Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

INTRODUCTION: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). METHODS: Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. RESULTS: Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). CONCLUSION: These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Source areas and long-range transport of pollen from continental land to Tenerife (Canary Islands).

The Canary Islands, due to their geographical position, constitute an adequate site for the study of long-range pollen transport from the surrounding land masses. In this study, we analyzed airborne pollen counts at two sites: Santa Cruz de Tenerife (SCO), at sea level corresponding to the marine boundary layer (MBL), and Izaña at 2,367 m.a.s.l. corresponding to the free troposphere (FT), for the years 2006 and 2007. We used three approaches to describe pollen transport: (1) a classification of provenances with an ANOVA test to describe pollen count differences between sectors; (2) a study of special events of high pollen concentrations, taking into consideration the corresponding meteorological synoptic pattern responsible for transport and back trajectories; and (3) a source-receptor model applied to a selection of the pollen taxa to show pollen source areas. Our results indicate several extra-regional pollen transport episodes to Tenerife. The main provenances were: (1) the Mediterranean region, especially the southern Iberian Peninsula and Morocco, through the trade winds in the MBL. These episodes were characterized by the presence of pollen from trees (Casuarina, Olea, Quercus perennial and deciduous types) mixed with pollen from herbs (Artemisia, Chenopodiaceae/Amaranthaceae and Poaceae wild type). (2) The Saharan sector, through transport at the MBL level carrying pollen principally from herbs (Chenopodiaceae-Amaranthaceae, Cyperaceae and Poaceae wild type) and, in one case, Casuarina pollen, uplifted to the free troposphere. And (3) the Sahel, characterized by low pollen concentrations of Arecaceae, Chenopodiaceae-Amaranthaceae, Cyperaceae and Poaceae wild type in sporadic episodes. This research shows that sporadic events of long-range pollen transport need to be taken into consideration in Tenerife as possible responsible agents in respiratory allergy episodes. In particular, it is estimated that 89-97% of annual counts of the highly allergenous Olea originates from extra-regional sources in southern Iberia and northern Africa.