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Dementia refers to a particular group of symptoms characterized by difficulties with memory, language, problem-solving, and other thinking skills that affect a person's ability to perform everyday activities. Alzheimer's disease (AD) is the most common form of dementia, affecting about 6.2 million Americans aged 65 years and older. Likewise, cardiovascular diseases (CVDs) are a major cause of disability and premature death, impacting 126.9 million adults in the USA, a number that increases with age. Consequently, CVDs and cardiovascular risk factors are associated with an increased risk of AD and cognitive impairment. They share important age-related cardiometabolic and lifestyle risk factors, that make them among the leading causes of death. Additionally, there are several premises and hypotheses about the mechanisms underlying the association between AD and CVD. Although AD and CVD may be considered deleterious to health, the study of their combination constitutes a clinical challenge, and investigations to understand the mechanistic pathways for the cause-effect and/or shared pathology between these two disease constellations remains an active area of research. AD pathology is propagated by the amyloid β (Aβ) peptides. These peptides give rise to small, toxic, and soluble Aβ oligomers (SPOs) that are nonfibrillar, and it is their levels that show a robust correlation with the extent of cognitive impairment. This review will elucidate the interplay between the effects of accumulating SPOs in AD and CVDs, the resulting ER stress response, and their role in vascular dysfunction. We will also address the potential underlying mechanisms, including the possibility that SPOs are among the causes of vascular injury in CVD associated with cognitive decline. By revealing common mechanistic underpinnings of AD and CVD, we hope that novel experimental therapeutics can be designed to reduce the burden of these devastating diseases. Graphical abstract Alzheimer's disease (AD) pathology leads to the release of Aβ peptides, and their accumulation in the peripheral organs has varying effects on various components of the cardiovascular system including endoplasmic reticulum (ER) stress and vascular damage. Image created with BioRender.com., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Ethanol consumption represents a significant public health problem, and excessive ethanol intake is a risk factor for cardiovascular disease (CVD), one of the leading causes of death and disability worldwide. The mechanisms underlying the effects of ethanol on the cardiovascular system are complex and not fully comprehended. The gut microbiota and their metabolites are indispensable symbionts essential for health and homeostasis and therefore, have emerged as potential contributors to ethanol-induced cardiovascular system dysfunction. By mechanisms that are not completely understood, the gut microbiota modulates the immune system and activates several signaling pathways that stimulate inflammatory responses, which in turn, contribute to the development and progression of CVD. This review summarizes preclinical and clinical evidence on the effects of ethanol in the gut microbiota and discusses the mechanisms by which ethanol-induced gut dysbiosis leads to the activation of the immune system and cardiovascular dysfunction. The cross talk between ethanol consumption and the gut microbiota and its implications are detailed. In summary, an imbalance in the symbiotic relationship between the host and the commensal microbiota in a holobiont, as seen with ethanol consumption, may contribute to CVD. Therefore, manipulating the gut microbiota, by using antibiotics, probiotics, prebiotics, and fecal microbiota transplantation might prove a valuable opportunity to prevent/mitigate the deleterious effects of ethanol and improve cardiovascular health and risk prevention.

Red blood cell distribution width (RDW) is a measurement of the variation in size and volume of red blood cells (RBCs). Increased RDW, indicating a high heterogeneity of RBCs, is prominently associated with a variety of illnesses, especially cardiovascular diseases. However, the significance of this association to the onset and progression of cardiovascular and renal diseases is unknown. We hypothesized that a genetic predisposition for increased RDW is an early risk factor for cardiovascular and renal comorbidities. Since there is no known animal model of increased RDW, we examined a CRISPR/Cas9 gene-edited rat model (Rffl TD ) that presented with features of hematologic abnormalities as well as severe cardiac and renal comorbidities. A mass spectrometry-based quantitative proteomic analysis indicated anemia of these rats, which presented with significant downregulation of hemoglobin and haptoglobin. Decreased hemoglobin and increased RDW were further observed in Rffl TD through complete blood count. Next, a systematic temporal assessment detected an early increased RDW in Rffl TD , which was prior to the development of other comorbidities. The primary mutation of Rffl TD is a 50 bp deletion in a non-coding region, and our study has serendipitously identified this locus as a novel quantitative trait locus (QTL) for RDW. To our knowledge, our study is the first to experimentally pinpoint a QTL for RDW and provides a novel genetic rat model mimicking the clinical association of increased RDW with poor cardio-renal outcome., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Cardio-oncology is a new and rapidly expanding field that merges cancer and cardiovascular disease. Cardiovascular disease is an omnipresent side effect of cancer therapy; in fact, it is the second leading cause of death in cancer survivors after recurrent cancer. It has been well documented that many cancer chemotherapeutic agents cause cardiovascular toxicity. Nonetheless, the underlying cause of cancer therapy-induced cardiovascular toxicity is largely unknown. In this review, we discuss the potential role of damage-associated molecular patterns (DAMPs) as an underlying contributor to cancer therapy-induced cardiovascular toxicity. With an increasing number of cancer patients, as well as extended life expectancy, understanding the mechanisms underlying cancer therapy-induced cardiovascular disease is of the utmost importance to ensure that cancer is the only disease burden that cancer survivors have to endure.

Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Immune system activation occurs not only due to foreign stimuli, but also due to endogenous molecules. As such, endogenous molecules that are released into the circulation due to cell death and/or injury alarm the immune system that something has disturbed homeostasis and a response is needed. Collectively, these molecules are known as damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs (mtDAMPs) are potent immunological activators due to the bacterial ancestry of mitochondria. Mitochondrial DAMPs are recognized by specific pattern recognition receptors of the innate immune system, some of which are expressed in the cardiovascular system. Cell death leads to release of mtDAMPs that may induce vascular changes by mechanisms that are currently not well understood. This review will focus on recently published evidence linking mtDAMPs and immune system activation to vascular dysfunction and cardiovascular disease.

The measurement of vascular function in isolated vessels has revealed important insights into the structural, functional, and biomechanical features of the normal and diseased cardiovascular system and has provided a molecular understanding of the cells that constitutes arteries and veins and their interaction. Further, this approach has allowed the discovery of vital pharmacological treatments for cardiovascular diseases. However, the expansion of the vascular physiology field has also brought new concerns over scientific rigor and reproducibility. Therefore, it is appropriate to set guidelines for the best practices of evaluating vascular function in isolated vessels. These guidelines are a comprehensive document detailing the best practices and pitfalls for the assessment of function in large and small arteries and veins. Herein, we bring together experts in the field of vascular physiology with the purpose of developing guidelines for evaluating ex vivo vascular function. By using this document, vascular physiologists will have consistency among methodological approaches, producing more reliable and reproducible results. [ABSTRACT FROM AUTHOR]

Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted. [ABSTRACT FROM AUTHOR]

Fifty percent of trauma patients who present sepsis-like syndrome do not have bacterial infections. This condition is known as systemic inflammatory response syndrome (SIRS). A unifying factor of SIRS and sepsis is cardiovascular collapse. Trauma and severe blood loss cause the release of endogenous molecules known as damage-associated molecular patterns. Mitochondrial N-formyl peptides (F-MIT) are damage-associated molecular patterns that share similarities with bacterial N-formylated peptides and are potent immune system activators. The goal of this study was to investigate whether F-MIT trigger SIRS, including hypotension and vascular collapse via formyl peptide receptor (FPR) activation. We evaluated cardiovascular parameters in Wistar rats treated with FPR or histamine receptor antagonists and inhibitors of the nitric oxide pathway before and after F-MIT infusion. F-MIT, but not nonformylated peptides or mitochondrial DNA, induced severe hypotension via FPR activation and nitric oxide and histamine release. Moreover, F-MIT infusion induced hyperthermia, blood clotting, and increased vascular permeability. To evaluate the role of leukocytes in F-MIT-induced hypotension, neutrophil, basophil, or mast cells were depleted. Depletion of basophils, but not neutrophils or mast cells, abolished F-MIT-induced hypotension. Rats that underwent hemorrhagic shock increased plasma levels of mitochondrial formylated proteins associated with lung damage and antagonism of FPR ameliorated hemorrhagic shock-induced lung injury. Finally, F-MIT induced vasodilatation in isolated resistance arteries via FPR activation; however, F-MIT impaired endothelium-dependent relaxation in the presence of blood. These data suggest that F-MIT may be the link among trauma, SIRS, and cardiovascular collapse. [ABSTRACT FROM AUTHOR]