Daniel M. Kolansky

A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia

The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL) cholesterol were demonstrated in three of five patients; in vivo LDL catabolism was increased 53% following gene therapy in a receptor negative patient, who realized a reduction in serum LDL equal to ∼150 mg dl−1. This study demonstrates the feasibility of engrafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least four months after gene therapy. The variable metabolic responses observed following low-level genetic reconstitution in the five patients studied precludes a broader application of liver-directed gene therapy without modifications that consistently effect substantially greater gene transfer.

Rapid arterial hemostasis and decreased access site complications after cardiac catheterization and angioplasty: Results of a randomized trial of a novel hemostatic device

OBJECTIVESnThis study was performed to test the safety and efficacy of a novel bioabsorbable hemostatic puncture closure device deployed through an arterial sheath.nnnBACKGROUNDnCardiac catheterization procedures are associated with a risk of complications at the arterial access site. Increasing numbers of interventional procedures requiring large sheaths or intense anticoagulation underline the need for secure, rapid methods of obtaining hemostasis at the time of sheath removal.nnnMETHODSnWe conducted a randomized, multicenter trial in 435 patients undergoing cardiac catheterization or angioplasty at eight participating centers. In 218 patients, hemostasis was achieved using the device (group I); 217 patients were assigned to the manual pressure control group (group II).nnnRESULTSnThere were no significant differences in baseline characteristics. Time to hemostasis was considerably shorter in group I (2.5 +/- 15.2 vs. 15.3 +/- 11.7 min [mean +/- SD], p < 0.0001). The deployment success rate for the device was 96%, and 76% of group I patients experienced immediate (within 1 min) hemostasis. Complication rates were lower in group I for bleeding, hematoma and occurrence of any complication. There was no difference in the small incidence of pseudoaneurysm formation. There was no change in either group in the ankle/brachial systolic blood pressure index. Ultrasound follow-up studies 60 days after device deployment revealed complete absorption of the device in all cases. Subgroup analysis revealed particular benefit in patients undergoing interventional procedures. The administration of heparin was associated with a significantly higher complication rate in the manual pressure control group, whereas heparin had no effect on hemostasis time or complication rates in the device group.nnnCONCLUSIONSnThis sheath-deployed, bioabsorbable device provides a safe and effective means of obtaining rapid arterial hemostasis after cardiac catheterization procedures. It appears to be particularly useful in those patients most at risk for access site complications.

Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest

BACKGROUNDnComatose survivors of out-of-hospital cardiac arrest (OHCA) have high in-hospital mortality due to a complex pathophysiology that includes cardiovascular dysfunction, inflammation, coagulopathy, brain injury and persistence of the precipitating pathology. Therapeutic hypothermia (TH) is the only intervention that has been shown to improve outcomes in this patient population. Due to the similarities between the post-cardiac arrest state and severe sepsis, it has been postulated that early goal-directed hemodyamic optimization (EGDHO) combined with TH would improve outcome of comatose cardiac arrest survivors.nnnOBJECTIVEnWe examined the feasibility of establishing an integrated post-cardiac arrest resuscitation (PCAR) algorithm combining TH and EGDHO within 6h of emergency department (ED) presentation.nnnMETHODSnIn May, 2005 we began prospectively identifying comatose (Glasgow Motor Score<6) survivors of OHCA treated with our PCAR protocol. The PCAR patients were compared to matched historic controls from a cardiac arrest database maintained at our institution.nnnRESULTSnBetween May, 2005 and January, 2008, 18/20 (90%) eligible patients were enrolled in the PCAR protocol. They were compared to historic controls from 2001 to 2005, during which time 18 patients met inclusion criteria for the PCAR protocol. Mean time from initiation of TH to target temperature (33 degrees C) was 2.8h (range 0.8-23.2; SD=h); 78% (14/18) had interventions based upon EGDHO parameters; 72% (13/18) of patients achieved their EGDHO goals within 6h of return of spontaneous circulation (ROSC). Mortality for historic controls who qualified for the PCAR protocol was 78% (14/18); mortality for those treated with the PCAR protocol was 50% (9/18) (p=0.15).nnnCONCLUSIONSnIn patients with ROSC after OHCA, EGDHO and TH can be implemented simultaneously.

Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (hoFH) is caused by mutations in the low-density lipoprotein receptor gene and is characterized by severe hypercholesterolemia from birth and onset of premature cardiovascular disease (CVD) during childhood. The onset and progression of CVD using currently available testing methods in children with hoFH have not been fully characterized. A large cohort of patients with hoFH referred to our subspecialty clinic was studied. Thirty-nine patients (22 aged < or =16 years) underwent extensive cardiovascular, lipid, and genetic evaluation. Sixteen children < or =16 years without known CVD when first evaluated were followed up longitudinally for up to 8 years. CVD was clinically evident in 88% of subjects aged >16 years and 9% of those < or =16 years. Markers of atherosclerosis correlated significantly with age at which lipid-lowering treatment was initiated (abnormal coronary angiogram, abnormal aortic valve using echocardiography, and high calcium score using electron beam computed tomography; all p <0.01; abnormal carotid Doppler result; p = 0.03). Twenty of 22 children had no clinical evidence of coronary artery disease, yet 7 of these children had angiographically confirmed mild coronary artery disease (<50%) and 8 had mild to moderate aortic regurgitation using echocardiography. Of noninvasive tests, only evaluation of aortic valve regurgitation using echocardiography predicted the presence of angiographic coronary stenosis (p <0.001). During follow-up, 7 children developed progression of coronary and/or aortic valvular disease during their teenage years and 4 required surgical interventions. In conclusion, in these patients aggressive lipid-lowering treatment initiated in early childhood is warranted. Careful coronary and valvular surveillance strategies and coronary revascularization when appropriate are also warranted in this high-risk population.

Three-year clinical follow-up after Palmaz-Schatz stenting

OBJECTIVESnOur goals were to examine late clinical outcome in a cohort of patients who electively received Palmaz-Schatz intracoronary stents, to identify specific predictors of outcome and to determine the time course of the development of ischemic cardiac events after stenting.nnnBACKGROUNDnShort-term results of Palmaz-Schatz intracoronary stenting have been promising, with a reduction in both angiographic restenosis and clinical cardiac events up to 1 year after stenting.nnnMETHODSnWe analyzed the clinical outcomes in 65 consecutive patients who underwent stenting at least 3 years before analysis. Demographic, clinical and procedural predictors of survival and event-free survival, defined as freedom from myocardial infarction, stent-site percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery or death, were analyzed at a mean follow-up of 39 +/- 17 months.nnnRESULTSnAbsolute survival and event-free survival at 3 years were 88% and 56%, respectively. Three-year freedom from stent-site revascularization was 66%. Predictors of decreased long-term survival (p < 0.05) included diabetes and a high angina score (Canadian Cardiovascular Society class III/IV) at 6 and 12 months after stenting. Predictors of decreased event-free survival (p < 0.05) included a high angina score at 3, 6 and 12 months after stenting, smaller stent deployment balloon size and greater number of stents implanted. Freedom from adverse events by 6 months after stenting also correlated with long-term event-free survival. Eighty-five percent of stent-site revascularizations occurred within 1 year. During late follow-up (>24 months), no patients had stent-site stenoses requiring revascularization, whereas 11% of patients required revascularization in nonstented coronary segments.nnnCONCLUSIONSnClinical predictors of worse long-term outcome included diabetes mellitus, higher angina score at follow-up, smaller stent deployment balloon size and greater number of stents at implantation. During follow-up, the majority of adverse events and stent-site revascularizations occurred early after stenting, and disease progression in nonstented vessels accounted for the majority of late revascularization events.

Neurologic prognostication and bispectral index monitoring after resuscitation from cardiac arrest

OBJECTIVEnWhile the use of therapeutic hypothermia (TH) has improved outcomes after resuscitation from cardiac arrest, prognostication of survival and neurologic function remains difficult during the post-arrest time period. Bispectral index (BIS) monitoring, a non-invasive measurement of simplified electroencephalographic data, is increasingly being considered for post-arrest neurologic assessment and outcomes prediction, although data supporting the technique are limited. We hypothesized that BIS values within 24 h after resuscitation would correlate with neurologic outcomes at discharge.nnnMETHODSnWe prospectively collected BIS data in consecutive patients initially resuscitated from cardiac arrest and treated with TH in one academic medical center. We assessed BIS values in context of cerebral performance category (CPC) assessment on the day of discharge.nnnRESULTSnData were collected in 62 post-arrest patients, of whom 26/62 (42%) survived to hospital discharge. Mean BIS values at 24 h post-resuscitation were significantly different in the survivors with CPC 1-2 (good outcome) vs those with CPC 3-5 (poor outcome) or death during hospitalization (49+/-13 vs 30+/-20; p<0.001). Receiver operator characteristic analysis suggested that 24 h BIS was most predictive of CPC 1-2 outcome compared to the other timepoints; a BIS cutpoint of 45 exhibited a sensitivity of 63% and a specificity of 86%, with a positive likelihood ratio of 4.67. Sixteen patients exhibited a BIS of zero during at least one timepoint; all of these patients died during hospitalization.nnnCONCLUSIONSnBIS monitoring values at 24 h post-resuscitation are correlated with neurologic outcomes in patients undergoing TH treatment. In 16/62 patients, a BIS of zero at any timepoint was observed, which was uniformly correlated with poor outcome after resuscitation from cardiac arrest; however, a non-zero BIS is insufficient as a sole predictor of good neurologic survival.

One-year clinical outcomes of protected and unprotected left main coronary artery stenting

Aims To evaluate outcomes for left main coronary artery (LMCA) stenting and compare results between protected (left coronary grafted) and unprotected LMCA stenting in the current bare-metal stent era.nnMethods We reviewed outcomes among 142 consecutive patients who underwent protected or unprotected LMCA stenting since 1997. All-cause mortality, myocardial infarction (MI), target-lesion revascularization (TLR), and the combined majoradverse clinical event (MACE) rates at one year were computed.nnResults Ninety-nine patients (70%) underwent protected and 43 patients (30%) underwent unprotected LMCA stenting. In the unprotected group, 86% were considered poor surgical candidates. Survival at one year was 88% for all patients, TLR 20%, and MACE 32%. At one year, survival was reduced in the unprotected group (72% vs. 95%, P <0.001) and MACE was increased in the unprotected patients (49% vs. 25%, P =0.005).nnConclusions In the current era, stenting for both protected and unprotected LMCA disease is still associated with high long-term mortality and MACE rates. Stenting for unprotected LMCA disease in a high-risk population should only be considered in the absence of other revascularization options. Further studies are needed to evaluate the role of stenting for unprotected LMCA disease.

Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B-100 Production

Objective—We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans. Methods and Results—Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. The FCRs of very-low-density lipoprotein 1 (VLDL1), VLDL2, intermediate-density lipoprotein (IDL), and LDL apoB were lower in FH than in controls, with the LDL apoB FCR being significantly lower (0.148±0.049 versus 0.499±0.099 pools · d−1; P=0.008). Whereas receptor-defective FH patients had a total apoB PR similar to controls, receptor-null FH patients had a significantly greater total apoB PR than controls (35.97±10.51 versus 21.32±4.21 mg · kg−1 · d−1, respectively; P=0.02). Conclusions—This first study of apoB metabolism in homozygous FH using endogenous labeling with stable isotopes demonstrates that the LDL receptor contributes significantly to the clearance of LDL from plasma but plays a lesser role in the clearance of larger apoB-containing lipoproteins. Furthermore, these data also indicate that absence of a LDL receptor in humans substantially influences the apoB PR in vivo.

Triple-lumen peripherally inserted central catheter in patients in the critical care unit: prospective evaluation.

PURPOSEnTo prospectively evaluate outcomes associated with use of a triple-lumen (TL) peripherally inserted central catheter (PICC) in the intensive care unit (ICU) setting.nnnMATERIALS AND METHODSnPatients were prospectively enrolled in this HIPAA-compliant, institutional review board-approved study. Informed consent was obtained. All patients were in one hospitals ICUs and needed intermediate-term central venous access requiring three lumina. A 6-F tapered TL PICC was placed by a bedside nursing-based team with backup from the Interventional Radiology department. Placement complications, as well as long-term complications, were recorded. At catheter removal, ultrasonography (US) of the veins containing the TL PICC was performed to detect occult venous thrombosis. Regardless of indication for removal, catheters were sent for culture to detect colonization.nnnRESULTSnThe study was stopped prematurely after 50 of a planned 167 patients were enrolled when a scheduled interim analysis detected a venous thrombosis rate that was considered unacceptably high by the study oversight committee (thrombosis was symptomatic in 20% of patients [10 of 50]). Venous thrombosis (symptomatic or asymptomatic) was detected in 26 of 45 patients (58%; 95% confidence interval [CI]: 43%, 72%) examined with US. Documented catheter-related bloodstream infection did not occur (0%; 95% CI: 0%, 7%); colonization was detected in three of 29 catheter tips sent for culture (10%; 95% CI: 2%, 27%). Catheter malfunction and dislodgment occurred in one patient each.nnnCONCLUSIONnThe TL PICC design used in this study resulted in unacceptably high venous thrombosis rates. Even when used in a high-risk setting for infection (ie, the ICU), rates of clinically evident infection and colonization were absent and low, respectively.

Time to awakening and neurologic outcome in therapeutic hypothermia-treated cardiac arrest patients

INTRODUCTIONnTherapeutic hypothermia (TH) has been shown to improve outcomes in comatose Post-Cardiac Arrest Syndrome (PCAS) patients. It is unclear how long it takes these patients to regain neurologic responsiveness post-arrest. We sought to determine the duration to post-arrest awakening and factors associated with times to such responsiveness.nnnMETHODSnWe performed a retrospective chart review of consecutive TH-treated PCAS patients at three hospitals participating in a US cardiac arrest registry from 2005 to 2011. We measured the time from arrest until first documentation of awakening, defined as following commands purposefully.nnnRESULTSnWe included 194 consecutive TH-treated PCAS patients; mean age was 57±16 years; 59% were male; 40% had an initial shockable rhythm. Mean cooling duration was 24±8h and mean rewarming time was 14±13h. Survival to discharge was 44%, with 78% of these discharged with a good neurologic outcome. Of the 85 patients who awakened, median time to awakening was 3.2 days (IQR 2.2, 4.5) post-cardiac arrest. Median time to awakening for a patient discharged in good neurological condition was 2.8 days (IQR 2.0, 4.5) vs. 4.0 days (IQR 3.5, 7.6) for those who survived to discharge without a good neurological outcome (p=0.035). There was no significant association between initial rhythm, renal insufficiency, paralytic use, post-arrest seizure, or location of arrest and time to awakening.nnnCONCLUSIONnIn TH-treated PCAS patients, time to awakening after resuscitation was highly variable and often longer than three days. Earlier awakening was associated with better neurologic status at hospital discharge.