Yin Tintut

The arterial vasculature is the second most frequently calcified structure in the human body after the skeleton. Calcification of the aorta and aortic valves occurs in most individuals in westernized societies with advancing age, with abdominal aortic calcification generally preceding ascending thoracic aortic disease. In cardiac valves and the thoracic aorta, however, calcification often arises earlier in common disease contexts characterized by metabolic, mechanical, or inflammatory injury (eg, metabolic syndrome, chronic kidney disease, irradiation). In these settings, calcification frequently involves the arterial media as a histoanatomic feature, and is associated with accelerated neurocognitive decline and increased cardiovascular mortality, reflecting a form of precocious aging. The term arteriosclerosis was coined nearly 2 centuries ago to describe the calcium-mediated hardening of the aorta and conduit arteries observed at autopsy with aging. However, much of our understanding of the causes, characterization, and consequences of aortic calcium deposition has emerged only within the past decade. Features of disease biology, including engagement of innate immunity, senescence (inflammaging), and ectopic activation of osteogenic mechanisms, are consistently revealed. In this article, we briefly review the burgeoning literature, highlighting recent advances in clinical and discovery science with translational implications. Given the current trajectory, after 2 centuries of disease recognition, the next decade of innovation promises meaningful progress toward effective medical treatments to prevent and treat the clinical consequences of calcific aortopathy.

CLINICAL PROBLEM: Vascular and valvular calcification significantly contributes to cardiovascular morbidity, particularly in patients with diabetes, atherosclerosis, advanced age, and chronic kidney disease. Currently, there are no effective treatments to prevent or reverse calcification, emphasizing the urgent need for robust preclinical models to help identify therapeutic targets and strategies. RECOMMENDATIONS: Preclinical models for vascular and valvular calcification should accurately reflect human disease pathology and progression, ideally including the influence of key underlying conditions and diseases (age, diabetes, renal disease, and hyperlipidemia), as well as sexual dimorphism, each of which may require a different model. Standardized and reproducible end points are essential, with preference for assessments that align with clinically utilized modalities (eg, computed tomography and echocardiography). SUMMARY: Murine models of cardiovascular calcification described herein have contributed substantially to our understanding of cardiovascular calcification though the translation toward clinically impactful therapies has, thus far, been limited. Improving clinical translation demands the use of models that replicate human comorbidities, disease progression, and outcomes. Further development of improved models, particularly those that demonstrate clinically important features such as plaque rupture, will facilitate effective translation of therapeutic strategies to clinical practice.

Electronic cigarettes (E-Cig) are a new way of delivering nicotine, gaining popularity among adolescents and young adults, who often do not realize their harmful effects. Although the adverse effects of E-Cigs on the liver and heart have been demonstrated, their effects on the skeletal muscle have not been well studied. In this study, we evaluated the skeletal muscle effects of E-Cig aerosol, delivered in a manner similar to human vaping, in a mouse model of obesity induced by a high-fat diet (HFD). C57BL/6 mice, fed either a normal chow diet (NCD) or HFD, were exposed to either saline aerosol control or aerosol generated from Blu PLUS^TM containing 0% or 2.4% nicotine for 12 weeks. Mice fed an NCD were included to distinguish whether E-Cig effects on the skeletal muscle required the presence of obesity induced by an HFD. The soleus muscle, an oxidative muscle rich in mitochondria, was assessed by Western blotting, electron microscopy, and biochemical assays. An NCD group was included to assess the baseline effects of HFD-induced obesity, on the skeletal muscle. The skeletal muscle from HFD-fed mice exposed to E-Cig 2.4% had reduced levels of phospho-AMPK compared with saline and E-Cig 0% groups, while E-Cigs had no effect on NCD-fed mice. Levels of phospho-adipose triglyceride lipase were also reduced in both E-Cig 2.4% and 0% compared with the saline group. These metabolic protein impairments were accompanied by increased levels of oxidative stress and phospho-p38 MAPK. Deregulation of the autophagy markers, microtubule-associated protein 1A/1B-light chain 3 (LC3-I; inactive form) and LC3-II (active form), was also observed, evidenced by decreased levels of LC3-II, ratio LC3-II/LC3-I, and increased levels of p62. Transmission electron microscopy analysis showed that E-Cig 2.4% induced damage to mitochondrial structure compared with the saline or E-Cig 0% groups. These findings suggest that E-Cig exposure on HFD impairs the skeletal muscle, adding to the growing list of affected organs for ongoing regulatory efforts concerning nicotine-containing substances.

Short-term tumor necrosis factor-α (TNF-α) treatment inhibits COL8A1 expression in human aortic endothelial cells (HAECs). COL8A1 inhibition decreases the expression of genes related to endothelial function and promotes endothelial-to-mesenchymal transition signaling. COL8A1 promotes the maintenance of endothelial traits in HAECs. TNF-α-induced COL8A1 inhibition helps to facilitate inflammatory EndMT via NF-κB/Snail signaling.

Effects of electronic cigarettes (E-cigs) compared with tobacco cigarettes (T-cigs) in the Western population are largely undetermined. Here, we assessed chronic, intermittent exposures to either E-cigs or T-cigs on cardiovascular parameters in hyperlipidemic mice with similar nicotine levels. Our findings suggest that both E-cigs and T-cigs imposed adverse effects on cardiac function, heart chamber size, and atherosclerotic lesions in diet and sex-dependent manners, suggesting that electronic cigarettes are not a safer alternative to conventional cigarettes.

Regular exercise is widely known to exert beneficial effects on the cardiovascular system. Despite the widely accepted and numerous benefits of exercise, whether there is an upper limit to these benefits is unclear, particularly with regard to atherosclerotic disease. Observational cohort studies over the past 2 decades have identified a consistent signal of increased coronary artery calcification in older men, who have been exposed to high volumes of endurance exercise over their lifetime. The clinical ramifications of these findings are not fully known, as outcomes studies in these athletic populations are needed, but given the strong associations of coronary artery calcification with adverse cardiovascular events, a deeper mechanistic understanding of the link between endurance exercise and coronary artery calcification is needed. In this review, we describe the possible underlying mechanisms that may explain this conundrum of the athlete calcification paradox at the molecular and cellular levels.

While exercise is known to benefit cardiovascular health, the optimum regimen, in terms of both speed and frequency, remains unclear, especially for those with existing calcific atherosclerosis. We previously found that, in atherosclerotic female mice, lower speed, but not higher speed, treadmill running had a beneficial effect on the morphology of aortic calcium mineral deposits, as determined by ¹⁸F‐NaF PET imaging, where ¹⁸F‐NaF tracer uptake reflects mineral surface area, which, in turn, reflects risk. To determine optimal exercise frequency at the lower speed, ¹⁸F‐NaF tracer uptake and histochemical analysis of alkaline phosphatase, calcium mineral, and CD68 in the aortas of aged Apoe^−/− mice exercising 0, 3, or 5 days/week were performed. Images were acquired at baseline and at the end of the study. Although by histochemistry, all 3 groups had similar levels of osteoblastic differentiation and similar numbers of aortic calcium deposits, ¹⁸F‐NaF tracer uptake increased significantly over the study duration in the 0‐ and 3‐days/week. groups but not in the 5‐days/week. group. Calcification also had a significant negative correlation with macrophage infiltration in the 5‐days/week. group. In summary, the findings suggest that greater frequency running regimens alter aortic calcification in ways that may provide better cardiovascular benefits.

The detection and assessment of atherosclerosis and cardiovascular calcification can inform risk stratification and therapies to reduce cardiovascular morbidity and mortality. In this review, we provide an overview of current and emerging imaging techniques for assessing atherosclerosis and cardiovascular calcification in animal models. Traditional imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), offer non-invasive approaches of visualizing atherosclerotic calcification in vivo; integration of these techniques with positron emission tomography (PET) imaging adds molecular imaging capabilities, such as detection of metabolically active microcalcifications with ¹⁸F-sodium fluoride. Photoacoustic imaging provides high contrast that enables in vivo evaluation of plaque composition, yet this method is limited by optical penetration depth. Light-sheet fluorescence microscopy provides high-resolution, three-dimensional imaging of cardiovascular structures and has been used for ex vivo assessment of atherosclerotic calcification, but its limited tissue penetration and requisite complex sample preparation preclude its use in vivo to evaluate cardiac tissue. Overall, with these evolving imaging tools, our understanding of cardiovascular calcification development in animal models is improving, and the combination of traditional imaging techniques with emerging molecular imaging modalities will enhance our ability to investigate therapeutic strategies for atherosclerotic calcification.