Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Appropriateness of Intensive Statin Treatment in People with Type Two Diabetes and Mild Hypercholesterolemia: A Randomized Clinical Trial.

BACKGROUND: The aim of this study was to compare moderate- versus high-intensity statin therapy in patients with type 2 diabetes and low-density lipoprotein (LDL) cholesterol less than 130 mg/dL. METHODS: This was a randomized, open-label, parallel design trial comprised of 79 patients randomly allocated into two groups receiving high-intensity [atorvastatin 40 mg (A40) or rosuvastatin 20 mg (R20) daily] or moderate-intensity [atorvastatin 20 mg (A20) or rosuvastatin 10 (R10) mg daily] statins for eight weeks. The variables investigated were lipid profile, high sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6). RESULTS: The percentage of decrease in LDL levels (±SD) for the high-intensity group (-35.5±25.5) was significantly greater than the moderate-intensity group (-24.6±23.5) (P=0.04). While 38.1% (n:8) of patients receiving A20 and 55% (n:11) of those being on R10 achieved the targets of≥30% reduction in the LDL level, these figures were 63.2% (n=12) and 73.8% (n=14) for A40 and R20 subgroups, respectively. Subsequently, the likelihood of achieving LDL reduction≥30%, was significantly greater with high-intensity statin therapy (OR: 3.1, 95% CI: 1.09, 8.90, P=0.03). Logistic regression analysis also showed that for every 1 mg/ dL increase in the baseline LDL level, the odds of achieving the LDL reduction≥30% increased by 1.04 times [95% CI: (1.01, 1.07), P=0.003]. CONCLUSION: Despite the general conception, moderate-intensity statins are not adequate for the majority of patients with T2DM and mild hyperlipidemia and greater numbers of patients could reach the LDL cholesterol target with high-intensity statin therapy.

Clinical Application of Melatonin in the Treatment of Cardiovascular Diseases: Current Evidence and New Insights into the Cardioprotective and Cardiotherapeutic Properties.

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, tending to happen in younger individuals in developed countries. Despite improvements in medical treatments, the therapy and long-term prognosis of CVDs such as myocardial ischemia-reperfusion, atherosclerosis, heart failure, cardiac hypertrophy and remodeling, cardiomyopathy, coronary artery disease, myocardial infarction, and other CVDs threatening human life are not satisfactory enough. Therefore, many researchers are attempting to identify novel potential therapeutic methods for the treatment of CVDs. Melatonin is an anti-inflammatory and antioxidant agent with a wide range of therapeutic properties. Recently, several investigations have been carried out to evaluate its effectiveness and efficiency in CVDs therapy, focusing on mechanistic pathways. Herein, this review aims to summarize current findings of melatonin treatment for CVDs.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Expression levels of miR-22, miR-30c, miR-145, and miR-519d and their possible associations with inflammatory markers among patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of death around the world. Micro-ribonucleic acid (miRNA) can be involved in forming of atherosclerotic plaques, inflammation, cholesterol metabolism, and other mechanisms involved in CAD development. This study aimed to evaluate the expression level of miR-22, miR-30c, miR-145, and miR-519d and their possible association with inflammatory markers among patients with CAD. METHODS: The expression level of miR-22, miR-30c, miR-145, miR-519d, interleukin 6 (IL-6), and transforming growth factor beta (TGF-ß) was determined in peripheral blood mononuclear cells (PBMCs) from 46 patients with CAD and 39 healthy controls using real-time quantitative polymerase chain reaction (qPCR) assay. RESULTS: 53.8% (n = 21) and 52.2% (n = 24) of controls and cases were men, respectively; the mean age was 59.8 ± 7.4 and 57.0 ± 9.8 years, respectively. The miRNA expression pattern of each group showed significantly different expression profiles. In the CAD patients group, miR-22, miR-30c, and miR-145 were down-regulated compared to the control group. On the opposite, miR-519d was up-regulated in patients with CAD compared to the control group. Our results also showed that the expression levels of IL-6 and TGF-ß were up-regulated among patients with CAD compared to the control group. In addition, the expression of miR-145 and miR-519d had a significantly negative and positive correlation with TGF-ß and IL-6, respectively. CONCLUSION: The change in expression levels of miR-22, miR-30c, miR-145, and miR-519d in PBMCs of patients with CAD could be considered as a potential biomarker for CAD.

Diagnostic value of chest spiral CT scan and Doppler echocardiography compared to right heart catheterization to predict pulmonary arterial hypertension in patients with scleroderma.

BACKGROUND: Because of invasive nature of catheterization, using other noninvasive tools is more preferred to assess pulmonary arterial hypertension (PAH). The present study assessed the value of chest spiral CT scan and Doppler echocardiography compared to right heart catheterization (RHC) to predict PAH in patients with scleroderma. METHODS: This cross-sectional study was performed on 15 patients with limited scleroderma. All subjects underwent Doppler echocardiography (to assess PAP) and chest spiral CT scan without injection (to assess pulmonary trunk length or PUL), followed by RHC to assess PAH. RESULTS: Comparing PUL in spiral CT scan with PAP in RHC yielded a sensitivity of 75.0% and a specificity of 100% for predicting PAH. Similarly, comparing PAP value in echocardiography with PAP in RHC achieved a sensitivity of 100% and a specificity of 63.6% to discriminate PAH from normal PAP condition. Analysis of the area under the ROC curve showed high power of CT scan to predict PAH (AUC = 1.000). The best cutoff point for PUL to predict PAH was 29.95 yielding a sensitivity of 100% and a specificity of 100%. Also, ROC curve analysis showed high value of echocardiography to discriminate PAH from normal PAP status (AUC = 0.841) that considering a cutoff value of 22.88 for PAP assessed by echocardiography reached to a sensitivity of 72.7% and a specificity of 100%.   Conclusion: Both chest spiral CT scan and Doppler echocardiography are very useful to diagnose PAH and its severity in patients with scleroderma.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Current practice of percutaneous coronary intervention on patients with acute coronary syndrome in Iran: A prospective observational study.

Background: Frequent Percutaneous Coronary Intervention (PCI) procedures are being performed on a daily basis in Iran. However, no study has been reported on the current PCI practice in patients with acute coronary syndrome (ACS) in Iran. We aimed to describe the clinical characteristics and treatment patterns in Iranian ACS patients treated with PCI. Methods: Between February 2017 and July 2017, ACS patients presented to 5 referral hospitals in two major cities of Iran (Tehran and Shiraz) were included in this observational study if aged > 18 years and underwent PCI for ACS during hospitalization; and their clinical and procedural characteristics were collected. All data were entered into SPSS v.21 and descriptive statistics were performed. Results: Of a total of 314 patients, 228 (73%) were males, 162 (52%) were diagnosed with ST-elevation myocardial infarction and 152 (48%) with Unstable angina/ Non-ST elevation myocardial infarction. Trans-femoral approach was more often (64%) used for PCI procedures. Stent placement was the most frequent (98%) treatment strategy on PCI, with drug-eluting stent selected in the majority of subjects (98%). The overall rate of PCI success was 95%, with 4.1% PCI-related complications, and 1.6% post-PCI bleeding events. The vast majority of the study patients (99%) were discharged with dual anti-platelet therapy. Conclusion: In this study, we observed a high level of adherence to the currently accepted guidelines in the current PCI practice on ACS patients in Iran. Also we found our practice is highly in line with the global reduction trend in the PCI-related complications.

The effect of prehospital telecardiology on the mortality and morbidity of ST-segment elevated myocardial infarction patients undergoing primary percutaneous coronary intervention: A cross-sectional study.

OBJECTIVES: The sooner the primary percutaneous coronary intervention (PPCI) is performed, the better prognosis is expected in patients with acute myocardial infarction. The objective is to evaluate the effect of prehospital triage based on electrocardiogram (ECG) and telecardiology on the mortality and morbidity of ST-segment elevated myocardial infarction (STEMI) patients undergoing PPCI. METHODS: This cross-sectional study was conducted based on the data extracted from the hospital information system (HIS) of one general hospital, which had the capability of performing PPCI 24 h a day, 7 days a week. All patients with STEMI who undergone PPCI during 1 year, transferred by emergency medical service (EMS) and their data were registered in the HIS were eligible. Besides the baseline characteristics, first medical contact (FMC)-to-balloon time was recorded. Morbidity based on predischarge left ventricular ejection fraction (LVEF) and mortality based on Global Registry of Acute Cardiac Events (GRACE) score were also recorded. Patients who were referred to the hospital by EMS with prehospital ECG and telecardiology were compared with those without prehospital ECG. RESULTS: Totally, 298 patients with STEMI were enrolled, of whom 183 patients (61.4%) had prehospital ECG (telecardiology), and 115 patients (38.6%) had not. The means of predischarge LVEF of the patients in the first and the second groups were 40.7 ± 10.4 and 40.6 ± 11.2, respectively (P = 0.946). The mean of the probability of 6-month mortality based on GRACE score in the first group was significantly less than that of the second group (P = 0.004). Analyses of multivariable ordinal logistic regression showed that 6-month mortality severity risk in the second group was 1.5 times more than the first group (95% confidence interval 0.8-2.6), although this difference was not statistically significant (P = 0.199). CONCLUSIONS: It is likely that prehospital telecardiology, with shortening FMC to balloon time result in reducing probability 6-month mortality in STEMI patients who undergone PPCI. However, the process of telecardiology had no effect on predischarge LVEF in the current study.

Ameliorative effect of gallic acid on sodium arsenite-induced spleno-, cardio- and hemato-toxicity in rats.

AIM: Arsenic is an important toxic chemical affecting millions of people around the world. Exposure to inorganic arsenic results in various health problems including skin lesions, hypertension, hematological disturbance, cardiovascular disease, spleen enlargement and cancer. Gallic acid (GA) is an important phenolic compound possessing various pharmacological properties including anti-inflammatory, antioxidant and free radical scavenging activities. The present study investigated effects of GA against sodium arsenite (SA)-induced spleno-, cardio- and hemato-toxicity. MAIN METHODS: Thirty-five adult male Wistar rats were randomly divided into five groups; group I received normal saline (2 ml/kg/day, p.o.) for 21 days, group II received SA (10 mg/kg/day, p.o.) for 14 days, group III and IV were treated with GA (10 and 30 mg/kg/day, respectively) for 7 days prior to receive SA and treatment was continued up to 21 days in parallel with SA administration, group V received GA (30 mg/kg/day, p.o.) for 21 days. The level of MDA, NO and glutathione (GSH) and the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase were measured in heart and spleen tissues. Creatine kinase-MB (CK-MB) activity and hematological and histopathological parameters were also assessed. KEY FINDINGS: GA significantly decreased SA-induced elevation of MDA and NO levels and reduction of GSH level and GPx and SOD activity in heart and spleen tissues. Furthermore, GA improved SA-induced alteration in hematological and histopathological parameters and reduced SA-induced elevation of serum CK-MB activity. SIGNIFICANCE: Our results suggest that GA inhibits SA-induced spleno-, cardio- and hemato-toxicity through reducing oxidative stress.

Protective Effect of Ellagic Acid Against Sodium Arsenite-Induced Cardio- and Hematotoxicity in Rats.

Ellagic acid (EA) is a phenolic constituent in certain fruits and nuts with wide range of biological activities, including potent antioxidant, antidiabetic, anti-inflammatory, anticancer and antimutagen properties. The aim of this study was to evaluate the effect of EA on sodium arsenic (SA)-induced cardio- and hematotoxicity in rats. Animals were divided into five groups. The first group was used as control. Group 2 was orally treated with sodium arsenite (SA, 10 mg/kg) for 21 days. Group 3 was orally treated with EA (30 mg/kg) for 14 days. Groups 4 and 5 were orally treated with SA for 7 days prior to EA (10 and 30 mg/kg, respectively) treatment and continued up to 21 days simultaneous with SA administration. Various biochemical, histological and molecular biomarkers were assessed in blood and heart. The results indicate that SA-intoxicated rats display significantly higher levels of plasma cardiac markers (AST, CK-MB, LDH and cTnI) than normal control animals. Moreover, an increase in MDA and NO with depletion of GSH and activities of CAT, SOD and GPx occurred in the heart of rats treated with SA. Furthermore, SA-treated rats showed significantly lower WBC, RBC, HGB, HCT and PLT and significantly higher MCV and MCH. Administration of EA (30 mg/kg) resulted in a significant reversal of hematological and cardiac markers in arsenic-intoxicated rats. These biochemical disturbances were supported by histopathological observations of the heart. In conclusion, the results of this study suggest that EA treatment exerts a significant protective effect on SA-induced cardio- and hematotoxicity.

Left Ventricular Mass Index and Pulmonary Artery Pressure in Patients with the Obstructive Sleep Apnea Syndrome.

BACKGROUND: Sleep apnea is accompanied by some cardiovascular complications. It has even been hypothesized that sleep apnea, itself, can induce some of these complications. Given such controversies, we assessed the left ventricular mass index (LVMI) and systolic pulmonary artery pressure in patients with sleep apnea. METHODS: Through convenience sampling, 56 patients with the obstructive sleep apnea syndrome (OSAS) were included in the present descriptive cross-sectional study. Patients with any past history of hypertension and diabetes mellitus were excluded. The apnea severity was assessed via the polysomnography-derived apnea-hypopnea index (AHI). All the patients underwent transthoracic echocardiography. In this cross-sectional study - data regarding age, gender, smoking, systolic and diastolic blood pressures, polysomnographic parameters (AHI, severity of disease, mean heart rate, mean oxygen saturation [SaO2], lowest SaO2, and duration of SaO2 below 90% [d.SaO2 < 90%]), and echocardiographic parameters (systolic pulmonary artery pressure and LVMI) were accumulated and processed. RESULTS: Fifty-two men and 14 women at a mean age of 49.29 ± 11.79 years participated in this study. Systolic and was significantly high in the severe group compared with the mild group (128.21 ± 9.73 mmHg vs. 119.23 ± 12.5 mmHg; p value = 0.007). The LVMI was increased parallel to an increase in the severity of the OSAS, but that increase was not statistically significant (p value = 0.161). The d.SaO2 < 90% was positively correlated with the LVMI, and this relationship remained true after adjustment for the body mass index (r = 0.27; p value = 0.042). CONCLUSION: Severe OSAS was accompanied by a higher blood pressure. The LVMI did not differ significantly between the patients with the OSAS and those who did not suffer from other risk factors of cardiac diseases.

Takotsubo Cardiomyopathy Coexisting with Acute Pericarditis and Myocardial Bridge.

Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy that occurs primarily in postmenopausal women. It mimics clinical picture of acute coronary syndrome with nonobstructive coronary arteries and a characteristic transient left (or bi-) ventricular apical ballooning at angiography. The exact pathogenesis of TCM is not well recognized. Hereby we present an unusual case of TCM that presents with signs and symptoms of acute pericarditis and was also found to have a coexisting coronary muscle bridge on coronary angiography. We discuss the impact of these associations in better understanding of the pathogenesis of TCM.

Remote ischemic preconditioning for prevention of contrast-induced acute kidney injury in diabetic patients.

INTRODUCTION: There are some clinical trials showing that short-term ischemia in one organ can protect different organs against higher intensity and longer ischemic insult. We designed a study to assess whether remote ischemic preconditioning (RIPC) on one organ can decrease the rate of contrast-induced acute kidney injury (AKI) in diabetic patients who undergo coronary artery angiography (CAA). MATERIALS AND METHODS: This randomized control trial included 96 diabetic patients who were candidates for CAA. Exclusion criteria were congestive heart failure and complications during CAA. All of the patients received 1000 mL of normal saline before CAA. The RIPC group underwent 3 cycles of 5-minute ischemia in their right arm. Serum creatinine was measured before and 24 hours after CAA. RESULTS: Contrast-induced AKI was reported in 5 cases in the control group and 1 case in the RIPC group (P = .13, odds ratio, 5.4). The differences in serum creatinine level before and after the procedure was significantly lower in RIPC group than that in the control group (P = .04, odds ratio, 0.08). Serum creatinine rise significantly correlated with contrast dose (P = .02) and a history of hypertension (P = .02) in both groups. CONCLUSIONS: Ischemic preconditioning had a protective effect on contrast-induced AKI in our study. Since this method is harmless and cost effective, further studies on patients with chronic kidney disease is required to evaluate addition of ischemic preconditioning to our clinical practice for prevention of contrast-induced AKI.