Effects of statin therapy on coronary plaque volume by decreasing CRP/hsCRP levels: A meta-regression of randomized controlled trials

Background and aims: Several clinical trials have indicated that statins stabilize and reverse atherosclerotic plaque. However, different studies have provided inconsistent findings regarding mechanisms and influencing factors of plaque regression under statin therapy. In this study, meta-analysis and meta-regression were used to determine the effect of statin medication on coronary plaque volume as determined by intravenous ultrasound. Meanwhile, the impact of statins on CRP/hsCRP reduction on plaque regression was discussed. Methods: Up to May 28, 2021, a systematic PubMed, EMBASE, and Cochrane search was performed for randomized controlled trials that assessed treatment effect using total atheroma volume (TAV), percent atheroma volume (PAV), or plaque volume (PV). Only CRP/hsCRP and LDL-C values reported before and after treatment were considered. Results: 12 studies fulfilled the inclusion criteria and were included in the systematic review. Compared with control groups, meta-analysis of 15 statin-treated arms reported change of TAV/PV showed standardized mean difference (SMD) at -0.27 (95% confidence intervals [CI]: -0.42, -0.12). Meta-analysis of 7 studies reported change of PAV revealed SMD at -0.16 (95% CI: -0.29, -0.03). Meta-regression analysis revealed percent change of CRP/hsCRP statistically influences SMD in change of TAV/PVafter adjusting for percent change of LDL-C, age and gender. Meta-regression analysis showed that percent change of CRP/hsCRP statistically influences SMD in change of PAV. Conclusion: In conclusion, statin therapy is beneficial for plaque regression. Statins promote plaque regression through their anti-inflammatory ability while lowering LDL-C is unaffected. Keywords: Statins; Reduction of atherosclerosis; C-reactive protein; Randomized controlled trial; Meta-analysis

Usefulness of MCP-1 Chemokine in the Monitoring of Patients with Coronary Artery Disease Subjected to Intensive Dietary Intervention: A Pilot Study

Monocyte chemotactic protein-1 (MCP-1) plays an important role in the entire atherosclerotic process, from atherogenesis to destabilisation of the atherosclerotic plaque. The purpose of this study is to evaluate the effect of the dietary approaches to stop hypertension (DASH) diet in patients with coronary artery disease on the MCP-1 plasma concentration and to evaluate the potential usefulness of this chemokine as a marker of change in the volume and composition of coronary plaque. Material and method. As part of the dietary intervention to stop coronary atherosclerosis in computed tomography (DISCO-CT) study, patients were randomised to an intervention group (n = 40) in which the DASH diet was introduced, and to a control group (n = 39) with no dietary intervention. In the DASH group, dietary counselling was provided at all follow-up visits within 12 months of the follow-up period. MCP-1 plasma concentration was determined using enzyme-linked immunosorbent assay (ELISA). Coronary plaque analysis was performed using a semi-automated plaque analysis software system (QAngioCT, Medis, the Netherlands). Results. In the DASH group, MCP-1 plasma concentration significantly decreased by 34.1 pg/mL (p = 0.01), while in the control group, the change in MPC-1 was not significant. Significant inverse correlations were revealed for the change in MCP-1 plasma concentration and change in the consumption of vitamin C and dietary fibre both in the DASH (r = −0.519, p = 0.0005; r = −0.353, p = 0.025, respectively) and in the control group (r = −0.488 p = 0.001; r = −0.502, p = 0.001, respectively). In patients with the highest decrease in percent atheroma volume (PAV), a significant positive correlation was observed between the change in MCP-1 plasma concentration and changes in PAV (r = 0.428, p = 0.033) and calcified plaque component (r = 0.468, p = 0.018), while the change in noncalcified plaque component correlated inversely with change in MCP1 (r = −0.459, p = 0.021). Conclusion. Dietary intervention based on the DASH diet model reduces the MCP-1plasma concentration, mostly due to an increased intake of plant-derived, fibre-rich foods and antioxidants. The change in MCP-1 plasma concentration seems to reflect changes in the atheroma volume and proportions between the calcified and non-calcified plaque elements.

Efficacy and Safety of High-Density Lipoprotein/Apolipoprotein A1 Replacement Therapy in Humans and Mice With Atherosclerosis: A Systematic Review and Meta-Analysis

Background: Although elevation of HDL-C levels by pharmaceutical drugs have no benefit of cardiovascular endpoint, the effect of high-density lipoprotein/apolipoprotein A1 (HDL/apoA-1) replacement therapy on atherosclerosis is controversial. The current meta-analysis analyzed the effects of HDL/apoA-1 replacement therapies on atherosclerotic lesions both in humans and mice.Methods: The PubMed, Cochrane Library, Web of Science, and EMBASE databases were searched through June 6, 2020. The methodological quality of the human studies was assessed using Review Manager (RevMan, version 5.3.). The methodological quality of the mouse studies was assessed using a stair list. STATA (version 14.0) was used to perform all statistical analyses.Results: Fifteen randomized controlled human trials and 17 animal studies were included. The pooled results showed that HDL/apoA-1 replacement therapy use did not significantly decrease the percent atheroma volume (p = 0.766) or total atheroma volume (p = 0.510) in acute coronary syndrome (ACS) patients (N = 754). However, HDL/apoA-1 replacement therapies were significantly associated with the final percent lesion area, final lesion area, and changes in lesion area (SMD, −1.75; 95% CI: −2.21~-1.29, p = 0.000; SMD, −0.78; 95% CI: −1.18~-0.38, p = 0.000; SMD: −2.06; 95% CI, −3.92~-0.2, p = 0.03, respectively) in mice.Conclusions: HDL/apoA-1 replacement therapies are safe but do not significantly improve arterial atheroma volume in humans. The results in animals suggest that HDL/apoA-1 replacement therapies decrease the lesion area. Additional studies are needed to investigate and explain the differences in HDL/apoA-1 replacement therapy efficacies between humans and animals.Trial registration number: Human pooled analysis: PROSPERO, CRD42020210772. prospectively registered.

Clinical impact of PCSK9 inhibitor on stabilization and regression of lipid-rich coronary plaques: a near-infrared spectroscopy study

Aims This study aimed to determine the effects of a proprotein convertase subtilisin-kexin type 9 inhibitor (PCSK9i) on coronary plaque volume and lipid components in patients with a history of coronary artery disease (CAD). Methods and results This prospective, open-label, single-centre study analysed non-culprit coronary segments using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) at baseline and follow-up angiography. Following changes in the lipid-lowering treatment based on the most recent guideline, the enrolled subjects were divided into two groups: treatment with PCSK9i and statins (PCSK9i: 21 patients and 40 segments) and statins only (control: 32 patients and 50 segments). The absolute and percent LDL-C reductions were significantly greater in the PCSK9i group than in the control group (between group difference: 59.3 mg/dL and 46.4%; P < 0.001 for both). The percent reduction in normalized atheroma volume and absolute reduction in percent atheroma volume (PAV) were also significantly greater in the PCSK9i group (P < 0.001 for both). Furthermore, the PCSK9i group showed greater regression of maximal lipid core burden index for each of the 4-mm segments (maxLCBI4mm) than the control group (57.0 vs. 25.5; P = 0.010). A significant linear correlation was found between the percent changes in LDL-C and maxLCBI4mm (r = 0.318; P = 0.002), alongside the reduction in PAV (r = 0.386; P < 0.001). Conclusion The lipid component of non-culprit coronary plaques was significantly decreased by PCSK9i. The effects of statin combined with PCSK9i might be attributed to the stabilization and regression of residual vulnerable coronary plaques in patients with CAD.

Association of Serum Lipoprotein (a) Levels and Coronary Atheroma Volume by Intravascular Ultrasound

Background Lp(a) (lipoprotein (a)) is a risk factor for cardiovascular events, but the mechanism of increased risk is uncertain. This study evaluated the relationship between Lp(a) and coronary atheroma volume by intravascular ultrasound. Methods and Results This was a post hoc analysis of 6 randomized trials of coronary atheroma by intravascular ultrasound. The population was stratified into high (≥60 mg/dL) and low (<60 mg/dL) baseline serum Lp(a). The primary outcome was baseline coronary percent atheroma volume. A mixed model adjusted for baseline low density lipoprotein, ApoB (apoliporotein B100), non‐high density lipoprotein, sex, age, race, history of myocardial infarction, statin use, and intravascular ultrasound study was used to provide estimates of baseline plaque burden. Of 3943 patients, 17.3% (683) had Lp(a) ≥ 60 mg/dL and 82.7% (3260) had Lp(a) < 60 mg/dL. At baseline, uncorrected low density lipoprotein level (107.7 ± 32.0 versus 99.1 ± 31.5) and statin therapy (99.0% versus 97.0%) were higher in patients with high Lp(a) levels, but low density lipoprotein corrected for Lp(a) was lower (80.6 ± 32.0 versus 94.0 ± 31.4) in patients with high Lp(a) levels. Percent atheroma volume was significantly higher in the high Lp(a) group in unadjusted (38.2% [32.8, 43.6] versus 37.1% [31.4, 43.1], P =0.01) and risk‐adjusted analyses (38.7%±0.5 versus 37.5%±0.5, P <0.001). There was a significant association of increasing risk‐adjusted percent atheroma volume across quintiles of Lp(a) (Lp(a) quintiles 1‐5; 37.3 ± 0.5%, 37.2 ± 0.5%, 37.3 ± 0.5%, 38.0 ± 0.5%, 38.5 ± 0.5%, P =0.002). Conclusions Elevated Lp(a) is independently associated with increased percent atheroma volume. Further work is needed to clarify the relationship of Lp(a)‐lowering treatment with cardiovascular outcomes.

Prognostic value of intracoronary imaging-derived measures for non-infarct related vessel revascularization throughout 7 years among patients with ST-elevation myocardial infarction

Background Underlying plaque characteristics that lead to future revascularization during long-term follow-up remain poorly understood. Purpose We aimed to explore intracoronary imaging-derived measures as assessed by intravascular ultrasound (IVUS) and optical coherence tomography (OCT) associated with non-infarct related vessel revascularization (non-TVR) arising from imaged segments during long-term (up to 7 years) follow-up among patients with ST-elevated myocardial infarction (STEMI). Methods A total of 94 STEMI patients enrolled into the IBIS-4 (Integrated Biomarker Imaging Study-4) study undergoing serial (baseline and 13 months) IVUS and OCT in 2 non-infarct-related coronary arteries under high-intensity statin therapy were analyzed in the present study. Patients were divided into 2 groups according to the occurrence of non-TVR within previously imaged vessel segments (non-TVR: n=14, no non-TVR: n=80). Results Baseline characteristics including LDL level were comparable between groups. At baseline, lesions with future non-TVR were associated with greater percent atheroma volume by IVUS (55.6±5.4% vs. 49.6±6.1%, P&lt;0.001), minimum lumen area by OCT (3.4±1.7 mm2 vs. 6.0±3.3 mm2, P=0.004), and a higher prevalence of fibroatheroma (60.0% vs. 20.1%, P=0.007) by OCT compared with those without. Among patients with serial imaging, lesions with non-TVR had a trend towards a less reduction of percent atheroma volume (−0.2±3.8% vs. −2.4±4.2%, P=0.083). Conclusion Greater plaque burden, smaller lumen area, and higher prevalence of OCT-detected fibroatheroma at baseline were associated with non-infarct related vessel revascularization. Lesions with non-TVR tend to have less-pronounced regression of coronary atheroma despite intensive statin therapy and achieved LDL levels. Non-TVR 7 years after index PCI Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation

Relationship between arterial remodelling and serial changes in coronary atherosclerosis by intravascular ultrasound: an analysis of the IBIS-4 study

Aims Arterial remodelling is an important determinant of coronary atherosclerosis. Assessment of the remodelling index, comparing a lesion to a local reference site, is a suboptimal correlate of serial vascular changes. We assessed a novel approach which, unlike the local-reference approach, uses the entire artery’s global remodelling as reference. Methods and results Serial (baseline and 13 months) intravascular ultrasound was performed in 146 non-infarct-related arteries of 82 patients treated with high-intensity statin. Arteries were divided into 3-mm segments (n = 1479), and focal remodelling was characterized in individual segments at both timepoints applying the global arterial reference approach. First, we compared preceding vascular changes in relation to follow-up remodelling. Second, we examined whether baseline remodelling predicts subsequent plaque progression/regression. At follow-up, segments with constrictive vs. compensatory or expansive remodelling had greater preceding reduction of vessel area (−0.67 vs. −0.38 vs. −0.002 mm2; P &lt; 0.001) and lumen area (−0.82 vs. −0.09 vs. 0.40 mm2; P &lt; 0.001). Overall, we found significant regression in percent atheroma volume (PAV) [−0.80% (−1.41 to −0.19)]. Segments with constrictive remodelling at baseline had greater subsequent PAV regression vs. modest regression in the compensatory, and PAV progression in the expansive remodelling group (−6.14% vs. −0.71% vs. 2.26%; P &lt; 0.001). Lesion-level analyses (n = 118) showed no differences when remodelling was defined by the local reference approach at baseline or follow-up. Conclusion Remodelling assessment using a global arterial reference approach, but not the commonly used, local reference site approach, correlated reasonably well with serial changes in arterial dimensions and identified arterial segments with subsequent PAV progression despite intensive statin treatment and overall atheroma regression.