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Background: Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low. Objective: To examine if pre-switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC. Patients/Methods: Adult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre-switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100-day prescription gap. Cumulative incidences of non-persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre-switch TTR levels with DOAC non-persistence was evaluated by Cox regression models. Results: A total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre-switch TTR ≤ 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3–17.0%) of the patients with a pre-switch TTR ≤ 45% became non-persistent to DOAC within 1 year, while 9.8% (95% CI 8.7–11.0%) did in those with a pre-switch TTR > 45%. In a multivariable model, a pre-switch TTR ≤ 45% was associated with a higher risk of non-persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22–1.97). Results were similar when using other cut-off points (60% or 70%) to define a low TTR. Conclusion: NVAF patients switching from VKA to DOAC due to a low pre-switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre-switch TTR.

Background Many patients who used vitamin K antagonists (VKAs) for long‐term prevention of thromboembolism are now actively switched to a direct oral anticoagulant (DOAC). Strict adherence to a DOAC is crucial for its success. However, therapy adherence and clinical factors that predict nonadherence are currently not well studied among patients who switched from a VKA to a DOAC. Methods A questionnaire was developed and sent to 2920 former patients of 3 anticoagulation clinics in the Netherlands, who switched from a VKA to a DOAC between January 2016 and December 2017. Questions concerned demographics, treatment persistence, adherence, and the occurrence of bleeding or thromboembolic events on DOACs. To identify predictors for nonadherence, logistic regression models were used to estimate crude and age/sex‐adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Results A total of 1399 questionnaires (response rate 48%) were used for analysis. DOAC treatment persistence (94%) and adherence (86%) rates were high. Several predictors of nonadherence were identified, including young age (OR, 5.9; 95% CI, 3.6‐9.8 for 75 years), low consultation frequency with a specialist (OR, 1.6; 95% CI, 1.1‐2.2), a history of minor bleeding on DOACs (OR, 1.9; 95% CI, 1.3‐2.8), and a twice‐daily dosing regimen (OR, 1.9; 95% CI, 1.3‐2.6). Conclusions Self‐reported treatment persistence and adherence were high in our study population, and several predictors of nonadherence were identified. Factors that can be influenced (low consult frequency with medical specialist, daily dosing regimen) may be used to improve therapy adherence.

Background Coagulopathy has been reported in severely ill patients with coronavirus disease 2019 (COVID‐19). It is unclear whether outpatients with COVID‐19 who are treated with vitamin K antagonists (VKAs) have unstable anticoagulation. Objective To assess the stability of VKA therapy in patients with COVID‐19 through a case‐crossover study. Methods Between February and July 2020, we included patients who tested positive for COVID‐19 from two anticoagulant clinics in the Netherlands. We collected international normalized ratios (INRs) determined between 26 weeks before infection and 12 weeks after. Time in therapeutic range (TTR) and the variance growth rate (VGR) were calculated within patients. Results Fifty‐one patients with COVID‐19 (mean age, 84 years) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks before COVID‐19 was 80% (95% confidence interval [CI], 75‐85) compared to 59% (95% CI, 51‐68) in the 6 weeks after infection. Mean TTR difference was −23% (95% CI, −32 to −14) with a time above therapeutic range of 38% (95% CI, 30‐47) in the 6 weeks after infection. The TTR rose again to 79% (95% CI, 69‐89) between 6 and 12 weeks after infection. Also, VGR increased, with a mean increase of 4.8 (95% CI, 2.1‐7.5) in the 6 weeks after infection. In the 26 weeks before infection, we registered 19 of 641 (3%) of INR ≥5.0 compared with 35 of 247 (14%) in the 6 weeks after (risk ratio, 4.4; 95% CI, 2.7‐7.3). Conclusions COVID‐19 is associated with a strong decrease in TTR and in therapeutic stability in patients taking VKAs. Additional monitoring in these patients is advised to maximize therapeutic stability.

Aims To validate the reported increased atherosclerotic cardiovascular disease (ASCVD) risk associated with very high lipoprotein(a) [Lp(a)] and to investigate the impact of routine Lp(a) assessment on risk reclassification. Methods and results We performed a cross-sectional case-control study in the Amsterdam UMC, a tertiary hospital in The Netherlands. All patients in whom a lipid blood test was ordered between October 2018 and October 2019 were included. Individuals with Lp(a) >99th percentile were age and sex matched to individuals with Lp(a) ≤20th percentile. We computed odds ratios (ORs) for myocardial infarction (MI) and ASCVD using multivariable logistic regression adjusted for age, sex, and systolic blood pressure. Furthermore, we assessed the additive value of Lp(a) to established ASCVD risk algorithms. Lipoprotein(a) levels were determined in 12 437 individuals, out of whom 119 cases [Lp(a) >99th percentile; >387.8 nmol/L] and 119 matched controls [Lp(a) ≤20th percentile; ≤7 nmol/L] were included. Mean age was 58 ± 15 years, 56.7% were female, and 30.7% had a history of ASCVD. Individuals with Lp(a) levels >99th percentile had an OR of 2.64 for ASCVD [95% confidence interval (CI) 1.45–4.89] and 3.39 for MI (95% CI 1.56–7.94). Addition of Lp(a) to ASCVD risk algorithms led to 31% and 63% being reclassified into a higher risk category for Systematic Coronary Risk Evaluation (SCORE) and Second Manifestations of ARTerial disease (SMART), respectively. Conclusion The prevalence of ASCVD is nearly three-fold higher in adults with Lp(a) >99th percentile compared with matched subjects with Lp(a) ≤20th percentile. In individuals with very high Lp(a), addition of Lp(a) resulted in one-third of patients being reclassified in primary prevention, and over half being reclassified in secondary prevention.

Background Since direct oral anticoagulants (DOACs) have been introduced for treatment and prevention of thromboembolic diseases, patients on vitamin K antagonists (VKA) have to decide whether to remain on VKA or switch to DOAC. The goal of this study was to evaluate treatment satisfaction, preferences, and concerns among those who already have switched from VKA to DOAC. Methods A questionnaire was sent to 2920 former patients of three anticoagulation clinics in the Netherlands, who switched from VKA to DOAC (2016‐2017). Questions concerned demographics, treatment satisfaction, concerns, perspectives on antidotes, and monitoring. To identify predictors for being concerned about adverse events, logistic regression was used to estimate crude‐ and adjusted (age and sex) odds ratios (OR) and 95% confidence intervals (95% CI). Results One thousand, three hundred ninety‐nine questionnaires (response rate 48%) were used for analysis. DOAC treatment satisfaction was high (mean 8.8 of a maximum 10‐point score). A quarter of patients expressed concerns about adverse events. Predictors for being concerned were age 75 years, OR 4.1, 95% CI 2.6‐6.4), female sex (OR 1.3, 95% CI 1.0‐1.6), and high education (OR 1.6, 95% CI 1.2‐2.2). Fifty‐nine percent of all patients indicated antidote availability as important, 73% would be willing to participate in DOAC monitoring. Conclusions DOAC treatment satisfaction was high. A substantial number of patients expressed concerns about adverse events, especially women, patients aged

Background: In January 2021, the Dutch vaccination programme against SARS-CoV-2 was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications. Aims: To investigate whether the BNT162b2 vaccine affects anticoagulation control in outpatients using Vitamin K antagonists (VKAs). Methods: A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. INR results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination. Results: A total of 3148 outpatient VKA users were included, with a mean age (standard deviation (SD)) of 86.7 (8.7) years, of whom 43.8% were male, 67.0% used acenocoumarol and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0-3.0). There was both an increased risk of supratherapeutic [OR=1.34 (95% CI 1.08-1.67)] and subtherapeutic levels [OR=1.40 (95% CI 1.08-1.83)] after first vaccination. In the high-intensity group (target INR 2.5-3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination [OR=2.29 (95% CI 1.22-4.28)] and 3.3 times higher after second vaccination [OR 3.25 (95% CI 1.06-9.97). Conclusion: BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with vitamin K antagonists, so it is advisable to monitor the INR short after vaccination, even in stable patients. Figure 1 Figure 1. Disclosures Kruip: Daiichi Sankyo: Research Funding; Bayer: Honoraria, Research Funding.

IntroductionClinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with AF.Methods and analysisThe FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate 2) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.Trial registration numberEudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study).

Objective— The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. Methods and Results— We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Δ139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (−25% [ P =0.005], −36% [ P P =0.02]), respectively). ApoAV-C271, -X139, -X148, and Δ139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. Conclusion— The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans , appears to be essential for their phenotypic expression.

Background— Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD. Methods and Results— LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43–85] versus 66 [46–92] ng/mL; P P P =0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size. Conclusions— Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C levels.

AIM: To assess whether early initiation of statin therapy for heterozygous familial hypercholesterolaemia favourably affects lipid profiles or vascular morphological changes. METHODS: Children and adolescents aged 10-16 y with heterozygous familial hypercholesterolaemia were administered fluvastatin (80 mg/d) for 2 y in a single-arm two-centre study. Carotid B-mode intima-media thickness (IMT) and M-mode arterial wall stiffness (beta) were recorded. Eighty of the 85 enrolled subjects completed the trial. RESULTS: The median decrease in low-density lipoprotein (LDL) cholesterol from baseline at last study visit was 33.9%; median decreases in total cholesterol, triglycerides and apolipoprotein B were 27.1%, 5.3% and 24.2%, respectively; the median increase in high-density lipoprotein (HDL) cholesterol was 5.3%. Changes in carotid arterial wall thickness and stiffness versus baseline were fractional and statistically non-significant (delta IMT -0.005 mm, 95% CI -0.018 to +0.007 mm, n=83; and delta beta = 0.017, 95% CI -0.219 to +0.253, n=79). Adverse events, all non-serious, were reported by 58 subjects (68.2%); four were suspected to be drug-related. Change in hormone levels and sexual maturation were appropriate for this age group. CONCLUSION: Fluvastatin lowered LDL cholesterol, total cholesterol and apolipoprotein B levels effectively over a prolonged period in children and adolescents with heterozygous familial hypercholesterolaemia. Carotid IMT and wall stiffness remained largely unchanged

Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.

Low levels of statin adherence may compromise treatment outcomes. The aim of this study was to investigate whether nurse-led cardiovascular risk-factor counseling could improve statin adherence and lipid levels without increasing patients' anxiety. Patients with indications for statin therapy for primary or secondary prevention of cardiovascular disease were randomly assigned to receive routine care or extended care (EC) at baseline and at months 3, 9, and 18. Patients in the EC group received a personalized risk-factor passport, showing modifiable and unmodifiable individual risk factors and a graphical presentation of their calculated absolute 10-year cardiovascular disease risk as well as the target risk that could be reached if all modifiable risk factors were optimally treated. Lipid levels were assessed at each visit. Carotid intima-media thickness was measured at baseline and at month 18. Adherence, anxiety, quality of life, symptoms, and smoking status were assessed using a self-administered questionnaire at each visit. A total of 201 patients were included in the study. Statin adherence was significantly higher (p

The relevance of apolipoprotein A-V (apoA-V) for human lipid homeostasis is underscored by genetic association studies and the identification of truncation-causing mutations in the APOA5 gene as a cause of type V hyperlipidemia, compatible with an LPL-activating role of apoA-V. An inverse correlation between plasma apoA-V and triglyceride (TG) levels has been surmised from animal data. Recent studies in human subjects using (semi)quantitative immunoassays, however, do not provide unambiguous support for such a relationship. Here, we used a novel, validated ELISA to measure plasma apoA-V levels in patients (n = 28) with hypertriglyceridemia (HTG; 1.8–78.7 mmol TG/l) and normolipidemic controls (n = 42). Unexpectedly, plasma apoA-V levels were markedly increased in the HTG subjects compared with controls (1,987 vs. 258 ng/ml; P < 0.001). In the HTG group, apoA-V and TG were positively correlated (r = +0.44, P = 0.02). In addition, we noted an increased level of the LPL-inhibitory protein apoC-III in the HTG group (45.8 vs. 10.6 mg/dl in controls; P < 0.001). The correlation between apoA-V and TG levels in the HTG group disappeared (partial r = +0.09, P = 0.65) when controlling for apoC-III levels. In contrast, apoC-III and TG remained positively correlated in this group when controlling for apoA-V (partial r = +0.43, P = 0.025). Our findings suggest that in HTG patients, increased TG levels are accompanied by high plasma levels of apoA-V and apoC-III, apolipoproteins with opposite modes of action. This study provides evidence for a complex interaction between apoA-V and apoC-III in patients with severe HTG.

Lipoprotein lipase (LPL) hydrolyzes triglycerides in the circulation and promotes the hepatic uptake of remnant lipoproteins. Since the gene was cloned in 1989, more than 100 LPL gene mutations have been identified, the majority of which cause loss of enzymatic function. In contrast to this, the naturally occurring LPL S447X variant is associated with increased lipolytic function and an anti-atherogenic lipid profile and can therefore be regarded as a gain-of-function mutation. This notion combined with the facts that 20% of the general population carries this prematurely truncated LPL and that it may protect against cardiovascular disease has led to extensive clinical and basic research into this frequent LPL mutant. It is only until recently that we begin to understand the molecular mechanisms that underlie the beneficial effects associated with LPL S447X . This review summarizes the current literature on this interesting LPL variant.

Lipoprotein lipase (LPL, triacylglycerol acylhydrolase; EC 3.1.1.3) deficiency (OMIM 238600) is an autosomal recessive inherited condition caused by mutations in the LPL gene, either in a homozygous or in a compound heterozygous state, leading to loss of lipolytic activity and resulting in severe hypertriglyceridaemia and subsequent risk for developing pancreatitis. Numerous LPL gene mutations leading to loss of catalytic function have been described. In this present study, we describe full clinical, biochemical and molecular analyses of severe hypertriglyceridaemic individuals in one Turkish and three Chinese families. We established one novel mutation (delCT1312–1313), a new combination of mutations (S193R and I194T) and four previously reported mutations (L252R, L252V, S193R and I194T) of the LPL gene and report phenotypes for these and four previously described mutations. Finally, we show that two patients homozygous for the LPL gene delCT1312–1313 mutations are characterized by absence of LPL activity that coincides with absence of LPL protein.

The frequent lipoprotein lipase S447X variant (LPLS447X) is firmly associated with a lower incidence of cardiovascular disease, the mechanisms for which remain to be established. To further unravel these beneficial effects, we studied the consequences of LPLS447X heterozygosity on LPL mass and activity, as well as on the postprandial lipoprotein profile. Fifteen male heterozygous LPLS447X carriers and 15 matched control subjects received an oral fat load (30 g/m(2)). Lipid parameters were evaluated at baseline and 2, 3, 4, and 6 hours after fat loading. LPL concentration and activity were analyzed, and endothelial function was evaluated noninvasively as flow-mediated dilation of the brachial artery. Although baseline apoprotein B-48 (apoB48) levels were similar, the rise in apoB48 was attenuated in LPLS447X carriers with 25% lower peak values compared with controls (P = .04). In conjunction, LPLS447X carriers were characterized by a 2.4-fold increase in preheparin LPL mass (P

OBJECTIVES: We sought to identify polymorphisms in genes that predispose to restenosis.BACKGROUND: Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis.METHODS: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process.RESULTS: Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement.CONCLUSIONS: The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.

Lipoprotein lipase (LPL) deficiency is a monogenetic disorder that underlies persistently elevated triglyceride (TG) levels and consequently predisposes patients to potentially life-threatening pancreatitis. In view of the absence of adequate therapy, we developed a gene replacement strategy to lower TG levels in these patients.1 This report summarizes the data of a first clinical trial (CT-AMT-010-01) in LPL-deficient individuals after intramuscular administration of a viral vector. In a 3-month open-label study, LPLS447X-adeno-associated virus subtype 1(AAV1) vector1,2 was injected in the leg musculature of 8 LPL-deficient patients at a dose of 1×1011 (n=4) or 3×1011 (n=4) genome copies per kilogram body weight (40 and 60 …

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life- threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno- associated virus serotype 1 (AAV1) vector encoding the human LPLS447X variant cDNA (AAV1-LPLS447X) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPLS447X in wild- type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti-AAV1 antibodies were generated. Histological analyses indicated a dose- dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short- term vector leakage from injection sites into the circulation, followed by liver- mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL- deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20 - 100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1- LPLS447X and secreted active LPL. These data support the initiation of a clinical trial in LPL- deficient patients, for which regulatory approval has been granted

Lipoprotein lipase (LPL) deficiency cannot be effectively treated and causes severe hypertriglyceridemia and pancreatitis. We have reported that adeno-associated virus serotype 1 (AAV1) based gene therapy normalizes triglyceride levels in LPL deficient mice and cats. The current study evaluates safety and biodistribution of the same vector, AAV1-LPLS447X, and addresses clinical application. Toxicological analysis after intramuscular administration of AAV1-LPLS447X (1E11-1E13 gc/kg) in murine dose-escalation studies did not reveal clinical or hematological changes. Shortly after administration (7 days), vector DNA was found in injected muscle, draining lymph nodes, and filtering organs while spread to reproductive organs was limited. 28 and 90 days post injection, vector DNA levels dissipated in all tissues except for injected muscle and lymph nodes. Furthermore, we studied 6 LPL deficient patients to assess eligibility for a first clinical trial. All presented with absence of LPL catalytic activity but LPL protein levels were 19-103% of normal. Infection of patient's myoblasts with AAV1-LPLS447X resulted in the secretion of catalytically active LPL in all cases. The efficacy and safety data obtained so far support the initiation of a clinical trial to test this vector in LPL deficient patients.