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The outcomes of patients with acute myocardial infarctions (AMI) have significantly improved with advances in early reperfusion strategies; however, patients with massive infarcts or those who do not receive timely revascularization may develop mechanical complications of AMI. The most common mechanical complications are ventricular septal rupture (VSR), acute mitral regurgitation (MR) due to papillary muscle rupture, and free-wall rupture. Each complication is associated with a high risk of morbidity and mortality, and requires a multidisciplinary approach for prompt diagnosis and hemodynamic stabilization. Surgery is the mainstay of therapy but is associated with poor outcomes if performed too early during the treatment course for VSR or if performed too late with MR and free wall rupture. Optimal timing for surgery in combination with temporary circulatory support may be a feasible strategy for better results.

Introduction Advanced age is a known risk factor for poor outcomes after veno-arterial extracorporeal membrane oxygenation (V-A ECMO) for cardiac support. The use of ECMO support in patients over the age of 80 is controversial, and sometimes its use is contraindicated. We aimed to assess the use of ECMO in octogenarian patients to determine survival and complication rates. Methods A single-center, retrospective analysis was completed at a large, urban academic medical center. Patients requiring V-A ECMO support between December of 2012 and November of 2019 were included as long as the patient was at least 80 years of age at the time of cannulation. Post cardiotomy shock patients were excluded. Results A total of 46 patients met eligibility criteria; all received V-A ECMO support. Overall, the majority of patients (71.7%; 33/46) survived to decannulation, and 43.5% (20/46) survived to discharge. Patients who were previously rescued from percutaneous interventions tend to have a better survival than other patients ( p = .06). The most common complications were renal and hemorrhagic. Conclusions We demonstrated that advanced age alone should not disqualify patients from cannulating and supporting with V-A ECMO.

The Impella CP (Abiomed Inc., Danvers, MA) is widely used in cardiac catheterization laboratories for patients presenting with cardiogenic shock, but it is also known to cause significant hemolysis. The risk of hemolysis can be reduced by properly positioning the device, ensuring an adequate volume status, and using full anticoagulation strategies; however, in some cases hemolysis persists. We present a case series of eight patients that were diagnosed with cardiogenic shock, underwent Impella CP placement, and then suffered from refractory hemolysis which was treated by upgrading the Impella device to the 5.0 or 5.5 version. Fifty percent (4/8) of the patients in this series were already receiving continuous renal replacement therapy, and the levels of plasma free hemoglobin (pFHb) and lactate dehydrogenase continued to increase after the implantation of the Impella CP. The median time between Impella CP placement and the diagnosis of refractory hemolysis was 16.5 hours (interquartile range [IQR], 8.0-26.0). The median time between the diagnosis of hemolysis to Impella upgrade was 6.0 hours (IQR, 4.0-7.0). A total of 87.5% (7/8) of patients experienced a drop in pFHb to below 40 mg/dl at 72 hours post-Impella upgrade, and they were discharged without any further need of dialysis. One patient expired due to irreversible multiple organ failure. We propose that early identification of hemolysis by close monitoring of pFHb and upgrading to the Impella 5.5 reduces hemolysis, prevents further kidney damage, and significantly improves clinical outcomes.

Bleeding associated with left ventricular assist device (LVAD) implantation has been attributed to the loss of large von Willebrand factor (VWF) multimers to excessive cleavage by ADAMTS-13, but this mechanism is not fully supported by the current evidence. We analyzed VWF reactivity in longitudinal samples from LVAD patients and studied normal VWF and platelets exposed to high shear stress to show that VWF became hyperadhesive in LVAD patients to induce platelet microvesiculation. Platelet microvesicles activated endothelial cells, induced vascular permeability, and promoted angiogenesis in a VWF-dependent manner. Our findings suggest that LVAD-driven high shear stress primarily activates VWF, rather than inducing cleavage in the majority of patients.

Background: Respiratory failure (RF) is a common cause of death and morbid complication in trauma patients. Extracorporeal membrane oxygenation (ECMO) is increasingly used in adults with RF refractory to invasive mechanical ventilation. However, use of ECMO remains limited for this patient population as they often have contraindications for anticoagulation. Study design: Medical records were retroactively searched for all adult patients who were admitted to the trauma service and received veno-venous ECMO (VV ECMO) support between June 2015 and August 2018. Survival to discharge and ECMO-related complications were collected and analyzed. Results: Fifteen patients from a large Level I trauma center met the criteria. The median PaO2/FiO2 ratio was 53.0 (IQR, 27.0–76.0), median injury severity score was 34.0 (IQR, 27.0–43.0), and the median duration of ECMO support was 11 days (IQR, 7.5–20.0). For this cohort, the survival-to-discharge rate was 87% (13/15). The incidence of neurologic complications was 13%, and deep vein thrombosis was reported in two cases (13%). Conclusions: Survival rates of trauma patients in this study are equivalent to, or may exceed, those of non-trauma patients who receive ECMO support for other types of RF. With the employment of a multidisciplinary team assessment and proper patient selection, early cannulation, traumatic RF may be safely supported with VV ECMO in experienced centers.

Patients supported by left ventricular assist devices (LVADs) often present with the loss of large von Willebrand factor (VWF) multimers. This VWF deficiency is believed to contribute to the bleeding diathesis of patients on LVAD support and is caused by excessive VWF cleavage by the metalloprotease ADAMTS-13 under high shear stress. However, only a small percentage of patients who have suffered the loss of large VWF multimers bleed. The actual rates of VWF cleavage in these patients have not been reported, primarily because of the lack of reliable detection methods. We have developed and validated a selected reaction monitoring (SRM) mass spectrometry method to quantify VWF cleavage as the ratio of the ADAMTS-13-cleaved peptide MVTGNPASDEIK to the ILAGPAGDSNVVK peptide. The rate of VWF cleavage was found to be 1.26% ± 0.36% in normal plasma. It varied significantly in patient samples, ranging from 0.23% to 2.5% of total VWF antigen, even though all patients had the loss of large VWF multimers. Von Willebrand factor cleavage was greater in post-LVAD samples from patients in whom bleeding had developed, but was mostly reduced in patients in whom thrombosis had developed. This SRM method is reliable to quantify the rate of VWF cleavage in patients on LVAD support.

We describe the case of a 57-year-old man who had severe mitral valve stenosis and regurgitation without significant annular calcification. He was not a candidate for surgical valve replacement or repair because of his substantial comorbid conditions, overall frailty, and elevated surgical risk. He underwent successful transcatheter mitral valve replacement of his native mitral valve with compassionate, off-label use of an Edwards Sapien 3 valve. A search of the literature produced no other cases like ours, which represents a further evolution of the transcatheter valve implantation concept. Further studies are needed to help define accurate valve sizing, intraprocedural positioning, and long-term device stability, as well as to determine which patients might benefit from this commercially available valve. In the meantime, our findings could present a means of treating patients who have no other options.

Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valves has been successfully performed, but there is a lack of published experience in percutaneous treatment of patients with unicuspid valves and severe aortic stenosis. We describe a case of TAVR in such a patient. A 31-year-old woman with Turner syndrome—who had undergone coarctation repair via subclavian flap at age 7 days and an aortic valvotomy at age 6 weeks—presented with severe symptomatic aortic stenosis. She was deemed inoperable because of her severe pulmonary hypertension and numerous comorbidities; consequently, a 20-mm Edwards Sapien 3 Transcatheter Heart Valve was offered for compassionate use. Postdeployment angiography and transesophageal echocardiography and aortography revealed no aortic insufficiency. Transcatheter aortic valve replacement for unicuspid aortic valve stenosis is technically feasible. Before implantation, particular attention should be paid to the interplay between the large single leaflet, coronary ostia, and stented valve, to select the correct size and position of the device. Some degree of intraoperative aortic migration should be anticipated.

Introduction Transcatheter aortic valve implantation (TAVI) in patients with degenerated bioprosthetic aortic valve has been successfully performed as an alternative to surgery. We describe our initial experience of valve-in-valve TAVI in five patients, using new generation Edwards Sapien 3 transcatheter heart valves implanted into degenerated 19 mm bioprosthetic valves. 20-mm Edwards S3 valves were offered for compassionate use. All patients had significant aortic valve stenosis. Methods and Results The main vascular access was achieved and pre-closed with two Proglide closure devices in one patient and Prostar closure devices in four patients. For each TAVI procedure an Edwards 14 French sheath was inserted without complication and sutured in place. The Sapien 3 Commander delivery system was inserted and the valve was aligned in the descending aorta. The 20-mm Sapien 3 valve was deployed with slow continuous inflation during rapid right ventricular pacing. The cranial edge of the Edwards S3 valve was aligned with the cranial radiopaque markers of bioprosthesis to minimize paravalvular leak. Post-deployment angiography, transesophageal echocardiography and aortogram confirmed absence of mild aortic insufficiency and no increase in trans-aortic gradient when compared to a naive 19 mm bioprosthetic valve. Conclusion Valve-in-valve TAVI with the Edwards S3 transcatheter heart valve for degenerative bioprosthetic aortic valves is technically feasible. The proper position of the stented valve minimizes the risk for post-procedure paravalvular insufficiency and provides good transaortic pressure gradient. © 2016 Wiley Periodicals, Inc.

Carcinoid heart disease presents as right-sided heart failure attributable to the dysfunction of the tricuspid and pulmonary valves. Although surgical valve replacement is the mainstay of treatment when patients become symptomatic, it is associated with substantial perioperative mortality rates. We present a case of severe pulmonary valve stenosis secondary to carcinoid heart disease, treated successfully with percutaneous valve replacement. A 67-year-old man with severe pulmonary valve stenosis was referred to our center for pulmonary valve replacement. The patient had a history of metastatic neuroendocrine tumor of the small bowel with carcinoid syndrome, carcinoid heart disease, and tricuspid valve regurgitation previously treated with surgical valve replacement. Because of the patient's severe chronic obstructive pulmonary disease and hostile chest anatomy seen on a computed tomographic scan dating from previous cardiothoracic surgery, we considered off-label percutaneous valve replacement a viable alternative to open-heart surgery. A 29-mm Edwards Sapien XT valve was successfully deployed over the native pulmonary valve. There were no adverse sequelae after the procedure, and the patient was discharged from the hospital the next day. This case report shows that percutaneous valve replacement can be a valid option in carcinoid heart disease patients who are not amenable to surgical valve replacement.

Because randomized coronary revascularization trials in stable coronary artery disease (CAD) have shown no reduced myocardial infarction (MI) or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI, or stroke after revascularization within 90 d after PET. Methods: In a prospective long-term cohort of stable CAD, regional, artery-specific, quantitative myocardial perfusion by PET, coronary revascularization within 90 d after PET, and all-cause death, MI, and stroke (DMS) at 9-y follow-up (mean ± SD, 3.0 ± 2.3 y) were analyzed by multivariate Cox regression models and propensity analysis. Results: For 3,774 sequential rest-stress PET scans, regional, artery-specific, severely reduced coronary flow capacity (CFC) (coronary flow reserve ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 d after PET (P = 0.0369), compared with moderate or mild CFC, coronary flow reserve, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Conclusion: CFC by PET provides objective, regional, artery-specific, size-severity physiologic quantification of CAD severity associated with high risk of DMS that is significantly reduced after revascularization within 90 d after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone.

Objectives Our study was designed to evaluate the outcomes of TandemHeart™ assistance during percutaneous coronary intervention, specifically in relationship to pre-procedural clinical and hemodynamic risk factors in patients ineligible for surgical revascularization. Background We have used the TandemHeart™ percutaneous left ventricular assist device during percutaneous coronary intervention (PCI) in patients for whom conventional PCI and aorto-coronary bypass would pose substantial risk owing to comorbidities and/or clinical presentations. Methods We retrospectively analyzed data from 626 consecutive PCIs at the Texas Heart Institute from 2005 to 2011. Among these, 74 interventions were performed with TandemHeart™ support. Mortality and morbidity were analyzed in relationship to presentation status (elective, urgent, emergent, or emergent salvage), and then we recorded outcomes and survival rates over the course of six years. Results At 30 days after PCI, survival rates were 94%, 88%, 79%, and 55% in the elective, urgent, emergent, and emergent salvage groups, respectively. Survival rates at one year were at 75% in the elective, 64% in the urgent, 52% in the emergent, and 45% in the emergent salvage groups. Survival rates at 6 years were 68% in the elective, 53% in the urgent, 31% in the emergent, and 41% in the emergent salvage groups, respectively. In elective and urgent groups, successful weaning from mechanical support was possible in all patients. In the emergent and emergent salvage groups, successful weaning from mechanical support was possible in 84% and 55% of patients, respectively. Conclusions TandemHeart™ assisted PCI is a viable option for revascularization in cases of profound cardiogenic shock or extremely risky intervention due to complex anatomy. © 2015 Wiley Periodicals, Inc.

We describe transcatheter aortic valve implantation in a patient who had severe peripheral artery disease. The patient's vascular condition required additional preliminary peripheral intervention to enable adequate vascular access. A 78-year-old man with severe aortic stenosis, substantial comorbidities, and severe heart failure symptoms was referred for aortic valve replacement. The patient's 20-mm aortic annulus necessitated the use of a 23-mm Edwards Sapien valve inserted through a 22F sheath, which itself needed a vessel diameter of at least 7 mm for percutaneous delivery. The left common femoral artery was selected for valve delivery. The left iliac artery and infrarenal aorta underwent extensive intervention to achieve an intraluminal diameter larger than 7 mm. After aortic valvuloplasty, valve deployment was successful, and the transaortic gradient decreased from 40 mmHg to less than 5 mmHg. The patient was discharged from the hospital 4 days postoperatively. We conclude that transcatheter aortic valve implantation can be successfully performed in patients with obstructed vascular access, including stenosis of the infrarenal aorta and the subclavian and coronary arteries.

A few case reports and case series have documented the outcomes in patients with tricuspid bioprosthetic valvular degeneration who underwent transcatheter implantation of the Medtronic Melody and the Edwards Sapien XT and Sapien 3 valves. In this report, we describe the case of a 49-year-old woman with severe bioprosthetic tricuspid valvular stenosis and multiple comorbidities who underwent transcatheter tricuspid valve replacement with a Sapien 3 valve.

Introduction: Cardiogenic shock that results from pulmonary embolus has a high mortality rate. Systemic thrombolysis is frequently used in submassive and massive pulmonary embolus and has been shown to restore circulation. However, in the event of impending or ongoing cardiac arrest, systemic thrombolysis or anticoagulation alone has not been always shown to be effective. Case reports have previously established that extracorporeal membrane oxygenation can effectively be used as an effective rescue strategy in cases of cardiac arrest as a result from massive pulmonary embolus. We report six cases of massive pulmonary embolism (PE), in which veno-arterial extracorporeal membrane oxygenation (VA ECMO) was utilized or used as a backup strategy with excellent outcomes. We highly recommend using this strategy at the bedside in a tertiary care facility where VA ECMO support is available. Methods: This is a retrospective study of all patients that underwent VA ECMO or utilized VA ECMO at the bedside as a rescue strategy in the setting of massive PE. We abstracted relevant clinical information from patient charts for this review. Results and analysis: Out of the 107 VA ECMO runs performed at our facility between 1 September 2013 and 31 December 2014, four patients utilized this strategy in the setting of massive PE with impending cardiac arrest; in two cases it was available to use as a backup strategy. All six patients (Table 1) had successful recovery with complete restoration of cognitive status, functional status, and without any clinical signs of right ventricular (RV) dysfunction on discharge.

Transcatheter aortic valve implantation (TAVI) in patients with degenerated bioprosthetic aortic valve has been successfully performed as an alternative to surgery. We describe our initial experience of valve-in-valve TAVI in five patients, using new generation Edwards Sapien 3 transcatheter heart valves implanted into degenerated 19 mm bioprosthetic valves. 20-mm Edwards S3 valves were offered for compassionate use. All patients had significant aortic valve stenosis.The main vascular access was achieved and pre-closed with two Proglide closure devices in one patient and Prostar closure devices in four patients. For each TAVI procedure an Edwards 14 French sheath was inserted without complication and sutured in place. The Sapien 3 Commander delivery system was inserted and the valve was aligned in the descending aorta. The 20-mm Sapien 3 valve was deployed with slow continuous inflation during rapid right ventricular pacing. The cranial edge of the Edwards S3 valve was aligned with the cranial radiopaque markers of bioprosthesis to minimize paravalvular leak. Post-deployment angiography, transesophageal echocardiography and aortogram confirmed absence of mild aortic insufficiency and no increase in trans-aortic gradient when compared to a naïve 19 mm bioprosthetic valve.Valve-in-valve TAVI with the Edwards S3 transcatheter heart valve for degenerative bioprosthetic aortic valves is technically feasible. The proper position of the stented valve minimizes the risk for post-procedure paravalvular insufficiency and provides good transaortic pressure gradient. © 2016 Wiley Periodicals, Inc.

The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)–c-Met and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas α-sarcomeric actin, cardiac myosin heavy chain, troponin I, and α-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.

Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit–positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplanted cells in the recipient heart. By this approach, we have demonstrated that BMCs, when properly administrated in the infarcted heart, efficiently differentiate into myocytes and coronary vessels with no detectable differentiation into hemopoietic lineages. However, BMCs have no apparent paracrine effect on the growth behavior of the surviving myocardium. Within the infarct, in 10 days, nearly 4.5 million biochemically and morphologically differentiated myocytes together with coronary arterioles and capillary structures were generated independently of cell fusion. In conclusion, BMCs adopt the cardiac cell lineages and have an important therapeutic impact on ischemic heart failure.

Purpose Bone-marrow and peripheral blood-derived stem cells can be used as stimulators of myogenesis and angiogenesis. We describe an original technique for collection and surgical intramyocardial injection of peripheral blood-derived stem cells. Description Stem cells are mobilized from the bone marrow by means of subcutaneous administration of Lenogastrim (Granocyte 34 [Aventis Pharma, Milan, Italy]) for 4 days. Then the day before the operation the peripheral blood-derived stem cells are collected by means of apheresis and processed in order to obtain the CD 133+ cells. Cells are injected into the myocardium in a beating heart in order to induce angiogenesis locally or myogenesis, or both. When necessary, off-pump coronary artery bypass grafting is previously accomplished. Evaluation Thus far we have investigated 4 patients (3 patients who have received off-pump peripheral blood stem cell injection and coronary bypass grafting through median sternotomies, and 1 patient who underwent cell transplant alone through a minimally-invasive transdiaphragmatic approach). No complications were noted at a mean of 4 months after surgery. Conclusions This novel method of peripheral bone marrow stem cell collection and intramyocardial injection seems to be safe, feasible, and reproducible. However, there is need of further evidence to definitely assess safety issues and clinical results.

A 30 year-old Hispanic man with no significant previous medical history presented with refractory hypoxemia after flu-like symptoms. Because of progressive hypoxemia despite appropriate ventilator strategies, venovenous extracorporeal membrane oxygenation (VV-ECMO) was initiated for severe acute respiratory distress syndrome (ARDS). His course was complicated at our hospital by subarachnoid hemorrhage, right ventricular failure, multiple pneumothoraces, and significant deconditioning. He was able to be weaned off VV-ECMO after 193 days and was ambulatory at discharge from the hospital.

Our study was designed to evaluate the outcomes of TandemHeart™ assistance during percutaneous coronary intervention, specifically in relationship to pre-procedural clinical and hemodynamic risk factors in patients ineligible for surgical revascularization.We have used the TandemHeart™ percutaneous left ventricular assist device during percutaneous coronary intervention (PCI) in patients for whom conventional PCI and aorto-coronary bypass would pose substantial risk owing to comorbidities and/or clinical presentations.We retrospectively analyzed data from 626 consecutive PCIs at the Texas Heart Institute from 2005 to 2011. Among these, 74 interventions were performed with TandemHeart™ support. Mortality and morbidity were analyzed in relationship to presentation status (elective, urgent, emergent, or emergent salvage), and then we recorded outcomes and survival rates over the course of six years.At 30 days after PCI, survival rates were 94%, 88%, 79%, and 55% in the elective, urgent, emergent, and emergent salvage groups, respectively. Survival rates at one year were at 75% in the elective, 64% in the urgent, 52% in the emergent, and 45% in the emergent salvage groups. Survival rates at 6 years were 68% in the elective, 53% in the urgent, 31% in the emergent, and 41% in the emergent salvage groups, respectively. In elective and urgent groups, successful weaning from mechanical support was possible in all patients. In the emergent and emergent salvage groups, successful weaning from mechanical support was possible in 84% and 55% of patients, respectively.TandemHeart™ assisted PCI is a viable option for revascularization in cases of profound cardiogenic shock or extremely risky intervention due to complex anatomy. © 2015 Wiley Periodicals, Inc.

Sinus of Valsalva aneurysms appear to be rare. They occur most frequently in the right sinus of Valsalva (52%) and the noncoronary sinus (33%). More of these aneurysms originate from the right coronary cusp than from the noncoronary cusp. Surgical intervention is usually recommended when symptoms become evident. We report the case of a 34-year-old woman who presented with a congenital, ruptured sinus of Valsalva aneurysm that originated from the noncoronary cusp. Moderate aortic regurgitation was associated with this lesion. Simple, direct patch closure of the ruptured aneurysm resolved the patient's left-to-right shunt and was associated with decreased aortic regurgitation to a degree that valve replacement was not necessary. Only trace residual aortic regurgitation was evident after 3 months, and the patient remained free of symptoms after 6 months. Our observations support the idea that substantial runoff blood flow in the immediate supra-annular region can be responsible for aortic regurgitation in the absence of a notable structural defect in the aortic valve, and that restoring physiologic flow in this region and equalizing aortic-cusp closure pressure can largely or completely resolve aortic insufficiency. Accordingly, valve replacement may not be necessary in all cases of ruptured sinus of Valsalva aneurysms with associated aortic valve regurgitation.

Continuous-flow left ventricular assist devices (LVADs) expose blood cells to high shear stress, potentially resulting in the production of microparticles that express phosphatidylserine (PS+) and promote coagulation and inflammation. In this prospective study, we attempted to determine whether PS+ microparticle levels correlate with clinical outcomes in LVAD-supported patients.We enrolled 20 patients undergoing implantation of the HeartMate II LVAD (Thoratec Corp, Pleasanton, CA) and 10 healthy controls who provided reference values for the microparticle assays. Plasma was collected before LVAD implantation, at discharge, at the 3-month follow-up, and when an adverse clinical event occurred. We quantified PS+ microparticles in the plasma using flow cytometry.During the study period, 8 patients developed adverse clinical events: ventricular tachycardia storm in 1, non-ST-elevation myocardial infarction in 2, arterial thrombosis in 2, gastrointestinal bleeding in 2, and stroke in 3. Levels of PS+ microparticles were higher in patients at baseline than in healthy controls (2.11% ± 1.26% vs 0.69% ± 0.46%, p = 0.007). After LVAD implantation, patient PS+ microparticle levels increased to 2.39% ± 1.22% at discharge and then leveled to 1.97% ± 1.25% at the 3-month follow-up. Importantly, levels of PS+ microparticles were significantly higher in patients who developed an adverse event than in patients with no events (3.82% ± 1.17% vs 1.57% ± 0.59%, p0.001), even though the 2 patient groups did not markedly differ in other clinical and hematologic parameters.Our results suggest that an elevation of PS+ microparticle levels may be associated with adverse clinical events. Thus, measuring PS+ microparticle levels in LVAD-supported patients may help identify patients at increased risk for adverse events.

Thrombosis involving a permanent infusion catheter in the subclavian vein and superior vena cava is relatively common, especially in cancer patients. Edema of the arms and head is a well-known clinical consequence of this thrombosis, with an intrinsic risk of pulmonary embolism; however, systemic embolization into the cerebral circulation has not been reported as a sequela. Herein, we describe the case of a 56-year-old man with metastatic prostate cancer who developed superior vena cava syndrome due to extensive thrombosis in the presence of a central venous catheter that was used for long-term chemotherapy. The patient's case was complicated by a cerebrovascular accident that was most likely caused by a paradoxical air embolism. A clear mechanism for the embolism was provided by a network of collateral veins, which developed between the brachiocephalic vein and the left atrium due to the superior vena cava obstruction and resulted in a right-to-left shunt. We discuss diagnosis and treatment of the condition in our patient and in general terms.

The Notch receptor mediates cell fate decision in multiple organs. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro . N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.

Cardiac progenitor cells (CPCs) have been identified in the adult heart. However, the molecular mechanisms involved in the commitment of CPCs to the myocyte lineage remain to be determined. Notch-1 is a transmembrane receptor activated by the DSL family of ligands which include Jagged1 and Delta-4. Upon ligand binding, the activated receptor undergoes cleavage by γ-secretase, and its intracellular portion (Notch intracellular domain, NICD) is released, translocates to the nucleus and exerts its function as a transcriptional regulator. The objective of this study was to determine whether the components of the Notch pathway are present in the CPCs of the adult mammalian heart and whether activation of the Notch-1 receptor promotes the differentiation of CPCs into myocytes. For this purpose, c-kit-positive CPCs were isolated from the mouse heart and analyzed by FACS and immunocytochemistry. Notch-1 receptor was detected in ~50% of c-kit-positive CPCs. CPCs were then plated on culture dishes coated with immobilized Jagged1 or Delta-4 and maintained in low-serum medium. Additional groups of cells were similarly exposed to the ligands but were also treated with γ-secretase inhibitor. After 5 days in culture, the number of CPCs was markedly lower in the presence of the Notch ligands and significantly higher in the presence of the γ-secretase inhibitor. After 8 days in culture, cells became confluent and did not express any longer c-kit. With respect to cells treated with the γ-secretase inhibitor, exposure to Jagged1 and Delta-4 resulted respectively in a 10-fold and 20-fold increase in the fraction of CPCs positive for Nkx2.5. These findings were consistent with a positive effect of Notch on CPC differentiation and Nkx2.5 upregulation. To establish whether Notch influenced cardiomyogenesis in vivo, infarcted mice were treated for 11 days with the γ-secretase inhibitor. The regenerative response of the infarcted heart, defined by the percentage of BrdU-positive myocytes distributed in the border zone, was 50% lower in animals that received the γ-secretase inhibitor. Thus, Notch1 modulates CPC differentiation in vitro and myocardial regeneration in vivo after infarction.

We sought to evaluate the outcomes of ECMO in a variety of clinical settings among patients presenting in cardiogenic shock and/or respiratory failure and underwent emergent venous-arterial (VA) ECMO and/or venous-venous (VV) ECMO placement. We retrospectively analyzed data from 163 consecutive

Cardiac stem cells (CSCs) have been identified in the adult heart, but the microenvironment that protects the slow-cycling, undifferentiated, and self-renewing CSCs remains to be determined. We report that the myocardium possesses interstitial structures with the architectural organization of stem cell niches that harbor long-term BrdU-retaining cells. The recognition of long-term label-retaining cells provides functional evidence of resident CSCs in the myocardium, indicating that the heart is an organ regulated by a stem cell compartment. Cardiac niches contain CSCs and lineage-committed cells, which are connected to supporting cells represented by myocytes and fibroblasts. Connexins and cadherins form gap and adherens junctions at the interface of CSCs–lineage-committed cells and supporting cells. The undifferentiated state of CSCs is coupled with the expression of α 4 -integrin, which colocalizes with the α 2 -chain of laminin and fibronectin. CSCs divide symmetrically and asymmetrically, but asymmetric division predominates, and the replicating CSC gives rise to one daughter CSC and one daughter committed cell. By this mechanism of growth kinetics, the pool of primitive CSCs is preserved, and a myocyte progeny is generated together with endothelial and smooth muscle cells. Thus, CSCs regulate myocyte turnover that is heterogeneous across the heart, faster at the apex and atria, and slower at the base–midregion of the ventricle.

Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 μm 3 at 16 days after treatment and reached 5100 μm 3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10 000 to 20 000 μm 3 . Moreover, there were 43±13 arterioles and 155±48 capillaries/mm 2 myocardium at 16 days, and 31±6 arterioles and 390±56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.

Purpose Left ventricular assist devices (LVADs) are associated with significant hemorrhagic and thrombotic complications, but the underlying mechanisms remain elusive. We examined whether cellular derived microparticles may be associated to adverse events in patients with LVADs. Methods and Materials We prospectively enrolled 15 patients undergoing elective implantation of a HeartMate II LVAD. Extensive coagulation profile including phosphatidylserine (PS+) cellular microparticles derived by platelets, leukocytes, erythrocytes, and endothelial cells was performed by flow cytometry. Samples were obtained upon admission (baseline), at discharge,at 3 months after discharge, and at the time of a clinically significant event. Patients were on an oral anticoagulation regimen of aspirin, warfarin (International Normalized Ratio, 2-3), and dipyridamole. Results Three patients had adverse events.At baseline, the mean percentage of PS+ microparticles in patients was higher than that in healthy controls (2.32%±1.65 vs. 0.98%±0.66) and gradually decreased during follow-up from 2.03%±1.35 (discharge) to 1.85%±1.22 (3 months). Patients with events had significantly more PS+ microparticles than did patients without events at 3 months (3.8%±0.75 vs. 1.85%±1.22, p Conclusions PS+ microparticles were elevated in patients before LVAD implantation, which is consistent with a hypercoagulable state. Anticoagulation after LVAD implantation appeared to reduce the amount of circulating PS+ microparticles in peripheral blood. Adverse thrombotic or bleeding events appeared to be preceded by elevated PS+ microparticles. The presence of these cell-derived particles may provide a procoagulant substrate that leads to significant adverse events.