M. Dionizovik-Dimanovski

Device exchange in HeartMate II recipients: long-term outcomes and risk of thrombosis recurrence.

Successful long-term use of the HeartMate II (HM II) left ventricular assist device has become commonplace but may be complicated by mechanical failure, infection, or thrombosis necessitating device exchange (DE). A subcostal approach to device exchange with motor exchange only is less traumatic, but long-term outcomes have not been reported. A retrospective chart review of all patients who required HM II to HM II device exchange at our institution was conducted. Of the 232 HM II patients implanted between January 2008 and July 2013, 28 required 36 device exchanges during a follow-up of 33.72 ± 17.25 months. The Kaplan–Meier 1 year survival was 63% for sternotomy exchanges and 100% for subcostal exchanges. Twenty-one exchanges were performed for initial or recurring device thrombosis. Although there was no difference in the risk of subsequent thrombosis after subcostal versus sternotomy exchange, the overall risk of recurring device thrombosis after device exchange for the same was high (31%). HM II device exchange via the subcostal approach has excellent short- and long-term outcomes. Device exchange performed for thrombosis is associated with a high recurrence risk irrespective of surgical approach

Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans

Targeting apoB synthesis with mipomersen (KYNAMRO) can be effective for lowering plasma levels of apoB lipoproteins without reducing the secretion of VLDL. Making sense of antisense Mipomersen is an FDA-approved antisense oligonucleotide that lowers low density lipoprotein (LDL) in patients with high cholesterol by targeting apolipoprotein B (apoB) synthesis. Although safe, how mipomersen works exactly in humans is unclear. Reyes-Soffer and colleagues found in healthy volunteers that the drug reduced levels of LDL and its precursor, very low density lipoproteins (VLDL), by increasing clearance of both of these vessel-clogging lipoproteins rather than reducing their secretion from the liver. The direct clearance of VLDL led to reduced production of LDL. Studies in mice and cell lines demonstrated how the liver compensates for reduced apoB synthesis to potentially avoid hepatic steatosis. Mipomersen is a 20mer antisense oligonucleotide (ASO) that inhibits apolipoprotein B (apoB) synthesis; its low-density lipoprotein (LDL)–lowering effects should therefore result from reduced secretion of very-low-density lipoprotein (VLDL). We enrolled 17 healthy volunteers who received placebo injections weekly for 3 weeks followed by mipomersen weekly for 7 to 9 weeks. Stable isotopes were used after each treatment to determine fractional catabolic rates and production rates of apoB in VLDL, IDL (intermediate-density lipoprotein), and LDL, and of triglycerides in VLDL. Mipomersen significantly reduced apoB in VLDL, IDL, and LDL, which was associated with increases in fractional catabolic rates of VLDL and LDL apoB and reductions in production rates of IDL and LDL apoB. Unexpectedly, the production rates of VLDL apoB and VLDL triglycerides were unaffected. Small interfering RNA–mediated knockdown of apoB expression in human liver cells demonstrated preservation of apoB secretion across a range of apoB synthesis. Titrated ASO knockdown of apoB mRNA in chow-fed mice preserved both apoB and triglyceride secretion. In contrast, titrated ASO knockdown of apoB mRNA in high-fat–fed mice resulted in stepwise reductions in both apoB and triglyceride secretion. Mipomersen lowered all apoB lipoproteins without reducing the production rate of either VLDL apoB or triglyceride. Our human data are consistent with long-standing models of posttranscriptional and posttranslational regulation of apoB secretion and are supported by in vitro and in vivo experiments. Targeting apoB synthesis may lower levels of apoB lipoproteins without necessarily reducing VLDL secretion, thereby lowering the risk of steatosis associated with this therapeutic strategy.

Correlation Between Home INR and Core Laboratory INR in Patients Supported with Continuous-Flow Left Ventricular Assist Devices.

It has been well established that patient self-testing (PST) of international normalized ratio (INR) using home monitoring devices increases the average therapeutic time and patient satisfaction. Long-term anticoagulation therapy with warfarin is used in patients with continuous-flow left ventricular assist device (CF-LVAD) to minimize the occurrence of thromboembolic events; however, PST devices have never been tested in patients with CF-LVADs. The purpose of this study was to determine the reliability of the PST device Alere INRatio 2 in patients supported with CF-LVADs. A correlation study was performed in 50 patients with CF-LVAD who were on stable warfarin therapy for a minimum of 3 weeks. Simultaneous INR values were determined from capillary whole blood samples using the Alere PST device and venous blood samples processed in the core laboratory at Columbia University Medical Center. There was a moderate correlation between the venous and the capillary INR values with a correlation coefficient of 0.83. The median difference between the methods was 0.39, with 44 of 50 patients recording higher INRs with Alere. Results remained unchanged after adjusting for use of amiodarone, abnormal hematocrit and liver enzymes, creatinine, and thyroid-stimulating hormone. Point of care testing with Alere correlates moderately well but consistently overestimates INR when compared with conventional laboratory testing in patients with CF-LVAD.