Cellular and molecular mechanisms driving cardiac tissue fibrosis: On the precipice of personalized and precision medicine.

Cardiac fibrosis is a significant contributor to heart failure, a condition that continues to affect a growing number of patients worldwide. Various cardiovascular comorbidities can exacerbate cardiac fibrosis. While fibroblasts are believed to be the primary cell type underlying fibrosis, recent and emerging data suggest that other cell types can also potentiate or expedite fibrotic processes. Over the past few decades, clinicians have developed therapeutics that can blunt the development and progression of cardiac fibrosis. While these strategies have yielded positive results, overall clinical outcomes for patients suffering from heart failure continue to be dire. Herein, we overview the molecular and cellular mechanisms underlying cardiac tissue fibrosis. To do so, we establish the known mechanisms that drive fibrosis in the heart, outline the diagnostic tools available, and summarize the treatment options used in contemporary clinical practice. Finally, we underscore the critical role the immune microenvironment plays in the pathogenesis of cardiac fibrosis.

Current concepts in the epigenetic regulation of cardiac fibrosis.

Cardiac fibrosis is a significant driver of congestive heart failure, a syndrome that continues to affect a growing patient population globally. Cardiac fibrosis results from a constellation of complex processes at the transcription, receptor, and signaling axes levels. Various mediators and signaling cascades, such as the transformation growth factor-beta pathway, have been implicated in the pathophysiology of cardiac tissue fibrosis. Our understanding of these markers and pathways has improved in recent years as more advanced technologies and assays have been developed, allowing for better delineation of the crosstalk between specific factors. There is mounting evidence suggesting that epigenetic modulation plays a pivotal role in the progression of cardiac fibrosis. Transcriptional regulation of key pro- and antifibrotic pathways can accentuate or blunt the rate and extent of fibrosis at the tissue level. Exosomes, micro-RNAs, and long noncoding RNAs all belong to factors that can impact the epigenetic signature in cardiac fibrosis. Herein, we comprehensively review the latest literature about exosomes, their contents, and cardiac fibrosis. In doing so, we highlight the specific transcriptional factors with pro- or antifibrotic properties. We also assimilate the data supporting these mediators' potential utility as diagnostic or prognostic biomarkers. Finally, we offer insight into where further work can be done to fill existing gaps to translate preclinical findings better and improve clinical outcomes.

Acute pericardial postischemic inflammatory responses: Characterization using a preclinical porcine model.

BACKGROUND: Pericardial fluid (PF) contains cells, proteins, and inflammatory mediators, such as cytokines, chemokines, growth factors, and matrix metalloproteinases. To date, we lack an adequate understanding of the inflammatory response that acute injury elicits in the pericardial space. OBJECTIVE: To characterize the inflammatory profile in the pericardial space acutely after ischemia/reperfusion. METHODS: Pigs were used to establish a percutaneous ischemia/reperfusion injury model. PF was removed from pigs at different time points postanesthesia or postischemia/reperfusion. Flow cytometry was used to characterize the immune cell composition of PF, while multiplex analysis was performed on the acellular portion of PF to determine the concentration of inflammatory mediators. There was a minimum of 3 pigs per group. RESULTS: While native PF mainly comprises macrophages, we show that neutrophils are the predominant inflammatory cell type in the pericardial space after injury. The combination of acute ischemia/reperfusion (IR) and repeatedly accessing the pericardial space significantly increases the concentration of interleukin-1 beta (IL-1ß) and interleukin-1 receptor antagonist (IL-1ra). IR significantly increases the pericardial concentration of TGFß1 but not TGFß2. We observed that repeated manipulation of the pericardial space can also drive a robust pro-inflammatory response, resulting in a significant increase in immune cells and the accumulation of potent inflammatory mediators in the pericardial space. CONCLUSION: In the present study, we show that both IR and surgical manipulation can drive robust inflammatory processes in the pericardial space, consisting of an increase in inflammatory cytokines and alteration in the number and composition of immune cells.

Post-Operative Adhesions: A Comprehensive Review of Mechanisms.

Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.

Ischemic heart disease: Cellular and molecular immune contributions of the pericardium.

Ischemic heart disease promotes complex inflammatory and remodeling pathways which contribute to the development of chronic heart failure. Although blood-derived and local cardiac mediators have traditionally been linked with these processes, the pericardial space has more recently been noted as alternative contributor to the injury response in the heart. The pericardial space contains fluid rich in physiologically active mediators, and immunologically active adipose tissue, which are altered during myocardial infarction. Key immune cells in the pericardial fluid and adipose tissue have been identified which act as mediators for cell recruitment and function after myocardial infarction have been identified in experimental models. Here, we provide an overview of the current understanding of the inflammatory mechanisms of the pericardial space and their role in post-myocardial infarction remodeling and the potential for the use of the pericardial space as a delivery vehicle for treatments to modulate heart healing.

Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies.

Post-operative adhesions affect patients undergoing all types of surgeries. They are associated with serious complications, including higher risk of morbidity and mortality. Given increased hospitalization, longer operative times, and longer length of hospital stay, post-surgical adhesions also pose a great financial burden. Although our knowledge of some of the underlying mechanisms driving adhesion formation has significantly improved over the past two decades, literature has yet to fully explain the pathogenesis and etiology of post-surgical adhesions. As a result, finding an ideal preventative strategy and leveraging appropriate tissue engineering strategies has proven to be difficult. Different products have been developed and enjoyed various levels of success along the translational tissue engineering research spectrum, but their clinical translation has been limited. Herein, we comprehensively review the agents and products that have been developed to mitigate post-operative adhesion formation. We also assess emerging strategies that aid in facilitating precision and personalized medicine to improve outcomes for patients and our healthcare system.