Kevin Morine

Pulmonary Artery Pulsatility Index Is Associated With Right Ventricular Failure After Left Ventricular Assist Device Surgery

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.

Mechanical Pre-Conditioning With Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction

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-3β. 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-3β 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.

Endoglin: a critical mediator of cardiovascular health

Endoglin (CD105) is a type III auxiliary receptor for the transforming growth factor beta (TGFβ) superfamily. Several lines of evidence suggest that endoglin plays a critical role in maintaining cardiovascular homeostasis. Seemingly disparate disease conditions, including hereditary hemorrhagic telangiectasia, pre-eclampsia, and cardiac fibrosis, have now been associated with endoglin. Given the central role of the TGFβ superfamily in multiple disease conditions, this review provides a detailed update on endoglin as an evolving therapeutic target in the management of cardiovascular disease.

Percutaneous Mechanical Circulatory Support for Cardiogenic Shock

Opinion statementThe use of percutaneous, non-durable mechanical circulatory support (MCS) for cardiogenic shock (CS) is growing; however, large, randomized clinical trials confirming benefit in this population do not exist. Guidelines and recommendations regarding optimal timing for MCS implementation, patient selection, device selection, and post-implantation management are beginning to emerge. A better understanding of (1) the distinct hemodynamic effects of each device option, (2) the need for early implementation of the appropriate device option for a particular clinical scenario, (3) the definition of non-salvageable CS to help clinicians know when to say “no” to non-durable MCS, and (4) best practices to monitor, wean, and optimize metabolic parameters while using non-durable MCS are required to continue improving clinical outcomes for patients with CS.

Mechanical Circulatory Support Devices for Acute Right Ventricular Failure

Right ventricular (RV) failure remains a major cause of global morbidity and mortality for patients with advanced heart failure, pulmonary hypertension, or acute myocardial infarction and after major cardiac surgery. Over the past 2 decades, percutaneously delivered acute mechanical circulatory support pumps specifically designed to support RV failure have been introduced into clinical practice. RV acute mechanical circulatory support now represents an important step in the management of RV failure and provides an opportunity to rapidly stabilize patients with cardiogenic shock involving the RV. As experience with RV devices grows, their role as mechanical therapies for RV failure will depend less on the technical ability to place the device and more on improved algorithms for identifying RV failure, patient monitoring, and weaning protocols for both isolated RV failure and biventricular failure. In this review, we discuss the pathophysiology of acute RV failure and both the mechanism of action and clinical data exploring the utility of existing RV acute mechanical circulatory support devices.

Reducing Endoglin Activity Limits Calcineurin and TRPC-6 Expression and Improves Survival in a Mouse Model of Right Ventricular Pressure Overload

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‐β1). TGF‐β1 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‐β1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. Methods and Results We first demonstrate that endoglin is required for TGF‐β1‐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‐β1 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.

Incidence, Management, and Outcome of Suspected Continuous-Flow Left Ventricular Assist Device Thrombosis.

Left ventricular assist device (LVAD) thrombosis is associated with high morbidity and mortality because of device malfunction, embolic events, and hemolysis. There remains uncertainty as to whether immediate device exchange versus an initial trial of anticoagulant and antiplatelet therapy is most appropriate in hemodynamically stable patients. We conducted a retrospective analysis of all LVAD implantations at a single center between January 2009 and June 2013 with follow-up through December 2013. Suspected LVAD thrombosis occurred in 20% of patients (N = 25) over a median follow-up of 275 days. Medical therapy led to resolution of hemolysis, and discharge to home, in 15 of 25 (60%) cases; however, this strategy was associated with intracranial hemorrhage in 4 patients and readmission with recurrent thrombosis in 10 patients. The 30 day, 6 month, and 1 year freedom from suspected LVAD thrombosis was 96.5, 85.9, and 80.3% in HeartMate II devices and 100, 92.9, and 87.1% in HeartWare ventricular assist devices, respectively (p = 0.11). Although medical treatment with intravenous heparin, antiplatelet agents, antithrombotic agents, or thrombolytic therapy can lead to initial resolution of hemolysis, the risks of recurrence after transition to warfarin and adverse events are high.

Circulating multimarker profile of patients with symptomatic heart failure supports enhanced fibrotic degradation and decreased angiogenesis

Abstract 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.

Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure

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 (TGFβ1) in right (RV) or left ventricular (LV) failure. Endoglin (Eng) is a transmembrane glycoprotein that promotes TRPC6 expression and TGFβ1 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 TGFβ1 coreceptor Eng selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.

Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure

INTRODUCTION Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), 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 β-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.