Atul Chugh

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.

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.

Human Cardiac Stem Cells Isolated from Atrial Appendages Stably Express c-kit

The in vivo studies of myocardial infarct using c-kit+/Lin− cardiac stem cells (CSCs) are still in the early stage with margin or no beneficial effects for cardiac function. One of the potential reasons may be related to the absence of fully understanding the properties of these cells both in vitro and in vivo. In the present study, we aimed to systematically examine how CSCs adapted to in vitro cell processes and whether there is any cell contamination after long-term culture. Human CSCs were enzymatically isolated from the atrial appendages of patients. The fixed tissue sections, freshly isolated or cultured CSCs were then used for identification of c-kit+/Lin− cells, detection of cell contamination, or differentiation of cardiac lineages. By specific antibody staining, we demonstrated that tissue sections from atrial appendages contained less than 0.036% c-kit+/Lin− cells. For the first time, we noted that without magnetic activated cell sorting (MACS), the percentages of c-kit+/Lin− cells gradually increased up to ∼40% during continuously culture between passage 2 to 8, but could not exceed >80% unless c-kit MACS was carried out. The resulting c-kit+/Lin− cells were negative for CD34, CD45, CD133, and Lin markers, but positive for KDR and CD31 in few patients after c-kit MACS. Lin depletion seemed unnecessary for enrichment of c-kit+/Lin− cell population. Following induced differentiation, c-kit+/Lin− CSCs demonstrated strong differentiation towards cardiomyocytes but less towards smooth and endothelial cells. We concluded that by using an enzymatic dissociation method, a large number, or higher percentage, of relative pure human CSCs with stable expression of c-kit+ could be obtained from atrial appendage specimens within ∼4 weeks following c-kit MACS without Lin depletion. This simple but cost-effective approach can be used to obtain enough numbers of stably-expressed c-kit+/Lin− cells for clinical trials in repairing myocardial infarction.

Acrolein exposure is associated with increased cardiovascular disease risk.

Background Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Methods and Results Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite—3‐hydroxypropylmercapturic acid (3‐HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3‐HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3‐HPMA levels were inversely related to levels of both early (AC133+) and late (AC133−) circulating angiogenic cells. In smokers as well as nonsmokers, 3‐HPMA levels were positively associated with both increased levels of platelet–leukocyte aggregates and the Framingham Risk Score. No association was observed between 3‐HPMA and plasma fibrinogen. Levels of C‐reactive protein were associated with 3‐HPMA levels in nonsmokers only. Conclusions Regardless of its source, acrolein exposure is associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased CVD risk.

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 µg/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 kidneys 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.

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.

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+/45dim/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.

Ten-year longitudinal change in aortic stiffness assessed by cardiac MRI in the second half of the human lifespan: the multi-ethnic study of atherosclerosis

AIMS Longitudinal determinants of aortic stiffness (AS) measured by magnetic resonance imaging (MRI) have not been assessed in a large community-based population. Our aim was to examine the determinants of change in thoracic AS over 10 years of follow-up in a multi-ethnic population of individuals 45 years of age and older measured by MRI. METHODS AND RESULTS We studied 1160 participants (mean age = 60 ± 9 years at baseline, 45% male) with aortic MRI at both the MESA Year 0 and Year 10 examinations. Ascending and descending aorta distensibility (AAD/DAD) and aortic arch pulse-wave velocity (PWV) were measured using MRI. Determinants of the change in AS parameters over 10 years were assessed using linear regression adjusted for baseline values, demographic variables, baseline risk factors and change in risk factors, and chronic risk exposure. AAD and DAD decreased slightly (5% decrease in median for AAD: 1.33-1.26 mmHg(-1) · 10(-3), P = 0.008; 5% decrease in median for DAD: 1.73-1.64 mmHg(-1) · 10(-3), P < 0.001), and PWV increased over 10 years (18% increase in median: 6.8-8.0 m/s P < 0.001). Baseline age was related to a reduction in AAD and DAD and an increase in PWV throughout the follow-up period. Baseline and change in mean blood pressure and continued smoking were associated with a reduction in AAD and an increase in PWV. Furthermore, baseline heart rate was also related to a reduction in AAD and DAD. Blood pressure normalization was related to less aortic stiffening throughout the follow-up period. CONCLUSIONS In our longitudinal, community-based cohort study of adult individuals aged 45 years or greater, greater mean blood pressure and a history of smoking history were associated with increased aortic stiffening over 10 years as assessed by MRI.

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.