Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review.

Importance: Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice. Objective: To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date. Evidence Review: Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 26, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review. Findings: Although adult stem cells were once believed to have the ability to create new heart tissue, preclinical studies suggest that these cells release cardioprotective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized clinical trials, most of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methods, discrepancies in reporting, and an overreliance on surrogate end points. Conclusions and Relevance: Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.

Pregnancy-induced changes in the long-term pharmacokinetics of 1.1 mg vs. 5 mg folic acid: a randomized clinical trial.

The objective of this randomized clinical trial was to compare steady-state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1 mg (regular dose) vs. 5 mg (high dose) folic acid. Thirty-seven pregnant women, who were not previously taking folic acid, were enrolled in this open-label, 2-arm, randomized clinical trial after informed consent. Participants were randomly assigned either 1.1 or 5 mg of folic acid-containing prenatals until gestational age (g.a.) 30 weeks. Plasma and RBC folate concentrations were measured at baseline, g.a.6 weeks, g.a.12 weeks, and g.a.30 weeks using a chemiluminescent immunoassay. Results showed sustained significant increase in RBC folate in the 5 mg group between g.a.6 weeks and g.a.30 weeks (P < 0.001), and between g.a.12 weeks and g.a.30 weeks (P < 0.01), whereas a significant increase in RBC folate concentrations was observed in the 1.1 mg group only between g.a.12 weeks to g.a.30 weeks (P < 0.05). Plasma folate increased in both groups from baseline to g.a.6 weeks, and then decreased between g.a.6 weeks and g.a.30 weeks, but this was not statistically significant. Plasma concentrations at g.a.30 weeks in both groups were comparable to their respective baseline concentrations. Thus, physiological changes in pregnancy alter long-term folate pharmacokinetics. Despite supplementation over an extended period of time, steady-state does not seem to be achieved in either dose group within our study.

Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity.

BACKGROUND: Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. METHODS AND RESULTS: Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations. CONCLUSIONS: We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

Predictors of prenatal multivitamin adherence in pregnant women.

There is no study available that has investigated determinants of prenatal multivitamin adherence among pregnant women, based on gastrointestinal (GI) adverse events. The objective of this study was to identify determinants predicting adherence to prenatal multivitamins in pregnant women who were randomized to take 2 different supplements. The authors recruited and interviewed 70 women on the importance of various factors that may have affected adherence to previous and assigned multivitamins. The different factors included GI symptoms and swallowing difficulty. The authors used a 5-point scale to measure degree of importance. The highest scoring factors for not taking or discontinuing any previous multivitamins were fear of or experience of nausea, vomiting, and gagging. For women who never took the assigned prenatal multivitamins, the highest scoring factors contributing to that decision were fear of nausea, fear of vomiting, and health care provider advice. For women who started taking the assigned supplements, the most important factors affecting adherence were dosing regimen, health care provider advice, and mode of product distribution. Adherence to assigned prenatal multivitamins significantly correlated only with the importance of constipation in deciding to discontinue any previous multivitamins. It is concluded that predictors of adherence to recommended prenatal multivitamins during pregnancy are rooted in women's prior experiences with multivitamin use.

Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age.

BACKGROUND: Synthetic folic acid (0.4-1.0 mg) consumed during the periconceptional period has been shown to reduce the risk of neural tube defects. Women with poor supplement adherence or a previous pregnancy affected by a neural tube defect may need to take higher doses of folic acid (4-5 mg). However, there are limited data on the pharmacokinetics of higher folic acid doses. OBJECTIVE: Our aim was to compare steady state folate concentrations in women of childbearing age who took 5 or 1.1 mg folic acid daily for 30 wk. DESIGN: Forty nonpregnant women aged between 18 and 45 y, who did not take folic acid supplements, were enrolled in the study. Subjects were randomly assigned to take either 5 or 1.1 mg folic acid daily for 30 wk. Plasma and red blood cell (RBC) folate concentrations were measured at baseline and at weeks 2, 4, 6, 12, and 30. RESULTS: There was no significant difference in baseline RBC folate concentrations between the 2 groups (1121 +/- 410 and 1035 +/- 273 nmol/L for the 5- and 1.1-mg folic acid groups, respectively). Significant differences in RBC folate were detected between groups at weeks 4, 6, 12, and 30. RBC folate concentrations by week 30 were 2339 +/- 782 and 1625 +/- 339 nmol/L for the 5- and 1.1-mg folic acid groups, respectively. CONCLUSION: The use of 5 mg folic acid among women of childbearing age produced higher blood folate concentrations, with a faster rate of folate accumulation, compared with 1.1 mg folic acid.

Comparing folic acid pharmacokinetics among women of childbearing age: single dose ingestion of 1.1 versus 5 MG folic acid.

BACKGROUND: A 2001 study suggested that supplementation with 5 mg folic acid, among women of childbearing age, is needed to render maximum protection against neural tube defects (NTD). No human study is presently available which examined the pharmacokinetics of 5 mg folic acid. OBJECTIVE: To compare the pharmacokinetics of ingesting a single dose of 5 mg versus 1.1 mg folic acid contained in 2 prenatal multivitamins (PregVit and PregVit-Folic 5), and to estimate its contribution to steady-state folate levels. METHOD: The pharmacokinetics of 1.1 mg folic acid was determined in a previously published study. The method was replicated among 6 healthy, non-pregnant women who were given 5 mg folic acid to ingest. Blood samples were drawn and serum folate concentrations were measured at various time points during 10 hours post-ingestion. Standard pharmacokinetic parameters were determined and compared with Student's t-test, when appropriate. RESULTS: The mean area under the curve (AUC) of 1.1 mg and 5 mg folic acid were 147.6 +/- 52.8 (ng/mL) x hr and 997.5 +/- 271.9 (ng/mL) x hr, respectively (p<0.0002). An approximate 5-fold difference was detected in the peak concentrations (Cmax) between the 2 groups (p<0.0005), alongside a slight difference in the times to peak (Tmax) (p=0.02). The estimated steady-state serum folate concentrations produced by 1.1 mg and 5 mg folic acid were 6.2 +/- 2.2 ng/mL and 41.6 +/- 11.3 ng/mL, respectively (p<0.0002), prior to its summation with initial (baseline) steady-state levels. CONCLUSION: Single dose administration between 1.1 mg and 5 mg folic acid demonstrated linear pharmacokinetics, with approximately a 5-fold difference between the 2 doses in serum folate contribution to steady-state levels, under ideal adherence.

Folate fortification and supplementation--are we there yet?

BACKGROUND: Folic acid fortification of flour has significantly decreased the incidence of neural tube defects (NTDs). We aimed at examining whether Ontario women of child-bearing age exhibit protective levels of RBC folate. METHODS: We reviewed laboratory databases on RBC folic acid from pre and post fortification years. The data included age, gender, RBC folate, hemoglobin, mean cell volume and pregnancy test. We examined a sub-set of females at ages 14-45 years who were non-anemic and normocytic. Complete protection against NTD was defined as RBC folate concentration above 900 nmol/L. RESULTS: In 2006, 40% of the women of child-bearing age and 36% of pregnant women, exhibited RBC folate levels below 900 nmol/L, rendering them sub-optimally protected against NTD. CONCLUSION: A considerable proportion of pregnant women is still at risk of having a baby with NTD. This should be remedied by increasing the mandatory concentrations of folic acid required in flour, complemented by public education and increasing the folic acid in prenatal supplements.

Effect of iron content on the tolerability of prenatal multivitamins in pregnancy.

BACKGROUND: Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation. In a previous study, suboptimal tolerability was observed among pregnant women taking a large tablet (18 mm x 8 mm x 8 mm) multivitamin with high elemental iron content (60 mg as ferrous fumarate). The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were randomized to commence supplementation with a small-tablet prenatal multivitamin, containing either low or high iron content. METHODS: Pregnant women who called the Motherisk Program (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospective, randomized, open-label, 2-arm study. Women were randomized to take a small-size (16 mm x 9 mm x 4 mm), low elemental iron content (35 mg as ferrous fumarate) multivitamin ('35 mg' group); or a small-size (5 mm radius, 5 mm thickness), high elemental iron content (60 mg as ferrous sulphate) multivitamin ('60 mg' group). Follow-up interviews documented pill intake and adverse events. Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves. RESULTS: Of 167 randomized women, 92 in the '35 mg' group and 75 in the '60 mg' group were included in the analysis. Despite ideal conditions and regular follow-ups, mean adherence based on pill intake recall, in both groups was approximately 50%. No statistically significant difference was detected in proportions of women who actually started taking either multivitamin. Among those who started, no difference was detected in rates of adherence or reported adverse events. CONCLUSION: The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins. Combined with our previous study, tablet size may be the more definitive factor affecting adherence.