Diego H. Delgado

Usefulness of the INTERMACS Scale to Predict Outcomes After Mechanical Assist Device Implantation

BACKGROUND The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) scale classifies advanced heart failure patients according to hemodynamic status. This study assessed the usefulness of the INTERMACS scale to predict outcomes in advanced heart failure patients undergoing mechanical circulatory support (MCS). METHODS Fifty-four patients underwent MCS implantation from 2001 to 2007. Group A included 27 patients at INTERMACS level 1 and 2. Group B included 27 at INTERMACS level 3 and 4. Patient characteristics pre-MCS implant, incidence of complications during support, and survival between groups were compared. RESULTS Before MCS implantation, Group A had significantly lower cardiac index, mean arterial blood pressure, systolic pulmonary pressure, higher central venous pressure, and lower urine output (p < .05). After MCS, Group A had a lower incidence of infections (17% vs 46%; odds ratio [OR], 0.25, 95% confidence interval [CI], 0.06-0.6) and a higher incidence of liver injury (39% vs 11%; OR 5, 95% CI, 1.15-25). Mortality at 30 days was higher in Group A (38% vs 11%; OR, 4.8; 95% CI, 1.1-21); however, the mortality after 30 days post-MCS support was significantly higher in Group B (0% vs 18%, p < .05). Cox model showed overall survival was poorer in Group A (hazard ratio, 2.7; 95% CI, 1.1-7). CONCLUSION INTERMACS levels identified patients at risk for developing complications after MCS support. INTERMACS is a valid score system that should be considered as a tool to assess patient profile and predict complications and mortality after MCS implantation.

Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway.

Background— Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone and pathological states such as ischemia/reperfusion (I/R) injury, coronary vasospasm, and cardiac allograft vasculopathy. We assessed the effects of elevated ET-1 levels as seen after I/R to determine if ET-1 modulates nitric oxide (NO) production via the translocation of specific protein kinase C (PKC) isoforms. Methods and Results— Human saphenous vein endothelial cells (HSVECs) (n=8) were incubated with ET-1 or phosphate-buffered saline (PBS) for 24 hours. NO production was determined in the supernatant by measuring nitrate/nitrite levels. Protein expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), caveolin-1 and PKC were determined. Lastly, PKC translocation and activity were assessed after exposure to the drug of interest. HSVECs exposed to ET-1 displayed decreased NO production. PKC inhibition reduced NO production, whereas PKC activation increased production. NO production was maintained when HSVECs exposed to ET-1 were treated with the PKC agonist, PMA. eNOS protein expression was reduced after ET-1 treatment. PKC inhibition also downregulated eNOS protein expression, whereas PMA upregulated expression. ET-1 exposure led to a significant increase in PKCΔ and PKCϵ translocation compared with control, whereas translocation of PKC&lgr; was inhibited. ET-1 exposure significantly reduced overall PKC activity compared with control. Conclusions— Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. ET-1 antagonism with bosentan stimulates translocation of PKC&lgr; and leads to increased PKC activity and NO production. ET-1 antagonism may provide a novel therapeutic strategy to improve vascular homeostasis.

Clinical Differences Between Continuous Flow Ventricular Assist Devices: A Comparison Between HeartMate II and HeartWare HVAD

The HeartWare ventricular assist device (HVAD) is a new generation centrifugal flow VAD recently introduced in Canada. The objective of this study was to compare the HVAD device to the HeartMate II (HMII) axial flow device. Very few studies have compared clinical outcomes between newer generation VADs.

mTOR inhibition induces endothelial progenitor cell death.

Immunosuppressants are necessary to prevent graft rejection after solid organ transplantation. However, they are also known to have significant side effects, including endothelial toxicity. Endothelial progenitor cells originate in the bone marrow and are recognized by their angiogenic and endothelial reparative properties. The effects of the immunosuppressants cyclosporine A (CyA), tacrolimus and rapamycin were analyzed on endothelial progenitor‐like cells. Rapamycin induced rapid cell death, even at concentrations much lower than those used clinically, in peripheral blood mononuclear cells (PBMC) cultured to favor outgrowth of endothelial progenitors. Cyclosporine A and tacrolimus had no significant effects at clinical concentrations. The effect of rapamycin was specific to endothelial progenitor cells, in particular to the early stages of differentiation, as a lesser effect was observed in late outgrowth endothelial progenitors, mature aortic endothelial cells, and macrophages derived from the same PBMCs. The mechanism of cell death appeared to be apoptosis; however, its induction was probably multifactorial and did not depend on caspase or cathepsin activation. In conclusion, rapamycin induces endothelial progenitor cell death, possibly because it blocks survival signals given by growth factors critically required by these cells.

Role Of Endothelin-1 and Nitric Oxide Bioavailability in Transplant-Related Vascular Injury Comparative Effects of Rapamycin and Cyclosporine

Background— Cyclosporine (CyA) is associated with many side effects, including endothelial dysfunction and transplant vasculopathy (TxV). We previously demonstrated that CyA results in impairment of nitric oxide bioavailability and enhanced sensitivity to endothelin-1 (ET-1). In this study, we evaluated rapamycin (SRL) for its effects on the endothelium. Methods and Results— Lewis rats (n =8) were injected with SRL (1.5 mg/kg), CyA (5 mg/Kg), or saline (Con) intraperitoneally daily for 2-weeks. Thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation after exposure to acetylcholine and sodium nitroprusside by deriving the percent maximum relaxation (Emax). ET-1 plasma levels were also measured. Thoracic aortic expression of endothelial nitric oxide synthase (eNOS), ETA and ETB receptors (Rc), were determined. Oxidative injury was assessed by changes in 8-isoprostane levels. CyA exposure resulted in lower Edep vasorelaxation compared with control and SRL (Emax: SRL, 58±4%; CyA, 24±7%; Con, 52±8%; P=0.001). No differences in Eind vasorelaxation were seen. CyA exposure also increased sensitivity to ET-1 (% maximum contraction [Cmax]: Con, 211±8%; SRL, 230±5%; CyA, 259±3%; P=0.04). Only SRL treatment reduced ET-1 plasma levels. CyA reduced eNOS expression by 30% and increased ETA Rc expression by 34% compared with both Con and SRL (P=0.02). CyA resulted in higher 8-isoprostane levels (CyA, 50±2%; SRL, 3±3%; Con, 2±5%; P=0.02). Conclusions— CyA results in vascular dysfunction characterized by impairment of Edep vasorelaxation and enhanced sensitivity to vasospasm. SRL did not impair Edep vasorelaxation or increase sensitivity to vasospasm while lowering ET-1 levels and preserving eNOS protein expression. We conclude that SRL is less deleterious to the vasculature than CyA and may prevent TxV by these mechanisms.

Mechanical Circulatory Assistance State of Art

Case presentation 1 : Patient 1 is a 24-year-old woman with a 3-day history of a flu-like syndrome who presented with cardiogenic shock. The patient has persistent cardiogenic shock without end-organ dysfunction despite appropriate hemodynamic support. Which type of mechanical assist device is indicated in this case? Case presentation 2 : Patient is a 47-year-old man with a 12-year history of chronic heart failure due to idiopathic dilated cardiomyopathy. He now presents with New York Heart Association class IV symptoms that are refractory to medical therapy. At what point should we consider this patient for mechanical circulatory support? Mechanical circulatory support (MCS) is an important adjunct to the management of the patient with severe heart failure. This article describes the current clinically available mechanical support devices, their indications for use, and the specific advantages and disadvantages associated with each device. MCS is life saving in patients who fail to improve or stabilize with intravenous inotropes or vasodilators, intra-aortic balloon pump support, and mechanical ventilation.1 Patients requiring mechanical support generally fall into 4 categories: those with (1) cardiogenic shock resulting from acute myocardial infarction (AMI); (2) postsurgical myocardial dysfunction; (3) acute cardiac failure from myocarditis (case presentation 1); and (4) decompensated chronic heart failure (case presentation 2). Patients who present in cardiogenic shock after an AMI are excellent candidates for either short- or long-term mechanical support because they have not developed the systemic organ dysfunction seen with chronic end-stage heart failure and have the potential for myocardial recovery. In our experience, however, temporary support is likely futile in patients with massive MI (peak creatine kinase ≥10 000, peak troponin I ≥300, or loss of QRS complexes in the precordial leads), as the probability of myocardial recovery is low. Urgent transplantation evaluation and consideration of long-term support should be initiated for …

Choices: a Study of Preferences for End-of-life Treatments in Patients With Advanced Heart Failure

BACKGROUND The purpose of this study is to describe the treatment preferences of patients with heart failure among three distinct treatment options--optimal medical management, oral inotropes or left ventricular device (LVAD) support--to determine if there were differences in preferences between patients with mild heart failure (New York Heart Association [NYHA] Class II) and severe heart failure (NYHA Class IV), and also to determine whether quality of life, perceived severity of symptoms and overall health influenced treatment preferences. METHODS We enrolled 91 patients who completed the Minnesota Living with Heart Failure Questionnaire (MLHFQ); visual analog scales for depicting their perceived severity of overall health, dyspnea and fatigue; and a treatment trade-off tool. RESULTS The most preferred treatment options were oral inotropes, LVAD and standard medical management. There were no differences in treatment preferences between NYHA II and NYHA IV patients. Patient preferences correlated poorly with MLHFQ, symptom and overall health scores. Although not statistically significant, there was a trend toward patients with worse quality of life and symptom scores preferring more aggressive treatment. CONCLUSIONS The results of our study identified two distinct groups of patients: one group preferring treatments that prolonged survival time and another group that favored strategies that improved quality of life but reduced survival time. Treatment preferences were independent of functional or symptom status, suggesting that preferences may be decided early in the course of illness.

Transplantation and Mechanical Circulatory Support in Congenital Heart Disease: A Scientific Statement From the American Heart Association.

Dramatic evolution in the medical and surgical care of children with congenital heart disease (CHD) has led to a growing number of adults with late-onset complications, including heart failure (HF).1 In parallel with an overall increase in hospital admissions for adults with CHD (ACHD) and HF,2 CHD complexity has increased substantially in survivors over the past 2 decades.3 Heart transplant (HTx) specialists face the challenge of determining eligibility for advanced HF treatments among an increasingly complex population of CHD patients in whom guidelines for HTx and mechanical circulatory support (MCS) are scant. The purpose of this review is to provide a state-of-the-art update on HTx and MCS in CHD. HTx remains the surgical procedure of choice for eligible patients with severe advanced HF,4,5 with little change in the number of transplants performed yearly over the past decade. The body of information related to transplantation for CHD is derived almost entirely from registry and single-center–based outcome data; no randomized clinical trial or meta-analysis data are available. CHD presents additional challenges to successful HTx compared with HTx in patients with acquired HF. Many CHD patients require complex vascular reconstruction at the time of transplantation. The presence of antibodies to human leukocyte antigen (HLA) and ABO blood group sensitization are also impediments to timely transplantation. The ability of patients with single-ventricle physiology to survive during the waiting period is also limited by the additional burden of “outgrowing” their pulmonary blood flow and the resultant cyanosis. It is not surprising that CHD remains a risk factor during the waiting period and after transplantation. Therefore, although the management of the CHD patient with end-stage HF must include the option of HTx, its indication and timing are very different from that for acquired HF. Patients with ACHD represent an increasing …

The effect of ventricular assist devices on long‐term post‐transplant outcomes: a systematic review of observational studies

Ventricular assist device (VAD) therapy is widely used as a bridge to cardiac transplant. Studies addressing the effect of VADs on post‐transplant outcomes have shown conflicting results. It is imperative to review this evidence to inform clinical decision making and future research. Our aim was to systematically evaluate the effect of VAD therapy on long‐term post‐transplant outcomes in heart transplant recipients.

Myocardial HLA-G Reliably Indicates a Low Risk of Acute Cellular Rejection in Heart Transplant Recipients

BACKGROUND Human leukocyte antigen-G (HLA-G), a non-classical MHC I protein with restricted tissue expression, plays an essential role in immune tolerance and has been negatively associated with acute and chronic rejection after heart transplantation. We assessed myocardial HLA-G expression in adult heart transplant patients in an attempt to determine the value of this protein in identifying patients with a low risk of acute cellular rejection. METHODS Two groups of patients were included in this study. Group A (non-rejecting) included 29 patients who had no moderate or severe rejection episodes (ISHLT Grade <2R) post-transplant. Group B (rejecting) included 38 patients with at least two moderate or severe rejection episodes (Grade >or=2R) within a 1-year period. Expression of HLA-G in three myocardial biopsies post-transplant from each patient was determined through immunohistochemical staining. RESULTS In Group A, 86% of patients had HLA-G(+) biopsies compared with 11% of patients in Group B (p < 0.001; sensitivity 86%, specificity 87%). Whereas 60% of non-rejecting HLA-G(+) patients had at least two positive biopsies, all rejecting HLA-G(+) patients had only one positive biopsy. CONCLUSIONS There is a significant negative association between myocardial HLA-G expression and acute cellular rejection after cardiac transplantation. Detection of HLA-G appears to reliably indicate a low risk of developing moderate or severe allograft rejection and may, subsequently, allow for a reduced immunosuppressive regimen.