Alessandro Barbone

Chronic Unloading by Left Ventricular Assist Device Reverses Contractile Dysfunction and Alters Gene Expression in End-Stage Heart Failure

BackgroundLeft ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca2+ transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca2+ handling. Methods and ResultsThe isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca2+-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na+-Ca2+ exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca2+ uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca2+ uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts. ConclusionsLVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca2+ cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

β-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure

Background—Chronic &bgr;-adrenergic receptor (&bgr;-AR) blockade improves cardiac contractility and prolongs survival in patients with heart failure; however, the mechanisms underlying these favorable responses are poorly understood. Stress-induced activation of the sympathetic nervous system results in protein kinase A (PKA)-mediated phosphorylation of the calcium (Ca2+) release channel/cardiac ryanodine receptor (RyR2), required for cardiac excitation-contraction (EC) coupling, activating the RyR2 channel, and increasing cardiac contractility. The hyperadrenergic state of heart failure results in leaky RyR2 channels attributable to PKA hyperphosphorylation and depletion of the stabilizing FK506 binding protein, FKBP12.6. We tested the hypothesis that improved cardiac muscle function attributable to &bgr;-AR blockade is associated with restoration of normal RyR2 channel function in patients with heart failure. Methods and Results—We assessed the effects of &bgr;-AR blockade on left ventricular volume using isolated perfused hearts and &bgr;-agonist responsiveness using muscle strips from patients undergoing transplantation. Twenty-four human hearts were examined, 10 from patients with heart failure treated with &bgr;-AR blockers (carvedilol, metoprolol, or atenolol), 9 from patients with heart failure without &bgr;-AR blocker treatment, and 5 normal hearts. RyR2 PKA phosphorylation was determined by back-phosphorylation, FKBP12.6 in the RyR2 macromolecular complex was determined by coimmunoprecipitation, and channel function was assayed using planar lipid bilayers. &bgr;-AR blockers reduced left ventricular volume (reverse remodeling) and restored &bgr;-agonist response in cardiac muscle from patients with heart failure. Improved cardiac muscle function was associated with restoration of normal FKBP12.6 levels in the RyR2 macromolecular complex and RyR2 channel function. Conclusions—Improved cardiac muscle function during &bgr;-AR blockade is associated with improved cardiac Ca2+ release channel function in patients with heart failure.

Inducible Nitric Oxide Synthase Expression in Smooth Muscle Cells and Macrophages of Human Transplant Coronary Artery Disease

BACKGROUND The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation. METHODS AND RESULTS We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells. CONCLUSIONS iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.

Left ventricle unloading by percutaneous pigtail during extracorporeal membrane oxygenation

Arterial-venous extracorporeal membrane oxygenation (ECMO) is more and more used as first line mechanical support in acute cardiopulmonary failure. Important pitfall of this technique is the inappropriate unloading of left ventricle (LV) in case of myocardial insufficiency, leading to pulmonary stasis and inadequate myocardial recovery. We report our experience of left side unloading by a 7-F pigtail, introduced in the LV through the aortic valve, connected to the venous drainage. Echographic guidance is sufficient to pigtail positioning and follow-up monitoring avoiding catheterization laboratory transport. With this approach we were able to support three different patients, resolving LV distension and preventing lung congestion, without major complication.

LVAD support in patients with bioprosthetic valves.

The presence of mechanical or bioprosthetic valves has traditionally excluded patients from mechanical circulatory support. However, several centers have now developed algorithms for the surgical management of native or prosthetic valve disease in patients requiring left ventricular assist device insertion. We report adverse events associated with bioprosthetic valves in the mitral and tricuspid positions in 2 patients who received long-term mechanical support. We recommend anticoagulation for all patients with prosthetic valves in the mitral or tricuspid position to avoid thromboembolism, inflow conduit occlusion, or valvular incompetence.

Assessment of synchrony relationships between the native left ventricle and the heartmate left ventricular assist device

BACKGROUND It has been suggested that the cardiac cycle becomes synchronized with the LVAD. Synchronization between the left ventricle and the LVAD may be important for ventricular unloading and coronary flow. In this study, we assessed the synchrony between the cardiac and LVAD cycles. METHODS We studied 24 patients with HeartMate LVAD support. Native heart rate from an electrocardiogram and LVAD rate were measured at rest and peak exercise. Three patients underwent simultaneous invasive pressure measurement from the left ventricle and the aorta, and 3 patients underwent simultaneous recording of electrocardiogram and LVAD electrical signal. RESULTS Resting heart rate was significantly higher than LVAD rate (96 +/- 17 vs 66 +/- 15 beats [b]/min, p < 0.0001), with no correlation between the 2 (r = 0.25). Peak heart rate was significantly higher than LVAD rate (142 +/- 16 vs 102 +/- 14 b/min, p < 0.0001), with no correlation observed (r = 0.31). Electrical signal recording confirmed the absence of cardiac-LVAD synchrony. Pressure measurements revealed a cyclical intraventricular pressure variation, determined by the relationship between the cardiac and LVAD cycles. Intraventricular pressure was lowest when left ventricular systole occurred during pump filling and highest when left ventricular systole occurred during pump ejection. CONCLUSIONS The cardiac and LVAD cycles are not in synchrony at rest or at peak exercise. However, a cyclical variation in left ventricular pressure exists, dependent upon the phasic relationship of the cardiac-LVAD cycles, which significantly effects ventricular loading. Better understanding of this relationship may be important in developing assist devices for optimal left ventricular unloading and improvement of myocardial recovery.

Endogenous endothelium-derived nitric oxide inhibits myocardial caspase activity: implications for treatment of end-stage heart failure

BACKGROUND Apoptosis contributes to ventricular remodeling in heart failure (HF). Nitric oxide (NO) inhibits caspase 3, a key effector apoptotic enzyme. We hypothesized that reduced endogenous NO in HF disinhibits cardiac caspase 3 to promote apoptosis. METHODS Caspase 3 activity was measured colorimetrically in myocardial cell lysates from endothelial NO synthase (eNOS)-deficient mice (eNOS -/-; n = 18), cardiomyopathic (CMP) hamsters (n = 8), and explanted failing human hearts (n = 10). We stimulated myocardial caspase 3 activity by adding upstream caspase 8 or 9. Cell lysates were incubated with 10(-4) mol/liter NO donor, S-nitroso-N-acetyl penicillamine; NOS inhibitor, nitro-L-arginine-methyl ester (L-NAME); or angiotensin-converting enzyme (ACE) inhibitor, enalaprilat. Hamsters underwent echocardiography so we could study the progression of ventricular dysfunction. RESULTS Stimulated caspase 3 activity was lower in myocardium of eNOS +/+ compared with eNOS -/- mouse hearts (5.1 +/- 0.5 vs 7.6 +/- 1.0 pmol/10 microg/min, p < 0.05). L-NAME increased enzyme activity only in eNOS +/+ mice, indicating that endogenous NO inhibits caspase 3. Stimulated caspase 3 activity was lower in control hamsters, 3.3 +/- 0.3 pmol/10 microg/min, compared with CMP hamsters, 9.6 +/- 0.7 and 6.9 +/- 0.4 pmol/10 microg/min at 4 and 9 months, respectively. This was associated with progressive ventricular dysfunction, thinning, and dilatation. L-NAME increased enzyme activity in normal but not in CMP hamsters. In failing human myocardium, L-NAME failed to alter caspase activity, indicating reduced NO availability. Enalaprilat inhibited caspase 3, which was reversed by L-NAME. S-nitroso-N-acetyl penicillamine reversed caspase 3 activation in all groups. CONCLUSIONS Nitric oxide reversibly inhibits myocardial caspase 3 independent of the apoptotic signaling pathway. Reduced NO in HF increases myocardial caspase 3 activity. Agents that promote NO synthesis, including ACE inhibitors, may prevent caspase activation in HF.

Outcome of open total arch replacement in the modern era

OBJECTIVE To shed light on contemporary results of open total aortic arch surgery, we undertook a systematic review to identify all reports on this procedure published in the last 10 years. METHODS Extensive electronic literature search was undertaken to identify all published articles from 2004 to 2014 that provided results on total aortic arch replacement. According to inclusion and exclusion criteria, 21 relevant studies were selected and meta-analyzed to assess outcomes. RESULTS The pooled estimate for operative mortality was 5.3%. Permanent and transient neurologic deficit occurred postoperatively at a pooled rate of 3.4% and 5.2%, respectively. Pooled rate of irreversible spinal cord injury was 0.6%, whereas renal failure occurred at a pooled rate of 4.1%. Prolonged intubation occurred at pooled rate of 15.4%. Among elective patients, pooled rate of mortality and permanent neurologic deficit was 2.9% and 2.2%, respectively, with a significant difference compared with urgent/emergency surgery cases. CONCLUSIONS The main findings from this meta-analysis indicate that total aortic arch replacement can be performed with satisfactory mortality and morbidity. The pooled rates of mortality and permanent neurologic deficit among elective cases were surprisingly low, and these data have an even greater prominence when they are compared with outcomes of hybrid arch series. Under urgent/emergency surgery, early mortality and neurologic complications showed an about threefold higher rate. Moderate hypothermic circulatory arrest and early rewarming seem to provide proper renal protection, with an intermediate risk of prolonged intubation.

Reoperation for Aortic False Aneurysms: Our Experience and Strategy for Safe Resternotomy

Abstract  Background and aim of the study: To review our experience with reoperation for aortic false aneurysms (FA) and to present an analysis of the relevant surgical approaches and risks. Methods: From May 1999 to June 2006, 11 patients underwent a total of 13 reoperations due to aortic false aneurysms, with an incidence of 3% of all thoracic aortic cases. Cardiopulmonary bypass (CPB) and cooling were started before sternotomy in all cases. Three different strategies were adopted for patients depending on the position of the FA in the mediastinum as indicated by a preoperative CT scan. These included: deep hypothermic circulatory arrest (18°C), moderate hypothermia (28°C), and mild hypothermia (32°C). In two patients, the sternotomy ruptured the FA causing profuse hemorrhaging. In all the other cases sternotomy was performed without complication. The repair consisted in simple repair by direct suture (10 cases) or extensive repair by refashioning the anastomosis (three cases). Results: Two hospital deaths occurred with a hospital mortality rate of 16.7%. Permanent neurological deficit developed in one patient. Transient neurological deficit in the form of left lower limb weakness was observed in one patient. False aneurysm recurrence developed in two cases. Among patients present at follow‐up (nine survivors), four are in NYHA class I and five in class II. Conclusions: Aortic false aneurysms carry a high mortality and morbidity rate. Nevertheless, we believe that selecting the right strategy according to the position of the FA in the chest can reduce surgical risk, thus permitting relatively safe resternotomy.

Circulatory support in elderly chronic heart failure patients using the CircuLite® Synergy® system

OBJECTIVE The Synergy(®) system, a miniature partial circulatory support device, is implanted with an off-pump, minimally invasive surgical approach. In our experience, implantation of this system is associated with fewer perioperative adverse events than current full support devices. This approach therefore offers the possibility of treating elderly chronic heart-failure patients who might not ordinarily be considered for long-term circulatory support. METHODS A total of 54 patients (12 patients ≥ 70 years) were implanted with the Synergy system in an off-pump minithoracotomy procedure. Mean age (54 ± 10 vs 73 ± 3), body surface area (1.9 ± 0.2 vs 1.7 ± 0.1), blood urea nitrogen (BUN) (59 ± 33 vs 91 ± 38), estimated glomerular filtration rate (eGFR) (71 ± 23 vs 50 ± 38) and haemoglobin (12.6 ± 1.9 vs 11.3 ± 1.3) differed significantly between young and old. RESULTS Older patients had longer mean durations of support (337 vs 188 days). On average, both groups showed similar improvements (changes from baseline) in haemodynamics (pulmonary capillary wedge pressure -9 ± 16 vs -10 ± 8 mmHg; CO +1.0 ± 0.7 vs 0.9 ± 1.0 l/min, periferical vascular resistance (PVR) -1.2 ± 1.5 vs = 0.8 ± 1.7 Wood) and 6 min walk (107 ± 120 vs 130 ± 121 m). Older patients showed less improvement in peak VO2 (0.5 ± 2.9 vs 1.9 ± 3.0 ml/kg/min). Major adverse events (old vs young) between groups included major bleeding (75 vs 38%), infection (25 vs 38%), renal dysfunction (0 vs 17%) and device-related stroke (8 vs 10%). Mortality rate was 20% for the young and 40% for the elderly. CONCLUSIONS Older patients implanted with Synergy had smaller body sizes and worse renal function than younger patients. Both groups experienced similar haemodynamic benefits and functional improvements, though peak VO2 is less improved in the elderly. Risks of bleeding and renal dysfunction appear to be increased in the elderly, though still within acceptable ranges compared with other full support devices. Minimally invasive long-term circulatory support devices, like Synergy, offer a new treatment option to the elderly chronic heart-failure population.