Pathogenesis Of Myocardial Damage Research Articles

P229 ROLE OF GENDER IN MINOCA PATIENTS

Abstract Background Myocardial Infarction (MI) with Non–Obstructive Coronary Arteries (MINOCA) accounts above 6 % of patients presenting with acute MI (AMI) and it’s known to be more prevalent in females. Differences in terms of clinical features and prognosis in MINOCA patients according to gender have been poorly understood. Purpose: To evaluate clinical and prognostic differences between male and female patients with MINOCA. Methods We included all consecutive patients with AMI undergoing coronary angiography between 2016 and 2020 in our multicentric Registry. We considered as MINOCA all patients fulfilling the European Society of Cardiology diagnostic criteria. We analyzed the baseline clinical characteristics of MINOCA patients by dividing the population according to gender. We performed a multivariate logistic regression analysis including all AMI patients to determine independent predictors of MINOCA at admission. We considered the composite endpoint (MACE) of death, re AMI, stroke and heart failure at follow–up (FU, mean of 36 ± 14.8 months). Outcomes were evaluated also using Kaplan–Meier survival curves. Results Among 289 patients affected by MINOCA, 191 were female (66%). Males were more frequently smokers (56.1% vs 33.9 %, p=0.001) while females were older (68.9± 13.1 vs 58.4±14.5 years, p=0.0001), more affected by hypertension (69.3% vs 55.1%, p=0.017) and dyslipidemia (65.6% vs 49%, p=0.005), more frequently on beta–blockers (39% vs 20%, p=0.002) and statins (33% vs 19%, p=0.015) and had a lower degree of coronary stenosis (9.1% vs 15.5%, p=0.019) than males. During follow–up, females had more MACE (33% vs 19.3%, p=0.015), also shown at Kaplan Meier curves (χ2 = 5.997, p=0.014). Finally, multivariate analysis revealed that age is an independent predictor of MINOCA (HR 1.04, CI 1.01–2.07, p=0.006), rather than sex, diabetes, and hypertension. Conclusions In our MINOCA population, females had a higher incidence of MACE than males: this could reflect the different pathogenesis of myocardial damage in our subgroups. Statins and estrogens have a well–known protective role towards the progression of atherosclerosis, but they have less impact on other causes of MINOCA more frequent in females.

1054 GENDER DIFFERENCES IN MINOCA POPULATION

Abstract Background Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is a clinical condition that includes acute myocardial infarction (AMI) occurring with non-obstructive coronary disease. This entity accounts above 6% (from 1% to 14%) of all patients presenting with AMI and it's known to be more prevalent in females. However, differences in terms of clinical features and prognosis in MINOCA patients according to gender have been poorly understood. Purpose To evaluate differences in clinical characteristics at admission and during follow-up between males and females with MINOCA. Methods We included all consecutive patients with AMI undergoing coronary angiogram between 2016 and 2020 at our center. According to 2016 ESC Position Paper criteria, we considered as MINOCA all patients with AMI and coronary stenosis <50% at coronary angiography without clinically apparent alternative diagnoses such as Takotsubo syndrome and myocarditis. Then, we analyzed the baseline clinical characteristics of MINOCA patients by dividing the population into two groups according to gender. Variables with a statistical significance lower than p<0.05 in univariable analysis were included in a logistic regression analysis to determine independent predictors of MINOCA. The predictive value of both groups was evaluated using Kaplan-Meier survival curves. Our aim was to evaluate composite endpoint of death, re IMA, stroke and heart failure in a follow up time mean of 36 ± 14.8 months. Results Among 289 patients affected by MINOCA according to the 2016 ESC criteria, 98 were male (34%) and 191 were female (66%). Females were older than males (68.9 ± 13.1 vs 58.4 ± 14.5 years, p =0.0001). About the traditional cardiovascular risk factors males were more frequently smokers (56.1% vs 33.9%, p=0.001) while there were no significant differences in others risk factors. Females were more frequently on beta-blockers (39% vs 20%, p=0.002) and statins (33% vs 19%, p=0.015) compared to males. No differences were found between the two groups regarding clinical characteristics and instrumental findings (EKG and echocardiography). At coronary angiography, males had more frequently severe coronary stenosis than females (15.5 ± 26.4 VS 9.1 ± 21.5, p =0.019). During follow up we did not find any differences in terms of death, reinfarction, stroke and heart failure while females had more MACEs than males (33% vs 19.4%, p=0.015); and this data was confirmed at Kaplan Meier curves (p = 0.014). Finally, the multivariate analysis showed that age is an independent predictor of MINOCA (HR 1.04, CI 1.01-2.07, p=0.006), rather than sex, diabetes, and hypertension. Conclusions In our MINOCA population we found that females were older than males, more frequently on statins and beta blockers at admission and they showed a lower degree of atherosclerotic disease. Nevertheless, after 36 ± 14.8 months of follow-up, we found a higher incidence of MACE in females than in males. We hypothesize that these findings could reflect the different pathogenesis of myocardial damage in our subgroups. Actually, statins and estrogens have a well-known protective role towards the progression of atherosclerosis, but they have no impact on other mechanisms of myocardial infarction which are more frequent in females, such as spontaneous coronary artery dissections, epicardial spasms or microvascular dysfunction.

Coronavirus and cardiovascular manifestations- getting to the heart of the matter.

Coronavirus disease has unarguably been the largest pandemic of recent times. Over 150 million cases have occurred worldwide, and more than 3 million have succumbed to the disease. Cardiac manifestations can have varied presentations from an asymptomatic troponin rise to fulminant myocarditis. The pathogenesis of myocardial damage could be direct or indirect, including inflammation, coronary spasm, plaque rupture, and cytokine storm. Thromboembolism is also an important feature of cardiovascular affliction with both arterial and venous systems being affected. Hence, anticoagulation has also been a matter of debate. Fulminant myocarditis is the most severe form and can lead to circulatory shock with a high mortality. Management of cardiac patients with coronavirus disease 2019 (COVID-19) infection is not considerably different from non-COVID-19 cardiovascular disease, but interaction between cardiovascular drugs and anti-COVID-19 therapy requires careful attention. More recently, vaccines have emerged as a ray of hope for the disease. But simultaneously, there have been reports of thromboembolism following vaccination. In this review, we discuss the various aspects of coronavirus disease affecting of heart and its management.

Сlinical and epidemiological profiles and tactics of patient’s management with myocardial infarction with non-obstructive coronary arteries

A comparative analysis of clinical and epidemiological data and results of treatment of 7 patients suffering from myocardial infarction without obstructive coronary artery disease (main group) and 54 patients with their lesions (control group) aged 45,69,3 and 62,714,2 years, respectively. Both groups were dominated by men (85,7% and 72,2%, respectively). In the main group, dyslipidemia and hypertension were less common (14,3 and 28,6%, respectively) than in the control group (61,1 and 72,2%, respectively). At the same time, the former had a more burdened history of early cardiovascular events in close relatives in 28,6% of cases, and the latter-only in 5,6% of cases. Surgical tactics and features of double antiplatelet therapy in myocardial infarction without obstructive coronary artery disease did not differ from the standard approach. In both groups, active surgical tactics prevailed, consisting in performing percutaneous coronary intervention and installing a coronary stent in the infarct-related artery (85,7 and 83,3%, respectively). The choice of dual antiplatelet therapy in the main group did not differ from the control group and was characterized by a significantly higher frequency of clopidogrel administration (71,4 and 72,2%, respectively). When comparing the left ventricular ejection fraction before and after percutaneous coronary intervention, it turned out that in patients of the main group, in contrast to the control group, the value of the left ventricular ejection fraction did not change significantly (52,56,4 and 51,39,5, respectively). The etiology and pathogenesis of myocardial damage in patients suffering from myocardial infarction without obstructive coronary artery disease is characterized by significant heterogeneity, which requires additional examinations and differential diagnostics to identify the underlying causes of this condition.

Role of metabolites of cyclophosphamide in cardiotoxicity

BackgroundThe dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger.MethodsH9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC.ResultsExposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations.ConclusionsIncreased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

Background/Aims: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. Methods: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. Results: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. Conclusion: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway.

The trace elements in congenital cyanotic heart disease

Background The trace elements are essential micronutrients that have important physiological, metabolic, and homeostatic roles in the human being. Up till now the actually role and effect of the trace elements on myocardial metabolism specifically on congenital cyanotic heart disease is not entirely clear. Objective This study aimed to detect the serum level of selected trace elements (zinc, copper and selenium), and evaluate its effect and relation in congenital cyanotic heart disease. Methodology This study had enrolled upon 50 children, included 30 patients with congenital cyanotic heart disease and 20 age matched normal healthy children as control group. All groups were subjected to thorough clinical history, examination and specific cardiac investigation as well as detection of serum levels of zinc, copper and selenium. All results were statistical analyzed. Results The current study revealed that a highly significant decrease in the serum level of both zinc and selenium (p 0.00l and p 0.01), however serum copper level has non significant increase in congenial cyanotic heart disease, were (p > 0.95). There was non significant correlation between the mean serum levels of trace elements and the hemodynamic parameters,. Also there were non significant correlations between the age and sex of the studied group and the mean serum levels of these trace elements (p > 0.05). Conclusion Congenital cyanotic heart disease were associated with a highly significant decrease in the mean serum selenium and zinc levels, when compared with control group and non significant increase the mean serum copper levels. Changes in these trace elements suggested to play an important role in the pathogenesis of myocardial damage in congenital cyanotic heart disease.

Mechanisms of cardioprotection by isoflurane against I/R injury

Myocardial infarction is responsible for most cardiovascular mortality as well as the pathogenesis of myocardial damage during and after infarction. Efforts are underway to modulate the development of ischemia-reperfusion (I-R) injury. Recently, the protective effect of isoflurane against myocardial I-R injury emerged as a possibility.Nitric oxide, nitric oxide synthases, factors related to energy metabolism, adenosine triphosphate-sensitive potassium channels, phosphatidylinositol-3-kinase and hypoxia-inducible factor1-alpha have been shown to participate in the mechanisms of cardioprotection elicited by isoflurane against I-R injury. In this review, we focus on the mechanisms of cardioprotection offered by isoflurane against I-R injury.

The cardioprotective potential of hydrogen sulfide in myocardial ischemia/reperfusion injury (Review)

Myocardial infarction is responsible for the majority of cardiovascular mortality and the pathogenesis of myocardial damage during and after the infarction involves reactive oxygen species. Serious efforts are under way to modulate the developing ischemia/reperfusion injury and recently the use of hydrogen sulfide (H2S) emerged as a new possibility. H2S has been best known for decades as a pungent toxic gas in contaminated environmental atmosphere, but it has now been recognized as a novel gasotransmitter in the central nervous and cardiovascular systems, similarly to nitric oxide (NO) and carbon monoxide (CO). This finding prompted the investigation of the potential of H2S as a cardioprotective agent and various in vitro and in vivo results demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction. Although several questions remain to be elucidated about the properties of this new gasotransmitter, increased H2S levels may have therapeutic potential in clinical settings in which ischemia/reperfusion injury is encountered. This review article overviews the current understanding of the effects of this exciting molecule in the setting of myocardial ischemia/reperfusion.

Glycaemic control in critically ill patients with cardiovascular disease

The role of hyperglycaemia in the pathogenesis of myocardial damage during cardiac surgery or patients with acute coronary syndromes has been the subject of increasing interest over the past few years. Several further trials and meta-analyses investigating the role of insulin treatment, either aimed at tight control of blood glucose concentration or as part of a regimen including glucose and potassium, have been reported recently and are the subject of this review. Good control of blood glucose has been demonstrated to improve outcomes for diabetic patients undergoing cardiac surgery and following acute myocardial infarction. In surgical intensive care patients, tight glucose control improved mortality--a finding that is awaiting confirmation in multicentre studies. The use of glucose-insulin-potassium regimens does not improve outcomes in patients with acute myocardial infarction who have undergone reperfusion therapy, but may be beneficial during cardiac surgery. Tight control of blood glucose has been shown to be beneficial in several patient groups. The optimal target glucose concentration and glucose and insulin regimens remain to be confirmed or determined in each clinical situation.

Moléculas de adhesión endoteliales ICAM-1, VCAM-1 y E-selectina en pacientes con síndrome coronario agudo

The acute inflammatory response is an important phenomenon in the pathogenesis of myocardial damage during acute coronary syndrome. Endothelial dysfunction has been found in unstable angina and acute myocardial infarction, although the results are controversial. The purpose of this study was to determine the levels of the soluble endothelial adhesion molecules ICAM-1, VCAM-1 and E-selectin, in patients with unstable angina and acute myocardial infarction, compare the results in both groups, and analyze their relation with the degree of myocardial injury. Serum concentrations of ICAM-1, VCAM-1, and E-selectin were measured in 37 control subjects and 43 patients (32 with acute myocardial infarction and 11 with unstable angina). Measurements were made at the time of admission and ten days later using commercial enzyme-linked immunoabsorbent assay (ELISA) kits (R&D Systems, UK). There was a significant increase in E-selectin (p < 0.05) in patients with unstable angina at admission and ten days later. In contrast, patients with acute myocardial infarction showed no significant differences in E-selectin compared with the control group at admission or ten days later. A significant increase in VCAM-1 levels was demonstrated in both groups of patients and ICAM-1 levels in acute myocardial infarction, but the concentrations of VCAM-1 and ICAM-1 in both groups of patients at admission and ten days later did not differ significantly. There was no relation between soluble endothelial adhesion molecule levels and the severity of myocardial damage estimated by cardiac enzymes or electrocardiographic changes. This study indicates that serum levels of E-selectin, measured at time of admission and ten days later, could be a marker for unstable angina and might be useful in the differential diagnosis with myocardial infarction.

Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on murine acute myocarditis caused by coxsackievirus B3.

In viral myocarditis, we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the pathogenesis of myocardial damage. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive costimulatory signals provided by costimulatory molecules expressed on antigen-presenting cells as well as main signals provided by binding of T-cell receptors to antigens. To investigate the roles of costimulatory molecules B7-1 and B7-2 in the development of acute viral myocarditis, we first analyzed the expression of B7-1/B7-2 in the hearts of mice with acute viral myocarditis induced by coxsackievirus B3 (CVB3). Second, we evaluated the induction of B7-1/B7-2 in cultured cardiac myocytes treated with interferon gamma (IFN-gamma). Third, we examined the effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies (mAbs) on the development of acute viral myocarditis. We found that CVB3-induced murine acute myocarditis resulted in enhanced expression of B7-1/B7-2 in cardiac myocytes. The expression of B7-1/B7-2 in cardiac myocytes could be induced in vitro by IFN-gamma. We found that in vivo anti-B7-1 mAb treatment markedly decreased myocardial inflammation, whereas anti-B7-2 mAb treatment abrogated the protective effect of anti-B7-1. Our findings indicate that distinct roles for B7-1 and B7-2 antigens are involved in the development of acute viral myocarditis and raise the possibility of immunotherapy with anti-B7-1 mAb to prevent T-cell-mediated myocardial damage in viral myocarditis.

Participation of Nitric Oxide and Peroxynitrite in the Development of Myocardial Tissue Damage in Acute Myocardial Infarction

Many factors, including superoxides, contribute to tissue damage in acute myocardial infarction (AMI). Excess nitric oxide (NO) produced by inducible NO synthase (iNOS) has also been reported to participate in myocardial injury associated with AMI, but its exact role remains unclear. To elucidate the role of NO and peroxynitrite in the pathogenesis of myocardial injury associated with AMI, we examined the expression of iNOS in the autopsied specimens of the left ventricle obtained from 15 patients with AMI and five with old MI by immunohistochemistry using an anti-iNOS polyclonal antibody. The distribution of nitrotyrosine was also examined immunohistochemically. In patients who died from 12 hours to 3 weeks after the infarction, positive immunoreactivity for iNOS was observed in residual myocytes, macrophages, and vascular endothelial cells in the peri-infarcted area. Degenerating myocytes in that area in all of that group showing positive staining for iNOS were also stained positive for anti-nitrotyrosine antibody selfsame. These findings were not observed in the myocardial specimens obtained from patients who died within 12 hours after the onset of AMI, showing a minimal number of inflammatory cells, or in the specimens from patients with an old myocardial infarction, which showed scar tissue and no cellular infiltration. Inducible NOS and nitrotyrosine were expressed in damaged myocardium from patients with AMI, suggesting that the NO radical and peroxynitrite are involved in the pathogenesis of myocardial damage.

Ultrastructural localization ofcalcium dependent adenosine triphosphatase (ATPase) in the myocardium of endotoxin-administered rats

Enzyme-cytochemical studies were performed to clarify the pathogenesis of myocardial damage in endotoxemia. The reaction product of Ca++-ATPase was localized on the pinocytotic vesicles and plasma membrane of endothelial cells of capillaries and sarcolemma, sarcoplasmic reticulum and mitochondria of cardiomyocytes in control rats. However, the enzyme reaction product was reduced in amount and irregularly distributed on the plasma membrane, and on the increased number of pinocytotic vesicles of the endothelial cells of capillaries and the sarcolemma and sarcoplasmic reticulum of edematous cardiomyocytes after endotoxin injection. It is concluded that endotoxin induces structural changes and decreased activity in Ca++-ATPase in the vascular endothelium and myocytes of the heart.

Effects of Escherichia coli Endotoxin on Structure and Permeability of Myocardial Capillaries

A study was carried out to investigate changes in myocardial capillaries induced by endotoxin, in order to clarify the pathogenesis of myocardial damage in endotoxemia. Wistar rats were injected intraperitoneally with 100 mg/kg Escherichia coli lipopolysaccharide and then sacrificed at 1, 2, 3,4, 5, 6, 8, and 24 h after injection. The myocardium was observed by electron microscopy with histochemistry using horseradish peroxidase and immunocytochemistry for Na+, K(+)-ATPase/TPase. The earliest evident endothelial alterations were swelling, increased numbers of pinocytotic vesicles, and formation of cytoplasmic projections. Interstitial edema and focal detachment of the endothelial cells from the basement membrane occurred with time. Vascular permeability was increased after endotoxin injection. Activity of Na+, K(+)-ATPase was reduced on the plasma membrane of the endothelial cells. It is concluded that endotoxin induces structural and enzymatic changes in the myocardial capillary endothelium and an increase of capillary permeability.

Experimental myocarditis. II. Cardiac lesions in rats induced by immunization with heterologous heart extracts.

The production of myocardial lesions and circulating anti-heart antibodies has been studied in the present experiment. Twenty-one of Wistar rats were divided into 3 groups: 9 rats immunized with heterologous heart extracts, Freund's complete adjuvant and diphtheria-tetanus-pertussis (DTP) vaccine, 8 rats injected phosphate buffered saline adjuvant mixture with DTP vaccine and 4 rats untreated as control. Injection of heterologous heart extracts emulsified with Freund's complete adjuvant and DTP vaccine developed focal myocardial lesions in all of the subjected rats. The lesions were characterized by focal and diffuse interstitial cellular infiltration with myocardial necrosis. The circulating antibodies reacted to rat heart extracts were detected in 77.8% of the subjects. The antigen, reacted with the antibodies, located intracellular spaces in myocardium. The severity of cardiac lesions were not functional to the titer of circulating anti-heart antibodies may play little role in the pathogenesis of myocardial damage at least in this experimental myocarditis.