Restoration of microcirculatory patency after myocardial infarction: results of current coronary interventional strategies and techniques.

We sought to evaluate the restoration of microcirculatory patency after primary percutaneous coronary intervention (PCI) in an unselected cohort of patients at a tertiary center.We retrospectively evaluated distributions of the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) and the myocardial blush grade (MBG) in all primary PCI procedures performed at our institution during 2008. We defined optimal microvascular perfusion as simultaneous TMPG 3 and MBG 3 at procedure's end.Ninety-nine patients (mean age, 61.5 ± 12.7 yr; 64 men) underwent primary PCI. Microvascular perfusion was optimal in 69 patients (69.7%) and was associated with lower peaks of enzymes than those occurring in patients with suboptimal perfusion. When optimal microvascular perfusion was achieved, early spontaneous recanalization was more frequently observed, as expressed by a higher frequency of TIMI-3 flow (34.8% vs 10%; P=0.006), TMPG 3 (26% vs 3.3%; P=0.004), and MBG 3 (24.6% vs 3.3%; P=0.004) on the initial angiogram before primary PCI. A higher frequency of MBG 3 (50% vs 20%; P=0.005) was seen after initial recanalization in patients with optimal microvascular perfusion. Multiple regression analysis showed that MBG after initial recanalization and the use of drug-eluting stents were associated with optimal perfusion.Despite successful recanalization of the culprit coronary artery, optimal microvascular perfusion was achieved in less than 75% of the patients. Restoration of the microvasculature was associated with smaller infarcts. Procedure-related variables associated with suboptimal perfusion were unlikely to be causative.

Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure.

BACKGROUND: The optimal type of stem cell for use in patients with ischemic heart disease has not been determined. A primitive population of bone marrow-derived hematopoietic cells has been isolated by the presence of the enzyme aldehyde dehydrogenase and comprises a multilineage mix of stem and progenitor cells. Aldehyde dehydrogenase-bright (ALDH(br)) cells have shown promise in promoting angiogenesis and providing perfusion benefits in preclinical ischemia studies. We hypothesize that ALDH(br) cells may be beneficial in treating ischemic heart disease and thus conducted the first randomized, controlled, double-blind study to assess the safety of the transendocardial injection of autologous ALDH(br) cells isolated from the bone marrow in patients with advanced ischemic heart failure. METHODS: Aldehyde dehydrogenase-bright cells were isolated from patients' bone marrow on the basis of the expression of a functional (aldehyde dehydrogenase) marker. We enrolled 20 patients (treatment, n = 10; control, n = 10). Safety (primary end point) and efficacy (secondary end point) were assessed at 6 months. RESULTS: No major adverse cardiovascular or cerebrovascular events occurred in ALDH(br)-treated patients in the periprocedural period (up to 1 month); electromechanical mapping-related ventricular tachycardia (n = 2) and fibrillation (n = 1) occurred in control patients. Aldehyde dehydrogenase-bright-treated patients showed a significant decrease in left ventricular end-systolic volume at 6 months (P = .04) and a trend toward improved maximal oxygen consumption. The single photon emission computed tomography delta analysis showed a trend toward significant improvement in reversibility in cell-treated patients (P = .053). CONCLUSIONS: We provide preliminary evidence that treatment with the novel cell population, ALDH(br) cells, is safe and may provide perfusion and functional benefits in patients with chronic myocardial ischemia.

A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF).

BACKGROUND: Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. METHODS: In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. RESULTS: Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months (P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P = .02) but not in treated patients (P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). CONCLUSIONS: ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.

A randomized, controlled study of autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia.

OBJECTIVES: The safety and efficacy of direct intramuscular injections of aldehyde dehydrogenase bright (ALDH(br)) cells isolated from autologous bone marrow mononuclear cells (ABMMNCs) and ABMMNCs were studied in patients with critical limb ischemia (CLI) who were not eligible for percutaneous or surgical revascularization. BACKGROUND: Many CLI patients are not candidates for current revascularization procedures, and amputation rates are high in these patients. Cell therapy may be a viable option for CLI patients. METHODS: Safety was the primary objective and was evaluated by occurrence of adverse events. Efficacy, the secondary objective, was evaluated by assessment of Rutherford category, ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO(2)), quality of life, and pain. RESULTS: ALDH(br) cells and ABMMNCs were successfully administered to all patients. No therapy-related serious adverse events occurred. Patients treated with ALDH(br) cells (n = 11) showed significant improvements in Rutherford category from baseline to 12 weeks (mean, 4.09 ± 0.30 to 3.46 ± 1.04; P = 0.05) and in ABI at 6 (mean, 0.22 ± 0.19 to 0.30 ± 0.24; P = 0.02), and 12 weeks (mean, 0.36 ± 0.18; P = 0.03) compared with baseline. Patients in the ABMMNC group (n = 10) showed no significant improvements at 6 or 12 weeks in Rutherford category but did show improvement in ABI from baseline to 12 weeks (0.38 ± 0.06 to 0.52 ± 0.16; P = 0.03). No significant changes from baseline were noted in ischemic ulcer grade or TcPO(2) in either group. CONCLUSIONS: Administration of autologous ALDH(br) cells appears to be safe and warrants further study in patients with CLI.

Single center experience with percutaneous endovascular repair of superior vena cava syndrome.

OBJECTIVES: To demonstrate short-term effectiveness and long-term efficacy of percutaneous transluminal angioplasty (PTA) with or without adjunctive therapy in treatment of superior vena cava syndrome (SVCS). BACKGROUND: Recently, PTA with or without adjunctive therapy has evolved as first-line therapy for SVCS. Despite growing evidence for PTA with or without adjunctive therapy, there are little data reflecting its short- and long-term outcomes. METHODS: We retrospectively reviewed 14 consecutive patients undergoing PTA with or without adjunctive therapy for SVCS, between July 2001 and September 2009. RESULTS: A total of 14 patients (nine women; mean age, 49 ± 15 years) with SVCS underwent attempted PTA with or without adjunctive therapy. Causes of SVCS were indwelling catheters or pacemaker wires (n = 5), idiopathic (n = 5), thoracic outlet syndrome (n = 2), and cancer-related thrombosis (n = 2). Obstruction of the SVC involved inflow branches in 86% of patients (n = 12). PTA with or without adjunctive therapy was attempted in all 14 patients and was angiographically successful in 93% (n = 13). PTA and stenting was performed in eight (57%) patients; three (21%) patients had PTA with thrombectomy/thrombolysis; one (7%) patient had PTA alone; and one (7%) patient had thrombectomy/thrombolysis alone. Symptom relief was seen in 86% (n = 12), and initial patency was 90%. There were no procedural complications. Mean follow-up was 12 months, and no deaths were reported. In the 11 (79%) patients with follow-up imaging, nine (82%) patients showed patency and two (18%) had residual symptoms, with one patient undergoing surgery. CONCLUSIONS: PTA with adjunctive endovascular stent therapy for SVCS is safe and effective at giving both rapid and sustained symptom relief.

Antithrombotics in acute coronary syndromes.

Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

Comparative healing response after sirolimus- and paclitaxel-eluting stent implantation in a pig model of restenosis.

OBJECTIVE: We compared local vessel healing and inflammatory responses associated with nonoverlapping sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). BACKGROUND: Sirolimus and paclitaxel may have different effects on vascular healing. In the present study, we analyzed the local histologic effects of drug-eluting stents (DES). METHODS: We placed 43 stents (22 PES and 21 SES) in 16 Yucatan minipigs. Stents were randomly assigned and placed in the left anterior descending, circumflex, or right coronary arteries (one stent per artery), covering a region previously injured by balloon angioplasty. RESULTS: Histopathologic analysis showed that the distribution of injury scores was similar between the two stent groups, reflecting the homogeneity of coronary injury secondary to balloon overstretch. Electron microscopy showed complete endothelialization in most cases. Incomplete endothelialization was present in 12.5% of PES and almost 20% of SES at 30 days. In the PES group, moderate to severe inflammation was found in eight arteries, whereas only one vessel had moderate inflammation in the SES group. Severe inflammation was observed significantly more often in the PES than in the sirolimus group (P = 0.006). With the PES group, stent struts overlying side branches had a significantly higher frequency of poor endothelialization scores than did stent struts that did not overlay side branches (P = 0.006). CONCLUSIONS: In this preclinical study in a pig model of in-stent restenosis, implantation of nonoverlapping DES was associated with local inflammatory reactions and decreased endothelial repair. Impaired endothelialization was visualized in the struts overlying side branches.

Validation of QwikStar Catheter for left ventricular electromechanical mapping with NOGA XP system.

Left ventricular electromechanical mapping (LVEM) is a method for mapping the left ventricular cavity in 3 dimensions by use of a catheter that samples points on the endocardial surface. These points provide data on unipolar voltage and linear local shortening, which can then be used to evaluate myocardial ischemia and viability. The new QwikStar multi-electrode catheter, which acquires data from multiple points simultaneously, potentially improves map quality and decreases mapping time in comparison with the single-point NogaStar catheter. Our study sought to validate the QwikStar catheter's LVEM capabilities in a porcine model of chronic ischemia.Eight pigs underwent ameroid placement over the proximal left circumflex artery, to induce chronic ischemia. In 60 days, LVEM was performed on each animal with the NogaStar and QwikStar catheters. Unipolar voltage and linear local shortening results were displayed in 9-segment polar maps. The unipolar voltage data from both maps were then correlated by means of linear regression.There were no adverse events during LVEM. Mapping time was similar for both groups (QwikStar, 44.6 +/- 25.62 min; NogaStar, 65.75 +/- 25.33 min; P = 0.13). Results of mean unipolar voltage maps acquired with the 2 catheters showed a moderate correlation (r =0.59, P <0.001). Selecting segments with more than 6 point samples increased the Pearson coefficient to 0.69 (P <0.001).Our findings show that the QwikStar catheter enables the reproducible performance of LVEM by sampling fewer points, which shortens procedure time, decreases manipulation of the left ventricular cavity, and might increase procedural safety.

Low-molecular-weight heparins : mechanisms, trials, and role in contemporary interventional medicine.

The clinical spectrum of acute coronary syndromes (ACS) encompasses unstable angina, non-ST-elevation, and ST-elevation myocardial infarction (STEMI). Within an atherosclerotic plaque, disruption of the endothelium can lead to exposure of tissue factor, with platelet adhesion, activation and aggregation, along with activation of the coagulation cascade, culminating in thrombin formation and the development of a cross-linked fibrin clot at the site of injury. Therapy aimed at blocking thrombin formation is now an integral part of the current cardiovascular guidelines in the treatment of ACS. Although unfractionated heparin (UFH) has been the mainstay of antithrombin therapy in the past, it has numerous clinical and biochemical limitations, including substantial protein binding (leading to inconsistent bioavailability), a need for frequent monitoring and adjustment, unreliable and variable degrees of anticoagulation, significant platelet activation, risk of heparin-induced thrombocytopenia, and the inability to block clot bound thrombin. With all of these limitations of UFH, low-molecular-weight heparins (LMWHs) have emerged as attractive alternatives. This review discusses the mechanism of action of LMWHs, and summarizes available literature concerning the use of LMWHs in a variety of clinical settings. Included in this review is an analysis of both current and prior data showing LMWH is as effective as UFH in the conservative and invasive management of patients with ACS. As well, very recent data are evaluated showing the safety and efficacy of LMWHs used in patients transitioning to the cardiac catheterization laboratory, and in those patients undergoing elective or urgent percutaneous coronary intervention (PCI). We also appraise the literature, along with the very recent studies investigating the use of LMWHs as adjunctive therapy to fibrinolytics in patients with STEMI. Finally, we set forth real-world conclusions concerning the use of LMWHs in contemporary interventional practice, including elective PCI and the treatment of ischemic coronary artery disease in the context of rapid invasive management of ACS.

Histopathological validation of electromechanical mapping in assessing myocardial viability in a porcine model of chronic ischemia.

BACKGROUND AND OBJECTIVE: Left ventricular electromechanical mapping (EMM) determines myocardial viability on the basis of endocardial electrograms. The aim of the present study was to validate EMM in differentiating infarcted myocardium from viable myocardium by histopathological analysis. METHODS: Sixty days after implanting an ameroid constrictor over the left circumflex artery to create chronic ischemia in 19 pigs, EMM was performed to construct unipolar voltage (UPV), bipolar voltage (BPV) and linear local shortening (LLS) maps. Noninfarcted and infarcted myocardium were identified by histopathology. Threshold determinations comparing noninfarcted tissue with scarred tissue were made by measuring the area under the receiver operating characteristic curves. RESULTS: From the 19 hearts, 149 myocardial segments were divided into noninfarcted myocardium (n=128) and transmural infarct (n=21). UPV, BPV and LLS values (4.7+/-1.2 mV, 2.8+/-2.5 mV and 10.0+/-5.1%, respectively) of infarcted segments were significantly lower than those in noninfarcted myocardium (10.9+/-3.4 mV, 4.5+/-2.4 mV and 15.7+/-9.5%, respectively; P<0.01 for each comparison). The threshold values of UPV, BPV and LLS differentiating noninfarcted from infarcted myocardium were 6.2 mV (98% sensitivity, 95% specificity, 97% accuracy), 2.8 mV (80% sensitivity, 72% specificity, 79% accuracy) and 12.3% (68% sensitivity, 67% specificity, 68% accuracy), respectively. The relative dispersion of voltage was lower for UPV versus BPV. CONCLUSION: UPV can accurately differentiate infarcted from noninfarcted tissue in the chronic ischemic heart of pigs; however, BPV and LLS results were less accurate.

First experience with remote left ventricular mapping and transendocardial cell injection with a novel integrated magnetic navigation-guided electromechanical mapping system.

AIMS: The purpose of this preclinical feasibility study was to evaluate a novel integrated platform in which magnetic navigation is used to remotely guide electromechanical mapping of the left ventricle (LV) and transendocardial cell injections. Using an integrated remote system would greatly facilitate intramyocardial delivery of stem cells for treating ischaemic heart disease. METHODS AND RESULTS: We used the computer-controlled Stereotaxis magnetic navigation system to guide the NOGA electromechanical mapping system in mapping viable myocardium in the LV of seven pigs. We then tested the feasibility of this system to perform transendocardial injections in three of the pigs and to deliver mesenchymal precursor cells (MPCs) to targeted myocardial segments in four of the pigs. The success or failure of each injection was determined by myocardial contrast staining in the first group and by histopathologic analysis in the last group. The mean time (+/-SD) spent mapping the LV for each pig was 49.3+/-10.6 min. The success rate for transendocardial injections was 94.4%, as indicated by myocardial contrast staining. There was a 95.8% success rate for targeted injections of MPCs, and 4',6-diamidino-2-phenylindole-labeled MPCs were detected in all but one segment of one pig. No epicardial haemorrhage or injury was observed, although there was some venous drainage. CONCLUSIONS: The integrated Stereotaxis/NOGA system has excellent remote navigability inside the LV cavity while sparing the operator from radiation exposure. This system also allows transendocardial cell injections to be performed with a high success rate. Further studies are needed to define the safety profile of this system for clinical use.

Sarcoidosis masquerading as an acute coronary syndrome.

Sarcoidosis is a common multisystem granulomatous disease that affects 20 per 100,000 people in the world. Although primarily a pulmonary disease, sarcoidosis can affect multiple organ systems. Cardiac involvement of sarcoidosis is most commonly manifested as ventricular ectopy and arrhythmias; atrioventricular conduction disturbances, including complete heart block; congestive heart failure; and even may result in sudden death. Although myocardial infarction is most commonly the result of epicardial coronary artery disease, an infiltrative process such as sarcoidosis may simulate an acute coronary syndrome. Given the high prevalence of sarcoidosis, it is important to be aware of the myriad of cardiac manifestations of this infiltrative process.