Stephen Heitner

Correction of a pathogenic gene mutation in human embryos

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

Induction Bortezomib in AL Amyloidosis Followed By High Dose Melphalan and Autologous Stem Cell Transplantation: A Single Institution Retrospective Study

INTRODUCTION/BACKGROUND High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) for light chain amyloidosis (AL) was performed in 31 patients at Oregon Health and Science University between 2005 and 2012. Fifteen patients had cardiac involvement. PATIENTS AND METHODS Patients received melphalan 200 mg/m(2) or dose-adjusted HDM (100-140 mg/m(2)) depending on high risk features. Thirteen patients proceeded directly to ASCT after diagnosis, 12 patients received a bortezomib-containing regimen, and 6 received a variety of other induction regimens. RESULTS The day 100 treatment-related mortality was 9.6%. Overall hematologic (ORR) and organ response rates (OR) in the whole cohort after ASCT were 77% and 58%. ORR and OR in the bortezomib pretreated group were 92% and 75% vs. 69% and 54% in the group that received no pretreatment. The median time to maximum hematologic response after ASCT was reduced in the group that received bortezomib induction (3 vs. 14 months). Overall cardiac response rate was 60%; 100% in patients pretreated with bortezomib and 43% in those without induction treatment. With a median follow-up of 2.9 years, the 3-year progression-free and overall survival rates in the entire cohort were 66% and 73% and in those with cardiac involvement, 73% and 80%. CONCLUSION We observed that bortezomib-based induction is well tolerated in patients with and without cardiac involvement and suggest that this approach be studied in prospective multi-institutional trials.

Assessing mNIS+7Ionis and International Neurologists' Proficiency in an FAP Trial.

Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.

Optimal right heart filling pressure in acute respiratory distress syndrome determined by strain echocardiography

Right ventricular (RV) systolic dysfunction is common in acute respiratory distress syndrome (ARDS). While preload optimization is crucial in its management, dynamic fluid responsiveness indices lack reliability, and there is no consensus on target central venous pressure (CVP). We analyzed the utility of RV free wall longitudinal strain (RVFWS) in the estimation of optimal RV filling pressure in ARDS.

Chronic GvHD-associated serositis and pericarditis.

Serositis is a rare manifestation of chronic GvHD (cGvHD). No risk factors or laboratory changes associated with this syndrome have been recognized to date, and outcomes have not been described in a large series. We searched our institutional database for patients undergoing allogeneic hematopoietic cell transplant identified as having serositis or pericarditis. Laboratory studies from prior to diagnosis, at diagnosis and post diagnosis of serositis, as well as outcomes from invasive procedures were included. Twenty patients met criteria for cGvHD-associated serositis, and all but three patients had a prior diagnosis of cGvHD. Fifteen were male, and the complication occurred in the setting of immunosuppressant taper in 12 cases. Ten patients required invasive interventions, including pericardial window or stripping. A significant increase in blood monocytes and decrease in serum albumin were identified at diagnosis compared with pre-diagnosis. Out of 20 patients, 17 were treated with steroids, with 12 demonstrating a complete response. These data suggest that cGvHD-associated serositis occurs mainly in the setting of treated as opposed to de novo cGvHD and biomarkers associated with the syndrome include a decrease in albumin and an increase in absolute monocyte count. Outcome data from larger series are required to better understand the optimal management of this rare complication.

The Role of Imaging with Cardiac Computed Tomography in Cardio-Oncology Patients.

Cardiovascular diseases and cancer represent the two most common causes of morbidity and mortality in industrialized countries. With the increase in long-term survival of cancer patients, cardiovascular diseases are the leading cause of mortality for many cancer survivors. In this article, we will review the most common cardiovascular toxicities of cancer therapies and will describe the role of cardiac CT in the detection and monitoring of cardiovascular disease. While there is limited evidence for the use of CT imaging in cancer patients, we will discuss the utility of cardiac CT in the detection and management of coronary artery disease, pericardial and valvular heart disease.

Routine Papillary Muscle Realignment and Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy

BACKGROUND Septal myectomy has been the mainstay of the surgical treatment of obstructive hypertrophic cardiomyopathy (HCM); however, recently there is growing appreciation for associated mitral valve abnormalities that contribute to left ventricular outflow tract (LVOT) obstruction. In this study, we describe our experience with combined papillary muscle realignment (PMR) and septal myectomy for the treatment of obstructive HCM. METHODS We identified 44 patients undergoing surgery for obstructive HCM whose anatomy was amenable to combined PMR and septal myectomy at our institution over a 20-month period. All patients underwent resting and stress echocardiography preoperatively and postoperatively. Demographic, clinical, and imaging data were prospectively collected in a cardiac surgery database. RESULTS Patient age ranged broadly, with mean age of 54 (range, 18 to 76) years. Preoperatively, 70% of patients were New York Heart Association functional class III or IV, the mean stress LVOT gradient was 144 mm Hg, and severe mitral regurgitation (MR) with stress was seen in 81%. Additional procedures included division of myocardial bands (50%) and chordae (43%) and resection of accessory papillary muscles (25%). Following the procedure, mean resting and stress gradients were reduced to normal (12 and 27 mm Hg, respectively; p < 0.0001). No patient had severe MR and only 3 (6.8%) had moderate MR (p < 0.0001). Mean length of stay was 6 days and there were no mortalities. CONCLUSIONS Septal myectomy combined with PMR is a safe, highly effective, and reproducible procedure that reliably relieves LVOT obstruction and corrects MR without the need for mitral valve repair or replacement.

INOTERSEN IMPROVES QUALITY OF LIFE IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS WITH POLYNEUROPATHY AND CARDIOMYOPATHY: RESULTS OF THE PHASE 3 STUDY NEURO-TTR

Hereditary transthyretin amyloid (hATTR) is a severe, progressive, disabling, and often fatal disease caused by deposition of amyloid in nerves and cardiac tissue that leads to multiorgan failure. Inotersen, a generation 2+ antisense oligonucleotide inhibitor of TTR protein production, was evaluated

Bortezomib-based Chemotherapy for Multiple Myeloma Patients Without Comorbid Cardiovascular Disease Shows No Cardiotoxicity

Background: Proteasome inhibitors used in the treatment of multiple myeloma act primarily through the disruption of intrinsic cellular protein quality maintenance, resulting in proteotoxic stress, cellular dysfunction, and, ultimately, cell death. We assessed whether evidence has shown off‐target myocardial dysfunction related to the administration of bortezomib‐based chemotherapy for multiple myeloma. Patients and Methods: Patients aged 18 to 70 years who were free of significant cardiovascular disease were included. They underwent evaluations before and after each dose of bortezomib to assess for clinical, subclinical, and transient cardiotoxicity using echocardiography and serum biomarker measurement. Cardiac magnetic resonance imaging was performed at 3 separately defined intervals. The primary modality for determining subclinical myocardial dysfunction was echocardiographic assessment of the global longitudinal strain (GLS). Results: Eleven patients (7 men) with an average age of 55 years were included. No evidence of cumulative myocardial dysfunction was found using echocardiographic markers, primarily GLS (average change in absolute GLS, −1.17; P = .064). Additionally, no echocardiographic evidence of transient cardiotoxicity was found. The left ventricular ejection fraction (LVEF) also did not show any significant changes (&Dgr;LVEF, −2.17%; P = .15). Magnetic resonance imaging confirmed no changes in structure or function (&Dgr;LVEF, −2.6%; P = .54) and extracellular volume fraction (&Dgr; = 2%; P = .46). The serum biomarker levels also did not change significantly over time. Conclusion: We did not observe cardiotoxicity from bortezomib‐based chemotherapy despite very intensive evaluation with multiple modalities. Neither cumulative nor transient alterations were found in our metrics, suggesting that bortezomib is safe from a cardiovascular standpoint for patients free of cardiovascular disease.