Sotirios Tsimikas’s research while affiliated with Ionis Pharmaceuticals and other places

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Publications (503)


Differential Effects of Volanesorsen on ApoC-III, Triglycerides and Pancreatitis in Familial Chylomicronemia Syndrome Diagnosed by Genetic or Non-Genetic Criteria
  • Article

December 2024

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12 Reads

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2 Citations

Journal of Clinical Lipidology

Sotirios Tsimikas

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Henry N. Ginsberg

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Veronica J. Alexander

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[...]

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Traditional Risk Factors, Optimal Cardiovascular Health, and Elevated Lipoprotein(a)

November 2024

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19 Reads

European Journal of Preventive Cardiology

Aims To assess the association of traditional risk factor burden and Life’s Simple 7 (LS7) score with incident atherosclerotic cardiovascular disease (ASCVD) across Lp(a) levels. Methods There were 6,676 participants without clinical ASCVD from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Low, intermediate, and elevated Lp(a) were defined as <30, 30-49, and >50 mg/dL, respectively. Cox proportional hazards regression assessed the association of traditional risk factors and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD across Lp(a) groups during a median follow-up of 17.7 years, adjusting for demographics and time-varying statin and aspirin therapy. Results The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 (IQR 8-41) mg/dL, 13% had Lp(a) 30-49 mg/dL, and 20% had Lp(a) >50 mg/dL. Individuals with Lp(a) >50 mg/dL had higher absolute event rates across all LS7 categories. There was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.60). Compared to a poor LS7 score, optimal LS7 conferred a lower risk for incident ASCVD among individuals with Lp(a) <30 (HR=0.45, 95% CI: 0.28-0.71), Lp(a) 30-49 (HR=0.12, 95% CI: 0.02-0.89), and Lp(a) >50 mg/dL (HR=0.35, 95% CI: 0.13-0.99). Conclusion Participants without clinical ASCVD who achieved an optimal LS7 score had ASCVD risk reduction regardless of Lp(a) level. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among individuals with elevated Lp(a).



Abstract 4119560: Oxidized Phospholipids and Calcific Aortic Valvular Disease

November 2024

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12 Reads

Circulation

Introduction: Oxidized phospholipids (OxPL) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) [Lp(a)]. Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). Aims: We aimed to evaluate the independent associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. Methods: OxPL-apoB and Lp(a) were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA) and a participant-level meta-analysis of four randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity (V max )) was evaluated using multivariable linear regression models. Results: In MESA, both OxPL-apoB and Lp(a) were independently associated with prevalent AVC (OR (95% CI) per SD: 1.19 (1.07-1.32) and 1.13 (1.01-1.27), respectively) with a significant interaction between the two (p<0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated independently (interaction p<0.01). The OxPL-apoB*Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. Mediation analyses demonstrated that Lp(a) partially mediated the association between OxPL-apoB and AVC. In a 2x2 analysis, the greatest risk for both prevalent and incident AVC was observed when Lp(a) and OxPL-apoB were both above the 80 th percentile ( Figure ). In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were independently associated with faster increase in V max , but when evaluated together, only OxPL-apoB remained significant (ß 0.07, 95% CI 0.01-0.12, Figure ). Conclusions: OxPL-apoB is an independent predictor of the presence, incidence and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels and may represent a novel therapeutic target for CAVD.


Abstract 4135861: Lipoprotein(a) and Its Impact on Left Ventricular Remodeling Over a Decade: The Multi-Ethnic Study of Atherosclerosis

November 2024

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4 Reads

Circulation

Background: Lipoprotein (a) (Lp[a]) is associated with an increased risk of cardiovascular disease and mortality, as well as heart failure and myocardial fibrosis. However, the link between Lp(a) and cardiac remodeling as a pathway to adverse cardiac outcomes remains unknown. Objectives: This study investigated the relationship between Lp(a) levels and longitudinal changes in the left ventricular (LV) remodeling over a decade among individuals without a previous history of cardiovascular disease. Methods: 2,366 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac MRI at Visit 1 (2000-02) and Visit 5 (2010-12) and had available Lp(a) at baseline were examined. Lp(a) was analyzed as a continuous and a categorical variable based on quartiles (Q1[<7.6 mg/dL], Q2[7.6-16.7 mg/dL], Q3[16.8-38.8 mg/dL], Q4[>38.8 mg/dL]). Multivariable linear regression analysis was used to examine the association of Lp(a) with changes in cardiac MRI measures of LV remodeling ( Table ). Results: Participants had a mean age 60±9 years and 53% were women. Over 10-year follow-up, LV indexed volumes decreased, while LV indexed mass and mass to volume ratio increased across all the Lp(a) quartiles. However, LV ejection fraction only decreased in the third and fourth Lp(a) quartiles. Lp(a) examined as a continuous variable was associated with an increase in LV end-systolic indexed volume (per log-unit Lp[a]; β 0.32 mL/m ² ; P = 0.01), LV indexed mass (per log-unit Lp[a]; β 0.38 g/m ² ; P = 0.02), and a decrease in LV ejection fraction (per log-unit Lp[a]; β -0.29 %; P = 0.02) over 10 years after adjusting for sociodemographic and traditional cardiovascular risk factors ( Table ). Similarly, the fourth Lp(a) quartile was associated with an increase in LV end-systolic indexed volume (β 1.07 mL/m ² ; P = 0.01), LV indexed mass (β 1.17 g/m ² ; P = 0.02) and a decrease in LV ejection fraction (β -1.01 %; P = 0.01) compared to the first Lp(a) quartile after controlling for risk factors. The observed associations remained significant after further adjusting for aortic valve calcium score at Visit 1 ( Table - Model 3), and baseline coronary artery calcium score and interim myocardial infarction ( Table - Model 4). Conclusions: In a multi-ethnic cohort of participants free of cardiovascular disease at baseline, higher Lp(a) levels were independently associated with an increase in LV end-systolic volume and LV mass as well as a decrease in LV ejection fraction over the span of a decade.


Abstract 4124446: Traditional Risk Factors, Cardiovascular Health, and Elevated Lipoprotein(a): The Multi-Ethnic Study of Atherosclerosis

November 2024

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8 Reads

Circulation

Introduction: One in five individuals have elevated lipoprotein(a) [Lp(a)], an inheritable risk factor that is causally associated with atherosclerotic cardiovascular disease (ASCVD). Whether individuals with elevated Lp(a) derive similar benefit from control of ASCVD risk factors has not been well-studied. Hypothesis: The magnitude of benefit associated with optimal cardiovascular health will be similar across the spectrum of Lp(a). Aim: To assess the association of traditional risk factor burden and Life’s Simple 7 (LS7) score with incident ASCVD across Lp(a) values. Methods: We studied 6,676 participants from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Elevated Lp(a) was defined as > 50 mg/dL. As defined by the American Heart Association, LS7 metrics included smoking, physical activity, body mass index, diet, total cholesterol, blood pressure, and glucose. Multivariable Cox proportional hazards regression assessed the association of traditional risk factor burden and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD for individuals with and without elevated Lp(a) during a median follow-up of 17.7 years. Results: The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 mg/dL and 20% had Lp(a) > 50 mg/dL. Individuals with Lp(a) > 50 mg/dL had the highest burden of traditional risk factors except cigarette smoking. Compared to those with a poor LS7 score, those with an optimal LS7 score had a lower ASCVD risk that was significant for participants with Lp(a) <50 mg/dL (HR=0.37, 95% CI: 0.25-0.55), but borderline significant for participants with Lp(a) > 50 mg/dL (HR=0.41, 95% CI: 0.16-1.02). Individuals with Lp(a) > 50 mg/dL had the highest absolute event rates across all LS7 categories, and there was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.64, Figure ). Conclusions: Participants with an optimal LS7 score had similar reduction in ASCVD risk regardless of their Lp(a) burden. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among patients with elevated Lp(a).


Abstract 4146940: External Validation of EchoNet-LVH, a Deep Learning Model for Cardiac Amyloidosis, for Association with Cardiomyopathy

November 2024

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2 Reads

Circulation

Background: Early diagnosis of cardiac transthyretin amyloidosis (ATTR) facilitates disease-modifying therapies. EchoNet-LVH is a deep learning model trained on 16062 echocardiograms which quantifies the likelihood of cardiac amyloidosis. Patients with ATTR polyneuropathy are at risk for cardiac involvement, highlighting the systemic nature of ATTR. Aim: To evaluate whether the EchoNet-LVH prediction of cardiac amyloidosis identifies patients in an ATTR polyneuropathy cohort who have known amyloid cardiomyopathy. Hypothesis: The EchoNet-LVH cardiac amyloidosis score will be associated with amyloid cardiomyopathy, cardiovascular symptoms, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods: The NEURO-TTRansform trial enrolled patients with hereditary ATTR polyneuropathy, regardless of cardiac involvement. ATTR cardiomyopathy at baseline was defined by a clinical diagnosis of cardiac amyloidosis or IVSd≥13mm in the absence of hypertension. We applied Echonet-LVH to echocardiograms performed at baseline. The association of EchoNet-LVH score with amyloid cardiomyopathy, abnormal cardiovascular symptoms (NYHA functional class II or greater) and NT-proBNP (>125 pg/mL) was estimated by logistic regression, adjusted for age and sex. Results: EchoNet-LVH score could be calculated in 130 out of 204 patients (64%). Mean age was 55 years, 28% were female, and 52 were defined as having ATTR cardiomyopathy. The EchoNet-LVH categorized 62 patients (48%) as not predicted to have cardiac involvement, 28 (22%) as intermediate risk, and 40 (31%) as positive. Higher EchoNet-LVH category was associated with higher odds of amyloid cardiomyopathy (OR 4.5 [95% CI 2.6-7.67] per level, p<0.001). Among patients with predicted cardiac involvement 85% had cardiomyopathy, compared to 20% in the predicted negative and intermediate categories. Higher score was associated with greater likelihood NYHA functional class II or greater and elevated NT-proBNP. Conclusion: These data show the feasibility of utilizing the EchoNet-LVH model to identify patients with a higher likelihood of amyloid cardiomyopathy. Automated deep learning tools like this may aid in the early diagnosis of cardiac amyloidosis.


Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis

November 2024

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30 Reads

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2 Citations

Circulation

BACKGROUND Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. METHODS A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. RESULTS Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1–77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06–1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46–2.48]). CONCLUSIONS These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.



The Effects of Colchicine on Lipoprotein(a) and Oxidized Phospholipid Associated Cardiovascular Disease Risk

October 2024

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46 Reads

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1 Citation

European Journal of Preventive Cardiology

Aims Inflammatory lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPLs) on lipoproteins convey residual cardiovascular disease risk. The LoDoCo2 (low-dose colchicine 2) trial showed that colchicine reduced the risk for cardiovascular events occurring on standard therapies in patients with chronic coronary disease (CCS). We explored the effects of colchicine on Lp(a) and oxidized lipoprotein associated risk in a LoDoCo2 biomarker subpopulation. Methods Lp(a), OxPLs on apolipoprotein(a) [OxPL-apo(a)] and apolipoprotein B (OxPL-apoB) levels were determined in the biomarker population of the LoDoCo2 trial (n = 1777). Cox regression analysis was used to compare the risk for the primary endpoint, consisting of myocardial infarction, ischemic stroke, or ischemia-driven revascularization by biomarker levels. Interactions between treatment, Lp(a) and OxPL levels were evaluated. Results Lp(a), OxPL-apo(a) and OxPL-apoB levels were similar between the colchicine and placebo groups. Consistent risk reduction by colchicine was observed in those with Lp(a) <125 nmol/L and ≥125 nmol/L, and the highest OxPL-apo(a) tertile compared to the lowest (Pinteraction=0.92 and 0.66). The absolute risk reduction for those with Lp(a) ≥125 nmol/L appeared higher compared to those with Lp(a) <125 nmol/L (4.4% vs 2.4%). A treatment interaction for colchicine was found in those with the highest OxPL-apoB tertile vs the lowest (Pinteraction=0.04). Conclusion In patients with CCS, colchicine reduces cardiovascular disease risk in those with and without elevated Lp(a) but absolute benefits appeared higher in those with Lp(a) ≥125 nmol/L. Patients with higher levels of OxPL-apoB experienced greater benefit of colchicine, suggesting colchicine may be more effective in subjects with heightened oxidation-driven inflammation.


Citations (59)


... The evidence from intervention studies is also conflicting [69][70][71][72][73][74][75][76] (Table 2). A recent meta-analysis by Bhatia et al., including 27,658 patients pooled from six placebocontrolled statin trials, was performed to assess the relationship between elevated LDL-C and Lp(a) levels on the risk of fatal or nonfatal CAD events, stroke, or any coronary or carotid revascularization. ...

Reference:

Interaction Between Lipoprotein(a) and Other Lipid Molecules: A Review of the Current Literature
Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis
  • Citing Article
  • November 2024

Circulation

... A conjugation to N-acetylgalactosamine facilitates its selective uptake by the asialoglycoprotein receptor 1 in the liver [65]. In the latest phase 1 trial performed in 28 healthy Japanese Americans with plasma TG ≥ 90 mg/dL (≥1 mmol/L), a maximum TG reduction was achieved with 60 mg single-dose olezarsen reaching −52.7% at 15 days and −73.8% at 92 days [66]. ...

Efficacy and safety of olezarsen in lowering apolipoprotein C-III and triglycerides in healthy Japanese Americans
  • Citing Article
  • Full-text available
  • October 2024

Lipids in Health and Disease

... Thus, new therapeutic alternatives are needed. Furthermore, a related hyperlipoproteinemia, namely elevated lipoprotein(a) (Lp[a]), is associated with an increased risk of ASCVD and aortic valve disease, but this dyslipidemia cannot be effectively managed with existing therapies [3,4]. In addition, patients with severe hypertriglyceridemia (HTG) are at a high risk of acute pancreatitis [5], while those with mild-to-moderate HTG have an increased ASCVD risk [6], but traditional therapies including statins and fibrates show minimal evidence of clinical benefit. ...

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis
  • Citing Article
  • July 2024

... Higher plasma oxLDL concentrations have been observed in subjects with atherosclerotic plaques [30], and are indicative of future cardiovascular risk prediction in healthy populations [31]. Similarly, Lp(a), a lipoprotein resembling LDL, but containing apolipoprotein(a), contributes to the CVD progression by promoting both atherosclerosis and thrombosis [32]. The independent contributions of elevated Lp(a) levels in cardiovascular events highlight importance of this in guiding primary prevention strategies for CVD [33]. ...

Lipoprotein(a) in the Year 2024: A Look Back and a Look Ahead
  • Citing Article
  • June 2024

Arteriosclerosis Thrombosis and Vascular Biology

... A study by Masson et al. [73] demonstrated a positive relationship between Lp(a) levels and HF. Among individuals with stage A or B HF, higher Lp(a) and OxPL concentrations are independent risk factors for progression to symptomatic HF or cardiovascular death [74]. Given the close relationship between HF and AF, elevated Lp(a) levels may impact the development and progression of both conditions through various mechanisms. ...

Lipoprotein(a), Oxidized Phospholipids, and Progression to Symptomatic Heart Failure: The CASABLANCA Study

Journal of the American Heart Association

... En este contexto, es posible que cierto grupo de pacientes se beneficien de la utilización de ácido acetilsalicílico en prevención primaria 16 , pero aún no hay una recomendación específica que lo avale. Llamativamente, nuestro trabajo demostró que un tercio de los cardiólogos participantes la utilizan, conducta muy en línea con algunas publicaciones recientes que demuestran la reducción de la mortalidad CV y los eventos coronarios 17,18 . ...

Aspirin Use for Primary Prevention Among US Adults With and Without Elevated Lipoprotein(a)

American Journal of Preventive Cardiology

... The therapeutic potential of E06 lies in its capacity to neutralize OxPC bioactivity, and there are multiple recent reports of therapeutic properties, including anti-inflammatory, anti-atherogenic, and anti-nociceptive effects, as well as promoting inflammation resolution. Examples include decreased infarct size with intracoronary E06 in a porcine model of ischemia/reperfusion injury [64], increased macrophage uptake of oxidized lipids and lower lung inflammatory markers with intranasal E06 in cigarette smoke-exposed mice [60], and reduced OxPC-induced pain inflammation and hypersensitivity with local E06 application [26,36]. Transgenic mice that express high levels of the single-chain variable fragment of E06 (E06-scFv, a functional E06 component responsible for binding to OxPCs) in plasma are resistant to OxPC-induced inflammatory signaling in atherosclerosis, aortic stenosis, and hepatic steatosis [37]. ...

Abstract 12366: Intracoronary Delivery of E06 Antibody Directed to Oxidized Phospholipids Decreases Infarct Size in a Porcine Model of Ischemia/Reperfusion Injury
  • Citing Article
  • November 2021

Circulation

... The second key trial of olezarsen, called BRIDGE [69], was a double-blind, randomized, phase IIb trial of 154 adults either with moderate HTG (defined as a TG level of 150-499 mg/dL or 1.7-5.6 mmol/L) plus an elevated ASCVD risk or with severe HTG (defined as a TG level of ≥ 500 mg/dL or ≥ 5.6 mmol/L) to receive either olezarsen 50 mg or olezarsen 80 mg. Median patient age was 62 years and median TG level was 242 mg/dL (2.73 mmol/L). ...

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
  • Citing Article
  • April 2024

The New-England Medical Review and Journal

... Two important clinical trials have recently been published with olezarsen. The first, called BALANCE [68], was a double-blind, randomized, 52-week, phase III trial of 66 adults with FCS, of whom 22 were assigned to the olezarsen 80-mg group, 21 to the olezarsen 50-mg group, and 23 to the placebo group. Plasma TG levels at 6 months were significantly reduced with the olezarsen 80-mg dose by 43.5%, but not with the 50-mg dose. ...

Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome
  • Citing Article
  • April 2024

The New-England Medical Review and Journal

... The above three studies, which were not individually powered to detect an effect on pancreatitis risk, were subsequently meta-analyzed together [65]. This revealed that 2% of patients randomized to volanesorsen had incident pancreatitis events compared with 10% of those randomized to placebo, a significant 82% reduction in pancreatitis risk (odds ratio, 0.18; 95% CI 0.04-0.82). ...

Volanesorsen to Prevent Acute Pancreatitis in Hypertriglyceridemia
  • Citing Article
  • February 2024

The New-England Medical Review and Journal