The impact of revascularization strategy on clinical failure, hemodynamic failure, and chronic limb-threatening ischemia symptoms in the BEST-CLI Trial.

OBJECTIVE: Sustained clinical and hemodynamic benefit after revascularization for chronic limb-threatening ischemia (CLTI) is needed to resolve symptoms and prevent limb loss. We sought to compare rates of clinical and hemodynamic failure as well as resolution of initial and prevention of recurrent CLTI after endovascular (ENDO) vs bypass (OPEN) revascularization in the Best-Endovascular-versus-best-Surgical-Therapy-in-patients-with-CLTI (BEST-CLI) trial. METHODS: As planned secondary analyses of the BEST-CLI trial, we examined the rates of (1) clinical failure (a composite of all-cause death, above-ankle amputation, major reintervention, and degradation of WIfI stage); (2) hemodynamic failure (a composite of above-ankle amputation, major and minor reintervention to maintain index limb patency, failure to an initial increase or a subsequent decrease in ankle brachial index of 0.15 or toe brachial index of 0.10, and radiographic evidence of treatment stenosis or occlusion); (3) time to resolution of presenting CLTI symptoms; and (4) incidence of recurrent CLTI. Time-to-event analyses were performed by intention-to-treat assignment in both trial cohorts (cohort 1: suitable single segment great saphenous vein [SSGSV], N = 1434; cohort 2: lacking suitable SSGSV, N = 396), and multivariate stratified Cox regression models were created. RESULTS: In cohort 1, there was a significant difference in time to clinical failure (log-rank P < .001), hemodynamic failure (log-rank P < .001), and resolution of presenting symptoms (log-rank P = .009) in favor of OPEN. In cohort 2, there was a significantly lower rate of hemodynamic failure (log-rank P = .006) favoring OPEN, and no significant difference in time to clinical failure or resolution of presenting symptoms. Multivariate analysis revealed that assignment to OPEN was associated with a significantly lower risk of clinical and hemodynamic failure in both cohorts and a significantly higher likelihood of resolving initial and preventing recurrent CLTI symptoms in cohort 1, including after adjustment for key baseline patient covariates (end-stage renal disease [ESRD], prior revascularization, smoking, diabetes, age >80 years, WIfI stage, tissue loss, and infrapopliteal disease). Factors independently associated with clinical failure included age >80 years in cohort 1 and ESRD across both cohorts. ESRD was associated with hemodynamic failure in cohort 1. Factors associated with slower resolution of presenting symptoms included diabetes in cohort 1 and WIfI stage in cohort 2. CONCLUSIONS: Durable clinical and hemodynamic benefit after revascularization for CLTI is important to avoid persistent and recurrent CLTI, reinterventions, and limb loss. When compared with ENDO, initial treatment with OPEN surgical bypass, particularly with available saphenous vein, is associated with improved clinical and hemodynamic outcomes and enhanced resolution of CLTI symptoms.

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Relationship between WIfI stage and quality of life at revascularization in the BEST-CLI trial.

OBJECTIVE: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization. METHODS: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments. RESULTS: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments. CONCLUSIONS: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment.

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Predictors of Major Adverse Limb Events after Open Forefoot Amputation in Patients with Chronic Limb-Threatening Ischemia.

BACKGROUND: Management of patients with chronic limb-threatening ischemia (CLTI) and extensive foot necrosis presents a challenge for limb salvage. Our study evaluates preoperative risk factors that contributed to durability and efficacy of limb salvage after open transmetatarsal amputation (TMA) in patients with critical limb-threatening ischemia. METHODS: We abstracted data from patients who underwent open TMA at Los Angeles County-University of Southern California Medical Center and Keck Hospital of University of Southern California from 2009 to 2018. Multivariable logistic regression analysis, adjusting for preoperative risk factors, was used to examine predictors of major adverse limb events (MALE). The aim was to evaluate outcomes following open TMA with MALE as the primary outcome. Our hypotheses were that outcomes would be worse for patients with foot infections and renal failure. RESULTS: Forty-three open TMAs were done in 39 patients during the study period. The cohort had a mean age of 63 ± 11.6 years, 89% had a history of diabetes, 95% hypertension (HTN), 54% had end-stage renal disease (ESRD), and 26% were current smokers. MALE occurred in 39% of the cohort. Sex, race, indication, HTN, smoking status, and history of prior ipsilateral revascularization or minor amputations were not associated with MALE (P > 0.05). Multivariate logistic regression found ESRD to be an independent predictor of MALE (odds ratio 7.43, 95% confidence interval 1.12-49.17, P = 0.038) after adjusting for clinically significant covariates. CONCLUSIONS: Open TMA provides acceptable rates of limb salvage for complex patients with CLTI. ESRD is an independent risk factor for MALE following open TMA in these patients. Vigilant follow-up is essential for this morbid patient population given poorer outcomes after forefoot amputation.

Therapeutic Window of Clopidogrel and Ticagrelor in Patients With Critical Limb-Threatening Ischemia.

BACKGROUND: Critical limb-threatening ischemia (CLTI) is associated with an increased risk of major adverse limb events and mortality. High on-treatment platelet reactivity (HPR) is associated with an increased risk of ischemic events, while low on-treatment platelet reactivity (LPR) is associated with an increased risk of bleeding. This study investigates the frequency with which patients with CLTI on clopidogrel or ticagrelor achieve a "therapeutic window" (TW) of platelet inhibition. METHODS: Data from the "Switch To Ticagrelor in Critical Limb Ischemia Anti-Platelet Study" were assessed retrospectively to determine the incidence of TW of on-treatment platelet reactivity in 50 consecutive patients with CLTI (mean age: 65.2 ± 10.5 years, 54% male). The data included 4 measurements of patients' platelet reactivity using the VerifyNow P2Y12 Assay: baseline and steady state platelet reactivity on clopidogrel 75 mg daily and on ticagrelor 90 mg twice daily. RESULTS: At baseline, 46% of patients on clopidogrel were within TW of on-treatment platelet reactivity compared to 10% of patients on ticagrelor (P < .0001). At steady state, 42% of patients on clopidogrel were within the TW compared to 10% of patients on ticagrelor (P < .0001). Patients on ticagrelor exhibited higher rates of LPR compared to those on clopidogrel at baseline as well as at steady state (baseline 88% vs 18%, steady state 88% vs 28%; P < .0001). CONCLUSION: Although ticagrelor has been proposed as an alternative for patients with HPR on clopidogrel, the current study observes an excess of platelet inhibition with ticagrelor in most patients with CLTI at a dose of 90 mg twice daily.

In-Hospital Outcomes of Rotational Atherectomy in High-Risk Patients With Severely Calcified Left Main Coronary Artery Disease: A Single-Center Experience.

BACKGROUND: Severe coronary artery calcification is a challenge for percutaneous coronary intervention (PCI), particularly in left main coronary artery disease (LM-CAD). Rotational atherectomy (RA) is a useful tool for modification of calcified plaque prior to PCI. We report our experience with RA for severely calcified LM-CAD. METHODS: From January 2008 to January 2017, all patients who underwent RA-assisted LM-PCI were evaluated. The study population included both protected and unprotected LM-CAD patients. Clinical characteristics and in-hospital outcomes were collected retrospectively. In-hospital outcomes included post-PCI myocardial infarction, stroke, death, emergency coronary artery bypass graft surgery, and urgent repeat PCI. Angiographic success was defined by residual stenosis <20% and presence of TIMI 3 flow. RESULTS: Fifty-five consecutive patients who underwent RA-assisted PCI of LM-CAD were identified (mean age, 73.0 ± 10 years; 64% male). Mean left ventricular ejection fraction was 37.5 ± 15.7%. Fifty-one patients (93%) had multivessel disease and 39 patients (71%) underwent RA-assisted LM-PCI with use of a mechanical support device. The median largest burr size used was 1.5 mm. The mean number of LM stents implanted was 0.95 ± 0.3. The mean LM stent diameter and length were 3.7 ± 0.3 mm and 15.8 ± 7.5 mm, respectively. Intravascular ultrasound was used to assess vessel size and stent apposition in 20 patients (36.0%). Angiographic success was obtained in all patients (100%). CONCLUSION: Despite technical challenges, RA of the LM coronary artery can be performed safely and is associated with a high rate of angiographic success.

Comparison of devices used in carotid artery stenting: A vascular quality initiative analysis of commonly used carotid stents and embolic protection devices.

BACKGROUND: Data regarding efficacy of various stent and embolic protection device (EPD) combinations to prevent stroke during carotid artery stenting (CAS) is limited. We compared post-procedure inpatient neurologic outcomes across various carotid stent-EPD platforms recorded in the Vascular Quality Initiative (VQI) registry. METHODS: We analyzed 13,786 consecutive CAS procedures in the VQI registry performed between January 1, 2005 and December 31, 2015. The most commonly used stent-EPD combinations (n = 5407) were included in the analysis. Post-procedure inpatient neurologic outcomes included (1) ipsilateral stroke/transient ischemic attack (TIA) and (2) any stroke/TIA. Multivariate generalized estimating equation regression analysis was performed, adjusting for age, sex, tobacco use, coronary artery disease, congestive heart failure, prior stroke/TIA, hypertension, history of carotid revascularization, and presence of a second ipsilateral stenosis >70%, to determine whether risk of outcomes differed according to device. RESULTS: Of 13,786 CAS procedures, Xact-Emboshield (n = 2,438, 17.6%), Precise-Angioguard (n = 1,480, 10.7%), Acculink-Accunet (n = 829, 6.01%), and Acculink-Emboshield (n = 660, 4.8%) were the most commonly used combinations, accounting for a total of 5,407 procedures. Inpatient event rates for ipsilateral stroke/TIA and any stroke/TIA were 1.9 and 2.7% in the Accunet-Acculink, 3.0 and 3.2% in Acculink-Emboshield, 3.2 and 4.1% in Precise-Angioguard and 2.2 and 3.0% in Xact-Emboshield. There was no evidence of difference in risk of ipsilateral stroke/TIA or any stroke/TIA across device combinations (P = 0.15 and P = 0.16, respectively). CONCLUSION: CAS with current carotid stent-EPD combinations is associated with low rates of inpatient stroke/TIA. There is no statistically significant difference in rates of inpatient stroke/TIA across device combinations.

Switch to Ticagrelor in critical limb ischemia antiplatelet study (STT-CLIPS).

OBJECTIVE: To investigate platelet reactivity in patients with critical limb ischemia (CLI) after switching from clopidogrel to ticagrelor. BACKGROUND: High on-treatment platelet reactivity (HPR) is highly prevalent in patients with CLI treated with clopidogrel. The effect of ticagrelor in patients with CLI is not known, however. METHODS: We performed P2Y12 platelet receptor inhibition studies (VASP and VerifyNow) in 50 patients with CLI. Tests were performed before and 6±1h after daily 75mg clopidogrel dose. Patients were then switched to ticagrelor 90mg twice daily for two weeks and platelet assays repeated. Patients were divided based on VerifyNow P2Y12 reaction units (PRU). Group 1: HPR defined as PRU ≥208 and Group 2: Appropriate platelet inhibition (API), PRU <208. RESULTS: After two weeks of uninterrupted antiplatelet therapy, mean PRU results were 173 PRU and 71 PRU at baseline (p<0.0001) and 140 PRU and 63 PRU after 6h (p<0.0001) for clopidogrel and ticagrelor, respectively. Before daily clopidogrel dose, 36% of patients (n=18) demonstrated HPR and after 6h, 30% (n=15). One patient (2%) had HPR on ticagrelor. Ninety-four percent of patients with HPR on clopidogrel demonstrated appropriate platelet inhibition after switching to ticagrelor and all patients with API on clopidogrel remained with API after switching to ticagrelor. Six hours after daily dosing, VASP-PRI >50% was found in 42% of clopidogrel and 2% of ticagrelor treated patients. CONCLUSIONS: Among patients with CLI, ticagrelor achieved greater platelet inhibition than clopidogrel during maintenance treatment and at 6h after daily dosing. High on-treatment platelet reactivity to clopidogrel in patients with CLI can be overcome by switching to ticagrelor.

Prevalence of high on-treatment (aspirin and clopidogrel) platelet reactivity in patients with critical limb ischemia.

OBJECTIVES: The goal of this study is to establish the prevalence of high on-treatment platelet reactivity to aspirin (HPRA) and clopidogrel (HPRC) in patients with critical limb ischemia (CLI). BACKGROUND: CLI is associated with an increased risk of death and cardiovascular events. Unlike other patient populations with atherosclerotic cardiovascular disease, previous studies failed to demonstrate a benefit of antiplatelet therapy in patients with CLI. METHODS: From June 2014 to November 2016, we performed platelet reactivity studies for P2Y12 and thromboxane A2 (TXA2) inhibition in 100 CLI patients receiving daily treatment with aspirin and clopidogrel. P2Y12 inhibition was measured by two assays: vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 assays. HPRC was defined as VerifyNow P2Y12 reactive units (PRU) >208 and VASP-platelet reactivity index (VASP-PRI) >50%. TXA2 inhibition was measured with the VerifyNow aspirin test and HPRA was defined as aspirin reaction units (ARU) >550. RESULTS: Mean age was 67±11 years, 50% were male, 80% had diabetes mellitus, and 26% had chronic renal insufficiency. Thirty-three percent of patients had a PRU >208 and 46% a VASP-PRI >50%. HPRC was present in 26% of patients based on the criteria of both a PRU >208 and VASP-PRI >50%. HPRA was present in 25% of patients. The overall prevalence of HPR to ASA or clopidogrel was 35% and HPR to both drugs was present in 8% of patients. Clinical characteristics were similar between groups. CONCLUSIONS: HPR to aspirin or clopidogrel is highly prevalent in patients with CLI. Nearly one in ten patients with CLI is a hyporesponder to both aspirin and clopidogrel.

Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus.

BACKGROUND/PURPOSE: Diabetes mellitus (DM) disproportionately affects Hispanic patients. DM patients have enhanced platelet reactivity and reduced sensitivity to clopidogrel. Ticagrelor demonstrated a more rapid onset and greater magnitude of platelet inhibition than clopidogrel in Hispanic patients with stable coronary artery disease (CAD). This subgroup analysis examined the onset and level of platelet inhibition of ticagrelor and clopidogrel in Hispanic patients with DM. METHODS/MATERIALS: This was a subgroup analysis of a randomized, open-label, crossover study in which 40 Hispanic patients with stable CAD received ticagrelor 180 mg loading dose (LD)/90 mg twice-daily maintenance dose (MD) then clopidogrel 600 mg LD/75 mg once-daily MD, or vice versa. The primary end point was on-treatment platelet reactivity at 2 hours post-LD using the VerifyNow™ P2Y12 test. RESULTS: 21 patients had DM and 19 were non-diabetic. At 2 hours post-LD, mean platelet reactivity in the diabetic group was 34.5 PRU with ticagrelor versus 219.3 PRU with clopidogrel (P<0.001), and in the non-diabetic group was 33.7 PRU with ticagrelor versus 181.0 PRU with clopidogrel (P<0.001). In both diabetic and non-diabetic subgroups, mean platelet reactivity declined to a significantly greater extent with ticagrelor than clopidogrel at all time points evaluated (0.5, 2, and 8 hours post LD and after 7-9 days of MD). Patients were significantly more likely to have high on-treatment platelet reactivity (≥208 PRU) during treatment with clopidogrel compared with ticagrelor, regardless of diabetic status. CONCLUSIONS: Among Hispanic patients with stable CAD, ticagrelor achieves a faster onset and greater magnitude of platelet inhibition compared with clopidogrel, irrespective of diabetic status.

Use of regadenoson for measurement of fractional flow reserve.

OBJECTIVE: To compare the use of regadenoson to adenosine for measurement of fractional flow reserve (FFR). BACKGROUND: FFR is an accepted method to assess the functional significance of intermediate coronary artery stenoses and uses adenosine to induce maximal hyperemia. The use of the selective A2a receptor agonist regadenoson for FFR is not established. METHODS: Fifty-seven patients undergoing clinically indicated FFR assessment of intermediate coronary stenoses were included. For the initial assessment of FFR, hyperemia was achieved by a standard intravenous adenosine infusion (140 mcg/kg/min). After a washout period of 10 min, FFR was reassessed using regadenoson as a single 0.4 mg intravenous bolus. FFR measurements were recorded at baseline and following maximal hyperemia with both agents. RESULTS: Mean age was 57 ± 8 years and 47 were male. Sixty coronary lesions were evaluated and were located in the left anterior descending in 34, the left circumflex in 9, right coronary in 15, and left main coronary artery in 2. Mean ( ± SD) FFR following adenosine and regadenoson was 0.79 ( ± 0.09) and 0.79 (±0.09), respectively, P = NS. Time to FFR nadir was shorter with regadenoson compared to adenosine, 36.6 ± 24 versus 66 ± 0.19 sec, P < 0.0001, respectively. No patients experienced any significant side effects related to regadenoson. CONCLUSIONS: Regadenoson is a viable alternative to intravenous adenosine for achieving maximal hyperemia during FFR assessment. Compared to adenosine, regadenoson has a similar hemodynamic response, achieves more rapid hyperemia, is easier to use, and has an excellent side-effect profile.

Revascularization of carotid stenosis before cardiac surgery.

Carotid artery stenosis is often associated with advanced coronary artery disease. The coexistence of carotid and coronary artery disease adds complexity to the medical decision process and brings increasing challenge to the perioperative management of coronary artery bypass graft (CABG) surgery. Postoperative stroke remains one of the most devastating complications of CABG, thereby contributing to the increased risk of mortality following CABG. Carotid artery disease causes approximately a third of post-CABG stroke and thus needs to be addressed while preparing a patient for CABG. While carotid endarterectomy (CEA) has been the gold standard of carotid artery revascularization, carotid artery stenting may be noninferior to CEA in patients with increased surgical risks. Thus, a consensus as how to best revascularize patients with carotid artery stenosis before CABG is yet to emerge. We have reviewed the current literature and have addressed the pros and cons of the two modalities of carotid artery revascularization. Based on the current literature, the best management strategy for patients with concomitant surgical coronary artery disease in need of CABG and significant carotid artery stenosis should be based on individual patient characteristics, urgency of revascularization, prioritization based on the symptomatic vascular territory, local expertise with an integrated team approach by interventionalists, neurologists and cardiothoracic surgeons, preferably in high-volume centers.

Interanimal variability in preexisting collaterals is a major factor determining outcome in experimental angiogenesis trials.

Despite numerous animal trials reporting that cell therapy promotes collateral flow, clinical trials have not convincingly shown benefit. Patient-related risk factors are often used to explain these discrepancies. However, during the course of our own angiogenesis studies using mice, we noted large anatomical variability in collateral vessels. The purpose of the present investigation was to define how important this factor might be in determining intervention outcomes. Hindlimb ischemia was induced in BALB/c mice by ligating the superficial femoral artery. After 24 h, animals were treated by injecting the adductor muscle with either control media or cultured mesenchymal stem cells (MSCs). Blood flow recovery was measured using laser-Doppler [laser-Doppler perfusion imaging (LDPI) ratio]. In a second experiment, mice were stratified 24 h after arterial ligation before treatment by using a simple clinical score of the ligated leg: 1, able to flex, mild discoloration; 2, no flexion, mild discoloration; 3, severe discoloration; and 4, any necrosis. Without stratification, blood flow recovery significantly increased in the MSC-treated group (P < 0.05, n = 6 MSC group, n = 7 media group). In the experiment employing stratification, all differences between the groups disappeared (n = 11 MSC group, n = 10 media group; P = 0.3). Furthermore, we found a striking inverse correlation between clinical score on day 1 and the LDPI ratio on day 28 (P < 0.0001; n = 79). Anatomical confirmation of the disparity in preexisting collaterals was found in two different mouse strains using microscopic computed tomography. In conclusion, there is substantial interanimal variability in preexisting collateral flow, and this variability can importantly influence outcome. To overcome this, either animals must be stratified before treatment, the number of animals must be increased substantially, or, preferably, both.

Sirolimus-eluting stents and calcified coronary lesions: clinical outcomes of patients treated with and without rotational atherectomy.

This study examined the outcomes of patients who underwent sirolimus-eluting stent (SES) implantation for the treatment of heavily calcified coronary lesions (HCCL) with and without the use of rotational atherectomy (rotablator). We investigated 150 consecutive patients with angiographic evidence of HCCL who underwent SES implantation. Sixty-nine patients underwent SES implantation without the need of rotablator (SES), and 81 patients required rotational atherectomy to modify the plaque and facilitate the delivery of the stent (SES + rotational atherectomy). Clinical success was equivalent in both groups (>98%) and there were no in-hospital outcome differences. At 6 months, the target lesion revascularization rate was 4.9% in SES vs. 4.2% in SES + rotational atherectomy groups, respectively (P = NS). Mortality at 6 months was 7.9% in the SES group vs. 6.8% in the SES + rotational atherectomy group (P = NS). SES performs well in patients with complex HCCL, with a relative low event rate. Lesions requiring rotational atherectomy to facilitate dilation and stenting had similar outcomes after SES implantation to those that could be stented without the need for rotablator.

Effect of a rapid intra-arterial infusion of dextrose 5% prior to coronary angiography on frequency of contrast-induced nephropathy in high-risk patients.

Contrast-induced nephropathy (CIN) is a common complication of coronary angiography that is associated with significant morbidity and mortality. Preexisting renal dysfunction is the most important risk factor for the development of CIN. A novel strategy of infusing 1 L of 5% dextrose immediately before catheterization is associated with a lower rate of CIN in those at high risk (creatinine clearance < or = 60 ml/min). CIN occurred in 47 patients (5.7%) in the control group and 2 patients (1.4%) in the group treated with 5% dextrose. The relative risk decrease was 73% (p = 0.03). This is an effective, quick, and inexpensive method of improving outcomes in patients who undergo percutaneous coronary interventions.

The potential role of resistin in atherogenesis.

Resistin, an adipocyte-derived cytokine linked to insulin resistance and obesity, has recently been shown to activate endothelial cells (ECs). Using microarrays, we found that along with numerous other pro-atherosclerotic genes, resistin expression levels are elevated in the aortas of C57BL/6J apoE-/- mice; these findings led us to further explore the relation between resistin and atherosclerosis. Using TaqMan PCR and immunohistochemistry, we found that ApoE-/- mice had significantly higher resistin mRNA and protein levels in their aortas, and elevated serum resistin levels, compared to C57BL/6J wild-type mice. Incubation of murine aortic ECs with recombinant resistin increased monocyte chemoattractant protein (MCP)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 protein levels in the conditioned medium. Furthermore, human carotid endarterectomy samples stained positive for resistin protein, while internal mammary artery did not show strong staining. Patients diagnosed with premature coronary artery disease (PCAD) were found to have higher serum levels of resistin than normal controls. In summary, resistin protein is present in both murine and human atherosclerotic lesions, and mRNA levels progressively increase in the aortas of mice developing atherosclerosis. Resistin induces increases in MCP-1 and sVCAM-1 expression in murine vascular endothelial cells, suggesting a possible mechanism by which resistin might contribute to atherogenesis. Finally, PCAD patients exhibited increased serum levels of resistin when compared to controls. These findings suggest a possible role of resistin in cardiovascular disease.