Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI

Purpose: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Methods: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 106 CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7–12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. Results: In BMC-treated patients, there was a decrease in [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. −0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (−4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m2, p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (−0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. −5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). Conclusion: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo

The effect of bone marrow microenvironment on the functional properties of the therapeutic bone marrow-derived cells in patients with acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Treatment of acute myocardial infarction with stem cell transplantation has achieved beneficial effects in many clinical trials. The bone marrow microenvironment of ST-elevation myocardial infarction (STEMI) patients has never been studied even though myocardial infarction is known to cause an imbalance in the acid-base status of these patients. The aim of this study was to assess if the blood gas levels in the bone marrow of STEMI patients affect the characteristics of the bone marrow cells (BMCs) and, furthermore, do they influence the change in cardiac function after autologous BMC transplantation. The arterial, venous and bone marrow blood gas concentrations were also compared.</p> <p>Methods</p> <p>Blood gas analysis of the bone marrow aspirate and peripheral blood was performed for 27 STEMI patients receiving autologous stem cell therapy after percutaneous coronary intervention. Cells from the bone marrow aspirate were further cultured and the bone marrow mesenchymal stem cell (MSC) proliferation rate was determined by MTT assay and the MSC osteogenic differentiation capacity by alkaline phosphatase (ALP) activity assay. All the patients underwent a 2D-echocardiography at baseline and 4 months after STEMI.</p> <p>Results</p> <p>As expected, the levels of pO₂, pCO₂, base excess and HCO₃were similar in venous blood and bone marrow. Surprisingly, bone marrow showed significantly lower pH and Na⁺and elevated K⁺levels compared to arterial and venous blood. There was a positive correlation between the bone marrow pCO₂and HCO₃levels and MSC osteogenic differentiation capacity. In contrast, bone marrow pCO₂and HCO₃levels displayed a negative correlation with the proliferation rate of MSCs. Patients with the HCO₃level below the median value exhibited a more marked change in LVEF after BMC treatment than patients with HCO₃level above the median (11.13 ± 8.07% vs. 2.67 ± 11.89%, P = 0.014).</p> <p>Conclusions</p> <p>Low bone marrow pCO₂and HCO₃levels may represent the optimal environment for BMCs in terms of their efficacy in autologous stem cell therapy in STEMI patients.</p

Analysis of heart rate dynamics by methods derived from nonlinear mathematics:clinical applicability and prognostic significance

Abstract The traditional methods of analysing heart rate variability based on means and variance are unable to detect subtle but potentially important changes in interbeat heart rate behaviour. This research was designed to evaluate the clinical applicability and prognostic significance of new dynamical methods of analysing heart rate behaviour derived from nonlinear mathematics. The study covered four different patient populations, their controls and one general population of elderly people. The first patient group consisted of 38 patients with coronary artery disease without previous myocardial infarction, the second of 40 coronary artery disease patients with a prior Q-wave myocardial infarction, and the third of 45 patients with a history of ventricular tachyarrhythmia. The fourth group comprised 10 patients with a previous myocardial infarction who had experienced ventricular fibrillation during electrocardiographic recordings. The fifth group comprised a random sample of 347 community-living elderly people invited for a follow-up of 10 years after electrocardiographic recordings. Heart rate variability was analysed by traditional time and frequency domain methods. The new dynamical measures derived from nonlinear dynamics were: 1) approximate entropy, which reflects the complexity of the data, 2) detrended fluctuation analysis, which describes the presence or absence of fractal correlation properties of time series data, and 3) power-law relationship analysis, which demonstrates the distribution of spectral characteristics of RR intervals, but does not reflect the magnitude of spectral power in different spectral bands. Approximate entropy was higher in postinfarction patients (1.17 ± 0.22), but lower in coronary artery disease patients without myocardial infarction (0.93 ± 0.17) than in healthy controls (1.03 ± 014, p &lt; 0.01, p &lt; 0.05 respectively). It did not differ between patients with and without ventricular arrhythmia. The short term fractal-like scaling exponent of the detrended fluctuation analysis was higher in coronary artery disease patients without myocardial infarction (1.34 ± 0.15, p &lt; 0.001), but not in postinfarction patients without arrhythmia (1.06 ± 0.13) compared with healthy controls (1.09 ± 0.13). The short term exponent was markedly reduced in patients with life-threatening arrhythmia (0.85 ± 0.25 ventricular tachycardia patients, 0.68 ± 0.18 ventricular fibrillation patients, p &lt; 0.001 for both). The long term power-law slope of the power-law scaling analysis was lower in the ventricular fibrillation group than in postinfarction controls without arrhythmia risk (-1.63 ± 0.24 vs. -1.33 ± 0.23, p &lt; 0.01) and predicted mortality in a general elderly population with an adjusted relative risk of 1.74 (95% CI 1.42–2.13). The present observations demonstrate that dynamic analysis of heart rate behaviour gives new insight into analysis of heart rate dynamics in various cardiovascular disorders. The breakdown of the normal fractal-like organising principle of heart rate variability is associated with an increased risk of mortality and vulnerability to life-threatening arrhythmias

Antenatal hemodynamic findings and heart rate variability in early school-age children born with fetal growth restriction

Abstract Background: According to epidemiological studies, impaired intrauterine growth increases the risk for cardiovascular morbidity and mortality in adulthood. Heart rate variability (HRV), which reflects the autonomic nervous system function, has been used for risk assessment in adults while its dysfunction has been linked to poor cardiovascular outcome. Objective: We hypothesized that children who were born with fetal growth restriction (FGR) and antenatal blood flow redistribution have decreased HRV at early school age compared to their gestational age matched peers with normal intrauterine growth. Study design: A prospectively collected cohort of children born with FGR (birth weight &lt;10th percentile and/or abnormal umbilical artery flow, n = 28) underwent a 24-hour Holter monitoring at the mean age of 9 years and gestational age matched children with birth weight appropriate for gestational age (AGA, n = 19) served as controls. Time- and frequency domain HRV indices were measured and their associations with antenatal hemodynamic changes were analyzed. Results: Time- and frequency domain HRV parameters (standard deviation of R–R intervals, SDNN; low frequency, LF; high frequency, HF; LF/HF; very low frequency, VLF) did not differ significantly between FGR and AGA groups born between 24 and 40 weeks. Neither did they differ between children born with FGR and normal umbilical artery pulsatility or increased umbilical artery pulsatility. In total, 56% of the FGR children demonstrated blood flow redistribution (cerebroplacental ratio, CPR &lt; −2 SD) during fetal life and their SDNN (p = .01), HF (p = .03) and VLF (p = .03) values were significantly lower than in FGR children with CPR ≥ −2SD. Conclusions: Early school age children born with FGR and intrauterine blood flow redistribution demonstrated altered heart rate variability. These prenatal and postnatal findings may be helpful in targeting preventive cardiovascular measures in FGR

Physical activity and risk of atrial fibrillation in the general population:meta-analysis of 23 cohort studies involving about 2 million participants

Abstract Regular physical activity is well established to be associated with reduced risk of cardiovascular disease outcomes. Whether physical activity is associated with the future risk of atrial fibrillation (AF) remains a controversy. Using a systematic review and meta-analysis of published observational cohort studies in general populations with at least one-year of follow-up, we aimed to evaluate the association between regular physical activity and the risk of AF. Relevant studies were sought from inception until October 2020 in MEDLINE, Embase, Web of Science, and manual search of relevant articles. Extracted relative risks (RRs) with 95% confidence intervals (CIs) for the maximum versus the minimal amount of physical activity groups were pooled using random-effects meta-analysis. Quality of the evidence was assessed by GRADE. A total of 23 unique observational cohort studies comprising of 1,930,725 participants and 45,839 AF cases were eligible. The pooled multivariable-adjusted RR (95% CI) for AF comparing the most physically active versus the least physically active groups was 0.99 (0.93–1.05). This association was modified by sex: an increased risk was observed in men: 1.20 (1.02–1.42), with a decreased risk in women: 0.91 (0.84–0.99). The quality of the evidence ranged from low to moderate. Pooled observational cohort studies suggest that the absence of associations reported between regular physical activity and AF risk in previous general population studies and their aggregate analyses could be driven by a sex-specific difference in the associations – an increased risk in men and a decreased risk in women. Systematic review registration: PROSPERO 2020: CRD4202017281