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Aortic aneurysm is the most life-threatening complication in Marfan syndrome (MFS) patients. Doxycycline, a nonselective matrix metalloproteinases inhibitor, was reported to improve the contractile function and elastic fiber structure and organization in a Marfan mouse aorta using ex vivo small chamber myography. In this study, we assessed the hypothesis that a long-term treatment with doxycycline would reduce aortic root growth, improve aortic wall elasticity as measured by pulse wave velocity, and improve the ultrastructure of elastic fiber in the mouse model of MFS. In our study, longitudinal measurements of aortic root diameters using high-resolution ultrasound imaging display significantly decreased aortic root diameters and lower pulse wave velocity in doxycycline-treated Marfan mice starting at 6 months as compared to their non-treated MFS counterparts. In addition, at the ultrastructural level, our data show that long-term doxycycline treatment corrects the irregularities of elastic fibers within the aortic wall of Marfan mice to the levels similar to those observed in control subjects. Our findings underscore the key role of matrix metalloproteinases during the progression of aortic aneurysm, and provide new insights into the potential therapeutic value of doxycycline in blocking MFS-associated aortic aneurysm.

Postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block are serious postoperative complications for children with congenital heart disease. We hypothesize that ischemia-reperfusion (I/R) related changes exacerbate these postoperative arrhythmias in the neonate heart and administration of postoperative inotropes is contributory.The purpose of this study was to study the effects of I/R and postischemic dopamine application on automaticity and rhythmicity in immature and mature pacemaker cells and whole heart preparations.Single pacemaker cells and whole heart models of postoperative arrhythmias were generated in a rabbit model encompassing 3 primary risk factors: age, I/R exposure, and dopamine application. Single cells were studied using current clamp and line scan confocal microscopy, whereas whole hearts were studied using optical mapping.Four responses were observed in neonatal atrioventricular nodal cells (AVNCs): slowing of AVNC automaticity (from 62±10 to 36 ± 12 action potentials per minute, P.05); induction of arrhythmicity or increased beat-to-beat variability (0.08 ± 0.04 to 3.83 ± 1.79, P.05); altered automaticity (subthreshold electrical fluctuations); and disruption of calcium transients. In contrast, these responses were not observed in mature AVNCs or neonatal sinoatrial cells. In whole heart experiments, neonatal hearts experienced persistent postischemia arrhythmias of varying severity, whereas mature hearts exhibited no arrhythmias or relatively transient ones.Neonatal pacemaker cells and whole hearts demonstrate a susceptibility to I/R insults resulting in alterations in automaticity, which may predispose neonates to postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block.

Zebrafish (Danio rerio) are widely used as vertebrate model in developmental genetics and functional genomics as well as in cardiac structure-function studies. The zebrafish heart has been increasingly used as a model of human cardiac function, in part, due to the similarities in heart rate and action potential duration and morphology with respect to humans. The teleostian zebrafish is in many ways a compelling model of human cardiac function due to the clarity afforded by its ease of genetic manipulation, the wealth of developmental biological information, and inherent suitability to a variety of experimental techniques. However, in addition to the numerous advantages of the zebrafish system are also caveats related to gene duplication (resulting in paralogs not present in human or other mammals) and fundamental differences in how zebrafish hearts function. In this review, we discuss the use of zebrafish as a cardiac function model through the use of techniques such as echocardiography, optical mapping, electrocardiography, molecular investigations of excitation-contraction coupling, and their physiological implications relative to that of the human heart. While some of these techniques (e.g., echocardiography) are particularly challenging in the zebrafish because of diminutive size of the heart (~1.5 mm in diameter) critical information can be derived from these approaches and are discussed in detail in this article.

The zebrafish (Danio rerio) is an important organism as a model for understanding vertebrate cardiovascular development. However, little is known about adult ZF cardiac function and how contractile function changes to cope with fluctuations in ambient temperature. The goals of this study were to: 1) determine if high resolution echocardiography (HRE) in the presence of reduced cardiodepressant anesthetics could be used to accurately investigate the structural and functional properties of the ZF heart and 2) if the effect of ambient temperature changes both acutely and chronically could be determined non-invasively using HRE in vivo. Heart rate (HR) appears to be the critical factor in modifying cardiac output (CO) with ambient temperature fluctuation as it increases from 78 ± 5.9 bpm at 18°C to 162 ± 9.7 bpm at 28°C regardless of acclimation state (cold acclimated CA- 18°C; warm acclimated WA- 28°C). Stroke volume (SV) is highest when the ambient temperature matches the acclimation temperature, though this difference did not constitute a significant effect (CA 1.17 ± 0.15 μL at 18°C vs 1.06 ± 0.14 μl at 28°C; WA 1.10 ± 0.13 μL at 18°C vs 1.12 ± 0.12 μl at 28°C). The isovolumetric contraction time (IVCT) was significantly shorter in CA fish at 18°C. The CA group showed improved systolic function at 18°C in comparison to the WA group with significant increases in both ejection fraction and fractional shortening and decreases in IVCT. The decreased early peak (E) velocity and early peak velocity / atrial peak velocity (E/A) ratio in the CA group are likely associated with increased reliance on atrial contraction for ventricular filling.

Zebrafish (Danio rerio) are widely used as vertebrate model in developmental genetics and functional genomics as well as in cardiac structure-function studies. The zebrafish heart has been increasingly used as a model of human cardiac function, in part, due to the similarities in heart rate and action potential duration and morphology with respect to humans. The teleostian zebrafish is in many ways a compelling model of human cardiac function due to the clarity afforded by its ease of genetic manipulation, the wealth of developmental biological information, and inherent suitability to a variety of experimental techniques. However, in addition to the numerous advantages of the zebrafish system are also caveats related to gene duplication (resulting in paralogs not present in human or other mammals) and fundamental differences in how zebrafish hearts function. In this review, we discuss the use of zebrafish as a cardiac function model through the use of techniques such as echocardiography, optical mapping, electrocardiography, molecular investigations of excitation-contraction coupling, and their physiological implications relative to that of the human heart. While some of these techniques (e.g., echocardiography) are particularly challenging in the zebrafish because of diminutive size of the heart (~1.5 mm in diameter) critical information can be derived from these approaches and are discussed in detail in this article.

Introduction: Aortic aneurysm is the most life-threatening complication in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in fibrillin-1 gene. We have previously reported that doxycycline, an antibiotic and a general inhibitor of matrix metalloproteinases (MMPs), could improve aortic contractility and elastin fibers structure and organization in a mouse model of MFS. However, the in vivo effects of MMPs inhibition on the progression of aneurysm and pulse wave velocity (PWV) have not been investigated. In this study, we assessed the hypothesis that a long-term treatment with a sub-antibiotic dose of doxycycline would delay the progression of aortic aneurysm and improve the PWV in the Marfan mouse. Methods: In this study, we have used a high-resolution, high-contrast ultrasound imaging technique to conduct a longitudinal study in order to measure aortic diameter (dilatation) and PWV (indication of aortic elasticity/stiffness) in the animals. Marfan (n=12) and control (n=13) mice were given a sub-antibiotic dose of doxycycline in their drinking water at a concentration of 0.24 g/L/day beginning at 6 weeks of age, whereas another group of Marfan (n=12) and control (n=12) mice were given plain drinking water for comparison. At 3, and 6 months of age, aortic diameter and PWV of the experimental animals were measured by ultrasound imaging. Results: At 3 months of age, measurement of aortic root diameter showed significant dilatation in both treated and non-treated Marfan mice as compared to control groups (p < 0.01). However, at 6 months of age, the aortic root diameter in treated Marfan mice was not different from those in controls. The same observation was made for the Sinus of Valsalva region. Especially in this region, treated Marfan aorta showed significantly reduced diameter compared to non-treated Marfan groups (p < 0.05). With respect to the measurement of PWV, a significant increase was observed in 3- and 6-month Marfan mice aorta vs. control (p < 0.01). Interestingly, doxycycline treatment normalized the PWV in 6-month old Marfan mice compared to non-treated Marfan aorta. Conclusions: Our findings show that long-term doxycycline treatment has protective effects in terms of reduction of aortic dilatation and stiffness in Marfan mice.

Transgenic mouse models have been instrumental in the elucidation of the molecular mechanisms behind many genetically based cardiovascular diseases such as Marfan syndrome (MFS). However, the characterization of their cardiac morphology has been hampered by the small size of the mouse heart. In this report, we adapted optical coherence tomography (OCT) for imaging fixed adult mouse hearts, and applied tools from computational anatomy to perform morphometric analyses. The hearts were first optically cleared and imaged from multiple perspectives. The acquired volumes were then corrected for refractive distortions, and registered and stitched together to form a single, high-resolution OCT volume of the whole heart. From this volume, various structures such as the valves and myofibril bundles were visualized. The volumetric nature of our dataset also allowed parameters such as wall thickness, ventricular wall masses, and luminal volumes to be extracted. Finally, we applied the entire acquisition and processing pipeline in a preliminary study comparing the cardiac morphology of wild-type mice and a transgenic mouse model of MFS.