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Effect of Spironolactone on Blood Pressure in Subjects With Resistant Hypertension
- Neil Chapman,
- Joanna Dobson,
- Sarah Wilson,
- Björn Dahlöf,
- Peter S. Sever,
- Hans Wedel,
- Neil R. Poulter
Hypertension Volume 49, Issue 41 April 2007

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Spironolactone is recommended as fourth-line therapy for essential hypertension despite few supporting data for this indication. We evaluated the effect among 1411 participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm who received spironolactone mainly as a fourth-line antihypertensive agent for uncontrolled blood pressure and who had valid BP measurements before and during spironolactone treatment. Among those who received spironolactone, the mean age was 63 years (SD: ±8 years), 77% were men, and 40% had diabetes. Spironolactone was initiated a median of 3.2 years (interquartile range: 2.0 to 4.4 years) after randomization and added to a mean of 2.9 (SD: ±0.9) other antihypertensive drugs. The median duration of spironolactone treatment was 1.3 years (interquartile range: 0.6 to 2.6 years). The median dose of spironolactone was 25 mg (interquartile range: 25 to 50 mg) at both the start and end of the observation period. During spironolactone therapy, mean blood pressure fell from 156.9/85.3 mm Hg (SD: ±18.0/11.5 mm Hg) by 21.9/9.5 mm Hg (95% CI: 20.8 to 23.0/9.0 to 10.1 mm Hg; P<0.001); the BP reduction was largely unaffected by age, sex, smoking, and diabetic status. Spironolactone was generally well tolerated; 6% of participants discontinued the drug because of adverse effects. The most frequent adverse events were gynecomastia or breast discomfort and biochemical abnormalities (principally hyperkaliemia), which were recorded as adverse events in 6% and 2% of participants, respectively. In conclusion, spironolactone effectively lowers blood pressure in patients with hypertension uncontrolled by a mean of ≈3 other drugs. Although nonrandomized and not placebo controlled, these data support the use of spironolactone in uncontrolled hypertension.
Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future
- Douglas L. Mann
Circulation Research Volume 91, Issue 1129 November 2002

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Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
Early and Repetitive Stimulation of the Arm Can Substantially Improve the Long-Term Outcome After Stroke: A 5-Year Follow-up Study of a Randomized Trial
- Hilde Feys,
- Willy De Weerdt,
- Geert Verbeke,
- Gail Cox Steck,
- Chris Capiau,
- Carlotte Kiekens,
- Eddy Dejaeger,
- Gustaaf Van Hoydonck,
- Guido Vermeersch and
- Patrick Cras
Stroke Volume 35, Issue 41 April 2004

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Background and Purpose— Several studies have investigated the effect of therapeutic interventions for the arm in the acute phase after stroke, with follow-ups at a maximum of 12 months. The aim of this study was to examine the effect of repetitive sensorimotor training of the arm at 5 years after stroke.Subjects and Methods— One hundred consecutive stroke patients were randomly allocated either to an experimental group that received daily additional sensorimotor stimulation of the arm or to a control group. The intervention period was 6 weeks. Assessments of the patients were made before, midway, and after intervention, and at 6 and 12 months after stroke. In this study, 62 patients were reassessed at 5 years after stroke. The Brunnström-Fugl-Meyer (BFM) test, Action Research Arm (ARA) test, and Barthel index (BI) were used as the primary outcome measures.Results— At the 5-year follow-up, there was a statistically significant difference for both the BFM and ARA tests in favor of the experimental group. The mean differences in improvement between the groups from the initial evaluation to the 5-year assessment corresponded to 17 points on the BFM and 17.4 on the ARA. No effect was found for the BI. The treatment was most effective in patients with a severe initial motor deficit.Conclusions— Adding a specific intervention for the arm during the acute phase after a stroke resulted in a clinically meaningful and long-lasting effect on motor function. The effect can be attributed to early, repetitive, and targeted stimulation.
Effects of Clopidogrel and Aspirin in Combination Versus Aspirin Alone on Platelet Activation and Major Receptor Expression in Patients After Recent Ischemic Stroke: For the Plavix Use for Treatment of Stroke (PLUTO-Stroke) Trial
- Victor L. Serebruany,
- Alex I. Malinin,
- Wendy Ziai,
- Alex N. Pokov,
- Deepak L. Bhatt,
- Mark J. Alberts and
- Dan F. Hanley
Stroke Volume 36, Issue 101 October 2005

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Background and Purpose— Clopidogrel is widely used in patients after recent ischemic stroke; however, its ability to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study. To determine whether clopidogrel with aspirin (C+ASA) will produce more potent platelet inhibition than aspirin alone (ASA) in patients after ischemic stroke, we conducted the Plavix Use for Treatment of Stroke trial.Methods— Seventy patients after ischemic stroke were randomly assigned to C+ASA or ASA groups. Platelet studies included aggregometry; cartridge-based analyzers; expression of PECAM-1, P-selectin, GP IIb/IIIa (antigen and activity), vitronectin receptor, and formation of platelet-leukocyte microparticles by flow cytometry. Platelet tests were performed at baseline and after 30 days after randomization.Results— There were no deaths, hospitalizations, or serious adverse events. There were no differences in the baseline platelet characteristics between C+ASA and ASA groups, or significant changes in platelet parameters in the ASA group, except diminished collagen-induced aggregation (P=0.001). In contrast, therapy with C+ASA resulted in a significant inhibition of platelet activity assessed by ADP- (P=0.00001) and collagen-induced (P=0.02) aggregation; closure time prolongation (P=0.03), and reduction of platelet activation units with Ultegra (P=0.00001); expression of PECAM-1 (P=0.01), and GP IIb/IIIa activity with PAC-1 (P=0.02) when compared with ASA group. Therapy with C+ASA also resulted in the reduced formation of platelet–leukocyte microparticles (P=0.02).Conclusion— Treatment with C+ASA for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients after recent ischemic stroke in the frame of the small randomized trial.
Comparison of the National Institutes of Health Stroke Scale With Disability Outcome Measures in Acute Stroke Trials
Stroke Volume 36, Issue 101 October 2005

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Background and Purpose— Acute stroke trials typically use disability scales as their primary end point. Neurologic impairment scales such as the National Institutes of Health Stroke Scale (NIHSS) are possibly more sensitive to change in patient status. We aimed to compare a range of potential NIHSS end points with modified Rankin Scale (mRS) and Barthel Index (BI) end points.Methods— We simulated a total of 6000 clinical trials, each with 1400 patients. We estimated statistical power for a range of NIHSS end points, including prognosis-adjusted and fixed dichotomized end points. These end points were compared with the BI and mRS dichotomized at 95 and 1, respectively.Results— The most powerful fixed end point was the NIHSS dichotomized at 1. For prognosis-adjusted outcome, we found greatest power if we defined success as achieving a score of ≤1 or improvement by at least 11 points from baseline. We are more likely to achieve a statistically significant result by using this prognosis-adjusted end point instead of NIHSS ≤1 (odds ratio, 2.8; 95% confidence interval [CI], 2.5 to 3.2). Use of the optimal NIHSS prognosis-adjusted end point rather than BI ≥95 could justify a reduction in sample size of approximately 68% (95% CI, 67% to 69%) without loss of statistical power.Conclusions— The NIHSS neurologic scale appears more sensitive than the BI or mRS, allowing smaller sample sizes or greater statistical power. The use of an NIHSS prognosis-adjusted end point could allow therapeutic effects from drugs to be more easily identified.
Efficacy of B Vitamins in Lowering Homocysteine in Older Men: Maximal Effects for Those With B₁₂ Deficiency and Hyperhomocysteinemia
- Leon Flicker,
- Samuel D. Vasikaran,
- Jenny Thomas,
- John M. Acres,
- Paul Norman,
- Konrad Jamrozik,
- Graeme J. Hankey and
- Osvaldo P. Almeida
Stroke Volume 37, Issue 21 February 2006

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Background and Purpose— A higher plasma concentration of total homocysteine (tHcy) is associated with a greater risk of cardiovascular events. Previous studies, largely in younger individuals, have shown that B vitamins lowered tHcy by substantial amounts and that this effect is greater in people with higher tHcy and lower folate levels.Methods— We undertook a 2-year, double-blind, placebo-controlled, randomized trial in 299 men aged ≥75 years, comparing treatment with a daily tablet containing 2 mg of folate, 25 mg of B₆, and 400 μg of B₁₂ or placebo. The study groups were balanced regarding age (mean±SD, 78.9±2.8 years), B vitamins, and tHcy at baseline.Results— Among the 13% with B₁₂ deficiency, the difference in mean changes in treatment and control groups for tHcy was 6.74 μmol/L (95% CI, 3.94 to 9.55 μmol/L) compared with 2.88 μmol/L (95% CI, 0.07 to 5.69 μmol/L) for all others. Among the 20% with hyperhomocysteinaemia, the difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 μmol/L (95% CI, 0.6 to 4.9 μmol/L). Baseline vitamin B₁₂, serum folate, and tHcy were significantly associated with changes in plasma tHcy at follow-up (r=0.252, r=0.522, and r=−0.903, respectively; P=0.003, <0.001, and <0.001, respectively) in the vitamin group.Conclusions— The tHcy-lowering effect of B vitamins was maximal in those who had low B₁₂ or high tHcy levels. Community-dwelling older men, who are likely to be deficient in B₁₂ or have hyperhomocysteinemia, may be most likely to benefit from treatment with B vitamins.
New Approaches to Clinical Trials in Neuroprotection: Introduction
- Mark P. Goldberg
Stroke Volume 38, Issue 21 February 2007

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Abstract 295: The Stem Cell Therapy to Prevent Expansion of Abdominal Aortic Aneurysm (STOP-AAA) Trial: Rationale and Design
- Michael P Murphy
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 34, Issue suppl_11 May 2014

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Background: Abdominal aortic aneurysm (AAA) is the 13^th leading cause of death in the United States. The only options for treatment at present for AAA are open surgical and endovascular repair, both of which are associated with significant morbidity, mortality, and expense.Thus AAA represents an unmet medical need. AAA pathogenesis is a multifactorial inflammatory process characterized by activation of T-cells,macrophages and neutrophils resulting in degradation of the aortic wall. Mesenchymal stromal cells (MSCs) suppress T-cell and macrophage activation, inhibit matrix metalloproteinases and have been shown to decrease aneurysm expansion in murine models.Methods: The STOP-AAA trial, from the NHLBI funded Cardiovascular Cell Therapy Research Network, is a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of autologous bone marrow derived MSCs in suppressing expansion of small AAA (35-50mm).Forty patients will be randomized in a 1:1 fashion to receive systemic administration of placebo or 3 doses of 2x10⁶ MSC/kg. at baseline, 24, and 52 weeks. The primary endpoint will be change in AAA diameter at 18 months as measured by a single blinded observer using contrast enhanced helical computed tomographic angiography (CTA).The secondary endpoints include time to elective repair, incidence of AAA related deaths and rupture,change in aortic mural inflammation at 18 months as quantified by F18-fluorodeoxyglucose (FDG) uptake with integrated positron emission tomography and computed tomography (PET/CT), changes in circulating mRNA, microRNA, and inflammatory cell profiles, changes in serum cytokine levels, and major adverse cardiac events.Conclusion: The STOP-AAA will be the first in man study to assess the efficacy of autologous bone marrow derived MSCs to suppress AAA expansion. Furthermore the data collected from this novel trial will provide unique mechanistic insights in the immunomodulatory properties of this stem cell population.
Abstract 206: Randomized Double Blind Clinical Trial on the Effect of Oral Alpha-cyclodextrin on Serum Lipids
- Marcelo Amar,
- Maryann Kaler,
- Vida B Mokhtari,
- Robert D Shamburek,
- Maureen Sampson,
- Stewart J Levine and
- Alan T Remaley
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 36, Issue suppl_11 May 2016

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Despite numerous therapeutic advances, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in developed countries. Statins, currently the most effective therapeutic agents for reducing CVD risk, only reduce cardiovascular events by approximately 30%. One possible complementary approach for lowering LDL-C involves the use of oral agents that complex or associate with dietary fats, preventing their intestinal absorption. Bile acid sequestrants are among the oldest lipid-altering drugs and have been known for decades to improve lipid levels and also improve glucose control. Alpha-cyclodextrin (a-CD), a cyclical polymer containing 6 glucose sub-units, is found in many foods, drinks and is sold as an over the counter food supplement. a-CD has a hydrophobic central cavity that binds lipids; one gram of a-CD binds as much as 9 grams of dietary fat and animal studies as well as clinical trials showed that it reduces dietary lipid absorption.This is the first study that evaluated the effect of a-CD in healthy subjects and was designed as a single center, double-blinded, cross-over, placebo controlled clinical pilot study. We screened 103 subjects, males and females, and obtained 75 completed studies (42% male, 58% female, mean age 34 ±12 y.o., BMI 25±4 kg/m2). Eligible subjects were randomized into two arms and received placebo or a-CD (6 grams P.O. a day; two 1 gram tablets per meal) for 12-14 weeks with a one week of wash out period between arms. Several biochemistry and lipid parameters were analyzed and statistics were performed using paired t-test. a-CD was well tolerated and no serious adverse events related to a-CD were observed. Minor GI symptoms were the most common complaint but occurred in less than 7% of subjects on a-CD (vs 3% in placebo). No significant differences were detected on serum lipid and other lipid values but fasting serum glucose (-13% a-CD vs placebo), insulin (-7% a-CD vs placebo), HbA1C (-6% a-CD vs placebo) were decreased. Further positive alterations were present in individuals with higher glucose levels. In conclusion, in healthy subjects, a dose of 6 grams a day of a-CD was able to improve plasma glucose related indexes, in the population studied, but had no significant effect in lipid or lipoprotein plasma levels.
Biomarkers: A Challenging Conundrum in Cardiovascular Disease
- Peter Libby and
- Kevin King
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 35, Issue 121 December 2015

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The use of biomarkers has proven utility in cardiovascular medicine and holds great promise for future advances, but their application requires considerable rigor in thinking and methodology. Numerous confounding factors can cloud the clinical and investigative uses of biomarkers. Yet, the thoughtful and critical use of biomarkers can doubtless aid discovery of new pathogenic pathways, identify novel therapeutic targets, and provide a bridge between the laboratory and the clinic. Biomarkers can provide diagnostic and prognostic tools to the practitioner. The careful application of biomarkers can also help design and guide clinical trials required to establish the efficacy of novel interventions to improve patient outcomes. Point of care testing, technological advances, such as microfluidic and wearable devices, and the power of omics approaches all promise to elevate the potential contributions of biomarkers to discovery science, translation, clinical trials, and the practice of cardiovascular medicine.
Cholesteryl Ester Transfer Protein Inhibition Is Not Yet Dead—Pro
- Philip J. Barter and
- Kerry-Anne Rye
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 36, Issue 31 March 2016

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Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from nonatherogenic high-density lipoproteins to potentially proatherogenic non–high-density lipoprotein fractions. Human genetic studies and human cohort studies have concluded that CETP gene polymorphisms associated with decreased CETP activity are accompanied by a significantly lower risk of atherosclerotic cardiovascular disease. Inhibition of CETP in rabbits reduces development of diet-induced atherosclerosis. Inhibition of CETP in humans reduces non–high-density lipoprotein cholesterol while increasing high-density lipoproteins cholesterol, consistent with a reduced risk of having an atherosclerotic cardiovascular disease event. The failure of randomized human clinical outcome trials with 3 different CETP inhibitors may have been the consequence of either off-target adverse effects of the drug used or problems with the design of the trials. The hypothesis that CETP inhibition reduces atherosclerotic cardiovascular disease risk is still untested. The future of CETP inhibition as a cardio-protective strategy will depend on the outcome of the ongoing Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial with the CETP inhibitor, anacetrapib.
The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict?
- Robert S. Rosenson
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 36, Issue 51 May 2016

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Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter–mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins.
Ezetimibe Increases Endogenous Cholesterol Excretion in Humans
- Xiaobo Lin,
- Susan B. Racette,
- Lina Ma,
- Michael Wallendorf and
- Richard E. Ostlund
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 37, Issue 51 May 2017

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Objective—Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool.Approach and Results—In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d₇ in a lipid emulsion and dietary cholesterol with cholesterol-d₅ and sitostanol-d₄ solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, P<0.0001) and low-density lipoprotein cholesterol 19.8±1.9% (P=0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% (P<0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% (P<0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% (P=0.0096). Fecal bile acids were unchanged.Conclusions—Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis.Clinical Trials Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.
Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima–Media Thickness in Humans
- Xiaobo Lin,
- Susan B. Racette,
- Lina Ma,
- Michael Wallendorf,
- Victor G. Dávila-Román and
- Richard E. Ostlund
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 37, Issue 121 December 2017

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Objective—Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis.Approach and Results—Cholesterol metabolism and carotid intima–media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d₇ solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d₅ and the nonabsorbable stool marker sitostanol-d₄. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima–media thickness was negatively correlated with fecal excretion of endogenous cholesterol (r=−0.426; P<0.0001), total cholesterol (r=−0.472; P≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (r=−0.343; P=0.0012) and was positively correlated with percent cholesterol absorption (r=+0.279; P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008).Conclusions—Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima–media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.
Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function
- Mark A. Sarzynski,
- Jonathan J. Ruiz-Ramie,
- Jacob L. Barber,
- Cris A. Slentz,
- John W. Apolzan,
- Robert W. McGarrah,
- Melissa N. Harris,
- Timothy S. Church,
- Mark S. Borja,
- Yumin He,
- Michael N. Oda,
- Corby K. Martin,
- William E. Kraus and
- Anand Rohatgi
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 38, Issue 41 April 2018

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Objective—Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials.Approach and Results—Radiolabeled and boron dipyrromethene difluoride–labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL; P=0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, −2.4 to −8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2–10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, −1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study.Conclusions—Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function.Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00962962 and NCT01264406.
CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients
- Andreas Gille,
- Denise D’Andrea,
- Michael A. Tortorici,
- Gunter Hartel and
- Samuel D. Wright
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 38, Issue 41 April 2018

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Objective—CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers.Approach and Results—Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre–β1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1–mediated CEC at baseline (P<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P≤0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre–β1-HDL (P=0.5) or CEC (P=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I–normalized CEC; P=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure.Conclusions—CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events.
Novel Tissue Factor Inhibition for Thromboprophylaxis in COVID-19: Primary Results of the ASPEN-COVID-19 Trial
- Connie N. Hess,
- Judith Hsia,
- Ian A. Carroll,
- Mark R. Nehler,
- Wolfram Ruf,
- David A. Morrow,
- Jose C. Nicolau,
- Otavio Berwanger,
- Michael Szarek,
- Warren H. Capell,
- Shilpa Johri,
- Michael S. Pursley,
- Ryan Gupta,
- Patrick S. Meehan,
- Francesco Franchi,
- Mark B. Effron,
- Debra Marshall,
- Christopher A. Graybill,
- Sophia P. Huebler,
- Thomas Keuer,
- Michael R. Bristow and
- Marc P. Bonaca
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 43, Issue 81 August 2023

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BACKGROUND:Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown.METHODS:ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days.RESULTS:Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was −16.8% (interquartile range, −45.7 to 36.8; P=0.41) with rNAPc2 treatment and −11.2% (−36.0 to 34.4; P=0.91) with heparin (P_intergroup=0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [−14.9 to 145.2]; P=0.02) than the rNAPc2 group (median, 25.9% [−49.1 to 136.4]; P=0.14; P_intergroup=0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, −32.7% [−44.7 to 4.3]; P=0.007 and heparin median, −16.8% [−36.0 to 0.5]; P=0.008, P_intergroup=0.34).CONCLUSIONS:rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04655586.Graphical Abstract
Abstract 15978: The Lifestyle Physical Activity for Sedentary Older Women (LPAW) Study: Primary Outcomes From a Randomized Controlled Clinical Trial
- Leanne L Lefler,
- Jean C McSweeney,
- Shelly Y Lensing,
- Kimberly K Garner,
- Patricia K Dubbert and
- Kathy A Packard
Circulation Volume 132, Issue suppl_310 November 2015

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Introduction: Evidence is clear that a physically active lifestyle reduces the human and economic cost of heart disease in a dose-response relationship; but current efforts to increase long-term physical activity (PA) are inadequate.Purpose/hypothesis: To test whether a parsimonious and tailored motivational interviewing (MInt) intervention would increase home-based PA.Methods: We conducted a single-blinded randomized controlled study of sedentary women aged 60 years and older to test a MInt counseling intervention for PA. Lifestyle physical activity was promoted by 2 one-on-one counseling sessions and coaching telephone calls tapering in frequency over 6 months. Women wore Triaxial accelerometers for 7 days to collect data at 0-, 3-, and 6-months to include vector magnitude activity counts, time spent in sedentary, light, moderate and vigorous activity, time spent in lifestyle PA bouts, sedentary time and daily energy expenditure.Results: 123 older women (mean age 69; 64% White; 34% African American) without significant functional or cognitive impairment were randomized to the MInt intervention or PA information/attention control groups. Risk factor profiles designated participants at high-risk for coronary heart disease (70% hypertensive, 48% hyperlipidemic, 25% diabetic, mean BMI 31). At baseline (Time 0) PA was similar; at Time 3 and 6 months the MInt group increased step counts per day (0=3.3K vrs 3.7K; 3=4.2K vrs 3.8K; 6= 4.0K vrs 3.5K) vector magnitude activity counts (0=322K vrs 335K; 3=370K vrs 336K; 6=344K vrs 318K), time in moderate to vigorous activity (0=225 minutes/week vrs 244; 3=288 vrs 247; 6= 261 vrs 225) significantly greater when compared to Control (all with p < .05). PA bouts remained greater and overall sedentary behavior was reduced in the MInt group and maintained over time.Conclusions: The LPAW intervention was successful in improving home-based PA over 6 months and should be tested broadly in other populations.
Evaluation and Reduction of Asymptomatic Cerebral Embolism in Ablation of Atrial Fibrillation, But High Prevalence of Chronic Silent Infarction: Results of the Evaluation of Reduction of Asymptomatic Cerebral Embolism Trial
- Atul Verma,
- Philippe Debruyne,
- Stefano Nardi,
- Thomas Deneke,
- Yves DeGreef,
- Stefan Spitzer,
- Jörn O. Balzer and
- Lucas Boersma
and on behalf of the ERACE Investigators

Circulation: Arrhythmia and Electrophysiology Volume 6, Issue 51 October 2013

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Background—This prospective, multicenter study sought to evaluate the incidence of asymptomatic cerebral emboli (ACE) during ablation of atrial fibrillation (AF) using a multielectrode radiofrequency (MER) system when specific procedural changes were applied.Methods and Results—Sixty subjects (age 60±10 years; 87% paroxysmal; CHADS₂ score, 0.6±0.7) undergoing AF ablation with a circular MER catheter were studied. Three procedural changes were specified: (1) ablation was performed under therapeutic vitamin K antagonist and heparin to maintain activated clotting time >350 seconds; (2) submerged loading of the catheter into the introducer before sheath insertion to minimize air ingress; and (3) either the distal or proximal electrode of the circular MER catheter was deactivated to prevent inadvertent bipolar radiofrequency interaction. MRI was performed <7 days preablation and 2 days postablation. Subjects with new cerebral findings after ablation underwent repeat MRI after 1 month. An acute ACE lesion was defined by a new hyperintensity on diffusion-weighted and fluid-attenuated inversion recovery cerebral MRI sequences. Neurological function was evaluated at baseline, postablation, and 1 month. All target pulmonary veins were isolated. In 60% (36/60) of patients, pre-existing cerebral lesions were seen on the preprocedure MRI (8 lesions per subject; interquartile range, 3–22). New postprocedural ACE occurred in only 1/60 patients (incidence, 1.7%; 95% confidence interval, 0.04–8.9), which was no longer visible on MRI after 1 month.Conclusions—Applying procedural changes to MER ablation significantly reduces the ACE incidence to 1.7%, which is on the low end of reported ACE rates of any technology.Clinical Trial Registration Information—ClinicalTrials.gov; Identifier: NCT01520532.
The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism
- James A. Reiffel,
- A. John Camm,
- Luiz Belardinelli,
- Dewan Zeng,
- Ewa Karwatowska-Prokopczuk,
- Ann Olmsted,
- Wojciech Zareba,
- Spencer Rosero and
- Peter Kowey
and the HARMONY Investigators*

Circulation: Arrhythmia and Electrophysiology Volume 8, Issue 51 October 2015

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Background—Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety.Methods and Results—HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone’s negative inotropic effect—see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated.Conclusions—HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled.Clinical Trial Registration—ClinicalTrials.gov; Unique identifier: NCT01522651.

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