Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.

Progress and challenges in translating the biology of atherosclerosis

ContextStatin drugs reduce both atherogenic lipoproteins and cardiovascular
morbidity and mortality. However, the optimal strategy and target level for
lipid reduction remain uncertain.ObjectiveTo compare the effect of regimens designed to produce intensive lipid
lowering or moderate lipid lowering on coronary artery atheroma burden and
progression.Design, Setting, and PatientsDouble-blind, randomized active control multicenter trial (Reversal
of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) performed at
34 community and tertiary care centers in the United States comparing the
effects of 2 different statins administered for 18 months. Intravascular ultrasound
was used to measure progression of atherosclerosis. Between June 1999 and
September 2001, 654 patients were randomized and received study drug; 502
had evaluable intravascular ultrasound examinations at baseline and after
18 months of treatment.InterventionsPatients were randomly assigned to receive a moderate lipid-lowering
regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering
regimen consisting of 80 mg of atorvastatin.Main Outcome MeasuresThe primary efficacy parameter was the percentage change in atheroma
volume (follow-up minus baseline).ResultsBaseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL
[3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L)
in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin
group (P<.001). C-reactive protein decreased 5.2%
with pravastatin and 36.4% with atorvastatin (P<.001).
The primary end point (percentage change in atheroma volume) showed a significantly
lower progression rate in the atorvastatin (intensive) group (P = .02). Similar differences between groups were observed for secondary
efficacy parameters, including change in total atheroma volume (P = .02), change in percentage atheroma volume (P<.001), and change in atheroma volume in the most severely diseased
10-mm vessel subsegment (P<.01). For the primary
end point, progression of coronary atherosclerosis occurred in the pravastatin
group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P = .001) compared with baseline. Progression did not occur in the
atorvastatin group (−0.4%; CI −2.4% to 1.5%; P = .98) compared with baseline.ConclusionsFor patients with coronary heart disease, intensive lipid-lowering treatment
with atorvastatin reduced progression of coronary atherosclerosis compared
with pravastatin. Compared with baseline values, patients treated with atorvastatin
had no change in atheroma burden, whereas patients treated with pravastatin
showed progression of coronary atherosclerosis. These differences may be related
to the greater reduction in atherogenic lipoproteins and C- reactive protein
in patients treated with atorvastatin.

https://jamanetwork.com/journals/jama/articlepdf/198311/joc32467.pdf

Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis A Randomized Controlled Trial

ContextPrior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression.ObjectiveTo assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging.Design and SettingProspective, open-label blinded end-points trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion.PatientsBetween November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug. After 24 months, 349 patients had evaluable serial IVUS examinations.InterventionAll patients received intensive statin therapy with rosuvastatin, 40 mg/d.Main Outcome MeasuresTwo primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified.ResultsThe mean (SD) baseline low-density lipoprotein cholesterol (LDL-C) level of 130.4 (34.3) mg/dL declined to 60.8 (20.0) mg/dL, a mean reduction of 53.2% (P<.001). Mean (SD) high-density lipoprotein cholesterol (HDL-C) level at baseline was 43.1 (11.1) mg/dL, increasing to 49.0 (12.6) mg/dL, an increase of 14.7% (P<.001). The mean (SD) change in PAV for the entire vessel was −0.98% (3.15%), with a median of −0.79% (97.5% CI, −1.21% to −0.53%) (P<.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was −6.1 (10.1) mm3, with a median of −5.6 mm3 (97.5% CI, −6.8 to −4.0 mm3) (P<.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of −14.7 (25.7) mm3, with a median of −12.5 mm3 (95% CI, −15.1 to −10.5 mm3) (P<.001 vs baseline). Adverse events were infrequent and similar to other statin trials.ConclusionsVery high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. Further studies are needed to determine the effect of the observed changes on clinical outcome.Trial RegistrationClinicalTrials.gov Identifier: NCT00240318Published online March 13, 2006 (doi:10.1001/jama.295.13.jpc60002).

https://jamanetwork.com/journals/jama/articlepdf/202629/JPC60002.pdf

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.

Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.

Atherosclerosis: current pathogenesis and therapeutic options

During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events.

Pathophysiology of Coronary Artery Disease

ContextAlthough low levels of high-density lipoprotein cholesterol (HDL-C)
increase risk for coronary disease, no data exist regarding potential benefits
of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of
apolipoprotein A-I identified in individuals in rural Italy who exhibit very
low levels of HDL. Infusion of recombinant ApoA-I Milano–phospholipid
complexes produces rapid regression of atherosclerosis in animal models.ObjectiveWe assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid
complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes
(ACS).DesignThe study was a double-blind, randomized, placebo-controlled multicenter
pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma
burden measured by intravascular ultrasound (IVUS).SettingTen community and tertiary care hospitals in the United States.PatientsBetween November 2001 and March 2003, 123 patients aged 38 to 82 years
consented, 57 were randomly assigned, and 47 completed the protocol.InterventionsIn a ratio of 1:2:2, patients received 5 weekly infusions of placebo
or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed
within 2 weeks following ACS and repeated after 5 weekly treatments.Main Outcome MeasuresThe primary efficacy parameter was the change in percent atheroma volume
(follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary
efficacy measures included the change in total atheroma volume and average
maximal atheroma thickness.ResultsThe mean (SD) percent atheroma volume decreased by −1.06% (3.17%)
in the combined ETC-216 group (median, −0.81%; 95% confidence interval
[CI], −1.53% to −0.34%; P = .02 compared
with baseline). In the placebo group, mean (SD) percent atheroma volume increased
by 0.14% (3.09%; median, 0.03%; 95% CI, −1.11% to 1.43%; P = .97 compared with baseline). The absolute reduction in atheroma
volume in the combined treatment groups was −14.1 mm3 or
a 4.2% decrease from baseline (P<.001).ConclusionsA recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered
intravenously for 5 doses at weekly intervals produced significant regression
of coronary atherosclerosis as measured by IVUS. Although promising, these
results require confirmation in larger clinical trials with morbidity and
mortality end points.

https://jamanetwork.com/journals/jama/articlepdf/197579/jpc30068_2292_2300.pdf

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.

Context: Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. Objective: To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. Design, Setting, and Patients: Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. Interventions: Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n=839) and study completion (n=676). Main Outcome Measures: The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). Results: In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P=.22), respectively, and TAV decreased 2.2mm3 (-4.09 to -0.24) vs an increase of 0.88mm3 (-1.03 to 2.79) (P=.03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P=.13), and TAV decreased 1.95mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P=.02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P<.001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8mg/dL (4.9 to 6.8) (22.4%) vs 1.8mg/dL (0.9 to 2.7) (6.9%) (P<.001), and median triglyceride levels decreased 24.8mg/dL (-35.4 to -17.3) (20.5%) vs 8.9mg/dL (-14.2 to -1.8) (6.2%) (P<.001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11%[0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P<.001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P<.001). Conclusions: After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. Trial Registration: clinicaltrials.gov Identifier: NCT00124332.

https://jamanetwork.com/journals/jama/articlepdf/181727/joc80023_1547_1560.pdf

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial

Muhammad Yasin

Papers

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial

Type a aortic dissection during transcatheter aortic valve deployement, time for thoughtful pause

Aortic arch pseudoaneurysm causing ortner's syndrome

Symptomatic hemolytic anemia following transcatheter aortic valve replacement due to delayed paravalvular leak managed with balloon postdilation