Patients with prior autoimmune diseases such as sarcoidosis require special care when treated with checkpoint inhibitors (CPIs), given the risk for reactivation of inflammation. Here, we address the clinical dilemma of initiating CPIs for recurrent metastatic carcinoma in a patient with extensive sarcoidosis, controlled after prolonged immunosuppressive therapy when the tumor recurrence was detected. To achieve the best possible outcome, the case was discussed by an interdisciplinary team comprising specialists in rheumatology, oncology, and CPI-related myocarditis. Literature on this topic was very limited. Based on the pharmacodynamics of CPIs and the pathophysiology of CPI-related autoimmune diseases, we concluded that initiating CPIs alongside low-dose prednisolone would effectively suppress any reactivation of sarcoidosis without interfering with CPIs in a relevant way.

Clonal hematopoiesis (CH) is a prevalent condition that results from somatic mutations in hematopoietic stem cells. When these mutations occur in “driver” genes, they can potentially confer fitness advantages to the affected cells, leading to a clonal expansion. While most clonal expansions of mutant cells are generally considered to be asymptomatic since they do not impact overall blood cell numbers, CH carriers face long-term risks of all-cause mortality and age-associated diseases, including cardiovascular disease and hematological malignancies. While considerable research has focused on understanding the association between CH and these diseases, less attention has been given to exploring the regulatory factors that contribute to the expansion of the driver gene clone. This review focuses on the association between environmental stressors and inherited genetic risk factors in the context of CH development. A better understanding of how these stressors impact CH development will facilitate mechanistic studies and potentially lead to new therapeutic avenues to treat individuals with this condition.

Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.

The loss of skeletal muscle, also known as sarcopenia, is an aging-associated muscle disorder that is disproportionately present in heart failure (HF) patients. HF patients with sarcopenia have poor outcomes compared to the overall HF patient population. The prevalence of sarcopenia in HF is only expected to grow as the global population ages, and novel treatment strategies are needed to improve outcomes in this cohort. Multiple mechanistic pathways have emerged that may explain the increased prevalence of sarcopenia in the HF population, and a better understanding of these pathways may lead to the development of therapies to prevent muscle loss. This review article aims to explore the molecular mechanisms linking sarcopenia and HF, and to discuss treatment strategies aimed at addressing such molecular signals.

Introduction: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model.

Aim: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for Ryr2 variant p.Arg176Gln (R176Q/+).

Methods and Results: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day-old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total Ryr2 mRNA and a 38% reduction in RyR2 protein. Genome editing was well tolerated based on serial echocardiography, revealing unaltered cardiac function and structure up to 12 months after AAV9 injection.

Conclusion: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.

Lipoprotein(a) [Lp(a)] has emerged as a significant player in the realm of cardiovascular disease (CVD), exerting a pivotal role in atherosclerotic cardiovascular disease (ASCVD), aortic valve stenosis (AVS), and overall cardiovascular (CV) and all-cause mortality. Since its discovery in 1963 by Kåre Berg, our understanding of Lp(a) has undergone significant evolution. This comprehensive review delves into the genetics, structure, assembly, and inter-population differences of Lp(a), shedding light on its intricate involvement in CVD. Genetically, Lp(a) is primarily influenced by variations in the LPA gene. The LPA gene encodes apo(a) and the variation in the kringle domains is the main determinant of plasma Lp(a) levels. Other genetic variants, such as SNPs in the LPA gene region, the pentanucleotide repeat polymorphism, and specific SNPs in the coding sequences of kringle domains, have also been associated with varying Lp(a) concentrations. Additionally, genes outside the LPA locus, including APOE, APOH, and CEPT gene regions, contribute to Lp(a) variability across different populations. Inter-population differences in Lp(a) levels are evident, with ethnicity and sex playing significant roles. Racial disparities in median Lp(a) concentration have been observed, with black individuals often displaying higher levels compared to their white counterparts. The review underscores Lp(a) as an independent, heritable CV risk factor in both primary and secondary settings. High Lp(a) levels are closely linked to the recurrence of myocardial infarction, AVS, and CV events. The necessity of measuring Lp(a) concentration at least once in life to assess an individual's absolute global CV risk is emphasized. Despite substantial progress, many questions remain unanswered about Lp(a), including its physiological role in the cardiovascular system and its involvement in inflammatory and thrombotic processes. Ongoing research holds promise for the development of therapeutic interventions, such as pharmacological agents and apheresis, to mitigate the cardiovascular risks associated with elevated Lp(a) levels. This review highlights the multifaceted nature of Lp(a) in the context of cardiovascular health, emphasizing the importance of continued research efforts to unravel its complexities and develop innovative strategies for managing its associated risks.

Introduction: Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure.

Aim: We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia.

Methods and Results: We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence.

Conclusion: Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration.