Andrew B. Civitello

Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families

The Lesch-Nyhan (LN) syndrome is a genetically lethal human neurological disease that results from mutations that inactivate the hypoxanthine phosphoribosyltransferase (HPRT) gene. The elucidation of the complete DNA sequence of the human HPRT gene locus has enabled the construction of multiple oligonucleotide primer sets for the simultaneous in vitro amplification of all nine HPRT exons. The multiplex polymerase chain reaction provides a facile assay for the detection of HPRT exon deletions and the reaction products can be analyzed by direct automated fluorescent DNA sequencing to identify subtle alterations in the gene. Alterations have been identified in the HPRT genes from 15 independent LN cases, and 10 LN family studies were performed. The sequencing method uses solid supports and is sufficiently simple and sensitive to be a favored approach for LN diagnosis. LN heterozygotes can be diagnosed without reference to the affected male. In addition, these procedures will be useful for somatic mutagenesis studies.

A prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial U.S. experience

OBJECTIVES We sought to evaluate the safety and feasibility of the Impella 2.5 system (Abiomed Inc., Danvers, Massachusetts) in patients undergoing high-risk percutaneous coronary intervention (PCI). BACKGROUND The Impella 2.5 is a miniaturized percutaneous cardiac assist device, which provides up to 2.5 l/min forward flow from the left ventricle into the systemic circulation. METHODS In a prospective, multicenter study, 20 patients underwent high-risk PCI with minimally invasive circulatory support employing the Impella 2.5 system. All patients had poor left ventricular function (ejection fraction <or=35%) and underwent PCI on an unprotected left main coronary artery or last patent coronary conduit. Patients with recent ST-segment elevation myocardial infarction or cardiogenic shock were excluded. The primary safety end point was the incidence of major adverse cardiac events at 30 days. The primary efficacy end point was freedom from hemodynamic compromise during PCI (defined as a decrease in mean arterial pressure below 60 mm Hg for >10 min). RESULTS The Impella 2.5 device was implanted successfully in all patients. The mean duration of circulatory support was 1.7 +/- 0.6 h (range: 0.4 to 2.5 h). Mean pump flow during PCI was 2.2 +/- 0.3 l/min. At 30 days, the incidence of major adverse cardiac events was 20% (2 patients had a periprocedural myocardial infarction; 2 patients died at days 12 and 14). There was no evidence of aortic valve injury, cardiac perforation, or limb ischemia. Two patients (10%) developed mild, transient hemolysis without clinical sequelae. None of the patients developed hemodynamic compromise during PCI. CONCLUSIONS The Impella 2.5 system is safe, easy to implant, and provides excellent hemodynamic support during high-risk PCI. (The PROTECT I Trial; NCT00534859).

The Current Use of Impella 2.5 in Acute Myocardial Infarction Complicated by Cardiogenic Shock: Results from the USpella Registry

Objectives To evaluate the periprocedural characteristics and outcomes of patients supported with Impella 2.5 prior to percutaneous coronary intervention (pre-PCI) versus those who received it after PCI (post-PCI) in the setting of cardiogenic shock (CS) complicating an acute myocardial infarction (AMI). Background Early mechanical circulatory support may improve outcome in the setting of CS complicating an AMI. However, the optimal timing to initiate hemodynamic support has not been well characterized. Methods Data from 154 consecutive patients who underwent PCI and Impella 2.5 support from 38 US hospitals participating in the USpella Registry were included in our study. The primary end-point was survival to discharge. Secondary end-points included assessment of patients’ hemodynamics and in-hospital complications. A multivariate regression model was used to identify independent predictors for mortality. Results Both groups were comparable except for diabetes (P = 0.02), peripheral vascular disease (P = 0.008), chronic obstructive pulmonary disease (P = 0.05), and prior stroke (P = 0.04), all of which were more prevalent in the pre-PCI group. Patients in the pre-PCI group had more lesions (P = 0.006) and vessels (P = 0.01) treated. These patients had also significantly better survival to discharge compared to patients in the post-PCI group (65.1% vs.40.7%, P = 0.003). Survival remained favorable for the pre-PCI group after adjusting for potential confounding variables. Initiation of support prior to PCI with Impella 2.5 was an independent predictor of in-hospital survival (Odds ratio 0.37, 95% confidence interval: 0.17–0.79, P = 0.01) in multivariate analysis. The incidence of in-hospital complications included in the secondary end-point was similar between the 2 groups. Conclusions The results of our study suggest that early initiation of hemodynamic support prior to PCI with Impella 2.5 is associated with more complete revascularization and improved survival in the setting of refractory CS complicating an AMI.

Use of the Percutaneous Left Ventricular Assist Device in Patients with Severe Refractory Cardiogenic Shock as a Bridge to Long-term Left Ventricular Assist Device Implantation

BACKGROUND For patients with persistent cardiogenic shock refractory to intraaortic balloon pump (IABP) support, there are only limited means of resuscitation and bridging to surgical left ventricular assist device (LVAD) implantation. Extracorporeal membrane oxygenation and emergency surgical approaches have been attempted but are associated with significant morbidity and mortality. We evaluated the efficacy of a percutaneous left ventricular assist device (PVAD) as a bridge to LVAD implantation in patients in cardiogenic shock refractory to IABP and pressor support. METHODS Between May 2003 and April 2006, at our institution, 18 patients in severe refractory cardiogenic shock received a PVAD as a bridge to LVAD placement or orthotopic heart transplantation. Six patients had ischemic cardiomyopathy, and 12 had nonischemic cardiomyopathy. At the time of PVAD placement, 17 were receiving IABP support, and 10 were undergoing cardiopulmonary resuscitation. RESULTS The mean duration of PVAD support was 4.2 +/- 2.5 days. During this time, the cardiac index improved from 0.86 +/- 0.66 to 2.50 +/- 0.93 liters/min/m2 (p < 0.001), systolic blood pressure improved from 72 +/- 11 to 98 +/- 15 mm Hg (p = 0.001), and systemic mixed venous oxygenation improved from 37 +/- 7 to 62 +/- 6 mm Hg (p < 0.001). We terminated life support in 4 of the 18 patients before LVAD placement; 14 were successfully bridged to LVAD or heart transplantation. The mortality rate was 27% at 30 days and 33% at 6 months. There were no PVAD-associated deaths. CONCLUSION In patients with terminal hemodynamic collapse, PVAD support is an effective bridging therapy to LVAD and appears to be a viable alternative to other invasive methods of support.

Association between cell-derived microparticles and adverse events in patients with nonpulsatile left ventricular assist devices

BACKGROUND 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. METHODS 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. RESULTS 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%, p < 0.001), even though the 2 patient groups did not markedly differ in other clinical and hematologic parameters. CONCLUSIONS 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.

Improved Systemic Saturation after Ventricular Assist Device Implantation in a Patient with Decompensated Dextro-Transposition of the Great Arteries after the Fontan Procedure

We report the successful implantation of a HeartMate II left ventricular assist device after a failed Fontan procedure in a patient with dextro-transposition of the great arteries. The patient had developed significant intrapulmonary arteriovenous shunting. Despite the theoretical risk of worsening intrapulmonary shunting due to the decrease in systemic vascular resistance after device implantation, our patient did well. He was discharged from the hospital in stable condition and had better oxygen saturation than before the device was implanted. To our knowledge, ours is the 2nd report of the use of a ventricular assist device after the failure of a Fontan procedure, and the first report concerning the effect of ventricular assist device implantation on intrapulmonary shunting.

Bivalirudin for treatment of aortic valve thrombosis after left ventricular assist device implantation.

Ventricular assist devices are increasingly being used for mechanical support in patients with advanced heart failure. However, thromboembolism remains a leading cause of mortality in this population. We describe the successful treatment of native aortic valve thrombosis with bivalirudin in a patient with factor V Leiden mutation, who had undergone left ventricular assist device implantation, preventing the need for further surgical intervention.

Percutaneous Ventricular Assist Device in Hypertrophic Obstructive Cardiomyopathy With Cardiogenic Shock: Bridge to Myectomy

We present the case of a 69-year-old woman with end-stage hypertrophic obstructive cardiomyopathy who developed cardiogenic shock. She underwent emergent placement of a percutaneous left ventricular assist device (TandemHeart) in the catheterization lab as a bridge support device until a septal myectomy could be performed as definitive treatment. This case suggests a novel and promising use of the TandemHeart as a bridge to myectomy.

Total artificial heart implantation for biventricular failure due to eosinophilic myocarditis

Idiopathic hypereosinophilic syndrome is a condition of unknown etiology characterized by proliferation of eosinophils and their infiltration into tissues. Although cardiac involvement is rare, eosinophilic myocarditis can lead to life-threating fulminant congestive heart failure. Treatment of patients with eosinophilic myocarditis is challenging as heart failure can be caused by biventricular dysfunction. To our knowledge, this is the first case reported in the literature describing a patient with acute severe biventricular heart failure caused by eosinophilic myocarditis with mural left ventricular apical thrombus who was successfully treated with implantation of a total artificial heart as a bridge to heart transplant.

Preoperative Prealbumin Level as a Predictor of Outcomes in Patients Who Underwent Left Ventricular Assist Device Implantation

Malnutrition has been associated with an increased risk of morbidity and mortality in patients who undergo cardiac surgery. However, many measurements of malnutrition have been inadequate prognostic markers. In this study, we sought to determine whether low preoperative serum prealbumin level was associated with morbidity and mortality in patients who underwent continuous-flow left ventricular assist device (CF-LVAD) implantation. From November 2003 to March 2016, 526 patients with chronic heart failure underwent implantation of a CF-LVAD (HeartMate II, n = 403; HeartWare HVAD, n = 123). Our cohort comprised the 317 CF-LVAD recipients whose records included the preoperative serum prealbumin level. These patients were divided into 2 groups: those with a normal preoperative serum prealbumin level (>17 g/dL) and those with hypoprealbuminemia (≤17 g/dL). These groups were then compared with regard to preoperative demographics, incidence of postoperative complications, long-term survival rate, and cause of death. Kaplan-Meier survival analysis revealed that patients with a low preoperative prealbumin level had significantly decreased survival rates at 1, 6, 12, and 24 months (p <0.001) after CF-LVAD implantation and higher overall mortality (p = 0.04) than the patients with a normal prealbumin level, and that exacerbated heart failure made up the majority of this difference within the first 6 months. However, we found no significant correlations between low prealbumin level and postoperative complications. In conclusion, our findings demonstrate that preoperative serum prealbumin levels predict patient outcomes after CF-LVAD implantation.