Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. METHODS AND RESULTS: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. CONCLUSIONS: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

Long-term Results With CorMatrix Extracellular Matrix Patches After Carotid Endarterectomy.

BACKGROUND: Previous reports of extracellular matrix (ECM) patch use after carotid endarterectomy (CEA) have noted an approximately 10% rate of pseudoaneurysm (PSA) formation. PSA-related rupture of ECM patches has also been described after femoral artery repair. In these studies, different thicknesses (4-ply versus 6-ply) and no standard length of soaking the patch in saline before implantation were used. Herein, we describe our experience with ECM CorMatrix patches in 291 CEAs with 6-ply patches. METHODS: The records of 275 consecutive patients undergoing 291 CEAs with CorMatrix 6-ply patches beginning in November of 2011 and extending until 2015 were reviewed. Only 6-ply patches and a 1 min hydration time in saline were used in all patients. No shunts were used. RESULTS: There were three deaths within the first 30 d secondary to subsequent cardiac surgical procedures. Nine patients experienced a perioperative stroke (3.1%), only one of which occurred secondary to an occluded internal carotid artery. One patient had a transient ischemic attack with a patent endarterectomy site. In follow-up, 11 patients (4.5%) developed severe recurrent stenoses requiring reintervention. Only one patient (0.34%) developed a PSA at 2 years possibly secondary to chronic infection. The median follow-up was 72 mo. CONCLUSIONS: Our experience with 6-ply CorMatrix ECM patches and a brief period of soaking demonstrated that these patches performed well in patients requiring a CEA. Only one PSA was noted.

TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis.

RATIONALE: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function. OBJECTIVE: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. METHODS AND RESULTS: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). CONCLUSIONS: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment-elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure).

RATIONALE: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. OBJECTIVE: CONCERT-HF (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). METHODS AND RESULTS: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. CONCLUSIONS: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811.

Exercise-induced saphenous vein graft spasm prevented by stenting.

Recurrence of anginal symptoms following coronary artery bypass surgery is usually secondary to graft closure or progression of native vessel disease. The present case demonstrates severe exercise-induced saphenous vein graft (SVG) spasm associated with transmural ischemia refractory to maximal vasodilator therapy. Symptoms resolved and exercise electrocardiography normalized following stenting of SVG regions demonstrating spasm. © 2017 Wiley Periodicals, Inc.

Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells.

OBJECTIVES: Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells. APPROACH AND RESULTS: In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31(+)/AC133(+), AC133(+), CD34(+)/AC133(+), and CD34(+)/45(dim)/AC133(+) cells) and positively associated with road segment distance (CD31(+)/AC133(+), AC133(+), and CD34(+)/AC133(+) cells), traffic intensity (CD31(+)/AC133(+) and AC133(+) cells), and distance-weighted traffic intensity (CD31(+)/34(+)/45(+)/AC133(+) cells). CONCLUSIONS: Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133(+). This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.

Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance.

BACKGROUND: SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit(+) cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG). In the present study, we report the surgical aspects and interim cardiac magnetic resonance (CMR) results. METHODS AND RESULTS: A total of 33 patients (20 CSC-treated and 13 control subjects) met final eligibility criteria and were enrolled in SCIPIO. CSCs were isolated from the right atrial appendage harvested and processed during surgery. Harvesting did not affect cardiopulmonary bypass, cross-clamp, or surgical times. In CSC-treated patients, CMR showed a marked increase in both LVEF (from 27.5 ± 1.6% to 35.1 ± 2.4% [P=0.004, n=8] and 41.2 ± 4.5% [P=0.013, n=5] at 4 and 12 months after CSC infusion, respectively) and regional EF in the CSC-infused territory. Infarct size (late gadolinium enhancement) decreased after CSC infusion (by manual delineation: -6.9 ± 1.5 g [-22.7%] at 4 months [P=0.002, n=9] and -9.8 ± 3.5 g [-30.2%] at 12 months [P=0.039, n=6]). LV nonviable mass decreased even more (-11.9 ± 2.5 g [-49.7%] at 4 months [P=0.001] and -14.7 ± 3.9 g [-58.6%] at 12 months [P=0.013]), whereas LV viable mass increased (+11.6 ± 5.1 g at 4 months after CSC infusion [P=0.055] and +31.5 ± 11.0 g at 12 months [P=0.035]). CONCLUSIONS: Isolation of CSCs from cardiac tissue obtained in the operating room is feasible and does not alter practices during CABG surgery. CMR shows that CSC infusion produces a striking improvement in both global and regional LV function, a reduction in infarct size, and an increase in viable tissue that persist at least 1 year and are consistent with cardiac regeneration. CLINICAL TRIAL REGISTRATION: This study is registered with clinicaltrials.gov, trial number NCT00474461.

Stem cell therapy: promising treatment in heart failure?

Cardiac repair through the use of regenerative medicine has been a considerable research focus over the last decade. Several stem cell types have been investigated over this timeframe as potential candidates to target post-infarction heart failure. The progression of investigation through the rigors of clinical trial design has provided some answers as to the potential clinical utility of this therapy; although there are many questions that remain. This review will concentrate on the clinical trial results of stem cell therapy for cardiac repair since the turn of the century and discuss some of the points that need clarification before this form of therapy can be considered for widespread applicability.

Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

BACKGROUND: c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. METHODS: In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. FINDINGS: This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). INTERPRETATION: These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. FUNDING: University of Louisville Research Foundation and National Institutes of Health.

Cardiac stem cells in patients with ischemic cardiomyopathy: discovery, translation, and clinical investigation.

The increasing prevalence of heart failure, in the US and worldwide, poses a significant burden to patients, practitioners, and healthcare systems. Hence, there is a pressing need for alternative therapies to enhance the current treatment armamentarium. Accordingly, when considering heart failure of ischemic etiology, an intervention designed to regenerate the attending loss of myocardium could potentially result in improved cardiac function, functional status, and quality of life. Significant strides have been made by investigators in the study of stem cell therapy for cardiac repair; recently with cardiac-derived progenitor cells. These cells include cardiospheres, cardiosphere-derived cells, and c-kit positive cardiac stem cells. Herein, a review of both preclinical studies and phase I clinical trials of these cell types is presented. A detailed account of in vitro characterization, in vivo bioactivity, and safety and efficacy in humans is outlined. Thus far, encouraging results have been realized, although larger studies have yet to be undertaken.

Clinical Approach to Cardiovascular Toxicity of Oral Antineoplastic Agents: JACC State-of-the-Art Review.

Precision medicine has ushered in a new era of targeted treatments for numerous malignancies, leading to improvements in overall survival. Unlike traditional chemotherapy, many molecular targeted antineoplastic agents are available in oral formulation, leading to enhanced patient convenience and a perception of reduced risk of adverse effects. Although oral antineoplastic agents are generally well-tolerated, cardiovascular toxicities are being reported with increasing frequency in part due to U.S. Food and Drug Administration and manufacturer recommended cardiac monitoring. Monitoring strategies have focused on left ventricular dysfunction, hypertension, and QT prolongation/arrhythmias. Given the rapid pace of development and availability of new oral antineoplastic agents, the purpose of this review is to provide clinicians with an up-to-date practical approach to monitoring and management of cardiovascular toxicities with the aim of improving overall outcomes for patients with cancer.

Using Aspiration-Based Tricuspid Valve Endocarditis Debridement: Highlighting Imaging-Based Modification in a High-Risk Clinical Scenario.

This report describes a high-risk case of tricuspid valve endocarditis secondary to intravenous drug abuse. Information gleaned from intraoperative transesophageal echocardiographic imaging and real-time measurements was used to effectively modify procedural hardware and successfully treat the patient using an aspiration-based strategy. (Level of Difficulty: Advanced.).

A comparative evaluation of various methods for microalbuminuria screening.

BACKGROUND/AIMS: Microalbuminuria is a marker of abnormal vascular response and a predictor of cardiovascular morbidity and mortality. We evaluated a new quantitative office-based method to assess urinary albumin excretion (UAE) and compared it to other established methods. METHODS: Spot urine samples from 165 patients were analyzed at a single study site using the HemoCue system, Clinitek Microalbumin, and Chemstrip Micral test, as well as at a central laboratory, where UAE and creatinine levels were measured. The central laboratory UAE values were used as reference. We evaluated the validity of the HemoCue results and compared them to the respective data for the laboratory albumin-to-creatinine ratio (ACR). Additionally, we assessed, diagnostic sensitivity, specificity, and positive and negative predictive values of all four methods, as well as the reproducibility of the HemoCue measurements. RESULTS: Linear regression analysis demonstrated a good correlation for the HemoCue system (y = 0.9978x - 1.0217, R2 = 0.904) and ACR (y = 0.0815x + 0.3373, R2 = 0.784). Sensitivity and specificity for microalbuminuria diagnosis were 92 and 98% for HemoCue, 73 and 96% for ACR, 100 and 81% for Clinitek Microalbumin, and 70 and 83% for Chemstrip Micral dipstick, respectively. The correlation coefficient of duplicate HemoCue measurements was r = 0.98 (p < 0.001). CONCLUSIONS: The HemoCue system for microalbuminuria detection was as accurate and precise as laboratory ACR estimations. Its diagnostic performance was much better than that of widely used dipstick methods.

Microalbuminuria: what is it? Why is it important? What should be done about it? An update.

Microalbuminuria (MA) is defined as a persistent elevation of albumin in the urine of >30 to <300 mg/d (>20 to <200 microg/min). Use of the morning spot urine test for albumin-to-creatinine measurement (mg/g) is recommended as the preferred screening strategy for all patients with diabetes and with the metabolic syndrome and hypertension. MA should be assessed annually in all patients and every 6 months within the first year of treatment to monitor the impact of antihypertensive therapy. It is an established risk marker for the presence of cardiovascular disease and predicts progression of nephropathy when it increases to frank microalbuminuria>300 mg/d. Data support the concept that the presence of MA is the kidney's warning that there is a problem with the vasculature. The presence of MA is a marker of endothelial dysfunction and a predictor of increased cardiovascular risk. MA can be reduced, and progression to overt proteinuria prevented, by aggressive blood pressure reduction, especially with a regimen based on medications that block the renin-angiotensin-aldosterone system, and control of diabetes. The National Kidney Foundation recommends that blood pressure levels be maintained at or below 130/80 mm Hg in anyone with diabetes or kidney disease.

Aortic Arch Pulse Wave Velocity Assessed by Magnetic Resonance Imaging as a Predictor of Incident Cardiovascular Events: The MESA (Multi-Ethnic Study of Atherosclerosis).

The predictive value of aortic arch pulse wave velocity (PWV) assessed by magnetic resonance imaging for cardiovascular disease (CVD) events has not been fully established. The aim of the present study was to evaluate the association of arch PWV with incident CVD events in MESA (Multi-Ethnic Study of Atherosclerosis). Aortic arch PWV was measured using magnetic resonance imaging at baseline in 3527 MESA participants (mean age, 62±10 years at baseline; 47% men) free of overt CVD. Cox regression was used to evaluate the risk of incident CVD (coronary heart disease, stroke, transient ischemic attack, or heart failure) in relation to arch PWV adjusted for age, sex, race, and CVD risk factors. The median value of arch PWV was 7.4 m/s (interquartile range, 5.6-10.2). There was significant interaction between arch PWV and age for outcomes, so analysis was stratified by age categories (45-54 and >54 years). There were 456 CVD events during the 10-year follow-up. Forty-five to 54-year-old participants had significant association of arch PWV with incident CVD independent of CVD risk factors (hazard ratio, 1.44; 95% confidence interval, 1.07-1.95; P=0.018; per 1-SD increase for logarithmically transformed PWV), whereas >54-year group did not (P=0.93). Aortic arch PWV assessed by magnetic resonance imaging is a significant predictor of CVD events among middle-aged (45-54 years old) individuals, whereas arch PWV is not associated with CVD among an elderly in a large multiethnic population.

Reproducibility of functional aortic analysis using magnetic resonance imaging: the MESA.

AIMS: To assess the test-retest, intra- and inter-reader reliability of thoracic aorta measurements by magnetic resonance imaging (MRI). METHODS AND RESULTS: Twenty-five participants underwent aortic MRI twice over 13 ± 7 days. All aortic variables from baseline and repeat MR were analysed using a semi-automated method by the ARTFUN software. To assess the inter-study reproducibility of aortic variables, we calculated intraclass correlation coefficient (ICC) for individual aortic measurements. Intra- and inter-observer variability was also assessed using the baseline MR data. Mean ascending aortic strain had moderate inter-study reproducibility (11.53 ± 6.44 vs. 10.55 ± 6.64, P = 0.443, ICC = 0.53, P < 0.01). Mean descending aortic strain and arch pulse wave velocity (PWV) had good inter-study reproducibility (descending aortic strain: 8.65 ± 5.30 vs. 8.35 ± 5.26, P = 0.706, ICC = 0.74, P < 0.001; PWV: 9.92 ± 4.18 vs. 9.94 ± 4.55, P = 0.968, ICC = 0.77, P < 0.001, respectively). All aortic variables had excellent intra- and inter-observer reproducibility (intra-: ICC range, 0.87-0.99, inter-: ICC range, 0.56-0.99, respectively). CONCLUSION: Inter-study reproducibility of all aortic variables was acceptable. Intra- and inter-observer reproducibility of all aortic variables was excellent. MRI can provide a repeatable method of measuring aortic structural and functional parameters.

Association of Aortic Stiffness With Left Ventricular Remodeling and Reduced Left Ventricular Function Measured by Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: This study sought to assess cross-sectional associations of aortic stiffness assessed by magnetic resonance imaging with left ventricular (LV) remodeling and myocardial deformation in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: Aortic arch pulse wave velocity (PWV) was measured with phase contrast cine magnetic resonance imaging. LV circumferential strain (Ecc), torsion, and early diastolic strain rate were determined by tagged magnetic resonance imaging. Multivariable linear regression models were used to adjust for demographics and cardiovascular risk factors. Of 2093 participants, multivariable linear regression models demonstrated that higher arch PWV was associated with higher LV mass index (B=0.53 per 1 SD increase for log-transformed PWV, P<0.05) and LV mass to volume ratio (B=0.015, P<0.01), impaired LV ejection fraction (LVEF; B=-0.84; P<0.001), Ecc (B=0.55; P<0.001), torsion (B=-0.11; P<0.001), and early diastolic strain rate (B=-0.003; P<0.05). In sex stratified analysis, higher arch PWV was associated with higher MVR (B=0.02; P<0.05), impaired Ecc (B=0.60; P<0.001), and LVEF (B=-0.45; P<0.05), but with maintained torsion in women. Higher PWV was associated with impaired Ecc (B=0.49; P<0.001) and LVEF (B=-1.21; P<0.001), with lower torsion (B=-0.17; P<0.001) in men. CONCLUSIONS: Higher arch PWV is associated with LV remodeling, and reduced LV systolic and diastolic function in a large multiethnic population. Greater aortic arch stiffness is associated with concentric LV remodeling and relatively preserved LVEF with maintained torsion in women, whereas greater aortic arch stiffness is associated with greater LV dysfunction demonstrated as impaired Ecc, torsion, and LVEF, with less concentric LV remodeling in men.