Modeling Heart Diseases on a Chip: Advantages and Future Opportunities.

Heart disease is a significant burden on global health care systems and is a leading cause of death each year. To improve our understanding of heart disease, high quality disease models are needed. These will facilitate the discovery and development of new treatments for heart disease. Traditionally, researchers have relied on 2D monolayer systems or animal models of heart disease to elucidate pathophysiology and drug responses. Heart-on-a-chip (HOC) technology is an emerging field where cardiomyocytes among other cell types in the heart can be used to generate functional, beating cardiac microtissues that recapitulate many features of the human heart. HOC models are showing great promise as disease modeling platforms and are poised to serve as important tools in the drug development pipeline. By leveraging advances in human pluripotent stem cell-derived cardiomyocyte biology and microfabrication technology, diseased HOCs are highly tuneable and can be generated via different approaches such as: using cells with defined genetic backgrounds (patient-derived cells), adding small molecules, modifying the cells' environment, altering cell ratio/composition of microtissues, among others. HOCs have been used to faithfully model aspects of arrhythmia, fibrosis, infection, cardiomyopathies, and ischemia, to name a few. In this review, we highlight recent advances in disease modeling using HOC systems, describing instances where these models outperformed other models in terms of reproducing disease phenotypes and/or led to drug development.

Cardiovascular Damage in COVID-19: What We Know Two Years Later.

PURPOSE OF THE REVIEW: The Coronavirus disease 2019 (COVID-19) pandemic has profoundly influenced cardiological clinical and basic research in the past two years. In the present review, we summarize the current knowledge on myocardial involvement in COVID-19, providing an overview on the incidence, the pathogenetic mechanisms, and the clinical implications of cardiac injury in this setting. RECENT FINDINGS: The possibility of heart involvement in patients with COVID-19 has received great attention since the beginning of the pandemic. After more than two years, several steps have been taken in understanding the mechanisms and the incidence of cardiac injury during COVID-19 infection. Similarly, studies globally have clarified the implications of co-existing heart disease and COVID-19. Severe COVID-19 infection may be complicated by myocardial injury. To date, a direct damage from the virus has not been demonstrated. The presence of myocardial injury should be systematically assessed for a prognostication purpose and for possible therapeutic implications.

Left Ventricular Thrombus of Unknown Etiology in a Patient With COVID-19 Disease With No Significant Medical History.

The incidence of left ventricular thrombus is relatively low. Ventricular thrombi typically manifest in patients with reduced ejection fraction and post myocardial infarction [1]. The impact of COVID-19's hypercoagulability state is presented here. A 44 year old male who contracted COVID-19, progressed to moderate disease requiring inpatient treatment with supplemental oxygen. During the course of the hospital stay, while receiving National Institutes of Health guideline directed thromboembolism prophylaxis for COVID-19 infected patients [2], the patient developed a left ventricular thrombus which consequently embolized and occluded the left anterior descending and left circumflex coronary arteries requiring rheolytic thrombectomy.

The Impact of the COVID-19 Pandemic on Hospital Services for Patients with Cardiac Diseases: A Scoping Review.

This study aims to assess the impact of the COVID-19 pandemic on hospital cardiac care, as assessed by performance indicators. Scoping review methodology: performance indicators were extracted to inform on changes in care during January-June 2020. Database searches yielded 6277 articles, of which 838 met the inclusion criteria. After full-text screening, 94 articles were included and 1637 indicators were retrieved. Most of the indicators that provided information on changes in the number of admissions (n = 118, 88%) signaled a decrease in admissions; 88% (n = 15) of the indicators showed patients' delayed presentation and 40% (n = 54) showed patients in a worse clinical condition. A reduction in diagnostic and treatment procedures was signaled by 95% (n = 18) and 81% (n = 64) of the indicators, respectively. Length of stay decreased in 58% (n = 21) of the indicators, acute coronary syndromes treatment times increased in 61% (n = 65) of the indicators, and outpatient activity decreased in 94% (n = 17) of the indicators related to outpatient care. Telehealth utilization increased in 100% (n = 6). Outcomes worsened in 40% (n = 35) of the indicators, and mortality rates increased in 52% (n = 31). All phases of the pathway were affected. This information could support the planning of care during the ongoing pandemic and in future events.

Real world data on cardiometabolic diseases in U.S. adults during the SARS-CoV-2 pandemic: a decentralized registry study.

BACKGROUND: Pre-existing cardiometabolic comorbidities place SARS-CoV-2 positive patients at a greater risk for poorer clinical course and mortality than those without it. We aimed to analyze real-world registry data focused primarily on participants with cardiometabolic diseases (CMD), which were remotely obtained via a digital platform. METHODS: Participants were divided into two groups: CMD or no cardiometabolic disease (non-CMD). They were evaluated based on their medical history, current medications/supplements, COVID-19 status, demographics, and baseline characteristics. The frequency of medications/supplements for CMD were compared using relative risks and 95% confidence intervals. The WHO (Five) Well-Being Index (WHO-5) were collected monthly for 6 months to assess psychological well-being which included cheerfulness, calmness, vigor, rest, and engagement with daily activities of interest. RESULTS: The 791 enrollees represented 49 U.S. states. The CMD group had significantly higher (p < 0.0001) BMI (mean + 3.04 kg/m2) and age (mean + 9.15 years) compared to non-CMD group. In the CMD group, participants who tested positive for COVID-19 had lower (p < 0.0001) well-being scores than those without COVID-19. For the 274 participants on CMD medications/supplements, there was no statistical difference in risk of COVID-19 contracture based on medication/supplement type; however, all six participants who were not being treated for CMD were COVID-19 positive (RR ~ 104). For 89 participants who were on treatment for diabetes or insulin resistance, there was a 90% reduced risk of COVID-19 incidence (p = 0.0187). CONCLUSION: The well-being score of the CMD group was dependent on whether they tested positive for COVID-19. Type of CMD treatment did not impact COVID-19 status, but absence of treatment significantly increased COVID-19 incidence. With respect to SARS-CoV-2, our analysis supports continued use of the statins, ACE-I, ARBs, and diabetes medications in CMD patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04348942.

Myocardial Damage by SARS-CoV-2: Emerging Mechanisms and Therapies.

Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.

Biology of COVID-19 and related viruses: Epidemiology, signs, symptoms, diagnosis, and treatment.

Coronaviruses belong to the family Coronaviridae order Nidovirales and are known causes of respiratory and intestinal disease in various mammalian and avian species. Species of coronaviruses known to infect humans are referred to as human coronaviruses (HCoVs). While traditionally, HCoVs have been a significant cause of the common cold, more recently, emergent viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a global pandemic. Here, we discuss coronavirus disease (COVID-19) biology, pathology, epidemiology, signs and symptoms, diagnosis, treatment, and recent clinical trials involving promising treatments.

Echocardiography in suspected coronavirus infection: indications, limitations and impact on clinical management.

OBJECTIVES: To describe the use of echocardiography in patients hospitalised with suspected coronavirus infection and to assess its impact on clinical management. METHODS: We studied 79 adults from a prospective registry of inpatients with suspected coronavirus infection at a single academic centre. Echocardiographic indications included abnormal biomarkers, shock, cardiac symptoms, arrhythmia, worsening hypoxaemia or clinical deterioration. Study type (limited or complete) was assessed for each patient. The primary outcome measure was echocardiography-related change in clinical management, defined as intensive care transfer, medication changes, altered ventilation parameters or subsequent cardiac procedures within 24 hours of echocardiography. Coronavirus-positive versus coronavirus-negative patient groups were compared. The relationship between echocardiographic findings and coronavirus mortality was assessed. RESULTS: 56 patients were coronavirus-positive and 23 patients were coronavirus-negative with symptoms attributed to other diagnoses. Coronavirus-positive patients more often received limited echocardiograms (70% vs 26%, p=0.001). The echocardiographic indication for coronavirus-infected patients was frequently worsening hypoxaemia (43% vs 4%) versus chest pain, syncope or clinical heart failure (23% vs 44%). Echocardiography changed management less frequently in coronavirus-positive patients (18% vs 48%, p=0.01). Among coronavirus-positive patients, 14 of 56 (25.0%) died during hospitalisation. Those who died more often had echocardiography to evaluate clinical deterioration (71% vs 24%) and had elevated right ventricular systolic pressures (37 mm Hg vs 25 mm Hg), but other parameters were similar to survivors. CONCLUSIONS: Echocardiograms performed on hospitalised patients with coronavirus infection were often technically limited, and their findings altered patient management in a minority of patients.

Cardiac manifestations of COVID-19.

COVID-19 is a novel viral infection caused by severe acute respiratory syndrome (SARS) beta-coronavirus. Epidemiological status changes dynamically as the pandemy is far from ending. Several complications of presented virus may be similar to those observed in other viral infections. Despite lacking data, the heart involvement may be comparable to cardiac complications observed previously in those with SARS as well as Middle East Respiratory Syndrome (MERS). In COVID-19 we observe elevated levels of cardiac biomarkers, such as natriuretic peptides, troponins, myoglobin, C-reactive protein (CRP), interleukin-2 (IL-2), interleukin-6 (IL-6) and ferritin, which is likely the result of myocardial injury. The possible mechanisms of cardiovascular injury include direct toxicity through the viral invasion of cardiac myocytes, ACE-2 receptor-mediated CV (cardiac and endothelial) injury, microvascular dysfunction and thrombosis and cytokine release syndrome (mainly IL-6 mediated). Cardiac manifestations of COVID-19 are focal or global myocardial inflammation, necrosis, ventricular dysfunction, heart failure and arrhythmia.

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients.

AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19. METHODS AND RESULTS: This analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P < 0.0001). Plasma ACE2 was significantly higher in COVID-19 patients with hypertension compared with patients without hypertension (P = 0.0045). Circulating ACE2 was also significantly higher in COVID-19 patients with pre-existing heart conditions and kidney disease compared with patients without these pre-existing conditions (P = 0.0363 and P = 0.0303, respectively). CONCLUSION: This study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease.

Cardiac complications during the active phase of COVID-19: review of the current evidence.

Growing reports since the beginning of the pandemic and till date describe increased rates of cardiac complications (CC) in the active phase of coronavirus disease 2019 (COVID-19). CC commonly observed include myocarditis/myocardial injury, arrhythmias and heart failure, with an incidence reaching about a quarter of hospitalized patients in some reports. The increased incidence of CC raise questions about the possible heightened susceptibility of patients with cardiac disease to develop severe COVID-19, and whether the virus itself is involved in the pathogenesis of CC. The wide array of CC seems to stem from multiple mechanisms, including the ability of the virus to directly enter cardiomyocytes, and to indirectly damage the heart through systemic hyperinflammatory and hypercoagulable states, endothelial injury of the coronary arteries and hypoxemia. The induced CC seem to dramatically impact the prognosis of COVID-19, with some studies suggesting over 50% mortality rates with myocardial damage, up from ~ 5% overall mortality of COVID-19 alone. Thus, it is particularly important to investigate the relation between COVID-19 and heart disease, given the major effect on morbidity and mortality, aiming at early detection and improving patient care and outcomes. In this article, we review the growing body of published data on the topic to provide the reader with a comprehensive and robust description of the available evidence and its implication for clinical practice.

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.

Impact of diabetes in patients waiting for invasive cardiac procedures during COVID-19 pandemic.

BACKGROUND: During COVID-19 pandemic, elective invasive cardiac procedures (ICP) have been frequently cancelled or postponed. Consequences may be more evident in patients with diabetes. OBJECTIVES: The objective was to identify the peculiarities of patients with DM among those in whom ICP were cancelled or postponed due to the COVID-19 pandemic, as well as to identify subgroups in which the influence of DM has higher impact on the clinical outcome. METHODS: We included 2,158 patients in whom an elective ICP was cancelled or postponed during COVID-19 pandemic in 37 hospitals in Spain. Among them, 700 (32.4%) were diabetics. Patients with and without diabetes were compared. RESULTS: Patients with diabetes were older and had a higher prevalence of other cardiovascular risk factors, previous cardiovascular history and co-morbidities. Diabetics had a higher mortality (3.0% vs. 1.0%; p = 0.001) and cardiovascular mortality (1.9% vs. 0.4%; p = 0.001). Differences were especially important in patients with valvular heart disease (mortality 6.9% vs 1.7% [p < 0.001] and cardiovascular mortality 4.9% vs 0.9% [p = 0.002] in patients with and without diabetes, respectively). In the multivariable analysis, diabetes remained as an independent risk factor both for overall and cardiovascular mortality. No significant interaction was found with other clinical variables. CONCLUSION: Among patients in whom an elective invasive cardiac procedure is cancelled or postponed during COVID-19 pandemic, mortality and cardiovascular mortality is higher in patients with diabetes, irrespectively on other clinical conditions. These procedures should not be cancelled in patients with diabetes.

Early Triage of Cardioembolic Sources Using Chest Spectral Computed Tomography in Acute Ischemic Stroke.

OBJECTIVES: The present study investigated the potential usefulness of delayed-phase, low-dose, non-gated, chest spectral CT scans (DSCT) for the early triage of cardioembolic (CE) sources in patients admitted with acute ischemic stroke (AIS), and for the simultaneous detection of myocardial disease and thrombotic complications. MATERIAL AND METHODS: Since July 2020 and promoted by the COVID-19 pandemic, we implemented the use of DSCT after cerebrovascular CT angiography (CTA) among patients with AIS using a dual-layer spectral CT. We explored the presence of CE sources, as well as late myocardium iodine enhancement (LIE) and pulmonary thromboembolism. Among patients further undergoing transesophageal echocardiogram (TEE) or cardiac CTA, we explored the diagnostic performance. RESULTS: Fifty consecutive patients with AIS who underwent DSCT after cerebrovascular CTA comprised the patient population. The confidence degree for excluding cardiac thrombi was significantly higher than for LIE (4.4±0.8 vs. 3.4±1.3, p<0.0001). DSCT identified a CE source in 4 (8%) and LIE in 24 (48%) patients. The iodine ratio of CE sources was significantly lower compared to the left atrial appendage of patients with no CE sources (0.25±0.1 mg/mL vs. 0.91±0.2 mg/mL, p<0.0001). TEE/cardiac CT, performed in 20 (40%) patients, identified a CE source in 5 (25%) cases, whereas DSCT identified 4 (20%), leading to a sensitivity and specificity of 80% (95% CI 28-99%) and 100% (95% CI 78-100%) respectively (kappa 0.86). CONCLUSIONS: In this pilot study, we identified DSCT as a potential unsophisticated approach for the early triage of CE sources among patients with AIS undergoing CTA upon admission.

Cardiac Abnormalities in COVID-19 and Relationship to Outcome.

OBJECTIVE: To characterize the clinical and transthoracic echocardiographic features and 30-day outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: Retrospective cohort study that included consecutive inpatients with COVID-19 infection who underwent clinically indicated transthoracic echocardiography at 10 sites in the Mayo Clinic Health System between March 10 and August 5, 2020. Echocardiography was performed at bedside by cardiac sonographers according to an abbreviated protocol. Echocardiographic results, demographic characteristics, laboratory findings, and clinical outcomes were analyzed. RESULTS: There were 179 patients, aged 59.8±16.9 years and 111 (62%) men; events within 30 days occurred in 70 (39%) patients, including prolonged hospitalization in 43 (24%) and death in 27 (15%). Echocardiographic abnormalities included left ventricular ejection fraction less than 50% in 29 (16%), regional wall motion abnormalities in 26 (15%), and right ventricular systolic pressure (RVSP) of 35 or greater mm Hg in 44 (44%) of 101 in whom it was measured. Myocardial injury, defined as the presence of significant troponin level elevation accompanied by new ventricular dysfunction or electrocardiographic abnormalities, was present in 13 (7%). Prior echocardiography was available in 36 (20%) patients and pre-existing abnormalities were seen in 28 (78%) of these. In a multivariable age-adjusted model, area under the curve of 0.81, prior cardiovascular disease, troponin level, D-dimer level, and RVSP were related to events at 30 days. CONCLUSION: Bedside Doppler assessment of RVSP appears promising for short-term risk stratification in hospitalized patients with COVID-19 infection undergoing clinically indicated echocardiography. Pre-existing echocardiographic abnormalities were common; caution should be exercised in attributing such abnormalities to the COVID-19 infection in this comorbid patient population.

Intensive Care Unit Management of the Adult with Congenital Heart Disease.

PURPOSE: Adults with congenital heart disease (ACHD) are a rapidly growing population with ever-increasing complexity, and intensive care unit (ICU) management is often necessary. This review summarizes common cardiovascular and non-cardiovascular complications in ACHD and provides a framework for ICU care. RECENT FINDINGS: Heart failure is the leading cause of hospitalization and mortality in ACHD. Varied anatomy and repairs, as well as differing physiological complications, limit generalized application of management algorithms. Recent studies suggest that earlier mechanical support in advanced cases is feasible and potentially helpful. Cardiac arrhythmias are poorly tolerated and often require immediate attention. Other complications requiring intensive care include infections such as endocarditis and COVID-19, pulmonary hypertension, renal failure, hepatic dysfunction, coagulopathy, and stroke. Successful ICU care in ACHD requires a multi-disciplinary approach with careful consideration of anatomy, physiology, and associated comorbidities. Few studies have formally examined ICU management in ACHD and further research is necessary.