Nuclear Factor-κB is a Prime Candidate for the Diagnosis and Control of Inflammatory Cardiovascular Disease.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is responsible for the regulation of genes involved in inflammation and immune responses. NF-κB may play an important role in cardiovascular diseases (CVDs), atherosclerosis and diabetes. Several therapeutic agents used for the treatment of CVDs and diabetes, such as pimobendan and sodium-glucose cotransporter 2 inhibitors, exert anti-inflammatory effects by inhibiting NF-κB activation; anti-inflammatory therapy may have beneficial effects in CVDs and diabetes. Several pharmacological agents and natural compounds may inhibit NF-κB, and these agents alone or in combination may be used to treat various inflammatory diseases. Immunoglobulin-free light chains could be surrogate biomarkers of NF-κB activation and may be useful for evaluating the efficacy of these agents. This review discusses recent advances in our understanding of how the NF-κB signalling pathway controls inflammation, metabolism and immunity, and how improved knowledge of these pathways may lead to better diagnostics and therapeutics for various human diseases.

Myocarditis and autoimmunity.

INTRODUCTION: Autoimmune myocarditis may develop due to heterogeneous causes. Myocarditis is often caused by viral infections, but it can also be caused by systemic autoimmune diseases. Immune checkpoint inhibitors and virus vaccines induce immune activation, and they can cause the development of myocarditis, as well as several immune-related adverse events. The development of myocarditis is dependent on the genetic factors of the host, and the major histocompatibility complex (MHC) may be an important determinant of the type and severity of the disease. However, non-MHC immunoregulatory genes may also play a role in determining susceptibility. AREA COVERED: This review summarizes the current knowledge of the etiology, pathogenesis, diagnosis, and treatment of autoimmune myocarditis with a particular focus on viral infection, autoimmunity, and biomarkers of myocarditis. EXPERT OPINION: An endomyocardial biopsy may not be the gold standard for the diagnosis of myocarditis. Cardiac magnetic resonance imaging is useful in diagnosing autoimmune myocarditis. Recently identified biomarkers of inflammation and myocyte injury are promising for the diagnosis of myocarditis when measured simultaneously. Future treatments should focus on the appropriate diagnosis of the etiologic agent, as well as on the specific stage of the evolution of immune and inflammatory processes.

Targeting Inflammation in the Diagnosis, Management, and Prevention of Cardiovascular Diseases.

Inflammation plays an important role in the development and progression of cardiovascular diseases (CVDs). Hypertension and hyperlipidemia are the key risk factors of CVDs and induce inflammation in the heart and vessels. Unhealthy diet, infection, and smoking coupled with genetic factors lead to the development of CVDs as well as induce inflammation. Risk factors of CVDs such as hypertension and hyperlipidemia along with diabetes activate nuclear factor kappa B, which regulates the transcription of immunoglobulin free light chain (FLC) κ in B cells and the production of multiple inflammatory molecules, leading to inflammation. FLCs are novel biomarkers of inflammation, and their levels have been associated with overall mortality in a general population and with cardiovascular outcomes. In this review, the role of inflammation in the pathogenesis of CVDs, new biomarkers of inflammation, and dietary options counterbalancing inflammatory processes, such as the polyphenol-rich French maritime pine bark extract Pycnogenol, are discussed.

Cardiovascular Factors Associated with COVID-19 from an International Registry of Primarily Japanese Patients.

Aims: We developed an international registry to examine cardiovascular complications of COVID-19. Methods: A REDCap form was created in March 2020 at Mayo Clinic in collaboration with the International Society of Cardiomyopathy, Myocarditis and Heart Failure (ISCMF) and data were entered from April 2020 through April 2021. Results: Of the 696 patients in the COVID-19 Registry, 411 (59.2%) were male and 283 (40.8%) were female, with a sex ratio of 1.5:1 male to female. In total, 95.5% of the patients were from Japan. The average age was 52 years with 31.5% being >65 years of age. COVID-19 patients with a history of cardiovascular disease (CVD) had more pre-existing conditions including type II diabetes (p < 0.0001), cancer (p = 0.0003), obesity (p = 0.001), and kidney disease (p = 0.001). They also had a greater mortality of 10.1% compared to 1.7% in those without a history of CVD (p < 0.0001). The most common cardiovascular conditions in patients with a history of CVD were hypertension (33.7%), stroke (5.7%) and arrhythmias (5.1%). We found that troponin T, troponin I, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), C-reactive protein (CRP), IL-6 and lambda immunoglobulin free light chains (Ig FLC) were elevated above reference levels in patients with COVID-19. Myocarditis is known to occur mainly in adults under the age of 50, and when we examined biomarkers in patients that were ≤50 years of age and had no history of CVD we found that a majority of patients had elevated levels of troponin T (71.4%), IL-6 (59.5%), creatine kinase/CK-MB (57.1%), D-dimer (57.8%), kappa Ig FLC (75.0%), and lambda Ig FLC (71.4%) suggesting myocardial injury and possible myocarditis. Conclusions: We report the first findings to our knowledge of cardiovascular complications from COVID-19 in the first year of the pandemic in a predominantly Japanese population. Mortality was increased by a history of CVD and pre-existing conditions including type II diabetes, cancer, obesity, and kidney disease. Our findings indicate that even in cases where no abnormalities are found in ECG or ultrasound cardiography that myocardial damage may occur, and cardiovascular and inflammatory biomarkers may be useful for the diagnosis.

Novel Biomarkers of Inflammation for the Management of Diabetes: Immunoglobulin-Free Light Chains.

Virus infection, inflammation and genetic factors are important factors in the pathogenesis of diabetes mellitus. The nuclear factor-kappa B (NF-κB) is a family of transcription factors that bind the enhancer of the κ light chain gene of B cell immunoglobulin. NF-κB plays an essential role in the activation and development of B cells, and the activation of NF-κB is critical in the inflammation and development of diabetes mellitus. Recently, immunoglobulin-free light chain (FLC) λ was found to be increased in the sera of patients with diabetes mellitus, and the FLC λ and κ/λ ratios are more specific and sensitive markers for the diagnosis of diabetes relative to glycated hemoglobin A1c. Thus, FLCs may be promising biomarkers of inflammation that could relate to the activation of NF-κB. We suggest that NF-κB could be a target for an anti-inflammatory strategy in preventing and treating diabetes when FLCs are modified. FLCs could be a surrogate endpoint in the management of diabetes. In this review, the role of inflammation in the pathogenesis of diabetes, as well as the novel inflammatory biomarkers of FLCs for the management of diabetes, are discussed.

Management of Atrial Fibrillation Using Immunoglobulin Free Light Chains, Novel Biomarkers of Inflammation.

AF is the most common cardiac arrhythmia. There is growing evidence that inflammatory mechanisms play an important role in its pathogenesis; inflammasome activation contributes to the onset and progression of AF. An increase in NOD-like-receptor-pyrin domain-containing-3 (NLRP3) inflammasome activation releases proinflammatory cytokines that activate nuclear factor (NF)-κB, which regulates the production of immunoglobulin free light chains (FLCs). Serum FLC levels are increased in patients with AF, and FLCs are biomarkers of inflammation. Inflammasomes and NF-κB may be targets for anti-inflammatory strategies to prevent and treat AF when FLC levels are elevated. This review discusses the role of inflammation in the pathogenesis of AF, as well as FLCs as novel inflammatory biomarkers for the management of AF.

Diagnosis and treatment of HCV heart diseases.

INTRODUCTION: Hepatitis C virus (HCV) infection is an important cause of a variety of otherwise unexplained heart diseases and myocardial injury. A high prevalence of HCV infection has been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy and myocarditis. Various arrhythmias, conduction disturbances and QT prolongation were also associated with HCV infection. A possible role of HCV infection in the pathogenesis of diabetes and atherosclerosis, and the role of immunogenetics of HCV cardiomyopathies is discussed. Recent studies suggest that mononuclear cells may be the major target of HCV, and clinical applications to test this new hypothesis are discussed. AREAS COVERED: In this review, we will evaluate the evidence that HCV causes various cardiovascular diseases, and discuss on the pathogenesis of these disorders. EXPERT OPINION: HCV is the cause of many different forms of heart disease worldwide, but their existence has not been recognized by most of cardiologists. The recognition and diagnosis are indispensable for the early treatment of these diseases. The diverse clinical manifestation of HCV infection and the presence of multiple extrahepatic disease syndromes could be explained by a new hypothesis that the target of HCV is leukocytes.

Myocardial involvement in coronavirus disease 19.

BACKGROUND: In late 2019, a cohort of patients presenting with pneumonia of unclear etiology in Wuhan, China, heralded the outbreak of coronavirus disease 19 (COVID-19). Previous severe acute respiratory syndrome (SARS) beta-coronavirus infections have been associated with tachyarrhythmias and signs and symptoms of heart failure. The emergence of SARS coronavirus 2 (SARS-CoV-2), which causes COVID-19, has rapidly developed into a pandemic, and a large number of infected patients have been reported to have underlying cardiovascular disease. OBJECTIVE: Since there are only scant published data regarding cardiovascular burden in the wake of viral epidemics, this study aimed to evaluate cardiac involvement in COVID-19. MATERIAL AND METHODS: This prospective cohort study included 40 adult inpatients at two centers in Germany. Adult patients diagnosed with COVID-19 in accordance with World Health Organization (WHO) interim guidance were included in the study, which focused on the potential cardiac involvement of SARS-CoV­2. It was based on laboratory parameters as well as electro- and echocardiographic values to determine the impact of SARS-CoV­2 virus on heart tissues. RESULTS: The conducted investigations confirmed the relationship between the presence of acute cardiac injury and COVID-19. CONCLUSION: Myocardial injury and impaired myocardial function due to COVID-19 are common; however, no correlation was established between cardiac laboratory or echocardiographic values and mortality. Cardiovascular monitoring upon COVID-19 infection is crucial to determine the burden of cardiac involvement.

Dilated Cardiomyopathy Risk in Patients with Coronavirus Disease 2019: How to Identify and Characterise it Early?

Multiple lines of evidence have shown that elevated blood troponin is strongly associated with poor prognosis in patients with the novel coronavirus disease 2019 (COVID-19). Possible mechanisms of myocardial injury in COVID-19 include ischaemia due to circulatory and respiratory failure, epicardial or intramyocardial small coronary artery thrombotic obstruction due to increased coagulability, and myocarditis caused by systemic inflammation or direct binding of the virus to its receptor, angiotensin-converting enzyme-2 (ACE2), which is abundantly expressed in the heart. It is postulated that persistent immune activation upon viral infection increases the risk of developing dilated cardiomyopathy in COVID-19 patients.

Correction to: Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

In the original publication of this paper contains some typographical errors in Table 1.

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.

BACKGROUND: In this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis. METHODS: FLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay. RESULTS: The median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: This study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.

Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

OBJECTIVE: Inflammation is increasingly understood as playing an important role in type 2 diabetes mellitus (T2D) development. A critical mechanism of the inflammatory cascade in developing T2D is nuclear factor-kappa B (NF-kB) activation. As immunoglobulin free light chains (FLC) could be a biomarker of activation of NF-kB, we measured FLC in patients with T2D. SUBJECTS: The age range of the 77 patients with T2D and the 75 healthy control participants were 45-87 years (median 60) and 25-72 years (median 51), respectively. METHODS: Serum FLC kappa and lambda were assayed by a competitive-inhibition multiplex Luminex assay. RESULTS: The concentration of circulating FLC the kappa/lambda ratio was lower in patients with T2D than in healthy volunteers. The area under the receiver operating curve (ROC-AUC) of the FLC kappa/lambda ratio showed the largest ROC-AUC compared with other FLC variables and hemoglobin A1c (HbA1c). The diagnostic performance for distinguishing between T2D and healthy control was a sensitivity of 0.96 and a specificity of 1. The odds ratio was 0.000018. CONCLUSIONS: These results suggest that FLC kappa/lambda may be more specific and sensitive for the diagnosis of T2D than HbA1c, and thus represents a potentially promising biomarker of inflammation.

Dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.

Inhibitory effects of Pycnogenol® on hepatitis C virus replication.

Chronic hepatitis C virus (HCV) infection increases the risk of liver cirrhosis and hepatocellular carcinoma. In the last decade, the current standard HCV treatment, pegylated interferon and ribavirin, have limited efficacy and significant side effects. Novel direct acting antivirals show promise, but escape mutants are expected, along with potential side effects. Pycnogenol®, a French maritime pine extract, has been reported to have antioxidant and antiviral effects. Here, we evaluated the effect of Pycnogenol® on HCV replication. Wild-type and protease inhibitor (VX-950; telaprevir)-resistant HCV replicon cells were treated with Pycnogenol®, Pycnogenol® and interferon-alpha, and ribavirin and telaprevir. Pycnogenol® effects on replication were also evaluated in HCV-infected chimeric mice. Pycnogenol® treatment showed antiviral effects without cytotoxicity at doses up to 50 µg/mL. Pycnogenol® in combination with interferon-alpha or ribavirin showed synergistic effects. Moreover, Pycnogenol® inhibited HCV replication in telaprevir-resistant replicon cells; telaprevir and Pycnogenol® acted additively to reduce HCV RNA levels in wild-type HCV replicon cells without significantly increasing cytotoxicity. Pycnogenol® antiviral activity was higher than its components procyanidin and taxifolin. Further, treatment of infected chimeric mice with Pycnogenol® suppressed HCV replication and showed a synergistic effect with interferon-alpha. In addition, Pycnogenol® treatment resulted in dose-dependent reduction of reactive oxygen species in HCV replicon cell lines. Pycnogenol® is a natural product that may be used to improve the efficacy of the current standard antiviral agents and even to eliminate resistant HCV mutants.

The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study.

Myocarditis contributes to the global burden of cardiovascular disease primarily through sudden death and dilated cardiomyopathy. A systematic approach to identify the cardiovascular mortality and major morbidity attributable to myocarditis has not been performed. A writing group convened by the GBD 2010 (Global Burden of Diseases, Injuries and Risk Factors) Study systematically reviewed the world's literature by a manual review of all titles since 1966 on myocarditis identified using Ovid Medline, development of a disease model, and provision of estimates when possible of the incidence, prevalence, risk of death, and major morbidity for the world regions. Accurate population-based estimates of myocarditis incidence and prevalence are not directly available in any world region. However, a model that quantitates the risk of acute death and chronic heart failure following myocarditis was derived from the published data. Using hospital dismissal data, the burden of myocarditis as a percentage of prevalent heart failure varied by age and region from approximately 0.5% to 4.0%. The novel combination of multiple data sources may provide an estimate of the years of life lost and years of life disabled from myocarditis. Pending the integration of these data sources, the burden of dilated cardiomyopathy and myocarditis were reported together in the 2010 GBD report. The 2013 GBD project may refine these estimates with the inclusion of more comprehensive payor databases and more precise case definitions.

Dilated cardiomyopathy update: infectious-immune theory revisited.

Dilated cardiomyopathy is characterized by dilatation of the left or right ventricle, or both ventricles. The degree of myocardial dysfunction is not attributable to abnormal loading conditions. The infectious-immune theory has long been hypothesized to explain the pathogenesis of many etiologically unrecognized dilated cardiomyopathies. Inflammations followed by immune reactions, which may be excessive, in the myocardium, evoked by external triggers such as viral infections and/or autoimmune antibodies, continue insidiously, and lead to the process of cardiac remodeling with ventricular dilatation and systolic dysfunction. This ultimately results in dilated cardiomyopathy. Hepatitis C virus-associated heart diseases are good examples of cardiac lesions definitely induced by viral infections in humans that progress to a chronic stage through complicated immune mechanisms. Therapeutic strategies for myocarditis and dilated cardiomyopathy have been obtained through analyses of the acute, subacute, and chronic phases of experimental viral myocarditis in mice. The appropriate modulation of excessive immune reactions during myocarditis, rather than their complete elimination, appears to be a key option in the prevention and treatment of dilated cardiomyopathy. The clinical application of an NF-κB decoy and immune adsorption of IgG3 cardiac autoantibodies have been used as immunomodulating therapies and may provide novel approaches for the treatment of refractory patients with dilated cardiomyopathy. Conventional therapeutic agents for chronic heart failure such as ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in particular should be re-evaluated on the basis of their anti-inflammatory properties in the treatment of dilated cardiomyopathy.

Calcium channel blockers and modulation of innate immunity.

PURPOSE OF REVIEW: Researchers and physicians are gaining more understanding of the utility of calcium channel blockers (CCBs) especially in modulation of innate immunity, and choose suitable ones in clinical practice. This review summarizes the recent related research findings. RECENT FINDINGS: Sustained and/or dysregulated expression of pro-inflammatory cytokines is sufficient to produce tissue injury and provoke overt cardiac decompensation. The important question that remains to be addressed is whether or not it will be possible to modulate the inappropriate or maladaptive consequences of innate immune activation and pro-inflammatory cytokine expression in the mammalian heart. CCBs, such as nifedipine, amlodipine, diltiazem, and verapamil, promote the relaxation of cardiac and smooth muscle cells by inhibiting calcium influx through calcium channels and calcium release from intracellular stores, and are commonly used in the treatment of cardiovascular disorders. Recently, several in-vitro studies have shown that, besides the effects they exert on muscle cells, CCBs also suppress the activation of various participants in immune reactions, including T cells, mast cells and macrophages, suggesting that they can be immunosuppressant. SUMMARY: CCBs maybe suppress the activation of various participants in immune reactions.

The biomarker N-terminal pro-brain natriuretic peptide and liver diseases.

PURPOSE: NT-proBNP has emerged as a powerful diagnostic and prognostic biomarker in heart disease. Studies showed that NT-proBNP is a sensitive biomarker for identifying patients with heart failure caused by hepatitis C virus (HCV) related myocarditis. The purpose of this study was to evaluate the correlation between the serum concentration of NT-proBNP and hepatitis virus infection/liver disease. METHODS: 223 serum samples from blood donors (aged 19~50 years old) were collected as a control group, and 644 samples were obtained from patients infected by hepatitis viruses including 493 HBV: 364 chronic hepatitis (CH), 86 hepatocellular carcinoma (HCC) and 43 liver cirrhosis (LC) and 151 HCV (85 CH, 14 HCC, 52 LC). All samples were assayed with an Elecsys immunoassay analyzer for NT-proBNP concentration. RESULTS: The mean concentration of NT-proBNP in the control group was 21.77 pg/ml and showed no significant variation with either age or gender. Both the mean value and the rate of abnormality of NT-proBNP were significantly higher for the HBV- and HCV-infected groups in comparison with the control group. The mean NT-proBNP value (380.24 pg/ml) and abnormality rate (38.41%) in the HCV group were higher than that of the HBV group. For samples from patients with HBV/HCV-related hepatic disease/pathology, the mean NT-proBNP value (517.19 pg/ml/597.18 pg/ml) were the highest in the liver cirrhosis group. CONCLUSIONS: Hepatic pathologic lesions, particularly cirrhosis, may contribute to the elevation of NT-proBNP in subjects with HBV/HCV infection.

Assessment of cardiac involvement of hepatitis C virus; tissue Doppler imaging and NTproBNP study.

INTRODUCTION: Hepatitis C disease burden is substantially increasing in Egyptian community, it is estimated that prevalence of Hepatitis C virus (HCV) in Egyptian community reach 22% of total population. Recently there is a global alert of HCV cardiovascular complications. OBJECTIVE: To evaluate LV diastolic functions of HCV patients using tissue Doppler Imaging and NTPBNP. METHODS: 30 HCV patients of 30 years, sex & BMI matched controls were evaluated by PCR, ECG, Echocardiography "conventional Doppler, pulsed wave tissue Doppler (PW-TD), strain rate imaging" & NTPBNP to assess LV diastolic functions. Mean age was 32.8 years ± 5.1 in HCV group, 29.8 years ± 6.6 in control group. Cardiovascular anomalies and predisposing factors were excluded. RESULTS: HCV group has shown significant increase in QTc interval, significant statistical increase in A wave, deceleration time; (p < 0.05), highly significant decrease in tissue Doppler E a (p < 0.001), highly significant decrease in A a (p < 0.001), highly significant increased E/E a ratio (p value < 0.001), significant decrease in E a/A a ratio and significant increase in SRa (p < 0.05). NTPBNP levels showed highly significant increase with mean value 222 pg/ml ± 283 in HCV group and 32.7 pg/ml ± 21.2 in control group (p value < 0.001). The best cut-off value of NTPBNP to detect diastolic dysfunction in HCV group was 213 pg/ml. No statistical differences in SRe/SRa and E/SRe ratios were observed, however they had significant correlation with NTPBNP level and tissue Doppler parameters. The best cut-off value of E/SRe ratio to detect diastolic dysfunction in HCV group was 0.91, with 75% sensitivity and 100% specificity. CONCLUSION AND RECOMMENDATION: This data show the first direct evidence that HCV infection causes diastolic dysfunction without any other predisposing factors, probably due to chronic inflammatory reaction with mild fibrosis in the heart. Previous studies did not follow strict inclusion and exclusion criteria that confirm the independent role of HCV to cause diastolic dysfunction. Tissue Doppler was more sensitive to diagnose diastolic dysfunction than conventional Doppler.