The big squeeze: balancing the hemodynamics of cardiac tamponade and superior vena cava syndrome.

In this clinical vignette, we describe an unusual aetiology of shock that was precipitated by the drainage of malignant pericardial effusion. Therapeutic intervention of the patient's cardiac tamponade led to decreased venous pressures, increased external lung mass compression, worsening superior vena cava syndrome, and ultimately haemodynamic compromise leading to his expiration.

A Rare Single Case of COVID-19-Induced Acute Myocarditis and Encephalopathy Presenting Simultaneously.

The ongoing coronavirus disease 2019 (COVID-19) pandemic may result in cardiovascular complications such as myocarditis, while encephalitis is a potentially life-threatening COVID-19-associated central nervous system complication. This case illustrates the possibility of developing severe multisystem symptoms from a COVID-19 infection, despite having received the COVID-19 vaccine within the year. Delay in treatment for myocarditis and encephalopathy can lead to permanent and possibly fatal damage. Our patient, a middle-aged female with a complicated medical history, initially came in without characteristic manifestations of myocarditis such as shortness of breath, chest pain, or arrhythmia, but with an altered mental status. Through further laboratory tests, the patient was diagnosed with myocarditis and encephalopathy, which were resolved within weeks through medical management and physical/occupational therapy. This case presentation describes the first reported case of concomitant COVID-19 myocarditis and encephalitis after receiving a booster dose within the year.

Idiopathic pulmonary fibrosis: Current and future treatment.

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3-5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development. DATA SOURCE: The data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management. RESULTS: Etiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy. CONCLUSION: Clearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well-being.

Understanding Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Toward Better Treatment and Prevention.

Systemic lupus erythematosus (SLE) carries a significant risk of cardiovascular disease (CVD). The prevalence of premature CVD is especially noteworthy because it occurs in premenopausal women with SLE who would otherwise have very low rates of CVD. While traditional risk factors likely play a role in development of CVD in the setting of SLE, they do not fully explain the excess risk. The pathogenesis of CVD in SLE is not fully understood, but the inflammatory nature of SLE is believed to be a key factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, the inflammatory milieu of SLE plasma promotes endothelial dysfunction and vascular injury, early steps in the progression of atherosclerotic CVD. Despite the overall headway that has been achieved in treating lupus, innovative therapeutics specifically targeting the progression of atherosclerosis within the lupus population are currently lacking. However, there have been advancements in the development of promising modalities for diagnosis of subclinical atherosclerosis and detection of high CVD risk patients. Due to the significant impact of CVD on morbidity and mortality, research addressing prevention and treatment of CVD in SLE needs to be prioritized. This review explores the intricate interplay of SLE-specific properties that contribute to atherosclerosis and CVD within this population, as well as screening methods and possible therapies.

Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.

BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-ß and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages.

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.

Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy.

Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs.

BACKGROUND: Macrophage cholesterol efflux capacity has been identified as a predictor for cardiovascular disease. We assessed the relationship between adipocyte-derived extracellular vesicle microRNAs and macrophage cholesterol efflux capacity. METHODS: We assessed an adolescent cohort (n = 93, Age, median (IQR) = 17 (3) year, Female = 71, Male = 22) throughout the BMI continuum (BMI = 45.2 (13.2) kg/m2) for: (1) cholesterol efflux capacity and lipoprotein profiles; (2) adipocyte-derived extracellular vesicle microRNAs in serum; (3) the role of visceral adipose tissue extracellular vesicle in regulation of cholesterol efflux and cholesterol efflux gene expression in THP-1 macrophages in vitro. RESULTS: Efflux capacity was significantly associated with HDL (r = 0.30, p = 0.01) and LDL (r = 0.33, p = 0.005) particle size. Multivariate-analysis identified six microRNAs associated (p < 0.05) with cholesterol efflux capacity: miR-3129-5p (Beta = 0.695), miR-20b (0.430), miR9-5p (0.111), miR-320d (- 0.190), miR301a-5p (0.042), miR-155-5p (0.004). In response to increasing concentrations (1 µg/mL vs. 3 µg/mL) of VAT extracellular vesicle, cholesterol efflux (66% ± 10% vs. 49% ± 2%; p < 0.01) and expression of ABCA1 (FC = 1.9 ± 0.8 vs 0.5 ± 0.2; p < 0.001), CD36 (0.7 ± 0.4 vs. 2.1 ± 0.8, p = 0.02), CYP27A1 (1.4 ± 0.4 vs. 0.9 ± 0.5; p < 0.05), and LXRA (1.8 ± 1.1 vs. 0.5 ± 0.2; p < 0.05) was altered in THP-1 cells in vitro. CONCLUSION: Adipocyte-derived extracellular vesicle microRNAs may, in part, be involved macrophage cholesterol efflux regulation.

Macrophage lipid accumulation in the presence of immunosuppressive drugs mycophenolate mofetil and cyclosporin A.

OBJECTIVE: Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS: Differentiated M0, M1 and M2 subsets of THP-1 human macrophages were subjected to various concentrations of either MPA or CsA. Expression of proteins involved in reverse cholesterol transport (ABCA1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), were evaluated by real-time PCR and confirmed with Western blot. DiI-oxidized LDL internalization assay was used to assess foam cell formation. The influence of MPA was also evaluated in BMDM obtained from atherosclerosis-prone transgenic mice, ApoE-/- and ApoE-/-Fas-/-. RESULTS: In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS: Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Adenosine and the Cardiovascular System.

Adenosine is an endogenous nucleoside with a short half-life that regulates many physiological functions involving the heart and cardiovascular system. Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, impact platelet aggregation and inhibit the inflammatory response. Through modulation of forward and reverse cholesterol transport pathways, adenosine can improve cholesterol balance and thereby protect macrophages from lipid overload and foam cell transformation. The function of adenosine is controlled through four G-protein coupled receptors: A1, A2A, A2B and A3. Of these four, it is the A2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A2A receptor agonists are the focus of efforts by the pharmaceutical industry to develop new cardiovascular therapies, and pharmacological actions of the atheroprotective and anti-inflammatory drug methotrexate are mediated via release of adenosine and activation of the A2A receptor. Also relevant are anti-platelet agents that decrease platelet activation and adhesion and reduce thrombotic occlusion of atherosclerotic arteries by antagonizing adenosine diphosphate-mediated effects on the P2Y12 receptor. The purpose of this review is to discuss the effects of adenosine on cell types found in the arterial wall that are involved in atherosclerosis, to describe use of adenosine and its receptor ligands to limit excess cholesterol accumulation and to explore clinically applied anti-platelet effects. Its impact on electrophysiology and use as a clinical treatment for myocardial preservation during infarct will also be covered. Results of cell culture studies, animal experiments and human clinical trials are presented. Finally, we highlight future directions of research in the application of adenosine as an approach to improving outcomes in persons with cardiovascular disease.

PCSK9 in cholesterol metabolism: from bench to bedside.

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients. Moreover, gain-of-function PCSK9 mutations were discovered to be the root cause of familial autosomal dominant hypercholesterolemia. Inhibition of PSCK9 reduces plasma LDL levels, even in patients for whom statins are ineffective or not tolerated. Alirocumab and evolocumab, human monoclonal antibodies that inhibit PCSK9, have been approved to lower LDL levels. While there are drawbacks to these treatments, including adverse events, administration by subcutaneous injection, and high cost, these drugs are indicated for the treatment of atherosclerotic cardiovascular disease and familial hypercholesterolemia as adjunct to diet and maximally tolerated statin therapy. PCSK9 inhibitors may work synergistically with statins to lower LDL. Novel approaches to PCSK9 inhibition are currently in development with the aim of providing safe and effective treatment options to decrease cardiovascular event burden, ideally at lower cost and with oral bioavailability.

The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity.

Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these populations and significant residual risk remains despite current treatment approaches. Obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to chronic inflammation, and subjects with these disorders have characteristic shifts in their gut microbiome composition. Recent data suggest that alterations in gut microbial and metabolic composition may be responsible, in part, for induction of chronic inflammation, thus promoting cardiovascular disease. Common microbiome changes observed in obesity, T1DM, RA, and SLE include a decrease in the ratio of bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include alterations in the metabolic composition of the gut, hyper-activation of toll-like receptor 4 (TLR-4), upregulation of inflammatory pathways, e.g. c-Jun N-terminal kinase and nuclear factor-kappa B (NFκB), increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a female pro-inflammatory gut microbiome. Intervention at the level of the microbiota appears to attenuate symptoms in these inflammatory syndromes with probiotic treatment, such as Lactobacilli, playing a uniquely beneficial role in restoring intestinal health, decreasing inflammation, and reducing cardiovascular disease. This review will discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk.

Is intra-procedure three-dimensional transesophageal echocardiogram an alternative to preprocedure multidetector computed tomography for the measurement of the aortic annulus in patients undergoing transcatheter aortic valve replacement?

BACKGROUND: The role of three-dimensional transesophageal echocardiography (3DTEE) vs multidetector computed tomography (MDCT) in aortic annular sizing has been poorly defined in patients undergoing transcatheter aortic valve replacements (TAVR). We set to determine the correlation between 3DTEE and MDCT in measuring the aortic annulus prior to TAVR. METHODS: In an observational, retrospective study, we compared aortic annular areas measured by MDCT and 3DTEE in TAVR patients. The aortic annular area was measured by planimetry of images obtained by MDCT pre-TAVR and by intra-TAVR TEE using 3D rendering of the aortic annulus followed by planimetry. Our primary outcome was degree of correlation between mean aortic annulus area by 3DTEE and MDCT. RESULTS: Of the 111 consecutive patients undergoing TAVR who had measurements from both modalities available for comparison between February 2012 and April 2015, 87 met inclusion criteria. The mean aortic annular area by MDCT was 4.44±0.88 cm2 and by 3DTEE was 4.33±0.78 cm2 . There was a strong positive linear correlation between aortic annular area measurements obtained from these two modalities with mild relative underestimation by 3DTEE (ρ=.833). This relationship can be estimated using the predictive formula: [Formula: see text] CONCLUSIONS: Three-dimensional transesophageal echocardiography measurements have a high degree of correlation with MDCT measurements and thus can assist in proper valve prosthesis selection for TAVR. Our study thus supports use of 3DTEE as a reasonable alternative imaging modality in patients undergoing TAVR.

Resveratrol counters systemic lupus erythematosus-associated atherogenicity by normalizing cholesterol efflux.

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Numerous investigations by our group and others have indicated cardioprotective and anti-inflammatory properties of resveratrol. The present study explored potential atheroprotective actions of resveratrol on cholesterol efflux in cultured human macrophages exposed to plasma from systemic lupus erythematosus (SLE) patients. These results were confirmed in ApoE(-/-)Fas(-/-) double knockout mice, displaying a lupus profile with accelerated atherosclerosis. Resveratrol treatment attenuated atherosclerosis in these mice. THP-1 human macrophages were exposed to 10% pooled or individual plasma from patients who met diagnostic criteria for SLE. Expression of multiple proteins involved in reverse cholesterol transport (ABCA1, ABCG1, SR-B1, and cytochrome P450 27-hydroxylase) was assessed using QRT-PCR and Western blotting techniques. Ten-week-old ApoE(-/-)Fas(-/-) double knockout mice (n = 30) were randomly divided into two equal groups of 15, one of which received 0.01% resveratrol for 10 consecutive weeks. Atherosclerosis progression was evaluated in murine aortas. Bone marrow-derived macrophages (BMDM) were cultured and expression of cholesterol efflux proteins was analyzed in each group of mice. Our data indicate that inhibition of cholesterol efflux by lupus plasma in THP-1 human macrophages is rescued by resveratrol. Similarly, administration of resveratrol in a lupus-like murine model reduces plaque formation in vivo and augments cholesterol efflux in BMDM. This study presents evidence for a beneficial role of resveratrol in atherosclerosis in the specific setting of SLE. Therefore, resveratrol may merit investigation as an additional resource available to reduce lipid deposition and atherosclerosis in humans, especially in such vulnerable populations as lupus patients.

Impact of first contact on symptom onset-to-door time in patients presenting for primary percutaneous coronary intervention.

OBJECTIVES: To determine effect of first medical contact type on symptom onset-to-door time (SODT). BACKGROUND: Shorter total ischemic time is associated with improved outcomes in ST-elevation myocardial infarction. METHODS: From 2005 to 2009, we reviewed records of all consecutive patients treated with primary percutaneous coronary intervention for ST-elevation myocardial infarction at our tertiary care teaching hospital (median follow-up 3.85 years). We compared SODT in patients whose first medical contact was a private physician (in person or via telephone) vs patients who presented to the emergency department (ED) directly (in person or via Emergency Medical Services). RESULTS: Of 366 patients, 84 (23%) contacted a physician (group A) while 282 (77.6%) did not (group B). Group A had higher median SODT (239.5 vs 130 minutes, P = .0043) and significantly higher mortality (log rank P = .0392, Cox Proportional Hazard Model risk factors: physician contact first [P < .013], age [P < .0001] and peripheral vascular disease [P < .035]). Two factors associated with prolonged SODT: (1) contacting a physician first P = .002 and (2) personal mode of transportation, P = .002. Patients presenting during "on-hours" (weekdays) were more likely to first contact a physician compared with those presenting during "off-hours" (weeknights and weekends) (66.67% in group A vs 45.04% in group B, P < .001). CONCLUSIONS: Patients whose first medical contact was a physician had greater pre-hospital delays and worse survival compared to those who sought emergent medical care directly. This pattern occurred more often during "on-hours." Educational efforts aimed at both patient and physician office practices are warranted.