Circulation: Cardiovascular Interventions Editors’ Picks

Over the last 2 decades, numerous advancements in medical therapies have improved patient outcomes in heart failure (HF). However, a significant number of patients still progress to end-stage HF, in which treatment options are largely limited to cardiac transplantation. As patient demands for transplant continue to exceed the supply of available organs, mechanical assist devices—specifically, the left ventricular assist device (LVAD)—were initially introduced as a bridge to cardiac transplantation. LVADs have 2 important beneficial effects. First, LVADs are placed in parallel to the native left ventricle (LV), causing pressure and volume unloading of the LV. Second, LVADs restore cardiac output and subsequent perfusion to the organs. As a result of these 2 effects, it became evident that some patients had actual improvement in LV function after LVAD placement. The term reverse remodeling was used to describe the improvement in myocardial function that was observed in patients with a seemingly end-stage disease. With reverse remodeling, a new hope for the treatment of HF was born—using LVADs as a bridge to recovery; however, to date, this promise has largely been unrealized. This probably is reflective of the fact that the sequela of mechanical ventricular unloading are quite complex and appear to involve the engagement of competing biological pathways including regression of cardiomyocyte hypertrophy as well as progressive cell atrophy. Although the promise of ventricular recovery still persists, its actualization will await a more comprehensive dissection of these competing biological processes. This review will discuss the beneficial clinical effects of LVAD support as well as review what is known about the cellular and molecular response to mechanical unloading and mechanisms of reverse remodeling. Key research findings have been summarized in the Table. View this table: Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse …

Axial-flow LVADs have become an integral tool in the management of end-stage heart failure. Consequently, nonsurgical bleeding has emerged as a major source of morbidity and mortality in this fragile population. The mechanisms responsible for these adverse events include acquired von Willebrand disease, GI tract angiodysplasia formation, impaired platelet aggregation, and overuse of anticoagulation therapy. Because of ongoing concerns for pump thrombosis and thromboembolic events, the thrombotic/bleeding paradigm has led to a difficult clinical dilemma for those managing patients treated with axial flow LVADs. As the field progresses, advances in the understanding of the pathological mechanisms underlying bleeding/thrombosis risk, careful risk stratification, and potential use of novel anticoagulants will all play a role in the management of the LVAD patient.

The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

Heart failure has become one of the fastest growing cardiovascular diagnoses, with estimates as high as 500 000 new cases per year.1,2 This growth is in part a result of the reductions in death from acute coronary syndromes, increased use of implantable cardioverter defibrillators, and improved survival with most cardiovascular interventions, which have led to this continued increase in the number of patients who develop progressive heart failure (HF). The estimated number of people in the United States with the diagnosis of HF may exceed 7 million, based on the estimated average prevalence of 2.6%,3,4 and a census of >300 million population (Figure 1).5,6 HF is clearly age related,1,–,4 with prevalence as low as 0.5% in those 65 years of age.2 This is an important demographic, because it is estimated that the number of people >65 years of age will double in the next 20 to 30 years.4,–,7 HF is not a homogeneous condition. Based primarily on data from recent hospital registries8,9 and other studies,10 nearly half of all patients have HF with preserved systolic function, and the other half have varying degrees of severity of HF with reduced systolic function. Although the prevalence of HF is higher in males at <70 years of age, overall HF is equally common in men and women. Unfortunately, the average survival of patients with either preserved or reduced systolic function is only 40% at 5 years after diagnosis,10,11 and may be as high as 80% when it reaches a refractory stage.12 One study of 3500 patients in Minnesota suggested that there is …

Left Ventricular Assist Devices and Renal Ramifications.

For a man with end-stage heart failure, a left ventricular assist device prolongs life but brings dire complications.

Relation of Preoperative Serum Albumin Levels to Survival in Patients Undergoing Left Ventricular Assist Device Implantation

In end-stage heart failure, mechanical ventricular assist devices (VAD) are being used as bridge-to-transplantation, as a bridge-to-recovery, or as the definitive therapy. We tested the hypothesis that myocardial implantation of autologous bone marrow mononuclear cells (BMNC) increases the likelihood of successful weaning from left VAD (LVAD) support. Ten patients (aged 14-60 years) with deteriorating heart function underwent LVAD implantation and concomitant implantation of autologous BMNC. Bone marrow was harvested prior to VAD implantation and BMNC were prepared by density centrifugation. Two patients received a pulsatile, extracorporeal LVAD and eight a nonpulsatile implantable device. Between 52 and 164 x 10(7) BMNC containing between 1 and 12 x 10(6) CD34+ cells were injected into the LV myocardium. There was one early and one late death. The median time on LVAD support was 243 days (range 24-498 days). Repeated echocardiographic examinations under increased hemodynamic load revealed a significant improvement of LV function in one patient. Three patients underwent heart transplantation, and four patients remain on LVAD support >1 year without evidence of recovery. Only one patient was successfully weaned from LVAD support after 4 months, and LV function has remained stable ever since. In patients with endstage cardiomyopathy, intramyocardial injection of BMNC at the time of LVAD implantation does not seem to increase the likelihood of successful weaning from VAD support. Other cell-based strategies should be pursued to harness the potential of cell therapy in LVAD patients.

Cost-effectiveness analysis in cardiac surgery: A review of its concepts and methodologies

Objective: Bone marrow mononuclear cell (BM-MNC) implantation (BMI) for critical severe limb ischemia especially for Buerger's disease shows excellent clinical results but the mechanism of this treatment is still unknown. In this study, we investigated the changes in serum levels of angiogenesis-related factors after BMI treatment. Research design/methods: Twelve patients whose BMI treatments were clinically very effective was selected out of ninteen cases, nine patients had Buerger's disease, two patients had arteriosclerosis obliterans and one had systemic sclerosis. Venous bood from femoral vein or brachial vein of the recipient limbs of these patients. Results: Adrenomedulin (AM), soluble vascular cell adhesion molecule-1 (sVCAM-1), and C-reactive protein (CRP) serum levels 24 h after BMI treatment were significantly increased compared with those before BMI treatment (p < 0.05). Vascular endothelial growth factor (VEGF) serum levels after BMI treatment significantly increased between 1 week and 3 months after BMI treatment (p < 0.05). Nitric oxide (NO) serum levels after BMI treatment increased significantly 2 weeks after BMI treatment (p < 0.05). There was no correlation between the numbers of implanted cells and serum levels of measured angiogenesis-related factors that were significantly increased after BMI treatment. Conclusion: It was concluded that the mechanism underlying BMI treatment consists of early and late phases. The early phase involves the direct action by implanted cells, and the late phase involves indirect paracrine action. In addition, it was considered that BMI treatment is effective when we implant a sufficient level of bone marrow (600 ml) to treat severe limb ischemia.

Left ventricular assist devices (LVADs) are associated with major vascular complications including stroke and gastrointestinal bleeding (GIB). These adverse vascular events may be the result of widespread vascular dysfunction resulting from pre-LVAD abnormalities or continuous flow during LVAD therapy. We hypothesized that pre-existing large artery atherosclerosis and/or abnormal blood flow as measured in carotid arteries using ultrasonography are associated with a post-implantation composite adverse outcome including stroke, GIB, or death. We retrospectively studied 141 adult HeartMate II patients who had carotid ultrasound duplex exams performed before and/or after LVAD surgery. Structural parameters examined included plaque burden and stenosis. Hemodynamic parameters included peak-systolic, end-diastolic, and mean velocity as well as pulsatility index. We examined the association of these measures with the composite outcome as well as individual subcomponents such as stroke. After adjusting for established risk factors, the composite adverse outcome was associated with pre-operative moderate-to-severe carotid plaque (OR 5.08, 95% CI 1.67-15.52) as well as pre-operative internal carotid artery stenosis (OR 9.02, 95% CI 1.06-76.56). In contrast, altered hemodynamics during LVAD support were not associated with the composite outcome. Our findings suggest that pre-existing atherosclerosis possibly in combination with LVAD hemodynamics may be an important contributor to adverse vascular events during mechanical support. This encourages greater awareness of carotid morphology pre-operatively and further study of the interaction between hemodynamics, pulsatility, and structural arterial disease during LVAD support.

The field of cardiac mechanical assist devices has achieved a number of striking technical breakthroughs over the past 40 years.1 Emblematic of the type of important technical accomplishments that have been achieved in this field has been the development of the portable, battery-driven left ventricular assist device (LVAD) for patients with intractable cardiac failure. Although LVADs have been used primarily as a “bridge to transplantation,” a number of centers have now begun to implant LVADs as an alternative to transplantation.2 Indeed, as the technology in this field improves, it is entirely conceivable that LVADs will evolve into small, unobtrusive devices that will run on small, portable, long-lasting battery supplies that will not require external connection to the outside. This, in turn, will allow LVADs to serve as a very reliable alternative to transplantation for many patients with advanced heart failure who cannot receive transplants or who cannot be weaned from LVAD support. Thus far, the clinical experience with LVADs as a bridge to transplantation has consistently shown dramatic improvements in cardiac output3 4 and New York Heart Association functional class.4 5 Importantly, these clinical changes have been attended by concomitant decreases in levels of neurohormones6 7 and cytokines,8 suggesting that LVAD support may alter the heart failure “milieu.” In an effort to explain these salutary changes in clinical status, investigators have turned to more basic studies and begun to examine myocardial ultrastructure before and after LVAD implantation. These latter studies have shown decreased myocyte necrosis9 10 and apoptosis,11 decreased myocytolysis,3 and improved myocyte contractility.12 The beneficial changes in the biology of the failing myocardium after LVAD support have also been …

Serum albumin is an independent predictor of morbidity, including deep sternal wound infections, and mortality following cardiac surgery and left ventricular assist device (LVAD) implantation.1, 2 Preoperative hypoalbuminemia in patients being evaluated for LVAD implementation may be due to malnutrition and frailty, hepatic dysfunction due to both right and left heart failure, the cardiorenal syndrome, and systemic inflammation. Patients with hypoalbuminemia may potentially benefit from LVAD implantation since the combination of nutritional support and the reversal of heart failure may restore serum albumin to normal levels. On the other hand, the co-morbidities associated with hypoalbuminemia may increase perioperative morbidity and mortality and decrease long-term survival. Furthermore, patients with hypoalbuminemia undergoing LVAD implantation may not recover sufficiently to be considered candidates for heart transplantation. In view of the increasing costs associated with LVAD therapy,3 the known increased morbidity and mortality in patients with hypoalbuminemia, and the uncertainty of the option for heart transplantation, should patients with moderate and severe serum hypoalbuminemia undergo LVAD therapy? In this edition of the Journal, Critsinelis et al4 sought to determine short- and-long term survival in patients with low preoperative serum albumin levels who underwent continuous-flow LVAD implantation. In 526 patients who had undergone LVAD implantation at their center, 186 patients (35.4%) had moderate hypoalbuminemia (2.5-3.5 g/dL) and 18 (3.4%) had severe hypoalbuminemia (<2.5 g/dL). Patients with preoperative hypoalbuminemia were more likely to receive LVAD implementation for destination therapy, were more likely to have required preoperative circulatory support, had significantly lower preoperative hemoglobin levels and platelet counts, significantly higher white blood cell counts, and higher liver function enzyme levels. Hypoalbuminemia patients also had a higher incidence of postoperative morbidity, including infections and sepsis, gastrointestinal bleeding, neurological dysfunction, acute kidney injury, and an increased incidence of hospital readmissions. Preoperative hypoalbuminemia was also associated with significantly decreased early and long-term survival following LVAD implementation. However, hypoalbuminemia prior to LVAD implementation did not affect the success of bridge to transplantation and did not significantly affect survival after heart transplantation. Furthermore, there was no association between body mass index (BMI) and outcomes with LVAD implantation which suggests that the co-morbidities associated with hypoalbuminemia, and not preoperative BMI, are responsible for the increased morbidity and mortality associated with hypoalbuminemia. Patients with hypoalbuminemia, but with normal pre-albumin levels and a normal central venous pressure, had no difference in survival compared to patients with normal albumin levels. Should LVAD therapy be denied to patients with preoperative hypoalbuminemia? The answer lies in what co-morbidities responsible for preoperative hypoalbuminemia can be reversed following initiation of LVAD therapy. Reversing the sequelae of low cardiac output may improve appetite and absorption of nutrients, improve hepatic function, and reduce systemic inflammation. Critsinelis et al did not assess the effects of perioperative nutritional supplementation on perioperative morbidity and mortality in their patients. Furthermore, they limited their assessment to measuring only preoperative serum albumin levels. Hence, we do not know whether patients who had a significant increase in serum albumin levels post LVAD implantation had better short- and long-term survival. While deceased preoperative serum albumin levels are a marker for increased perioperative morbidity and decreased short- and long-term survival following LVAD implantation, the data from this study suggest that serum albumIn alone cannot be used to exclude patients for LVAD support who may be potential candidates for heart transplantation. These patients will require more aggressive perioperative nutritional supplementation and continued therapy for underlying co-morbidities in addition to LVAD support. Only then can we determine whether LVAD implementation can improve long- and short-time survival in patients with hypoalbuminemia.

Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and LV size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ-level changes. Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (before LVAD) and before cardiac transplantation (after LVAD). These were compared with 8 nonfailing hearts. Isolated skinned myocytes were purified and attached to a force transducer, and dimensions, maximum calcium-saturated force, calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0% to 25.6±11.0%, P=0.007), LV size decreased (LV internal dimension at end diastole, 7.6±1.2 to 4.9±1.4 cm; P<0.001), and myocyte dimensions decreased (cross-sectional area, 1247±346 to 638±254 μm(2); P=0.001). Maximum calcium-saturated force improved after LVAD (3.6±0.9 to 7.3±1.8 mN/mm(2), P<0.001) implantation but was still lower than in nonfailing hearts (7.3±1.8 versus 17.6±1.8 mN/mm(2), P<0.001). An increase in troponin I (TnI) phosphorylation after LVAD implantation was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD. There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was associated only with biochemical changes in TnI, suggesting that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ-level recovery.

Reverse Myocardial Remodeling with Centrifugal versus Axial-Flow Left Ventricular Assist Device in Chronic Heart Failure Patients