Guidelines for assessing maternal cardiovascular physiology during pregnancy and postpartum.

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.

Functions of RNA-Binding Proteins in Cardiovascular Disease.

Gene expression is under tight regulation from the chromatin structure that regulates gene accessibility by the transcription machinery to protein degradation. At the transcript level, this regulation falls on RNA-binding proteins (RBPs). RBPs are a large and diverse class of proteins involved in all aspects of a transcript's lifecycle: splicing and maturation, localization, stability, and translation. In the past few years, our understanding of the role of RBPs in cardiovascular diseases has expanded. Here, we discuss the general structure and function of RBPs and the latest discoveries of their role in pulmonary and systemic cardiovascular diseases.

Amnion responses to intrauterine inflammation and effects of inhibition of TNF signaling in preterm Rhesus macaque.

Intrauterine infection/inflammation (IUI) is a frequent complication of pregnancy leading to preterm labor and fetal inflammation. How inflammation is modulated at the maternal-fetal interface is unresolved. We compared transcriptomics of amnion (a fetal tissue in contact with amniotic fluid) in a preterm Rhesus macaque model of IUI induced by lipopolysaccharide with human cohorts of chorioamnionitis. Bulk RNA sequencing (RNA-seq) amnion transcriptomic profiles were remarkably similar in both Rhesus and human subjects and revealed that induction of key labor-mediating genes such as IL1 and IL6 was dependent on nuclear factor κB (NF-κB) signaling and reversed by the anti-tumor necrosis factor (TNF) antibody Adalimumab. Inhibition of collagen biosynthesis by IUI was partially restored by Adalimumab. Interestingly, single-cell transcriptomics, flow cytometry, and immunohistology demonstrated that a subset of amnion mesenchymal cells (AMCs) increase CD14 and other myeloid cell markers during IUI both in the human and Rhesus macaque. Our data suggest that CD14+ AMCs represent activated AMCs at the maternal-fetal interface.

17 ß-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice.

Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 ß-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 ß-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 ß-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 ß-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 ß-estradiol modulated a set of genes that function through TNFα mediated NF-κB signaling. In addition, 17 ß-estradiol suppressed the induction of these TNFα induced genes in aortic smooth muscle cells in vitro in an NF-κB dependent manner, and 17 ß-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 ß-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNFα-NF-κB signaling.

Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives.

Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches.

Myocardial fibrosis and calcification are attenuated by microRNA-129-5p targeting Asporin and Sox9 in cardiac fibroblasts.

Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR-129-5p and upregulation of its targets small leucine-rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR-129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR-129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR-129-5p that inhibit downstream ß-catenin expression. Chronic Angiotensin II infusion downregulated miR-129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR-129-5p mimic. Importantly, miR-129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR-129-5p/ASPN and miR-129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR-129-5p.

Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.

Tm4sf1-marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension.

The identification and role of endothelial progenitor cells in pulmonary arterial hypertension (PAH) remain controversial. Single-cell omics analysis can shed light on endothelial progenitor cells and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA sequencing of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic data sets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (endothelial arterial type 2 [EA2]) marked by Tm4sf1 (transmembrane 4 L six family member 1), a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted that EA2 has a less differentiated state compared with other endothelial subpopulations. Analysis of independent data sets revealed that TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45, and formed tubules in coculture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.

Intralipid fails to rescue bupivacaine-induced cardiotoxicity in late-pregnant rats.

Background: Females routinely receive bupivacaine for obstetric and regional anesthesia. An accidental overdose of bupivacaine can result in cardiotoxicity and cardiac arrest. Intralipid (ILP) rescues bupivacaine-induced cardiotoxicity in male rats. However, bupivacaine cardiotoxicity and ILP rescue have not been studied in non-pregnant and late-pregnant female rats. Here, we tested the hypothesis that an appropriate dose of ILP would rescue non-pregnant and late-pregnant rats from bupivacaine-induced cardiotoxicity. Methods: Non-pregnant (n = 6) and late-pregnant (n = 7) female rats received intravenous bupivacaine (10-mg/kg bolus) to induce asystole. Resuscitation with 20% ILP (5-ml/kg actual body weight, single bolus, and 0.5-ml/kg/min maintenance) and chest compressions were continued for 10-min. Serial heart rate (HR), left ventricular ejection-fraction (LVEF%), and LV-fractional shortening (LVFS%) were recorded at baseline and 10-min after bupivacaine-induced cardiac arrest. Data are mean ± SD followed by 95% CI. P-values < 0.05 were considered statistically significant. Results: All rats developed cardiac arrest within a few seconds after bupivacaine. All non-pregnant rats were successfully rescued by ILP, with a HR of 280 ± 32 bpm at baseline vs. 212 ± 18 bpm at 10-min post ILP (p < 0.01), LVEF of 70 ± 6% vs. 68 ± 5% (p = ns), and LVFS of 41 ± 5% vs. 39 ± 4% (p = ns). Interestingly, 6 out of 7 late-pregnant rats did not recover with ILP. Baseline HR, LVEF and LVFS for late-pregnant rats were 330 ± 40 bpm, 66 ± 5% and 38 ± 4%, respectively. At 10-min post ILP, the HR, LVEF, and LVFS were 39 ± 102 bpm (p < 0.0001), 8 ± 22% (p < 0.0001), and 5 ± 12% (p < 0.001), respectively. Conclusions: ILP successfully rescued bupivacaine-induced cardiac arrest in non-pregnant rats, but failed to rescue late-pregnant rats.

HNRNPA2B1: RNA-Binding Protein That Orchestrates Smooth Muscle Cell Phenotype in Pulmonary Arterial Hypertension.

BACKGROUND: RNA-binding proteins are master orchestrators of gene expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs. Thus, characterizing RNA-binding proteins targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RNA-binding protein targets, limiting our understanding of their function. In cancer, the RNA-binding protein HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1; A2B1) promotes the pro-proliferative/anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMCs) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH. METHOD: Through the integration of computational and experimental biology, the authors investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA sequencing allowed them to investigate the transcriptome-wide function of A2B1, and RNA immunoprecipitation and A2B1 silencing experiments allowed them to decipher the intricate molecular mechanism at play. In addition, they performed a preclinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity. RESULTS: They found that A2B1 expression and its nuclear localization are increased in human PAH-PASMC. Using bioinformatics, they identified 3 known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, they demonstrated the complementary nonredundant function of A2B1 motifs because all motifs are implicated in different aspects of the cell cycle. In addition, they showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC led to a decrease of all tested mRNAs carrying an A2B1 motif and a concomitant decrease in proliferation and resistance to apoptosis. Last, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. CONCLUSIONS: Through the integration of computational and experimental biology, the study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.

Y-Chromosome Gene, Uty, Protects Against Pulmonary Hypertension by Reducing Proinflammatory Chemokines.

Rationale: Idiopathic pulmonary arterial hypertension (PAH) is a terminal pulmonary vascular disease characterized by increased pressure, right ventricular failure, and death. PAH exhibits a striking sex bias and is up to four times more prevalent in females. Understanding the molecular basis behind sex differences could help uncover novel therapies. Objectives: We previously discovered that the Y chromosome is protective against hypoxia-induced experimental pulmonary hypertension (PH), which may contribute to sex differences in PAH. Here, we identify the gene responsible for Y-chromosome protection, investigate key downstream autosomal genes, and demonstrate a novel preclinical therapy. Methods: To test the effect of Y-chromosome genes on PH development, we knocked down each Y-chromosome gene expressed in the lung by means of intratracheal instillation of siRNA in gonadectomized male mice exposed to hypoxia and monitored changes in right ventricular and pulmonary artery hemodynamics. We compared the lung transcriptome of Uty knockdown mouse lungs to those of male and female PAH patient lungs to identify common downstream pathogenic chemokines and tested the effects of these chemokines on human pulmonary artery endothelial cells. We further inhibited the activity of these chemokines in two preclinical pulmonary hypertension models to test the therapeutic efficacy. Measurements and Main Results: Knockdown of the Y-chromosome gene Uty resulted in more severe PH measured by increased right ventricular pressure and decreased pulmonary artery acceleration time. RNA sequencing revealed an increase in proinflammatory chemokines Cxcl9 and Cxcl10 as a result of Uty knockdown. We found CXCL9 and CXCL10 significantly upregulated in human PAH lungs, with more robust upregulation in females with PAH. Treatment of human pulmonary artery endothelial cells with CXCL9 and CXCL10 triggered apoptosis. Inhibition of Cxcl9 and Cxcl10 expression in male Uty knockout mice and CXCL9 and CXCL10 activity in female rats significantly reduced PH severity. Conclusions:Uty is protective against PH. Reduction of Uty expression results in increased expression of proinflammatory chemokines Cxcl9 and Cxcl10, which trigger endothelial cell death and PH. Inhibition of CLXC9 and CXLC10 rescues PH development in multiple experimental models.

Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy.

Coronary artery disease remains the leading cause of death. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting in cardiomyocytes death. The most effective strategy for treating an MI is early and rapid myocardial reperfusion, but restoring blood flow to the ischemic myocardium can induce further damage, known as ischemia-reperfusion (IR) injury. Novel therapeutic strategies are critical to limit myocardial IR injury and improve patient outcomes following reperfusion intervention. miRNAs are small non-coding RNA molecules that have been implicated in attenuating IR injury pathology in pre-clinical rodent models. In this review, we discuss the role of miR-1 and miR-21 in regulating myocardial apoptosis in ischemia-reperfusion injury in the whole heart as well as in different cardiac cell types with special emphasis on cardiomyocytes, fibroblasts, and immune cells. We also examine therapeutic potential of miR-1 and miR-21 in preclinical studies. More research is necessary to understand the cell-specific molecular principles of miRNAs in cardioprotection and application to acute myocardial IR injury.

Radiosensitizing Pancreatic Cancer via Effective Autophagy Inhibition.

Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.

A novel miRNA biomarker panel associated with mortality in pediatric patients with ARDS.

We identified a novel microRNA biomarker panel consisting of 6 microRNAs predicting mortality in pediatric acute respiratory distress syndrome patients. Each of the identified mRNA have potential mechanistic importance in acute respiratory distress syndrome and may lead to the development of pharmacologic targets.

Single-Cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning.

Rationale: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.Objectives: To determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.Methods: Single-cell RNA sequencing was performed on the lungs of monocrotaline (MCT), Sugen-hypoxia (SuHx), and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.Measurements and Main Results: Distinct changes in genes and pathways in numerous cell types were identified in SuHx and MCT lungs. Widespread upregulation of NF-κB signaling and downregulation of IFN signaling was observed across cell types. SuHx nonclassical monocytes and MCT conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.research.idre.ucla.edu/PVDSingleCell/).Conclusions: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.

Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights.

Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent co-morbidity. The high prevalence of PH in PF patients is very concerning since the presence of PH is a strong predictor of mortality in PF patients. Until recently, PH was thought to arise solely from fibrotic destruction of the lung parenchyma, leading to hypoxic vasoconstriction and loss of vascular bed density. Thus, potential cellular and molecular dysregulation of vascular remodeling as a driver of PF-PH has been under-investigated. The recent demonstrations that there is no correlation between the severity of the fibrosis and development of PH, along with the finding that significant vascular histological and molecular differences exist between patients with and without PH have shifted the etiological paradigm of PF-PH. This review aims to provide a comprehensive translational overview of PH in PF patients from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.

The Role of MicroRNAs in Acute Respiratory Distress Syndrome and Sepsis, From Targets to Therapies: A Narrative Review.

Acute respiratory distress syndrome (ARDS) is a significant cause of morbidity and mortality in the intensive care unit (ICU) and is characterized by lung epithelial and endothelial cell injury, with increased permeability of the alveolar-capillary membrane, leading to pulmonary edema, severe hypoxia, and difficulty with ventilation. The most common cause of ARDS is sepsis, and currently, treatment of ARDS and sepsis has consisted mostly of supportive care because targeted therapies have largely been unsuccessful. The molecular mechanisms behind ARDS remain elusive. Recently, a number of microRNAs (miRNAs) identified through high-throughput screening studies in ARDS patients and preclinical animal models have suggested a role for miRNA in the pathophysiology of ARDS. miRNAs are small noncoding RNAs ranging from 18 to 24 nucleotides that regulate gene expression via inhibition of the target mRNA translation or by targeting complementary mRNA for early degradation. Unsurprisingly, some miRNAs that are differentially expressed in ARDS overlap with those important in sepsis. In addition, circulatory miRNA may be useful as biomarkers or as targets for pharmacologic therapy. This can be revolutionary in a syndrome that has neither a measurable indicator of the disease nor a targeted therapy. While there are currently no miRNA-based therapies targeted for ARDS, therapies targeting miRNA have reached phase II clinical trials for the treatment of a wide range of diseases. Further studies may yield a unique miRNA profile pattern that serves as a biomarker or as targets for miRNA-based pharmacologic therapy. In this review, we discuss miRNAs that have been found to play a role in ARDS and sepsis, the potential mechanism of how particular miRNAs may contribute to the pathophysiology of ARDS, and strategies for pharmacologically targeting miRNA as therapy.

Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19.

The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, cardiovascular injury is reported to contribute to a substantial proportion of COVID-19 deaths. Preexisting cardiovascular disease (CVD) is among the most common risk factors for hospitalization and death in COVID-19 patients, and the pathogenic mechanisms of COVID-19 disease progression itself may promote the development of cardiovascular injury, increasing risk of in-hospital death. Sex differences in COVID-19 are becoming more apparent as mounting data indicate that males seem to be disproportionately at risk of severe COVID-19 outcome due to preexisting CVD and COVID-19-related cardiovascular injury. In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.