the online modules, discuss in small group sessions and later encouraged to draft their QI projects using the Charter form and PDSA form available on the HI website. Online surveys were conducted a week prior and 3 months after completion of the curriculum Results: 80% (100/117) of residents completed the pre-curriculum survey and 52% (61/117) completed the survey post curriculum. 96.7% of residents report that physicians should lead QI projects and training rather than the hospital administrators. Residents had 20% increase in understanding and confidence in leading quality improvement projects post curriculum once initiated. Most Residents (72%) feel QI should be taught during residency. Active involvement of residents with interest was seen after the initiation of Open School Institute of health improvement (IHI) curriculum as compared to Institutional led QI's. The resident interventions, pitfalls with change processes with an example of PDSA cycle are discussed. Conclusion: A Dedicated QI curriculum is necessary to prepare the physicians deliver quality care in an increasing complex health care delivery system. The strength of the curriculum is the ease of understanding the material, easily available to all, and can be easily replicated in a Community Hospital program with limited resources. Participation in QI by residents may promote constructive competitiveness among related hospitals in public system to improve delivery of safe care. Abbreviations: ACGME: Accreditation Council for Graduate Medical Education; IHI: Institute of Healthcare Improvement; PDSA: Plan-Do-Study-Act; PGY: QI: Quality improvement.

RESUMEN

BACKGROUND: The utility of intra-aortic balloon counterpulsation pumps (IABPs) in low cardiac output states is unknown and no studies have explored the impact of IABP therapy on ventricular workload in patients with advanced heart failure (HF). For these reasons, we explored the acute hemodynamic effects of IABP therapy in patients with advanced HF. METHODS: We prospectively studied 10 consecutive patients with stage D HF referred for IABP placement before left ventricular assist device (LVAD) surgery and compared with 5 control patients with preserved left ventricular (LV) ejection fraction (EF) who did not receive IABP therapy. Hemodynamics were recorded using LV conductance and pulmonary artery catheters. Cardiac index (CI)-responder and CI-nonresponder status was assigned a priori as being "equal to or above" or below the median of the IABP effect on CI, respectively, within 24 hours after IABP activation. RESULTS: Compared with controls, patients with advanced HF had lower LVEF, lower LV end-systolic pressure, lower LV stroke work, and higher LV end-diastolic pressures and volumes before IABP activation. IABP activation reduced LV stroke work primarily by reducing end-systolic pressure. IABP therapy increased CI by a median of 20% as well as increased diastolic pressure time index and the myocardial oxygen supply:demand ratio. Compared with CI-nonresponders, CI-responders had higher systemic vascular resistance, lower right heart filling pressures, and a trend toward lower left heart filling pressures with improved indices of right heart function. Compared with CI-nonresponders, the diastolic pressure time index was increased among CI-responders. CONCLUSIONS: IABP therapy may be effective at reducing LV stroke work, increasing CI, and favorably altering the myocardial oxygen supply:demand ratio in patients with advanced HF, especially among patients with low right heart filling pressures and high systemic vascular resistance.

Asunto(s)

Contrapulsación/tendencias , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/terapia , Hemodinámica/fisiología , Contrapulsador Intraaórtico/tendencias , Adulto , Anciano , Contrapulsación/métodos , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Contrapulsador Intraaórtico/métodos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento

RESUMEN

Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFß) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n = 5) and vehicle treated AlK-1-cKO mice (cKO-CON; n = 5) served as controls for tamoxifen treated AlK-1-cKO mice (cKO-TAM; n = 15). AlK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13 vs 100%, respectively, p < 0.01). Seven days after treatment, cKO-TAM mice exhibited reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV AlK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFß-family ligands and receptors (AlK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFß1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of ß-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Global deletion of AlK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of AlK-1 in cardiac remodeling independent of systemic AVMs are required.

Asunto(s)

Receptores de Activinas Tipo I/genética , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , ARN/genética , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/fisiología , Receptores de Activinas Tipo I/biosíntesis , Receptores de Activinas Tipo II , Alelos , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal

RESUMEN

INTRODUCTION: Transient receptor potential (TRP) channels are broadly expressed cation channels that mediate diverse physiological stimuli and include canonical (TRPC), melastatin (TRPM), and vanilloid (TRPV) subtypes. Recent studies have implicated a role for TRPC6 channels as an important component of signaling via the cytokine, transforming growth factor beta 1 (TGFß1) in right (RV) or left ventricular (LV) failure. Endoglin (Eng) is a transmembrane glycoprotein that promotes TRPC6 expression and TGFß1 activity. No studies have defined biventricular expression of all TRP channel family members in heart failure. HYPOTHESIS: We hypothesized that heart failure is associated with distinct patterns of TRP channel expression in the LV and RV. METHODS: Paired viable LV and RV free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for cardiac transplantation or biventricular assist device implantation. Paired LV and RV samples from human subjects without heart failure served as controls (n=3). To explore a functional role for Eng as a regulator of TRP expression in response to RV or LV pressure overload, wild-type (Eng+/+) and Eng haploinsufficient (Eng+/-) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 8weeks. Biventricular tissue was analyzed by real-time polymerase chain reaction. RESULTS: Compared to nonfailing human LV and RV samples, mRNA levels of TRPC1, 3, 4, 6, and TRPV-2 were increased and TRPM2, 3, and 8 were decreased in failing LV and RV samples. TRPC1 and 6 levels were higher in failing RV compared to failing LV samples. After TAC, murine LV levels of TPRC1 and 6 were increased in both Eng+/+ and Eng+/- mice compared to sham controls. LV levels of TRPC4, TRPM3 and 7, TRPV2 and 4 were increased in Eng+/+, not in Eng+/- mice after TAC. After PAC, all TRP channel family members were increased in the RV, but not LV, of Eng+/+ compared to sham controls. In contrast to Eng+/+, PAC did not increase RV or LV levels of TRP channels in Eng+/- mice. CONCLUSIONS: This is the first study to demonstrate that TRP channels exhibit distinct profiles of expression in the LV and RV of patients with heart failure and in murine models of univentricular pressure overload. We further introduce that the TGFß1 coreceptor Eng selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.

Asunto(s)

Endoglina/metabolismo , Insuficiencia Cardíaca/metabolismo , Canales de Potencial de Receptor Transitorio/biosíntesis , Adulto , Anciano , Animales , Femenino , Regulación de la Expresión Génica , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma , Adulto Joven

RESUMEN

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and the TandemHeart left ventricular (LV) assist device are increasingly employed as mechanical circulatory support devices during acute LV injury. We examined the effects of right atrial to femoral artery (RA-FA; VA-ECMO) bypass versus left atrial to femoral artery (LA-FA; TandemHeart) bypass using a centrifugal pump (Cardiac Assist Inc, Pittsburgh, PA) on LV hemodynamics in a swine model of acute LV injury. In eight male swine, the RA-FA bypass group employed a 21 Fr inflow cannula in the right atrial (RA) and a 17 Fr FA outflow cannula. The LA-FA bypass group employed a 21 Fr inflow cannula in the LA and a 17 Fr FA outflow cannula. Both pump configurations were activated at 3,500 rotations per minute (RPMs) followed by balloon angioplasty-mediated occlusion of the left circumflex (LCx) artery. After 30 minutes of LCx occlusion, RPMs through the centrifugal pump were increased from 3,500, 5,500 then to a maximum at 7,500 RPMs. At 7,500 RPMs, RA-FA and LA-FA bypass generated 3.5 ± 0.1 and 3.6 ± 0.2 liters/minute (LPM) of flow, respectively. At maximum flow, RA unloading increased LV end-systolic pressure and estimated wall stress, whereas LA unloading reduced LV end-diastolic pressure, end-diastolic volume, and native stroke volume without changing estimated wall stress. Veno-arterial extracorporeal membrane oxygenation acutely increases mean arterial pressure (MAP) without unloading the LV, whereas the TandemHeart maintains MAP and unloads the LV. These findings indicate that RA versus LA cannulation for circulatory support have distinct acute hemodynamic effects on the LV.

Asunto(s)

Cateterismo Cardíaco , Oxigenación por Membrana Extracorpórea , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Función Ventricular Izquierda/fisiología , Animales , Modelos Animales de Enfermedad , Atrios Cardíacos , Masculino , Porcinos

RESUMEN

BACKGROUND: Right ventricular failure (RVF) is a major cause of morbidity and mortality after CF-LVAD implantation. We explored the association of pulmonary artery compliance (PAC), pulmonary artery elastance (PAE), and pulmonary artery pulsatility index (PAPi) in addition to established parameters as preoperative determinants of postoperative RVF after CF-LVAD surgery. METHODS AND RESULTS: We retrospectively reviewed 132 consecutive CF-LVAD implantations at Tufts Medical Center from 2008 to 2013. Clinical, hemodynamic, and echocardiographic data were studied. RVF was defined as the unplanned need for a right ventricular assist device or inotrope dependence for ≥14 days. Univariate analysis was performed. RVF occurred in 32 of 132 patients (24%). PAC and PAE were not changed, whereas the PAPi was lower among patients with versus without postoperative RVF (1.32 ± 0.46 vs 2.77 ± 1.16; P < .001). RA pressure, RA to pulmonary capillary wedge pressure ratio (RA:PCWP), and RV stroke work index (RVSWI) were also associated with RVF. Using receiver operating characteristic curve-derived cut-points, PAPi < 1.85 provided 94% sensitivity and 81% specificity (C-statistic = 0.942) for identifying RVF and exceeded the predictive value of RA:PCWP, RVSWI, or RA pressure alone. CONCLUSIONS: PAPi is a simple hemodynamic variable that may help to identify patients at high risk of developing RVF after LVAD implantation.

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Insuficiencia Cardíaca/etiología , Ventrículos Cardíacos/cirugía , Corazón Auxiliar/efectos adversos , Arteria Pulmonar/fisiopatología , Presión Esfenoidal Pulmonar , Disfunción Ventricular Derecha/etiología , Adulto , Anciano , Ecocardiografía , Femenino , Insuficiencia Cardíaca/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Disfunción Ventricular Derecha/prevención & control

RESUMEN

BACKGROUND: Heart failure (HF) involves myocardial fibrosis and dysregulated angiogenesis. OBJECTIVE: We explored whether biomarkers of fibrosis and angiogenesis correlate with HF severity. METHODS: Biomarkers of fibrosis [procollagen types I and III (PIP and P3NP), carboxyterminal-telopeptide of type I collagen (ICTP), matrix metalloproteases (MMP2 and MMP9), tissue inhibitor of MMP1 (TIMP1)]; and angiogenesis [placental growth factor (PGF), vascular endothelial growth factor (VEGF), soluble Fms-like tyrosine kinase-1 (sFlt1)] were measured in 52 HF patients and 19 controls. RESULTS: P3NP, ICTP, MMP2, TIMP1, PGF, and sFlt1 levels were elevated in HF, while PIP/ICTP, PGF/sFlt1, and VEGF/sFlt1 ratios were reduced. PIP/ICTP, MMP-9/TIMP1, and VEGF/sFlt1 ratios were lowest among patients with severe HF. CONCLUSIONS: Severe HF is associated with collagen breakdown and reduced angiogenesis. A multimarker approach may guide therapeutic targeting of fibrosis and angiogenesis in HF.

Asunto(s)

Insuficiencia Cardíaca/sangre , Miocardio/patología , Anciano , Proteínas Angiogénicas/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Fisiológica , Estudios Prospectivos

RESUMEN

OBJECTIVES: This study tested the hypothesis that first reducing myocardial work by unloading the left ventricle (LV) with a novel intracorporeal axial flow catheter while delaying coronary reperfusion activates a myocardial protection program and reduces infarct size. BACKGROUND: Ischemic heart disease is a major cause of morbidity and mortality worldwide. Primary myocardial reperfusion remains the gold standard for the treatment of an acute myocardial infarction (AMI); however, ischemia-reperfusion injury contributes to residual myocardial damage and subsequent heart failure. Stromal cell-derived factor (SDF)-1α is a chemokine that activates cardioprotective signaling via Akt, extracellular regulated kinase, and glycogen synthase kinase-3ß. METHODS: AMI was induced by occlusion of the left anterior descending artery (LAD) via angioplasty for 90 min in 50-kg male Yorkshire swine (n = 5/group). In the primary reperfusion (1° Reperfusion) group, the LAD was reperfused for 120 min. In the primary unloading (1° Unloading) group, after 90 min of ischemia the axial flow pump was activated and the LAD left occluded for an additional 60 min, followed by 120 min of reperfusion. Myocardial infarct size and kinase activity were quantified. RESULTS: Compared with 1° Reperfusion, 1° Unloading reduced LV wall stress and increased myocardial levels of SDF-1α, CXCR4, and phosphorylated Akt, extracellular regulated kinase, and glycogen synthase kinase-3ß in the infarct zone. 1° Unloading increased antiapoptotic signaling and reduced myocardial infarct size by 43% compared with 1° Reperfusion (73 ± 13% vs. 42 ± 8%; p = 0.005). Myocardial levels of SDF-1 correlated inversely with infarct size (R = 0.89; p < 0.01). CONCLUSIONS: Compared with the contemporary strategy of primary reperfusion, mechanically conditioning the myocardium using a novel axial flow catheter while delaying coronary reperfusion decreases LV wall stress and activates a myocardial protection program that up-regulates SDF-1α/CXCR4 expression, increases cardioprotective signaling, reduces apoptosis, and limits myocardial damage in AMI.

Asunto(s)

Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Daño por Reperfusión Miocárdica/prevención & control , Reperfusión Miocárdica , Animales , Biomarcadores/metabolismo , Quimiocina CXCL12/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3/metabolismo , Hemodinámica , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/mortalidad , Reperfusión Miocárdica/instrumentación , Reperfusión Miocárdica/métodos , Reperfusión Miocárdica/mortalidad , Fosfotransferasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Estrés Mecánico , Sus scrofa

RESUMEN

OBJECTIVE: Several recent trials have examined the clinical utility of intraaortic balloon counterpulsation pumps (IABPs) in cardiogenic shock and acute coronary syndromes. More recently, a larger-capacity 50 cc IABP was introduced into practice. No data comparing the hemodynamic effects of the 40 cc vs 50 cc IABP exist. Our aim was to explore the hemodynamic effects of the 50 cc IABP in real-world clinical practice. METHODS: Demographic, hemodynamic, and laboratory data were retrospectively examined in 26 consecutive subjects treated with a 50 cc IABP and compared with 26 patients receiving a 40 cc IABP between 2012 and 2013. IABP tracings were analyzed within 24 hours of implantation in all patients. Pulmonary artery catheter data were available before and after IABP implantation in 20 subjects. RESULTS: Baseline demographics, including body surface area, were similar between groups. Compared with the 40 cc IABP group, 50 cc IABP recipients showed higher augmented diastolic blood pressure, greater systolic unloading, and a larger reduction in pulmonary capillary occlusion pressure (PCOP). Percent diastolic augmentation was higher among 50 cc IABP recipients. Only 58% of subjects achieved <10 mm Hg of systolic unloading in the 40 cc group compared with 27% in the 50 cc group. For both the 40 cc and 50 cc IABPs, the magnitude of systolic unloading correlated inversely with PCOP and directly with the magnitude of diastolic augmentation. CONCLUSION: In real-world practice, greater systolic unloading and diastolic augmentation were observed among 50 cc vs 40 cc IABP recipients. Future trials evaluating the clinical utility of the 50 cc IABP are required.

Asunto(s)

Síndrome Coronario Agudo/terapia , Hemodinámica , Contrapulsador Intraaórtico/instrumentación , Choque Cardiogénico/terapia , Humanos , Estudios Retrospectivos

RESUMEN

Our objective was to examine the hemodynamic effects of a trans-aortic axial flow catheter (Impella CP) in the left ventricle (LV) versus left atrial (LA) to femoral artery bypass using a centrifugal pump (TandemHeart: TH) in a bovine model of acute LV injury. In three male calves, we performed sequential activation of a CP then TH device in each animal. After 60 minutes of left anterior descending artery ligation, a CP was activated at maximal power. The CP was then removed and the TH activated at 5,500 then a maximum of 7,500 rotations per minute (RPM). The CP generated a maximum 3.1 ± 0.2 L/minute (LPM) of flow, whereas the TH at 5,500 and 7,500 RPM generated 3.1 ± 0.4 and 4.4 ± 0.3 LPM. At 3.1 LPM, the CP and TH reduced LV stroke work (LVSW) similarly. The TH reduced stroke volume, whereas the CP did not. The CP reduced end-systolic pressure, whereas the TH did not. At a maximum flow of 4.4 LPM, the TH provided a greater reduction in LVSW than maximal CP activation. This is the first report to compare the hemodynamic effects of trans-aortic LV unloading versus LA-to-femoral artery (FA) bypass.

Asunto(s)

Ventrículos Cardíacos/fisiopatología , Corazón Auxiliar , Hemodinámica/fisiología , Infarto del Miocardio/fisiopatología , Función Ventricular Izquierda/fisiología , Animales , Bovinos , Modelos Animales de Enfermedad , Masculino

RESUMEN

BACKGROUND: Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-ß1). TGF-ß1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-ß1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. METHODS AND RESULTS: We first demonstrate that endoglin is required for TGF-ß1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (α-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/α-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control. CONCLUSION: These data establish endoglin as a regulator of TGF-ß1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease.

Asunto(s)

Calcineurina/genética , Hipertensión Pulmonar/genética , Péptidos y Proteínas de Señalización Intracelular/genética , ARN Mensajero/metabolismo , Canales Catiónicos TRPC/genética , Disfunción Ventricular Derecha/genética , Actinas/genética , Actinas/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Calcineurina/metabolismo , Modelos Animales de Enfermedad , Endoglina , Fibroblastos/metabolismo , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/metabolismo , Humanos , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Noqueados , Miofibroblastos/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Tasa de Supervivencia , Canales Catiónicos TRPC/metabolismo , Canal Catiónico TRPC6 , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología

Asunto(s)

Endocardio/patología , Ventrículos Cardíacos/cirugía , Corazón Auxiliar , Infarto del Miocardio/complicaciones , Volumen Sistólico , Disfunción Ventricular Izquierda/cirugía , Remoción de Dispositivos , Diseño de Equipo , Fibrosis , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología

RESUMEN

UNLABELLED: The aim of this study was to assess myocardial blush (MB) using a novel software algorithm that quantifies time-density curves (TDC) after percutaneous coronary intervention (PCI). METHODS: Thirty-two patients referred for elective PCI were enrolled. TDC curves were generated and mean maximal myocardial contrast density (Dmax) was calculated from 5 regions of interest in the PCI territory. Dmax was normalized to contrast injected in the proximal coronary artery (DI). RESULTS: Mean DI significantly increased after PCI in all subjects. Dmax correlated directly with subjective grading of Thrombolysis in Myocardial Infarction (TIMI) myocardial blush (R=0.47; P<.01). In 7 subjects referred for PCI of a chronic total occlusion (CTO), mean DI remained increased after PCI. Mean DI was lower in CTO versus non-CTO subjects; however, fold-improvement was higher after PCI of CTO lesions. CONCLUSION: Quantifying MB using TDC analysis is feasible and correlates with subjective MB grading. The clinical utility of MB quantitation after PCI requires further study.

Asunto(s)

Algoritmos , Estenosis Coronaria/terapia , Vasos Coronarios/fisiopatología , Imagen de Perfusión Miocárdica/métodos , Intervención Coronaria Percutánea/métodos , Flujo Sanguíneo Regional/fisiología , Anciano , Estudios de Casos y Controles , Angiografía Coronaria , Circulación Coronaria/fisiología , Estenosis Coronaria/diagnóstico , Estenosis Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Programas Informáticos , Resultado del Tratamiento

RESUMEN

UNLABELLED: Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFß1). METHODS: Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis. RESULTS: Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtmax) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFß1 expression was increased in both groups. CONCLUSION: These data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways.

Asunto(s)

Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatología , Presión Ventricular , Remodelación Ventricular , Animales , Calcineurina/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Sistema de Conducción Cardíaco , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Hemodinámica , Masculino , Ratones , Tamaño de los Órganos , Factor de Crecimiento Transformador beta1/metabolismo , Disfunción Ventricular Derecha/metabolismo

RESUMEN

BACKGROUND: Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI. METHODS AND RESULTS: MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial-to-femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm(2); stroke work, 2823 versus 655 mm Hg·mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload). CONCLUSIONS: These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.

Asunto(s)

Corazón Auxiliar , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Reperfusión Miocárdica , Función Ventricular Izquierda/fisiología , Animales , Modelos Animales de Enfermedad , Ecocardiografía Tridimensional , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hemodinámica/fisiología , Masculino , Infarto del Miocardio/diagnóstico por imagen , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/terapia , Estrés Mecánico , Sus scrofa

RESUMEN

OBJECTIVES: The aim of this study was to explore the clinical utility of a commercially available centrifugal flow pump as a centrifugal flow-right ventricular support device (CF-RVSD) in patients with right ventricular failure (RVF). BACKGROUND: RVF is associated with high in-hospital mortality. Limited data regarding efficacy of the CF-RVSD for RVF exist. METHODS: We retrospectively reviewed data from 46 patients receiving a CF-RVSD for RVF from a registry comprising data from 8 tertiary-care hospitals in the United States. CF-RVSD use was recorded in the setting of acute myocardial infarction; myocarditis; chronic left heart failure; after valve surgery, orthotopic heart transplantation, left ventricular assist device surgery, coronary bypass grafting. Devices were implanted via the percutaneous (n = 22) or surgical (n = 24) route. RESULTS: No intraprocedural mortality was observed. Mean time from admission to CF-RVSD implantation was 5.7 ± 8.5 days, with a mean of 6,769 ± 789 rotations/min, providing 4.2 ± 1.3 l/min of flow. Mean duration of support was 5.4 ± 5.1 days. Mean arterial pressure (65 ± 12 mm Hg vs. 73 ± 14 mm Hg; p < 0.05), right atrial pressure (21 ± 8 mm Hg vs. 16 ± 7 mm Hg; p = 0.05), pulmonary artery systolic pressure (43 ± 15 mm Hg vs. 33 ± 15 mm Hg; p = 0.01), and cardiac index (1.7 ± 0.7 vs. 2.2 ± 0.6; p = 0.01) were improved within 48 h of CF-RVSD implantation. Total in-hospital mortality was 57% and was lowest in the setting of left ventricular assist device implantation, chronic left heart failure, and acute myocardial infarction. Increased age, biventricular failure, and Thrombolysis In Myocardial Infarction-defined major bleeding were associated with increased in-hospital mortality. CONCLUSIONS: Use of the CF-RVSD for RVF is clinically feasible and associated with improved hemodynamic status. Observations from the registry of patients who have received this device may support the development of prospective studies that will examine the role of percutaneous circulatory support for RVF.

Asunto(s)

Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos