Adjuvants in COVID-19 vaccines: innocent bystanders or culpable abettors for stirring up COVID-heart syndrome.

COVID-19 infection is a multi-system clinical disorder that was associated with increased morbidity and mortality. Even though antiviral therapies such as Remdesvir offered modest efficacy in reducing the mortality and morbidity, they were not efficacious in reducing the risk of future infections. So, FDA approved COVID-19 vaccines which are widely administered in the general population worldwide. These COVID-19 vaccines offered a safety net against future infections and re-infections. Most of these vaccines contain inactivated virus or spike protein mRNA that are primarily responsible for inducing innate and adaptive immunity. These vaccines were also formulated to contain supplementary adjuvants that are beneficial in boosting the immune response. During the pandemic, clinicians all over the world witnessed an uprise in the incidence and prevalence of cardiovascular diseases (COVID-Heart Syndrome) in patients with and without cardiovascular risk factors. Clinical researchers were not certain about the underlying reason for the upsurge of cardiovascular disorders with some blaming them on COVID-19 infections while others blaming them on COVID-19 vaccines. Based on the literature review, we hypothesize that adjuvants included in the COVID-19 vaccines are the real culprits for causation of cardiovascular disorders. Operation of various pathological signaling events under the influence of these adjuvants including autoimmunity, bystander effect, direct toxicity, anti-phospholipid syndrome (APS), anaphylaxis, hypersensitivity, genetic susceptibility, epitope spreading, and anti-idiotypic antibodies were partially responsible for stirring up the onset of cardiovascular disorders. With these mechanisms in place, a minor contribution from COVID-19 virus itself cannot be ruled out. With that being said, we strongly advocate for careful selection of vaccine adjuvants included in COVID-19 vaccines so that future adverse cardiac disorders can be averted.

Role of COVID-19 vaccines in casuation of cardiovascular diseases COVID-19 infection is a multi-system clinical disorder that was associated with increased morbidity and mortality. Even though antiviral therapies such as Remdesvir offered modest efficacy in reducing the mortality and morbidity, they were not efficacious in reducing the risk of future infections. So, FDA approved COVID-19 vaccines which are widely administered in the general population worldwide. These COVID-19 vaccines offered safety net against future infections and re-infections. Most of these vaccines contain inactivated virus or spike protein mRNA that are primary responsible for inducing innate and adaptive immunity. These vaccines were also formulated to contain supplementary adjuvants that are beneficial in boosting the immune response. During the pandemic, clinicians all over the world witnessed an uprise in the incidence and prevalence of cardiovascular diseases (COVID-Heart Syndrome) in patients with and without cardiovascular risk factors. Clinical researchers were not certain the underlying reason for upsurge of cardiovascular disorder with some blaming them on COVID-19 infections while others blaming them on COVID-19 vaccines. Based on the literature review, we hypothesize that adjuvants included in the COVID-19 vaccines the real culprits for causation of cardiovascular disorders. Operation of various pathological signaling events under the influence of these adjuvants including autoimmunity, bystander effect, direct toxicity, anti-phospholipid syndrome (APS), anaphylaxis, hypersensitivity, genetic susceptibility, epitope spreading, and anti-idiotypic antibodies were partially responsible for stirring up the onset of cardiovascular disorders. With these mechanisms in place, a minor contribution from COVID-19 virus itself cannot be ruled out. With that being said, we strongly advocate for careful selection of vaccine adjuvants included in COVID-19 vaccines so that future adverse cardiac disorders can be averted.

Do COVID-19 viral infection and its mRNA vaccine carry an equivalent risk of myocarditis? Review of the current evidence, insights, and future directions.

According to recent epidemiological analysis, the percentage of world population infected with COVID-19 by end of December 2020 is approximately 12.56%1. COVID induced acute care and ICU hospitalization rates are around 9.22 (95% CI: 18.73-19.51), and 4.14 (95% CI: 4.10-4.18) per 1000 population1. Although therapeutic strategies such as antivirals, intravenous immunoglobulins and corticosteroids have shown modest efficacy in reducing the disease progression, they are not disease specific and only temper the immune mediated attack on the systemic tissues. Therefore, clinicians started to rely on mRNA COVID-19 vaccines, which are clinically efficacious in reducing the incidence, disease severity and systemic complications of COVID-19 infections. Nevertheless, usage of COVID-19 mRNA vaccines is also associated with cardiovascular complications such as myocarditis and pericarditis. On the other hand, COVID-19 infections itself are associated with cardiovascular complications such as myocarditis. The underlying signaling pathways for occurrence of COVID-19 and mRNA COVID-19 vaccine induced myocarditis are quite different although there is some overlap in autoimmunity and cross reactivity mechanisms. With media reports highlighting the cardiovascular complications of COVID-19 vaccines such as myocarditis, general population have become more hesitant and uncertain regarding the safety and efficacy of these mRNA vaccines. We plan to review the current literature and provide insights into their pathophysiological mechanisms for myocarditis and offer recommendations for further research studies in this regard. This will hopefully dispel some doubts and encourage more people to be vaccinated for preventing the risk of COVID-19 induced myocarditis and other associated cardiovascular complications.

Protease-activated receptors in kidney diseases: A comprehensive review of pathological roles, therapeutic outcomes and challenges.

Studies have demonstrated that protease-activated receptors (PARs) with four subtypes (PAR1-4) are mainly expressed in the renal epithelial, endothelial, and podocyte cells. Some endogenous and urinary proteases, namely thrombin, trypsin, urokinase, and kallikrein released during diseased conditions, are responsible for activating different subtypes of PARs. Each PAR receptor subtype is involved in kidney disease of distinct aetiology. PAR1 and PAR2 have shown differential therapeutic outcomes in rodent models of type-1 and type-2 diabetic kidney diseases due to the distinct etiological basis of each disease type, however such findings need to be confirmed in other diabetic renal injury models. PAR1 and PAR2 blockers have been observed to abolish drug-induced nephrotoxicity in rodents by suppressing tubular inflammation and fibrosis and preventing mitochondrial dysfunction. Notably, PAR2 inhibition improved autophagy and prevented fibrosis, inflammation, and remodeling in the urethral obstruction model. Only the PAR1/4 subtypes have emerged as a therapeutic target for treating experimentally induced nephrotic syndrome, where their respective antibodies attenuated the podocyte apoptosis induced upon thrombin activation. Strikingly PAR2 and PAR4 subtypes involvement has been tested in sepsis-induced acute kidney injury (AKI) and renal ischemia-reperfusion injury models. Thus, more studies are required to delineate the role of other subtypes in the sepsis-AKI model. Evidence suggests that PARs regulate oxidative, inflammatory stress, immune cell activation, fibrosis, autophagic flux, and apoptosis during kidney diseases.

COVID-19 HEART unveiling as atrial fibrillation: pathophysiology, management and future directions for research.

BACKGROUND: COVID-19 infections are known to cause numerous systemic complications including cardiovascular disorders. In this regard, clinicians recently noticed that patients recovering from COVID-19 infections presented with diverse set of cardiovascular disorders in addition to those admitted to ICU (intensive care unit). COVID-19 heart has multifaceted presentation ranging from dysrhythmias, myocarditis, stroke, coronary artery disease, thromboembolism to heart failure. Atrial fibrillation is the most common cardiac arrhythmia among COVID-19 patients. In the background section, we briefly discussed epidemiology and spectrum of cardiac arrhythmias in COVID-19 patients. MAIN BODY: In this state-of-the-art review we present here, we present the information regarding COVID-19-induced A-fib in sections, namely mechanism of action, clinical presentation, diagnosis and treatment. Unfortunately, its occurrence significantly increases the mortality and morbidity with a potential risk of complications such as cardiac arrest and sudden death. We included separate sections on complications including thromboembolism and ventricular arrhythmias. Since its mechanism is currently a gray area, we included a separate section on basic science research studies that are warranted in the future to comprehend its underlying pathogenic mechanisms. CONCLUSIONS: Taken together, this review builds upon the current literature of COVID-19-induced A-fib, including pathophysiology, clinical presentation, treatment and complications. Furthermore, it provides recommendations for future research moving forward that can open avenues for developing novel remedies that can prevent as well as hasten clinical recovery of atrial fibrillation in COVID-19 patients.

Metabolic effects of the left atrial appendage exclusion (the heart hormone study).

INTRODUCTION: The effect of epicardial left atrial appendage (LAA) occlusion therapy on lipid and glucose metabolism in atrial fibrillation (AF) patients over the long-term follow-up are unclear. METHODS: In a single-center prospective observational study, 60 patients with longstanding persistent AF with cardiovascular risk factors had undergone an epicardial exclusion procedure. Anthropometric parameters and glucose, glycated hemoglobin (HbA1c), insulin, leptin, adiponectin, free fatty acids, beta-hydroxybutyrate, and total cholesterol levels were evaluated on fasting at baseline before the procedure and compared with levels at 24 h, 7 days, 1, 3, 6, and 24 months follow the procedure. RESULTS: The mean age of the patients was 67.5 ± 8.1. Insulin levels significantly increased at 7 days, 1, 3, 6, 12, and 24 months follow-up. The leptin levels showed a significant increase in 6, 12, and 24 months when compared to baseline. Whereas the adiponectin levels showed a significant decrease at 3, 6, 12, and 24 months when compared to baseline levels. In patients with the epicardial procedure, when compared to baseline, glucose, glycated hemoglobin, total cholesterol, and beta-hydroxybutyrate levels did not show any significant changes at baseline and 24 months follow-up. CONCLUSION: The epicardial exclusion ligation in AF patients was associated with significant changes in insulin, leptin, and adiponectin over long follow-up.

Long Term Impact of Epicardial Left Atrial Appendage Ligation on Systemic Hemostasis: LAA HOMEOSTASIS-2.

BACKGROUND: Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. OBJECTIVE: To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. METHODS: In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. RESULTS: In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. CONCLUSIONS: Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction.

Diagnostic Utility of Smartwatch Technology for Atrial Fibrillation Detection - A Systematic Analysis.

BACKGROUND: Smartphone technologies have been recently developed to assess heart rate and rhythm, but their role in accurately detecting atrial fibrillation (AF) remains unknown. OBJECTIVE: We sought to perform a meta-analysis using prospective studies comparing Smartwatch technology with current monitoring standards for AF detection (ECG, Holter, Patch Monitor, ILR). METHODS: We performed a comprehensive literature search for prospective studies comparing Smartwatch technology simultaneously with current monitoring standards (ECG, Holter, and Patch monitor) for AF detection since inception to November 25th, 2019. The outcome studied was the accuracy of AF detection. Accuracy was determined with concomitant usage of ECG monitoring, Holter monitoring, loop recorder, or patch monitoring. RESULTS: A total of 9 observational studies were included comparing smartwatch technology, 3 using single-lead ECG monitoring, and six studies using photoplethysmography with routine AF monitoring strategies. A total of 1559 patients were enrolled (mean age 63.5 years, 39.5% had an AF history). The mean monitoring time was 75.6 days. Smartwatch was non-inferior to composite ECG monitoring strategies (OR 1.06, 95% CI 0.93 - 1.21, p=0.37), composite 12 lead ECG/Holter monitoring (OR 0.90, 95% CI 0.62 - 1.30, p=0.57) and patch monitoring (OR 1.28, 95% CI 0.84 - 1.94, p=0.24) for AF detection. The sensitivity and specificity for AF detection using a smartwatch was 95% and 94%, respectively. CONCLUSIONS: Smartwatch based single-lead ECG and photoplethysmography appear to be reasonable alternatives for AF monitoring.

Localization of Right Ventricular Outflow Tract Premature Ventricular Complexes Using a Novel Mapping System.

Premature ventricular complexes (PVCs) are common in the general population, usuallyasymptomatic, and deemed to be benign in structurally normal hearts. The spectrum of "benign" outflow tract PVCs ranges from single PVCs to recurrent non-sustained ventricular tachycardia (NSVT). Short-coupled right ventricular outflow tract (RVOT) PVCs may trigger polymorphic ventricular tachycardia (VT) in some patients and can be high risk. In many patients, PVCs can be morefrequent and cause symptoms ofpalpitations, shortness of breath, dizziness, and heart failure.In the presence of underlying heart disease, they may indicate an increasedrisk of adverse cardiovascular outcomes. A high PVC burdenmay lead to ventricular dysfunction and worsen underlying cardiomyopathy.PVCs may also be a marker of underlying pathophysiologic processes such as myocarditisand other acquired and inherited infiltrative cardiomyopathies. In this unique case report, we describe the use of a novel non-contact mapping array for mapping RVOT PVCs.

Current practice and future prospects in left atrial appendage occlusion.

The thromboembolic complications of Atrial fibrillation (AF) remain a major problem in contemporary clinical practice. Despite advances and developments in anticoagulation strategies, therapy is complicated by the high risk of bleeding complications and need for meticulous medication compliance. Over the past few decades, the left atrial appendage has emerged as a promising therapeutic target to prevent thromboembolic events while mitigating bleeding complications and compliance issues. Emerging data indicates that it is a safe, effective and feasible alternative to systemic anticoagulation in patients with non-valvular AF. A number of devices have been developed for endocardial or epicardial based isolation of the left atrial appendage. Increasing experience has improved overall procedural safety and ease while simultaneously reducing device related complication rates. Furthermore, increasing recognition of the non-mechanical advantages of this procedure has led to further interest in its utility for further indications beyond the prevention of thromboembolic complications. In this review, we present a comprehensive overview of the evolution of left atrial appendage occlusion, commercially available devices and the role of this modality in the current management of AF. We also provide a brief outline of the landmark trials supporting this approach as well as the ongoing research and future prospects of left atrial appendage occlusion.

Impact of Yoga on Cardiac Autonomic Function and Arrhythmias.

With the expanding integration of complementary and alternative medicine (CAM) practices in conjunction with modern medicine, yoga has quickly risen to being one of the most common CAM practices across the world. Despite widespread use of yoga, limited studies are available, particularly in the setting of dysrhythmia. Preliminary studies demonstrate promising results from integration of yoga as an adjunct to medical therapy for management of dysrhythmias. In this review, we discuss the role of autonomic nervous system in cardiac arrhythmia,interaction of yoga with autonomic tone and its subsequent impact on these disease states. The role of yoga in specific disease states, and potential future direction for studies assessing the role of yoga in dysrhythmia.

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cutaneous Conundrums in Cardiac Sarcoidosis: A Series on Skin Disease in Immunosuppression.

Sarcoidosis is a complex systemic condition resulting in formation of non-caseating granulomas. Infiltrative disease in cardiac sarcoidosis can have significant ramifications on mortality and is one of the few indications for systemic immunosuppressive therapy. In the patient on immunosuppressive medication, resultant sequelae such as skin and soft tissue infections are common and must be differentiated from cutaneous forms of sarcoidosis and other skin pathologies. Patients with humoral or cellular immunodeficiencies may have cutaneous lesions secondary to endemic fungi, mycobacterium, viral diseases, parasites, or encapsulated organisms. We report a rare case of cardiac sarcoidosis on immunosuppressive therapy, with a series of cutaneous sequelae due to opportunistic infection.

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants.

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

Role of Ox-LDL and LOX-1 in Atherogenesis.

Oxidized LDL (ox-LDL) plays a central role in atherosclerosis by acting on multiple cells such as endothelial cells, macrophages, platelets, fibroblasts and smooth muscle cells through LOX-1. LOX-1 is a 50 kDa transmembrane glycoprotein that serves as receptor for ox-LDL, modified lipoproteins, activated platelets and advance glycation end-products. Ox- LDL through LOX-1, in endothelial cells, causes increase in leukocyte adhesion molecules, activates pathways of apoptosis, increases reactive oxygen species and cause endothelial dysfunction. In vascular smooth muscle cells and fibroblasts, they stimulate proliferation, migration and collagen synthesis. LOX-1 expressed on macrophages inhibit macrophage migration and stimulate foam cell formation. They also stimulate generation of metalloproteinases and contribute to plaque instability and thrombosis. Drugs that modulate LOX-1 are desirable targets against atherosclerosis. Many naturally occurring compounds have been shown to modulate LOX-1 expression and atherosclerosis. Currently, novel drug design techniques are used to identify molecules that can bind to LOX-1 and inhibit its activation by ox-LDL. In addition, techniques using RNA interference and monoclonal antibody against LOX-1 are currently being investigated for clinical use.

Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs.

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article.

Next generation MicroRNA sequencing to identify coronary artery disease patients at risk of recurrent myocardial infarction.

BACKGROUND AND AIMS: Variation in micro-RNA (miRNA) levels in blood has been associated with alterations of physiological functions of the cardiovascular system. Circulating miRNA have the potential to become reliable biomarkers for risk stratification and early detection of cardiovascular events. Recurrent thrombotic events in patients with established coronary artery disease (CAD) demonstrate the need for personalized approaches to secondary prevention, especially in light of recent novel treatment approaches. METHODS: In a single center cohort study, whole blood samples were collected from 437 subjects undergoing cardiac catheterization, who were followed for recurrent cardiovascular events during a mean follow up of 1.5 years. We selected a case cohort (n = 22) with recurrent thrombotic events on standard medical therapy (stent thrombosis (n = 6) or spontaneous myocardial infarction (MI) (n = 16)) and a matched cohort with CAD, but uneventful clinical follow up (n = 26), as well as a control group with cardiovascular risk factors, but without angiographic CAD (n = 24). We performed complete miRNA next generation sequencing of RNA extracted from whole blood samples (including leukocytes and platelets). RESULTS: A differential pattern of miRNA expression was found among controls, CAD patients with no events, and CAD patients with recurrent events. MiRNA previously associated with MI, CAD, endothelial function, vascular smooth muscle cells, platelets, angiogenesis, heart failure, cardiac hypertrophy, arrhythmia, and stroke were found variably expressed in our case-control cohorts. Seventy miRNA (FDR <0.05) were linked to the risk of recurrent myocardial infarction and future stent thrombosis, as compared to CAD patients with subsequently uneventful follow up. CONCLUSIONS: MiRNA next generation sequencing demonstrates altered fingerprint profile of whole blood miRNA expression among subjects with subsequent recurrent thrombotic events on standard medical therapy ('non-responders'), as compared to subjects with no recurrent cardiovascular events. MiRNA profiling may be useful to identify high risk subjects and provide additional insights into disease mechanisms not currently attenuated with standard medical therapy used in CAD treatment.

Pharmacogenomic studies of hypertension: paving the way for personalized antihypertensive treatment.

INTRODUCTION: Increasing clinical evidence supports the implementation of genotyping for anti-hypertensive drug dosing and selection. Despite robust evidence gleaned from clinical trials, the translation of genotype guided therapy into clinical practice faces significant challenges. Challenges to implementation include the small effect size of individual variants and the polygenetic nature of antihypertensive drug response, a lack of expert consensus on dosing guidelines even without genetic information, and proper definition of major antihypertensive drug toxicities. Balancing clinical benefit with cost, while overcoming these challenges, remains crucial. AREAS COVERED: This review presents the most impactful clinical trials and cohorts which continue to inform and guide future investigation. Variants were selected from among those identified in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR), the Genetic Epidemiology of Responses to Antihypertensives study (GERA), the Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, the SOPHIA study, the Milan Hypertension Pharmacogenomics of hydro-chlorothiazide (MIHYPHCTZ), the Campania Salute Network, the International Verapamil SR Trandolapril Study (INVEST), the Nordic Diltiazem (NORDIL) Study, GenHAT, and others. EXPERT COMMENTARY: The polygenic nature of antihypertensive drug response is a major barrier to clinical implementation. Further studies examining clinical effectiveness are required to support broad-based implementation of genotype-based prescribing in medical practice.