Incidence, predictors and longer-term impact of troponin elevation following hybrid chronic total occlusion percutaneous coronary intervention.

OBJECTIVES: We examined the incidence of periprocedural cardiac enzyme rise (PCER) [troponin T (TnT) or high-sensivity (hs)TnT >5× the upper limit of normal (ULN)] and periprocedural myocardial infarction (PMI), predictors of PCER and impact of PCER on the longer-term major adverse cardiac events (MACE) following hybrid chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: PCER and PMI after CTO PCI, risk factors for PCER and its impact on longer-term MACE are not fully understood. METHODS: Among 469 CTO PCI cases performed between 01/2010 and 12/2015, next-day TnT or hsTnT was measured in 455 (97%). We examined the incidence of PCER and PMI (with clinical context or TnT ≥70× ULN). In 269 successful cases who had TnT measured, longer-term MACE (death, MI or target-vessel revascularisation/re-occlusion) were assessed. RESULTS: Overall, 420 CTOs (92.3%) were treated successfully. PCER was documented in 34%, while PMI in 2.9%. By multivariable analyses, higher J-CTO score (OR = 1.3 per point; P = 0.002), lower creatinine clearance (OR = 1.01 per each cc/min decrease; P < 0.0001) and recent MI (OR = 2.4; P = 0.007) were independent pre-PCI risk factors for PCER. Among procedural variables, retrograde approach (OR = 1.9; P = 0.014) and procedure duration (OR = 1.2 per 30 min; P = 0.007) were associated with PCER. At a median follow-up of 396 days following successful CTO PCI, PCER was not associated with higher MACE (9.3% vs. 8.1%; P = 0.60), and was not a predictor of MACE in multivariable analysis. CONCLUSIONS: PCER following hybrid CTO PCI is detected in 1/3 of patients. However, true PMI occurs in 2.9%. PCER does not predict adverse long-term outcomes.

Midterm Angina-Related Quality of Life Benefits After Percutaneous Coronary Intervention of Chronic Total Occlusions.

BACKGROUND: Data on the impact of coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on quality of life (QOL) are limited. To date, studies have been limited in sample size and have focused on only a few domains of the Seattle Angina Questionnaire (SAQ). We evaluated the relationship between coronary CTO PCI and QOL in patients with symptoms of angina, incorporating all aspects of the SAQ. METHODS: The SAQ was used to interrogate patients at baseline and at 12 months after CTO PCI. The primary end point was improvement in SAQ scores. RESULTS: A total of 184 patients answered the baseline SAQ. One hundred twenty-two patients answered both questionnaires. SAQ responders were more likely to be men, more like to be in stable medical condition, and more likely to have undergone a successful procedure. We observed statistically significant improvement (P < 0.0001) in physical limitation (mean difference [MD], +27; 95% confidence interval [CI], +23 to +32), angina stability (MD, +16; 95% CI, +10 to +21), angina frequency (MD, +27; 95% CI, +22 to +32), treatment satisfaction (MD, +10; 95% CI, +6 to +13), and QOL domains (MD, +28; 95% CI, +24 to +32). Patients with coronary artery bypass grafting, dissection re-entry techniques, and high complexity (Japanese CTO [J-CTO] ≥ 3) had a similar degree of improvement when compared with their counterparts. CONCLUSIONS: CTO PCI is associated with a significant improvement in QOL at 12 months. Patients with complex CTOs derive benefits similar to those in patients with less complex CTOs.

Safety and effectiveness of the surfing technique to cross septal collateral channels during retrograde chronic total occlusion percutaneous coronary intervention.

AIMS: Septal surfing and distal tip injections are two techniques used for septal crossing in retrograde chronic total occlusion (CTO) percutaneous coronary interventions (PCI). The aim of this study was to examine for the first time the safety and feasibility of the septal surfing technique. METHODS AND RESULTS: Among 470 consecutive CTO PCIs performed in the Quebec hybrid CTO PCI program between January 2010 and December 2015, 240 (51%) involved a retrograde attempt. In the septal crossing subgroup, we evaluated whether the Werner collateral channel (CC) classification, CTO location, tortuosity, and number of large septal CCs influenced retrograde crossing success, time, and perforation. Septal channels were used in the majority (n=152, 63%) of cases. Patients in the septal subgroup were younger, had less bypass surgery, were more likely to have RCA CTO and had previous failure. Septal channels were successfully crossed with the wire using the surfing technique in 81%, irrespective of the CC size. Septal crossing success and time were not influenced by Werner CC class but by septal CC tortuosity. One quarter of cases had septal perforations; all were minor and asymptomatic. CONCLUSIONS: Septal surfing is a safe and highly successful technique for crossing septal CCs when a retrograde approach is mandated for CTO PCI. The Werner class does not affect retrograde CC crossing success or time.

Recanalization of Chronic Total Occlusions in Patients With Previous Coronary Bypass Surgery and Consideration of Retrograde Access via Saphenous Vein Grafts.

BACKGROUND: The prevalence of native coronary chronic total occlusions (CTOs) after coronary artery bypass grafts (CABGs) is higher than in non-CABG population. We examined outcomes of CTO percutaneous coronary intervention (PCI) post-CABG versus without CABG. Then, we looked at feasibility and outcomes of retrograde CTO PCI via patent or occluded saphenous vein graft. METHODS AND RESULTS: We compared patient and procedural characteristics of 470 CTO cases treated from January 2010 to December 2015 depending on history of CABG. We assessed major adverse cardiac events, including cardiac death, myocardial infarction, ischemia-driven target-vessel revascularization, or reocclusion 1 year after successful CTO PCI in patients treated before February 2015. Post-CABG patients (175 cases) had a higher J-CTO score (2.5 versus 2.1; P=0.002). In-hospital complications were similar, although the incidence of contrast-induced nephropathy was higher in post-CABG patients (4.6% versus 1%; P=0.01). With multivariable analysis, post-CABG status was associated with higher incidence of 1-year major adverse cardiac event (hazards ratio=2.2; P=0.02). As a second level analysis, we looked at the feasibility and safety of CTO PCI via saphenous vein grafts (19% of post-CABG cases) versus collateral channels (36%) versus with an antegrade-only approach (45%), and assessed short-term outcomes and complications. High success was achieved in the saphenous vein graft group. In-hospital events were similar in the 3 groups. CONCLUSIONS: Post-CABG CTO PCI is associated with similar high success and low complications compared with CTO PCI in patients who never had CABG. However, it is associated with higher recurrent events at 1 year. To achieve high success rate, use of saphenous vein grafts as retrograde conduits seems to be safe and effective.

Effectiveness and Safety of the Transradial 8Fr Sheathless Approach for Revascularization of Chronic Total Occlusions.

The experience with the transradial approach in percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) in the United States is limited. We looked at the safety and feasibility of a home-made sheathless transradial technique (STT) with regular 8Fr catheters in CTO PCI. In March 2013, we developed an 8Fr STT for CTO PCI. We compared 119 patients who had the STT versus 122 treated with a standard transradial or transfemoral approach. The primary outcomes of interest were major vascular or bleeding site access complications. In a subgroup of patients with bilateral transradial approach, we assessed and compared radial patency 3 to 6 months after the procedure. Technical success rate of the CTO PCI was 93% in both groups. There were no major vascular or bleeding complications in the STT group. Radial hematomas were frequent but grade III occurred in 4 patients (3%) treated with the STT, not different to the incidence in the other group. The STT did not result in any increase in procedure time, contrast use, or radiation dose. Radial Doppler follow-up in 28 patients revealed 2 occlusions (7.1%) on the 8Fr shealthless side and one on the 6Fr side. In conclusion, our STT with regular 8Fr guides for CTO PCI is feasible, safe, and associated with low complication rate. We show that the hybrid CTO PCI nowadays can be performed through transradial access in the majority, with limited use of transfemoral approach.

Partial neurorescue effects of DHA following a 6-OHDA lesion of the mouse dopaminergic system.

Pre-clinical data collected in mouse models of Parkinson's disease (PD) support the neuroprotective potential of omega-3 polyunsaturated fatty acids (n-3 PUFA)-enriched diet on the dopaminergic (DAergic) system. In this study, we investigated the effects of an n-3 PUFA-rich diet using a neurorescue/neurorestorative paradigm. C57BL/6 adult mice were submitted to a striatal stereotaxic injection of the neurotoxin 6-hydroxydopamine (6-OHDA) to induce striatal DAergic denervation and subsequent nigral DAergic cell loss. Three weeks post-lesion, mice received either a docosahexaenoic acid (DHA)-enriched or a control diet for a period of 6 weeks. HPLC analyses revealed a 111% post-lesion increase in striatal dopamine levels in the DHA-fed animals compared to controls (ctrl, P<0.05), although no improvement in the motor behavior was observed. DHA treatment led to a 89% rise in tyrosine-hydroxylase (TH)-immunoreactive terminals within the striatum (P<0.05) in lesioned animals. Despite the fact that DHA did not change the number of TH+ neurons in the substantia nigra pars compacta (SNpc), morphological analyses revealed an increased in perimeters (+7%) and areas (+21%) of DAergic cell bodies in treated animals. Collectively, our results suggest that DHA induces a partial neurorescue/neurorestoration of the DAergic system and support further studies to investigate the potential of a diet-based intervention, or at least the combination of such approach, to current treatments in PD.

The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration.

BACKGROUND: Mounting evidence supports a significant role of inflammation in Parkinson's disease (PD) pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD. METHODS: Based on the fact that the myeloid differentiation primary response gene (88) (MyD88) is the most common adaptor protein implicated in toll-like receptor (TLR) signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-), following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence. RESULTS: Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice. CONCLUSIONS: Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in the central nervous system is MyD88-independent, in contrast to our recent observations that this pathway, in the same cohort of animals, is critical in the loss of dopaminergic neurons in the enteric nervous system.

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases.

Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 µM) was 0.15 ± 0.02 µL/g/s and was increased up to 0.34 ± 0.07 µL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.

Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions.

Animal models are invaluable tools to study neurodegenerative disorders but a general consensus on the most accurate rodent model of Parkinson's disease has not been reached. Here, we examined how different methods of MPTP administration influence the degeneration of the dopaminergic (DA) system. Adult male C57BL/6 mice were treated with the same cumulative dose of MPTP following four distinct procedures: (i) subacute i.p. injections; (ii) 28-day chronic s.c. infusion; (iii) 28-day chronic i.p. infusion; and (iv) 14-day chronic i.p. infusion. Subacute MPTP treatment significantly affected all aspects of the DA system within the nigral and striatal territories. In contrast, the 28-day chronic s.c. infusion did not significantly alter any components of the DA system. The 28- and 14-day chronic i.p. infusions induced loss of tyrosine hydroxylase (TH)-positive cells correlated with a decrease in Nurr1 mRNA levels, but no significant decrease in the density of TH striatal fibers. Importantly, however, only the 14-day chronic MPTP i.p. infusion protocol promoted the formation of neuronal inclusions as noted by the expression of alpha-synuclein protein within the cytoplasm of TH nigral neurons. Overall, we found that the 14-day chronic MPTP i.p. infusion reproduces more accurately the pathological characteristics of early stage Parkinson's disease.