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2.
Am Heart J ; 247: 33-41, 2022 05.
Article in English | MEDLINE | ID: covidwho-1652480

ABSTRACT

BACKGROUND: Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size. DESIGN: Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days. CONCLUSION: The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.


Subject(s)
Acute Coronary Syndrome , Anterior Wall Myocardial Infarction , Myocardial Infarction , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Acute Coronary Syndrome/drug therapy , Arrhythmias, Cardiac , Double-Blind Method , Everolimus/therapeutic use , Humans , Magnetic Resonance Imaging , Myocardial Infarction/drug therapy , Prospective Studies , ST Elevation Myocardial Infarction/drug therapy , TOR Serine-Threonine Kinases/therapeutic use , Treatment Outcome , Ventricular Remodeling
3.
Eur Heart J Cardiovasc Imaging ; 23(3): 326-327, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1598506
4.
Int J Mol Sci ; 22(24)2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1580692

ABSTRACT

Although blood-heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.


Subject(s)
COVID-19/complications , Heart Failure/metabolism , Heart/virology , Animals , Blood/virology , Blood Physiological Phenomena/immunology , COVID-19/physiopathology , Cardiomegaly/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Physiological Phenomena/immunology , Disease Models, Animal , Endothelium/metabolism , Heart/physiopathology , Heart Failure/virology , Hydroxychloroquine/pharmacology , Male , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Muscle Cells/metabolism , Myocardium/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Ventricular Remodeling/physiology
5.
Minerva Obstet Gynecol ; 73(4): 471-481, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1348831

ABSTRACT

Fetal growth restriction is one of the most common obstetric complications, affecting 7-10% of all pregnancies. Affected fetuses are exposed to an adverse environment in utero during a critical time of development and may face long-term health consequences such as increased cardiovascular risk in adulthood. Growth restricted fetuses develop remodeled hearts with signs of systolic and diastolic dysfunction. Cardiac adaptations are more evident in early severe cases, but also present in late onset fetal growth restriction. Cardiovascular remodeling persists into postnatal life, from the neonatal period to adolescence, encompassing an increased susceptibility to adult disease. In this review, we summarize the current evidence on cardiovascular programming associated to fetal growth restriction, its postnatal consequences and potential strategies to reduce their cardiovascular risk.


Subject(s)
Cardiovascular System , Fetal Growth Retardation , Adolescent , Adult , Female , Fetus , Heart , Humans , Infant, Newborn , Pregnancy , Ventricular Remodeling
6.
Cardiovasc Res ; 117(10): 2148-2160, 2021 08 29.
Article in English | MEDLINE | ID: covidwho-1266112

ABSTRACT

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.


Subject(s)
COVID-19/virology , Heart Diseases/virology , Heart/virology , Myocytes, Cardiac/virology , SARS-CoV-2/pathogenicity , Animals , Biomarkers/metabolism , Blood Coagulation , COVID-19/complications , Fibrosis , Heart/physiopathology , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/physiopathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Ventricular Remodeling
7.
Circ Res ; 128(8): 1214-1236, 2021 04 16.
Article in English | MEDLINE | ID: covidwho-1186415

ABSTRACT

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Cardiovascular Diseases/virology , Myocytes, Cardiac/virology , SARS-CoV-2/physiology , Virus Internalization , Biomarkers/metabolism , COVID-19/complications , COVID-19/epidemiology , COVID-19/therapy , Cardiomyopathies/virology , Gene Expression , Humans , Immune System/physiology , Myocardium/enzymology , Myocytes, Cardiac/enzymology , Neuropilin-1/metabolism , Platelet Activation , RNA, Messenger/metabolism , Renin-Angiotensin System/physiology , Return to Sport , Risk Factors , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/metabolism , Troponin/metabolism , Ventricular Remodeling , Virus Attachment , Virus Internalization/drug effects
8.
J Am Coll Cardiol ; 77(13): 1701, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1147714
10.
Heart Fail Rev ; 26(4): 961-971, 2021 07.
Article in English | MEDLINE | ID: covidwho-1009158

ABSTRACT

The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that was discovered two decades ago. The ACE2 exists as a transmembrane protein and as a soluble catalytic ectodomain of ACE2, also known as the soluble ACE2 that can be found in plasma and other body fluids. ACE2 regulates the local actions of the renin-angiotensin system in cardiovascular tissues, and the ACE2/Angiotensin 1-7 axis exerts protective actions in cardiovascular disease. Increasing soluble ACE2 has been associated with heart failure, cardiovascular disease, and cardiac remodelling. This is a review of the molecular structure and biochemical functions of the ACE2, as well we provided an updated on the evidence, clinical applications, and emerging potential therapies with the ACE2 in heart failure, cardiovascular disease, lung injury, and COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Heart Failure/metabolism , Ventricular Remodeling/physiology , Biomarkers/metabolism , COVID-19/complications , Heart Failure/complications , Humans , Renin-Angiotensin System , SARS-CoV-2/isolation & purification
11.
Expert Rev Cardiovasc Ther ; 19(1): 5-14, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-894500

ABSTRACT

Introduction: COVID-19 is causing considerable morbidity and mortality worldwide. Serious respiratory complications aside, the heart is also frequently involved. The mechanisms and the extent of the myocardial injury, along with the short and long-term cardiovascular (CV) outcomes in COVID-19 survivors remain unclear. Areas covered: myocardial injury has been found in a considerable proportion of hospitalized COVID-19 patients and is associated with a worse prognosis. The late onset of CV complications with myocarditis-like changes revealed by CMR has been reported in COVID-19 survivors. Previous observational studies on viral myocarditis provide evidence of a significant incomplete recovery with residual dysfunction and remodeling of left ventricle. Incomplete recovery is thought to be the result of persistent myocardial inflammation due to a post-viral autoimmune response. Considering the significant inflammatory nature of COVID-19, COVID-19 survivors may be at risk of developing persistent residual myocardial injury, the sequelae of which are unclear. Expert commentary: COVID-19 is an emerging threat for the heart. The extent of CV injury, along with the short and long-term sequelae, requires further investigation. The early detection of residual myocardial changes in COVID-19 survivors is of utmost importance in order to identify those patients at risk of CV complication development.


Subject(s)
COVID-19/physiopathology , Cardiomyopathies/physiopathology , Heart Failure/physiopathology , Myocarditis/physiopathology , COVID-19/diagnostic imaging , COVID-19/epidemiology , Cardiac Imaging Techniques , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/epidemiology , Early Diagnosis , Heart , Heart Diseases , Heart Failure/diagnostic imaging , Heart Failure/epidemiology , Humans , Inflammation , Magnetic Resonance Imaging , Myocarditis/diagnostic imaging , Myocarditis/epidemiology , Myocardium , Prospective Studies , Recovery of Function , SARS-CoV-2 , Ventricular Remodeling
13.
J Am Coll Cardiol ; 76(17): 1965-1977, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-872172

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a growing pandemic that confers augmented risk for right ventricular (RV) dysfunction and dilation; the prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. OBJECTIVES: The purpose of this study was to test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. METHODS: Consecutive COVID-19 inpatients undergoing clinical transthoracic echocardiography at 3 New York City hospitals were studied; images were analyzed by a central core laboratory blinded to clinical and biomarker data. RESULTS: In total, 510 patients (age 64 ± 14 years, 66% men) were studied; RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p = 0.007). During inpatient follow-up (median 20 days), 77% of patients had a study-related endpoint (death 32%, discharge 45%). RV dysfunction (hazard ratio [HR]: 2.57; 95% confidence interval [CI]: 1.49 to 4.43; p = 0.001) and dilation (HR: 1.43; 95% CI: 1.05 to 1.96; p = 0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR: 1.39; 95% CI: 1.01 to 1.90; p = 0.041). RV indices provided additional risk stratification beyond biomarker strata; risk for death was greatest among patients with adverse RV remodeling and positive biomarkers and was lesser among patients with isolated biomarker elevations (p ≤ 0.001). In multivariate analysis, adverse RV remodeling conferred a >2-fold increase in mortality risk, which remained significant (p < 0.01) when controlling for age and biomarker elevations; the predictive value of adverse RV remodeling was similar irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. CONCLUSIONS: Adverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.


Subject(s)
Coronavirus Infections/diagnostic imaging , Echocardiography , Heart/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Ventricular Remodeling , Aged , Aged, 80 and over , Betacoronavirus , Biomarkers/blood , COVID-19 , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Female , Heart/physiopathology , Humans , Male , Middle Aged , New York City/epidemiology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Risk Assessment , SARS-CoV-2
14.
Cardiovasc Toxicol ; 20(5): 463-473, 2020 10.
Article in English | MEDLINE | ID: covidwho-734059

ABSTRACT

Fibrotic diseases cause annually more than 800,000 deaths worldwide, where of the majority accounts for cardiovascular fibrosis, which is characterized by endothelial dysfunction, myocardial stiffening and reduced dispensability. MicroRNAs (miRs), small noncoding RNAs, play critical roles in cardiovascular dysfunction and related disorders. Intriguingly, there is a critical link among miR-122, cardiovascular fibrosis, sirtuin 6 (SIRT6) and angiotensin-converting enzyme 2 (ACE2), which was recently identified as a coreceptor for SARS-CoV2 and a negative regulator of the rennin-angiotensin system. MiR-122 overexpression appears to exacerbate the angiotensin II-mediated loss of autophagy and increased inflammation, apoptosis, extracellular matrix deposition, cardiovascular fibrosis and dysfunction by modulating the SIRT6-Elabela-ACE2, LGR4-ß-catenin, TGFß-CTGF and PTEN-PI3K-Akt signaling pathways. More importantly, the inhibition of miR-122 has proautophagic, antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic effects. Clinical and experimental studies clearly demonstrate that miR-122 functions as a crucial hallmark of fibrogenesis, cardiovascular injury and dysfunction. Additionally, the miR-122 level is related to the severity of hypertension, atherosclerosis, atrial fibrillation, acute myocardial infarction and heart failure, and miR-122 expression is a risk factor for these diseases. The miR-122 level has emerged as an early-warning biomarker cardiovascular fibrosis, and targeting miR-122 is a novel therapeutic approach against progression of cardiovascular dysfunction. Therefore, an increased understanding of the cardiovascular roles of miR-122 will help the development of effective interventions. This review summarizes the biogenesis of miR-122; regulatory effects and underlying mechanisms of miR-122 on cardiovascular fibrosis and related diseases; and its function as a potential specific biomarker for cardiovascular dysfunction.


Subject(s)
Atrial Remodeling , Cardiovascular Diseases/metabolism , MicroRNAs/metabolism , Myocardium/metabolism , Ventricular Remodeling , Animals , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Cardiovascular Diseases/physiopathology , Fibrosis , Gene Expression Regulation , Humans , MicroRNAs/genetics , Myocardium/pathology , Prognosis , Signal Transduction
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