Potential Therapeutic Role of Purinergic Receptors in Cardiovascular Disease Mediated by SARS-CoV-2.

Novel coronavirus disease 2019 (COVID-19) causes pulmonary and cardiovascular disorders and has become a worldwide emergency. Myocardial injury can be caused by direct or indirect damage, particularly mediated by a cytokine storm, a disordered immune response that can cause myocarditis, abnormal coagulation, arrhythmia, acute coronary syndrome, and myocardial infarction. The present review focuses on the mechanisms of this viral infection, cardiac biomarkers, consequences, and the possible therapeutic role of purinergic and adenosinergic signalling systems. In particular, we focus on the interaction of the extracellular nucleotide adenosine triphosphate (ATP) with its receptors P2X1, P2X4, P2X7, P2Y1, and P2Y2 and of adenosine (Ado) with A2A and A3 receptors, as well as their roles in host immune responses. We suggest that receptors of purinergic signalling could be ideal candidates for pharmacological targeting to protect against myocardial injury caused by a cytokine storm in COVID-19, in order to reduce systemic inflammatory damage to cells and tissues, preventing the progression of the disease by modulating the immune response and improving patient quality of life.

Cytomegalovirus Infection and Relative Risk of Cardiovascular Disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): A Meta-Analysis of Prospective Studies Up to 2016.

BACKGROUND: Several studies have suggested that cytomegalovirus infection is likely associated with an increased relative risk of cardiovascular disease (CVD); however, the results are inconsistent. We aimed to provide a systematic review and meta-analysis of community-based prospective studies assessing the association between cytomegalovirus infection and relative risk of CVD. METHODS AND RESULTS: We searched Medline and EMBASE to retrieve prospective studies that reported risk estimates of the association between cytomegalovirus infection and relative risk of CVD. The search yielded 10 articles including a total of 34 564 participants and 4789 CVD patients. Overall, exposure to cytomegalovirus infection was associated with a 22% (relative risk: 1.22, 95% CI: 1.07-1.38, P=0.002) increased relative risk of future CVD. We estimated that 13.4% of CVD incidence could be attributable to cytomegalovirus infection. CONCLUSIONS: In conclusion, cytomegalovirus infection is associated with a significantly increased relative risk of CVD.

'If you have a problem with your heart, you have a problem with your life': Self-perception and behaviour in relation to the risk of ischaemic heart disease in people living with HIV.

BACKGROUND: Ischaemic heart disease (IHD) is a global health problem and specifically relevant in the African context, as the presence of risk factors for IHD is increasing. People living with the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (PLWHA) are at increased risk for IHD due to increased longevity, treatment-specific causes and viral effects. AIM: To determine the self-perception and behaviour in relation to risk for IHD in a cohort of South African PLWHA. METHODS: A qualitative study using semi-structured interviews with a card-sort technique was used to gather data from 30 individuals at an HIV clinic in Johannesburg. Descriptive analysis and conventional content analysis were done to generate the findings. RESULTS: The median age of the cohort was 36.5 (31.8-45.0) years and they were mostly women (n = 25; 83.3%) who were employed (n = 17; 56.7%) and supporting dependents (n = 26; 86.7%). Fifteen (50%) participants did not perceive themselves at risk of IHD and reported having adequate coping behaviour, living a healthy lifestyle and being healthy since initiating therapy. Twelve (40%) did feel at risk because they experienced physical symptoms and had poor behaviour. Knowledge and understanding related to IHD, insight into own risk for IHD and health character in a context of HIV infection were three themes. CONCLUSION: This study highlights that participants did not perceive themselves to be at risk of IHD due to their HIV status or antiretroviral management. Education strategies are required in PLWHA to inform their personal risk perception for IHD.

Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients.

RATIONALE: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals. OBJECTIVE: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients. METHODS AND RESULTS: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/µL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001). CONCLUSIONS: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.

The importance of CD4 count, viral load and highly active antiretroviral therapy in HIV-associated thrombotic thrombocytopenic purpura (TTP).

A case is reported of HIV-associated thrombotic thrombocytopenic purpura with normal CD4 count but high HIV viral load, developing neurological and cardiac complications up to 36 days after initiation of plasma exchange, but remitting within 18 days of the start of highly active antiretroviral therapy and steroids. In addition to plasma exchange, prompt initiation of highly active antiretroviral therapy in patients with HIV-associated thrombotic thrombocytopenic purpura may be justified despite a normal CD4 count.

No mutation but high mRNA expression of Coxsackie-Adenovirus Receptor was observed in both dilated and ischemic cardiomyopathy.

The most common causes of acute myocarditis and the possible consequence of dilated cardiomyopathy are virus infections. The receptor of the two most common viruses connected to these myocardial diseases was identified as Coxsackie-Adenovirus Receptor. The purpose of this study was to assess Coxsackie-Adenovirus Receptor mRNA expression in the myocardium and search for mutations in the Coxsackie-Adenovirus Receptor gene to compare dilated, inflammatory and ischemic cardiomyopathy with control group. All the myocardial samples were obtained from 35 explanted hearts during heart transplantation, than DNA and RNA were isolated from the muscle samples. cDNA was generated from RNA using reverse transcription, and real-time PCR was performed with relative quantification by ß-actin gene as endogenous control. Using DNA extracted from the myocardial samples, we sequenced all the seven exons of the Coxsackie-Adenovirus Receptor gene. Coxsackie-Adenovirus Receptor mRNA expression was higher in both ischemic and dilated cardiomyopathy groups than in inflammatory cardiomyopathy and healthy control groups. Sequencing of CAR gene showed no sign of mutation. Therefore, the sequences result of CAR exons did not show any mutation or polymorphism, that explains a determinant role of CAR in dilated or ischemic CM. Our results suggest that high mRNA expression of Coxsackie-Adenovirus Receptor may support its role in regeneration of the damaged myocardium rather than having any role in viral mediated heart disease.

Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study.

BACKGROUND: There are concerns about highly active antiretroviral therapy (HAART) causing a progressive increase in the risk of ischemic heart disease. We examined this issue in a nationwide cohort study of patients with human immunodeficiency virus (HIV) infection and a population-based control group. METHODS: We determined the rate of first hospitalization for ischemic heart disease in all Danish patients with HIV infection (3953 patients) from 1 January 1995 through 31 December 2004 and compared this rate with that for 373,856 subjects in a population-based control group. Data on first hospitalization for ischemic heart disease and comorbidity were obtained from the Danish National Hospital Registry for all study participants. We used Cox's regression to compute the hospitalization rate ratio as an estimate of relative risk, adjusting for comorbidity. RESULTS: Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81-2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62-2.76), but the relative risk did not further increase in the initial 8 years of HAART. CONCLUSIONS: Compared with the general population, HIV-infected patients receiving HAART have an increased risk of ischemic heart disease, but the relative risk is stable up to 8 years after treatment initiation.

Myocardial ischaemia in a child infected with influenza B.

Cardiac involvement is a rare complication of infection by the influenza B virus. It usually presents with ventricular dysfunction, arrhythmias, or both. We report a 13-year-old boy with clinical, electrocardiographic, and laboratory findings of myocardial ischaemia during an otherwise silent acute infection with influenza B. Coronary endothelial injury constituted a potential underlying mechanism, and microthrombosis was promoted by high levels of lipoprotein(a) in the serum.

Acute coronary syndrome and chronic infection in the Cork coronary care case-control study.

OBJECTIVE: To examine the association between chronic infection and cumulative burden of infection and acute coronary syndrome. DESIGN: The 5C (Cork coronary care case-control) study was a community based case-control study. Patients and controls underwent a standard physical examination and had blood samples taken for serological analysis for Helicobacter pylori (IgG), Chlamydia pneumoniae (IgA, IgM, and IgG), cytomegalovirus (IgG), and herpes simplex virus types 1 and 2 (IgG). SETTING: Patients were recruited from four hospitals in Cork City and Mallow Town. Controls, individually matched on age and sex, were selected by incident density sampling from the same general practices as the referent case. MAIN OUTCOME MEASURES: Age and sex adjusted and fully adjusted odds ratios for acute coronary syndrome by seropositivity and by increasing number of infections. RESULTS: Cases and controls did not differ significantly in seropositivity to C pneumoniae, cytomegalovirus, herpes simplex viruses, and H pylori. In unconditional logistic regression analysis adjusted for age, sex, waist to hip ratio, smoking, physical activity, alcohol consumption, and social class there was no evidence of an increasing risk for acute coronary syndrome with increasing burden of infection. CONCLUSIONS: The findings do not support an association between specific infectious agents and acute coronary syndrome and do not provide evidence of a burden of infection effect.

[Laboratory diagnostics of enterovirus cardiac infections]. / Laboratornaia diagnostika énterovirusnykh infektsii serdtsa.

Diagnostic efficacy of different markers of enterovirus cardiac infection (EVCI) has been evaluated. Testing of clinical samples from patients with myocarditis (n=50), dilatation cardiomyopathy (n=122), ischemic heart disease (n=34) and from healthy donors (n=50) revealed diagnostically significant markers in patients suspected for enterovirus cardiac infection: antienterovirus IgM in the patient's blood serum, the expression of viral proteins by myocardium cells and the presence of genome RNA and replicative intermediate in cardiac cells. The results obtained were used for developing up-to-date scheme of the EVCI diagnosis which included the data from the case history, the preliminary rapid diagnosis and the molecular biological study of the cardiac biopsies.

[Influenza viruses and atherosclerosis: the role of atherosclerotic plaques in prolonging the persistent form of influenza infection]. / Virusy grippa i ateroskleroz: rol' ateroskleroticheskikh bliashek v podderzhanii persistentnoi formy grippoznoi infektsii.

It was established that viral particles, like low-density lipoproteins (LDLP), when subjected to some modification changes, lost their ability to be internalized by tissue somatic cells and acquired tropism to macrophage cells. The data, obtained by us by using the polymerase chain reaction (PCR) method, made it possible to assert that atherosclerotic plaques, isolated from vessels of patients with ischemic heart disease (IHD) who underwent coronary bypass, contained RNA of the A(HINI) and AH3N3) influenza viruses. Whereas, the vessel portions, undamaged by atherosclerosis, did not contain any genetic substances of influenza viruses. It was for the first time that an experimentally supported understanding was expressed on that the atherosclerotic plaques serve as a "reservoir" for influenza viruses. It is also suggested that the mentioned plaques can be the carriers of influenza viruses for a long time, thus, prolonging the persistent form of influenza infection in the human body.

Enteroviruses can persist with or without active viral replication in cardiac tissue of patients with end-stage ischemic or dilated cardiomyopathy.

To investigate enterovirus replication versus persistence in end-stage cardiac diseases, endomyocardial biopsies from explanted hearts of 70 patients with idiopathic dilated cardiomyopathy (IDCM), 64 patients with chronic coronary disease (CCD), and 45 donors of healthy hearts (controls) were examined by reverse transcriptase-polymerase chain reaction for genomic and antigenomic enterovirus RNA and by VP1 antigen immunohistochemistry. Enterovirus genome was detected in 25 of 70 patients with IDCM and in 21 of 64 patients with CCDs (35.7 vs. 32.8%, respectively; P=.12). Of the 46 patients positive for genomic RNA, only 3 exhibited antigenomic RNA and VP1 antigen that demonstrated active viral replication, whereas 43 had latent infection characterized by the absence of antigenomic RNA associated with or not with VP1 antigen expression. No viral component was detected in control subjects. The findings demonstrate that a small percentage of patients with end-stage chronic cardiac diseases had active enterovirus replication in their myocardium.

The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis.

BACKGROUND: The biological properties of some herpesviruses such as the ability of latent persistency in the host cells and the presence of viral DNA in atherosclerotic lesions, suggest the possible role of herpesviruses in the development of atherosclerosis. Although many authors proved the presence of viral DNA in arterial wall tissue, the role of herpesviruses in the origin and progress of atherogenesis still remains unclear. OBJECTIVES: The aim of this study was to confirm the presence of viral DNA in arterial wall and to associate the presence of these viruses with the development of atherosclerosis in patients with ischemic heart disease (IHD). STUDY DESIGN: A possible role of HCMV, EBV and HHV6 in the development of atherosclerosis was tested in 244 IHD patients and 87 coronarographically negative controls. The presence of viral DNA in aortic and venous walls, as well as in a peripheral blood samples was tested by the use of polymerase chain reaction (PCR) accompanied by, immunological tests for anti-virus antibodies IgM and IgG types for all experimental groups. RESULTS: The genomic DNA of HCMV was found in 76 and 59%, DNA of EBV in 59 and 50%, and DNA of HHV6 in 0.08 and 0.0%, of arterial walls of IHD patients and non-ischemic control group, respectively. No viral DNA was found in venous samples. Significant association (P < 0.01) has been proved between CMV infection and IHD. CONCLUSIONS: Our results suggest that HCMV and EBV can be found in the arterial wall, so that the arterial wall could be a potential site of persistency of those viruses. We also proved a significant association between the presence of HCMV DNA in aortic walls and atherosclerosis. Despite of the high genetic and biological similarity between CMV and HHV6 no substantial role of HHV6 in atherosclerosis has been proved.

Cytomegalovirus seropositivity and incident ischaemic heart disease in the Caerphilly prospective heart disease study.

OBJECTIVE: To assess the role of cytomegalovirus (CMV) infection in primary ischaemic heart disease. METHODS: Plasma specimens collected during 1979-83 from men in Caerphilly, south Wales, were analysed for IgG antibodies to CMV by enzyme linked immunosorbent assay and latex tests. Incident ischaemic heart disease events were ascertained after five and 10 years from death certificates, hospital records, and ECG changes; 195 incident ischaemic heart disease cases were compared with 216 controls of a similar age drawn from the rest of the cohort. RESULTS: 164 cases (84%) and 180 controls (83%) were seropositive for CMV. Optical density, an indicator of CMV antibody titre, was similar for cases and controls. Among controls, seropositivity was not associated with age, socioeconomic status currently or in childhood, smoking, height, body mass index, blood pressure, total cholesterol, fibrinogen, plasma viscosity, or leucocyte count. The unadjusted odds ratio relating CMV seropositivity to incident ischaemic heart disease was 1.06 (95% confidence interval 0.63 to 1.79) and was little changed (1.11, 0.63 to 1.97) after adjustment for age, smoking, body mass index, systolic blood pressure, total cholesterol, and socioeconomic status currently and in childhood. CONCLUSIONS: CMV infection is unlikely to be a strong risk factor for development of myocardial infarction in middle aged men.

Detection of enterovirus-specific RNA sequences in explanted myocardium biopsy specimens from patients with dilated or ischemic cardiomyopathy.

Enteroviral RNA (EV-RNA) was detected in endomyocardial tissue by means of retrotranscription and polymerase chain reaction (RT-PCR) followed by slot-blot hybridization. The myocardial biopsy specimens studied were taken at the time of heart transplantation from 15 patients with dilated cardiomyopathy (DCM) and from 10 patients with ischemic cardiomyopathy (ICM). Specimens from 18 (72%) of the 25 patients were positive for EV-RNA, whereas no control specimens (myocardial specimens from 29 healthy organ donors and atrial specimens from 15 patients with acute myocardial infarction treated by anatomic bypass) yielded evidence of EV-RNA. The rates of EV-RNA detection for the two groups requiring heart transplantation did not differ significantly (66.7% vs. 80.0%; chi 2 test). Our findings support a link between enteroviral infection in both DCM and ICM and suggest a pathogenic role for the enteroviruses.