Niamh Hynes

Tensile and compressive properties of fresh human carotid atherosclerotic plaques

Accurate characterisation of the mechanical properties of human atherosclerotic plaque is important for our understanding of the role of vascular mechanics in the development and treatment of atherosclerosis. The majority of previous studies investigating the mechanical properties of human plaque are based on tests of plaque tissue removed following autopsy. This study aims to characterise the mechanical behaviour of fresh human carotid plaques removed during endarterectomy and tested within 2h. A total of 50 radial compressive and 17 circumferential tensile uniaxial tests were performed on samples taken from 14 carotid plaques. The clinical classification of each plaque, as determined by duplex ultrasound is also reported. Plaques were classified as calcified, mixed or echolucent. Experimental data indicated that plaques were highly inhomogeneous; with variations seen in the mechanical properties of plaque obtained from individual donors and between donors. The mean behaviour of samples for each classification indicated that calcified plaques had the stiffest response, while echolucent plaques were the least stiff. Results also indicated that there may be a difference in behaviour of samples taken from different anatomical locations (common, internal and external carotid), however the large variability indicates that more testing is needed to reach significant conclusions. This work represents a step towards a better understanding of the in vivo mechanical behaviour of human atherosclerotic plaque.

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

Objective It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. Setting, participants and outcome measures We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population. Results We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. Conclusions High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

One-Year Results of the Multilayer Flow Modulator Stent in the Management of Thoracoabdominal Aortic Aneurysms and Type B Dissections:

Purpose To report 1-year results from the first subgroup of patients treated with the Multilayer Flow Modulator (MFM) stent for aortic aneurysm and dissection. Methods Up to December 2012, 243 patients have been treated worldwide for aortic aneurysm and dissection with the Cardiatis MFM under the established indications for use. This retrospective review encompasses the first 55 of these patients (41 men; mean age 64.5±18 years), who were treated on a compassionate basis in 11 countries. There were 31 thoracoabdominal aortic aneurysms (8 Crawford type I, 3 type II, 9 type III, and 11 type IV), 7 arch aneurysms, 3 infrarenal abdominal aortic aneurysms, 8 suprarenal aortic aneurysms, and 6 type B dissections. Mean aneurysm diameter was 6.04±1.66 cm, and the mean length was 11.58±7.62 cm. The primary endpoint at 1 year was a composite of rupture and aneurysm-related death. The secondary endpoints were all-cause mortality, visceral branch occlusion, adverse events (i.e., stroke and paraplegia), and reintervention. Results Technical success was 98.2%; there was no paraplegia or perioperative visceral or renal insult. The mean number of side branches covered was 3.7±1.3 per case (range 0–6); 108 stents were deployed (range 1–5). At 1 year, aneurysm-related survival was 93.7%, all-cause survival was 84.8%, intervention-free survival was 92.4%, and all of the 202 side branches were patent. There were no stent fractures. At 6 months, the mean rate of sac volume increase was 0.36% per month, resulting in a mean volume increase of 2.14%. At 12 months, the rate of increase had slowed to 0.28% per month, resulting in a total average increase in sac volume of 3.26%. The ratio of thrombus to total volume stayed almost constant over the 12 months at 0.48, while the ratio of flow to total volume fell from 0.21 to 0.12 at 12 months. Conclusion MFM implantation instigates a process of aortic remodeling involving initial thrombus deposition, which slowed between 6 and 12 months. Increasing sac size did not herald rupture, and the MFM was not associated with loss of native side branches. With physiological modulation of the aneurysm, the MFM offers promise for resolution of complex thoracoabdominal pathology with off-the-shelf availability, but this disruptive technology requires further development and technical refinement. Long-term follow-up of the registry patients is mandatory before establishing a randomized controlled study.

Subintimal angioplasty as a primary modality in the management of critical limb ischemia: comparison to bypass grafting for aortoiliac and femoropopliteal occlusive disease.

Purpose: To compare the 30-day morbidity, mortality, length of hospital stay, and patency rates in patients with critically ischemic limbs treated with subintimal angioplasty (SA) versus standard bypass surgery. Method: Between October 2001 and August 2003, 137 patients (74 women; mean age 70 years, range 43–92) with critical limb ischemia underwent subintimal angioplasty (n=88) or bypass surgery (n=49) for superficial femoral artery (SFA) or aortoiliac lesions. All patients had lesions classified as C or D according to the TransAtlantic Inter-Society Consensus. Data was retrieved from hospital inpatient inquiry and VascuBase. Parallel group comparison was used in performing a prospective observational study. Results: Primary technical success was 100% for both SA and bypass grafting. Thirty-day survival was 100% in the SFA-SA and aortoiliac bypass groups and 96% and 93%, respectively, in the SFA bypass and aortoiliac SA groups. Limb salvage was 97% and 82% in the SFA-SA and SFA bypass groups, respectively; at the aortoiliac levels, the rates were 100% and 86% for SA versus bypass. Subintimal angioplasty significantly reduced hospital stay (p<0.001). Primary patency was not statistically different in the SA versus bypass groups; however, secondary patency was higher in the SFA bypass group. Conclusions: Frequent clinical follow-up and a duplex surveillance program are necessary to maintain patency in this cohort. Subintimal angioplasty is increasingly replacing bypass surgery in the management of critical limb ischemia without compromising primary patency, limb salvage, patient survival, or subsequent vascular intervention.

A Prospective Clinical, Economic, and Quality-of-Life Analysis Comparing Endovascular Aneurysm Repair (EVAR), Open Repair, and Best Medical Treatment in High-Risk Patients with Abdominal Aortic Aneurysms Suitable for EVAR: The Irish Patient Trial

Purpose: To report the results of a trial comparing endovascular aneurysm repair (EVAR) to open repair (OR) and best medical therapy (BMT) involving high-risk patients with abdominal aortic aneurysms (AAA) suitable for EVAR. Methods: From 2002 to 2007, 1083 patients with aortic aneurysm disease were referred to a tertiary care university hospital. Of these, 162 (119 men; mean age 76 years) were high-risk patients with AAAs anatomically suitable for EVAR. Following comprehensive consultation with the patient, the family, and the primary physician, elective treatment was selected: OR (n=52), EVAR (n=66), or BMT (n=44). Outcomes were compared using Kaplan-Meier survival analyses and a parameter that measured the quality time spent without symptoms of disease or toxicity of treatment (Q-TWIST). Results: Four-year freedom from aneurysm-related death following EVAR (96.7%) was markedly better compared to BMT (66.8%; p=0.002) and was similar to OR (93.9%, p=0.483). Four-year freedom from major adverse clinical events was significantly better with EVAR (78%) compared with BMT (28%; p=0.001) and was equivalent to OR (75%; p=0.519). The 4-year intervention-free survival rate for EVAR (95%) almost matched OR (98%; p=0.410). At 4 years, Q-TWIST was 3.64 years for EVAR patients, 3.60 years for OR, and 2.22 years for BMT. Q-TWIST significantly improved with EVAR compared to OR (p<0.003). In the cost analysis, 52 high-risk patients were treated with OR over the 5-year period (2002–2007) at a total inpatient cost of €1,257,457. The 66 patients treated with EVAR (14 patients more than OR) incurred a lower cost of €1,129,138. Including the cost of follow-up over 4 years, the mean cost per patient was €18,476 for EVAR and €24,252 for OR, a savings of €5,776 per patient treated with EVAR. Conclusion: In high-risk patients, EVAR reduces aneurysm-related death compared to BMT. Equated to the gold standard of open repair, EVAR, as a “one-time procedure,” substantially reduces operative morbidity, hospital stay, costs, and utilization of intensive care facilities if performed in a high-volume center.

Five-year Irish trial of CLI patients with TASC II type C/D lesions undergoing subintimal angioplasty or bypass surgery based on plaque echolucency.

Purpose: To report a 5-year observational parallel group study comparing the effectiveness of subintimal angioplasty (SIA) to bypass grafting (BG) for treatment of TASC II type C/D lesions in the lower limb arteries of patients with critical limb ischemia (CLI). Methods: Of 1076 patients referred with PVD from 2002 to 2007, 206 SIAs in 190 patients (104 women; mean age 73±13 years) and 128 bypass grafts in 119 patients (77 men; mean age 70±14 years) were enrolled in the study. All patients had Rutherford classification 4–6 ischemia manifested as rest pain and/or tissue loss. Primary endpoints were (1) survival free from amputation and (2) sustained clinical improvement [+2 Rutherford category and/or ABI increase >0.15 without target lesion revascularization (TLR)]. Secondary endpoints were major adverse events (MAE), the binary restenosis rate, freedom from TLR, and a special quality-adjusted life year (QALY) endpoint (Q-TWiST) that incorporated both length and quality of life to evaluate treatments. A cost analysis was also performed. Results: At 5 years, clinical improvement was sustained in 82.8% of the SIA group versus 68.2% of the BG patients (p=0.106). Five-year all-cause survival was similar for SIA (78.6%) and BG (80.1%; p=0.734), as was amputation-free survival (SIA 72.9% versus BG 71.2%; p=0.976). Hyperfibrinogenemia (p=0.009) and C-reactive protein (p=0.019) had negative effects on survival without amputation. Five-year freedom from binary restenosis rates were 72.8% for SIA versus 65.3% for BG (p=0.700). While the 5-year freedom from TLR rates (SIA 85.9% versus BS 72.1%, p=0.262) were not statistically significant, the risk of MAE (p<0.002) and length of hospital stay (p<0.0001) were significantly reduced in the SIA group. Q-TWiST significantly improved (p<0.001) and cost-per-QALY (SIA €5663 versus BG €9172, p<0.002) was reduced with SIA. The 5-year risk of re-intervention (p>0.05) and mean number of procedures (p=0.078) were similar. Conclusion: Five-year freedom from MAE was enhanced by 20% in the SIA group, with substantial cost reduction and better Q-TWiST. SIA is a minimally invasive technique that expands amputation-free and symptom-free survival. SIA is poised to bring about a paradigm shift in the management of CLI.

When Not to Implant the Multilayer Flow Modulator: Lessons Learned From Application Outside the Indications for Use in Patients With Thoracoabdominal Pathologies

Purpose To scrutinize registry data on thoracoabdominal repairs performed using the Multilayer Flow Modulator (MFM) outside the indications for use (IFU) and analyze the adverse outcomes. Methods Of 380 patients from Europe registered in the MFM Global Registry after treatment for thoracoabdominal aortic aneurysm (TAAA) or dissection, 38 (10%) patients (30 men; median age 71 years, range 30–91) treated on a compassionate basis outside the IFU were analyzed. Thirteen patients had chronic Stanford type B dissection with aneurysmal dilatation >6 cm. There were 6 mycotic and 4 saccular aneurysms in addition to 15 primary TAAAs. The mean aneurysm diameter was 7.1 cm. Ten patients presented with rupture, and 23 patients had previous open or thoracic endovascular aortic repair (TEVAR). Results Although no death, paraplegia, stroke, or renovisceral compromise was documented during the initial hospital stay, technical success was zero. There were 31 (81.6%) cases in which there was failure to land the device in normal aorta. Other violations of the IFU included 12 with inadequate stent overlap and 11 cases involving a small MFM being deployed inside a larger one. Five of the 9 cases in which an undersized device was used resulted in a type I endoleak (failure mode I). During a mean follow-up of 10.0±6.9 months, all-cause mortality was 89.5% (34/38), of which 27 (71.1%) were aneurysm-related deaths. Overall survival, freedom from aneurysm-related death, and rupture-free survival estimates were 17.5%, 25.0%, 31.5%, respectively, at 18 months. There were 8 visceral branch complications; in all, 14 secondary endovascular interventions were required in 11 patients for endoleak (failure modes I and II) or stent foreshortening. No false lumen was completely thrombosed in the dissecting aneurysms. All aneurysms showed a mean sac growth rate of 0.12±0.16 cm/month. Factors having a significance influence on risk of aneurysm-related death included maximum aneurysm diameter (p=0.025, HR 1.37, 95% CI 1.04 to1.82), previous TEVAR (p=0.03, HR 2.44, 95% CI 1.10 to 2.08), and inadequate overlap between MFM devices (p<0.002, HR 4.02, 95% CI 1.70 to 9.49). Conclusion There are clinical scenarios in which the MFM does not perform well. The MFM is not a solution for patients living on borrowed time and should not be used indiscriminately in patients in whom other modalities of aortic repair are not feasible. Its use must adhere to the IFU, and robust clinical data are required before constructing a randomized controlled trial.

Finite element modelling of diseased carotid bifurcations generated from in vivo computerised tomographic angiography

It has been hypothesised that the stress distribution within the arterial wall may provide an indicator of atherosclerotic plaque rupture. This study presents an automated method for the generation of finite element models of the carotid bifurcation from in vivo computerised tomographic angiography. Models generated using this method have been used to investigate plaque vulnerability, assessing the influence of geometric factors and the stress distribution within the wall. Structured hexahedral meshes of the carotid bifurcation were created using a custom built automated system. Systolic pressure and appropriate boundary conditions were applied to each of the models. Six symptomatic patients were considered, generating models from each of their left and right carotid bifurcations (12 in total). Results from their symptomatic bifurcation were compared with their contralateral asymptomatic side. K(delta), a measure of the difference in curvature of the inner and outer plaque surfaces, was found to be significantly higher in symptomatic arteries than in asymptomatic arteries (p<0.05). The location of maximum K(delta) (the plaque shoulders) was also found to be a region of high von Mises stress yet no significant difference was found in maximum von Mises stress between the symptomatic and asymptomatic groups. Results suggest that K(delta) is an important factor in the development of a symptomatic plaque and with further investigation could be a useful indicator of plaque rupture.

Sequential compression biomechanical device in patients with critical limb ischemia and nonreconstructible peripheral vascular disease

OBJECTIVES Critical limb ischemia (CLI) patients who are unsuitable for intervention face the dire prospect of primary amputation. Sequential compression biomechanical device (SCBD) therapy provides a limb salvage option for these patients. This study assessed the outcome of SCBD in severe CLI patients who otherwise would face an amputation. Primary end points were limb salvage and 30-day mortality. Secondary end points were hemodynamic outcomes (increase in popliteal artery flow and toe pressure), ulcer healing, quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TwiST), and cost-effectiveness. METHODS From 2004 to 2009, we assessed 4538 patients with peripheral vascular disease (PVD). Of these, 707 had CLI, 518 underwent intervention, and 189 were not suitable for any intervention. A total of 171 patients joined the SCBD program for 3 months. RESULTS All patients were Rutherford category ≥4. Median follow-up was 13 months. Mean toe pressure increased from 39.9 to 55.42 mm Hg, with a mean difference in toe pressure of 15.49 mm Hg (P = .0001). Mean popliteal flow increased from 35.44 to 55.91 cm/s, with mean difference in popliteal flow of 20.47 cm/s (P < .0001). Mortality at 30 days was 0.6%. Median amputation-free survival was 18 months. Limb salvage at 3.5 years was 94%. Freedom from major adverse clinical events (MACE) at 4.5 years was 62.5%. We treated 171 patients with SCBD at a cost of €681,948, with an estimated median per-patient cost of treatment with SCBD of €3988. CONCLUSION SCBD therapy is a cost-effective and clinically efficacious solution in CLI patients with no option of revascularization. It provides adequate limb salvage and ameliorated amputation-free survival while providing relief of rest pain without any intervention.

Inelasticity of Human Carotid Atherosclerotic Plaque

Little mechanical test data exists regarding the inelastic behavior of atherosclerotic plaques. As a result finite element (FE) models of stenting procedures commonly use hyperelastic material models to describe the soft tissue response thus limiting the accuracy of the model to the expansion stage of stent implantation and leave them unable to predict the lumen gain. In this study, cyclic mechanical tests were performed to characterize the inelastic behavior of fresh human carotid atherosclerotic plaque tissue due to radial compressive loading. Plaques were classified clinically as either mixed (M), calcified (Ca), or echolucent (E). An approximately linear increase in the plastic deformation was observed with increases in the peak applied strain for all plaque types. While calcified plaques generally appeared stiffest, it was observed that the clinical classification of plaques had no significant effect on the magnitude of permanent deformation on unloading. The test data was characterized using a constitutive model that accounts for both permanent deformation and stress softening to describe the compressive plaque behavior on unloading. Material constants are reported for individual plaques as well as mean values for each plaque classification. This data can be considered as a first step in characterizing the inelastic behavior of atherosclerotic plaques and could be used in combination with future mechanical data to improve the predictive capabilities of FE models of angioplasty and stenting procedures particularly in relation to lumen gain.