Effect of intracoronary bone marrow-derived mononuclear cell injection early and late after myocardial infarction on CMR-derived myocardial strain.

BACKGROUND: Studies indicate no clear impact of intracoronary injection of bone-marrow unselected mononuclear cells (BM-MNC) after acute myocardial infarction (AMI) on left-ventricular function (LVEF). Strain parameters by cardiovascular magnetic resonance (CMR) have been proposed to be more sensitive to functional changes of the heart. The aim of the present study was to assess changes of global longitudinal (GLS) and circumferential strain (GCS) in a group of patients treated with BM-MNC after AMI. METHODS: One-hundred and forty-nine patients with successfully reperfused AMI and LV dysfunction (LVEF<45%) were retrospectively included into this sub-study of the SWISS-AMI multicentre trial. Patients were divided into control (N = 54), early (5-7 days after AMI, N = 51) and late BM-MNC treatment groups (3-4 weeks, N = 44). The endpoint was the change of GLS and GCS as obtained from cine sequences 4 and 12 months after AMI using feature tracking algorithm. RESULTS: In unadjusted analyses, the absolute change of GLS for the early treatment group from baseline to 4 months was 2.5 ± 4.3 (p < 0.01), to 12 months 2.7 ± 5.7% (p = 0.004). For late treatment, it was 1.5 ± 4.0% (p = 0.039, 4 months) and 2.5 ± 5.6% (p = 0.015, 12 months). For controls 0.7 ± 4.7% (p = 0.378), 0.8 ± 3.9% (p = 0.253) respectively. Adjusting for different baseline values, neither an overall treatment effect (both time-points) of BM-MNC nor a treatment time-related (only early or late) effect could be shown for all functional parameters. CONCLUSIONS: Among patients after AMI with successful reperfusion and LV dysfunction, intracoronary infusion of BM-MNC early or late after AMI did not improve global strain parameters at 4- or 12-months follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Analysis and functional characterization of alternatively spliced angiotensin II type 1 and 2 receptor transcripts in the human heart.

Expression levels of angiotensin II type 1 and type 2 receptors (AT1, AT2) vary at different cardiac localizations and are regulated in cardiac diseases. Differential splicing of the 5' untranslated exons of the primary AT1 mRNA transcripts may modulate translational efficiency and thus receptor expression. We therefore searched for AT1 and AT2 mRNA splice patterns specific to chamber localization or to cardiac performance and analyzed their effect on protein expression in transfection experiments. The exon composition of the AT1 and AT2 mRNA transcripts in normal and diseased human hearts were analyzed using a reverse transcription polymerase chain reaction followed by HPLC quantitation of the amplificates. We compared atrial (n=18) and ventricular (n=28) samples and endomyocardial biopsies (n=10) from patients with normal and severely impaired cardiac function and one donor heart, which was not used for transplantation. AT1 transcripts with the exon composition 1/2/5 and 1/5 represented about 93-98% of all AT1 mRNAs; transcript 1/2/3/5 represented 8% in the atria and 2% in ventricles. Since exon 2 reduces translational efficiency in vitro, the ratios of transcripts with and without exon 2, (1/2/5+1/2/3/5) to (1/5), were compared. These were 1.24+/-0.07 in normal atria, 0.96+/-0.09 in atria from failing hearts (P<0.05), 0.68 in the left ventricle of the donor heart, and 0.58+/-0.03 in failing left ventricles. Endomyocardial biopsy specimens showed significant differences between controls and heart failure (controls 0.63+/-0.04 vs. heart failure 0.52+/-0.02, P<0.05). Of the two identified AT2 transcripts, mRNA 1/2/3 was the most abundant in the human heart (92%). Luciferase reporter gene assays were performed to test the effect of the various 5' untranslated regions (5' UTRs) on protein expression. Among the constructs which contained the AT1 promoter/AT1 5' UTRs the plasmid Ex 1/2/5 exhibited 27% lower luciferase activity than Ex 1/5 (n=24, P<0.001), and Ex 1/2/3/5 expressed only 35.9% of Ex 1/5 activity (P<0.001). Among the reporter gene plasmids with the AT2 promoter/AT2 5' UTRs the construct Ex 1/2/3 expressed a 31% lower luciferase activity than Ex 1/3 (n=20, P<0.001). In conclusion, alternative splicing may represent a mechanism of ATR regulation in vivo. In the human heart, AT1 splice patterns differ distinctly between atria and ventricles and to a lesser degree between controls and failing hearts. This may lead to differences in AT1 mRNA translation into protein in the various cardiac areas and under different pathophysiological conditions.