Noninvasive Quantification of Contractile Dynamics in Cardiac Cells, Spheroids, and Organs-on-a-Chip Using High-Frequency Ultrasound.

Cell-based models that mimic in vivo heart physiology are poised to make significant advances in cardiac disease modeling and drug discovery. In these systems, cardiomyocyte (CM) contractility is an important functional metric, but current measurement methods are inaccurate and low-throughput or require complex setups. To address this need, we developed a standalone noninvasive, label-free ultrasound technique operating at 40-200 MHz to measure the contractile kinetics of cardiac models, ranging from single adult CMs to 3D microtissue constructs in standard cell culture formats.

Multi-omic analyses and network biology in cardiovascular disease.

Heart disease remains a leading cause of death in North America and worldwide. Despite advances in therapies, the chronic nature of cardiovascular diseases ultimately results in frequent hospitalizations and steady rates of mortality. Systems biology approaches have provided a new frontier toward unraveling the underlying mechanisms of cell, tissue, and organ dysfunction in disease.

Proteomics and phosphoproteomics of failing human left ventricle identifies dilated cardiomyopathy-associated phosphorylation of CTNNA3.

The prognosis and treatment outcomes of heart failure (HF) patients rely heavily on disease etiology, yet the majority of underlying signaling mechanisms are complex and not fully elucidated. Phosphorylation is a major point of protein regulation with rapid and profound effects on the function and activity of protein networks. Currently, there is a lack of comprehensive proteomic and phosphoproteomic studies examining cardiac tissue from HF patients with either dilated dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM).

Disrupting circadian control of peripheral myogenic reactivity mitigates cardiac injury following myocardial infarction.

Aims: Circadian rhythms orchestrate important functions in the cardiovascular system: the contribution of microvascular rhythms to cardiovascular disease progression/severity is unknown. This study hypothesized that (i) myogenic reactivity in skeletal muscle resistance arteries is rhythmic and (ii) disrupting this rhythmicity would alter cardiac injury post-myocardial infarction (MI).

Methods And Results: Cremaster skeletal muscle resistance arteries were isolated and assessed using standard pressure myography.

A brief morning rest period benefits cardiac repair in pressure overload hypertrophy and postmyocardial infarction.

Rest has long been considered beneficial to patient healing; however, remarkably, there are no evidence-based experimental models determining how it benefits disease outcomes. Here, we created an experimental rest model in mice that briefly extends the morning rest period. We found in 2 major cardiovascular disease conditions (cardiac hypertrophy, myocardial infarction) that imposing a short, extended period of morning rest each day limited cardiac remodeling compared with controls.

α Knockout Reduces Ethanol Consumption and Preference in Male and Female Mice.

Alcohol use is a contributor in the premature deaths of approximately 3 million people annually. Among the risk factors for alcohol misuse is circadian rhythm disruption; however, this connection remains poorly understood. Inhibition of the circadian nuclear receptor REV-ERBα is known to disrupt molecular feedback loops integral to daily oscillations, and impact diurnal fluctuations in the expression of proteins required for reward-related neurotransmission.

The Impact of Sex, Circadian Disruption, and the Clock Genotype on Alcohol Drinking in Mice.

Shift work is associated with increased alcohol drinking, more so in males than females, and is thought to be a coping mechanism for disrupted sleep cycles. However, little is presently known about the causal influence of circadian rhythm disruptions on sex differences in alcohol consumption. In this study, we disrupted circadian rhythms in female and male mice using both environmental (i.

Mitochondrial autophagy and cell survival is regulated by the circadian gene in cardiac myocytes during ischemic stress.

Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia.

Circadian mutant mice with obesity and metabolic syndrome are resilient to cardiovascular disease.

Obesity and metabolic syndrome commonly underlie cardiovascular disease. mice fed a normal diet develop obesity and metabolic syndrome; however, it is not known whether they develop or are resilient to cardiovascular disease. We found that mice do not develop cardiac dysfunction, despite their underlying conditions.

Circadian influence on the microbiome improves heart failure outcomes.

Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood.

Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption.

Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes).

SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome.

Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed that the circadian mechanism is a critical regulator of reperfusion injury. However, whether pharmacological targeting using circadian medicine limits reperfusion injury and protects against HF is unknown.

The Clock Mechanism Influences Neurobiology and Adaptations to Heart Failure in Clock Mice With Implications for Circadian Medicine.

In this study we investigated the role of the circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that the circadian mechanism is an important regulator of healthy cognitive system neurobiology. Normal Clock mice had neurons with smaller apical dendrite trees in the medial prefrontal cortex (mPFC), and hippocampus, showed impaired visual-spatial memory, and exhibited lower cerebrovascular myogenic tone, versus wild types (WT).

Implications of disturbances in circadian rhythms for cardiovascular health: A new frontier in free radical biology.

Cell autonomous circadian "clock" mechanisms are present in virtually every organ, and generate daily rhythms that are important for normal physiology. This is especially relevant to the cardiovascular system, for example the circadian mechanism orchestrates rhythms in heart rate, blood pressure, cardiac contractility, metabolism, gene and protein abundance over the 24-h day and night cycles. Conversely, disturbing circadian rhythms (e.

Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy.

Aims: Circadian rhythms are important for healthy cardiovascular physiology and they are regulated by the molecular circadian mechanism. Previously, we showed that disruption of the circadian mechanism factor CLOCK in male ClockΔ19/Δ19 mice led to development of age-dependent cardiomyopathy. Here, we investigate the role of biological sex in protecting against heart disease in aging female ClockΔ19/Δ19 mice.

Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease.

The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging.

Day-night dependence of gene expression and inflammatory responses in the remodeling murine heart post-myocardial infarction.

Diurnal or circadian rhythms are fundamentally important for healthy cardiovascular physiology and play a role in timing of onset and tolerance to myocardial infarction (MI) in patients. Whether time of day of MI triggers different molecular and cellular responses that can influence myocardial remodeling is not known. This study was designed to test whether time of day of MI triggers different gene expression, humoral, and innate inflammatory responses that contribute to cardiac repair after MI.

Disruption of Circadian Rhythms and Sleep on Critical Illness and the Impact on Cardiovascular Events.

The cardiovascular system exhibits significant daily rhythms in physiologic processes (heart rate, blood pressure, cardiac contractility and function), and molecular gene and protein expression. An increasing number of clinical and experimental studies demonstrate the circadian system is an important underlying mechanism that coordinates these rhythmic processes for the health of the cardiovascular system. However, what happens when rhythms are disturbed has been generally clinically unappreciated.

Consequences of Circadian and Sleep Disturbances for the Cardiovascular System.

Circadian rhythms play a crucial role in our cardiovascular system. Importantly, there has been a recent flurry of clinical and experimental studies revealing the profound adverse consequences of disturbing these rhythms on the cardiovascular system. For example, circadian disturbance worsens outcome after myocardial infarction with implications for patients in acute care settings.

Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice.

This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+ transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice.